Avastin concentrate for solution for infusion 100 mg/4 ml vial No. 1

Instructions Avastin concentrate for solution for infusion 100 mg/4 ml vial No. 1

Composition

active ingredient: bevacizumab;

1 vial (4 ml concentrate for solution for infusion) contains 100 mg (25 mg/ml) bevacizumab or

1 vial (16 ml concentrate for solution for infusion) contains 400 mg (25 mg/ml) bevacizumab;

Excipients: α,α-trehalose dihydrate; sodium dihydrogen phosphate, monohydrate; sodium hydrogen phosphate anhydrous; polysorbate 20; water for injections.

Dosage form

Concentrate for solution for infusion.

Main physicochemical properties: clear or opalescent liquid, colorless or light brown.

Pharmacotherapeutic group

Antineoplastic agents. Monoclonal antibodies and antibody-drug conjugates. Vascular endothelial growth factor/vascular endothelial growth factor receptor inhibitors.

ATX code L01F G01.

Pharmacological properties

Pharmacodynamics.

Mechanism of action

Bevacizumab is a recombinant humanized monoclonal antibody produced by DNA technology in Chinese hamster ovary cells. Bevacizumab binds to vascular endothelial growth factor (VEGF), a key factor in vasculogenesis and angiogenesis, thereby inhibiting the binding of VEGF to its receptors Flt-1 (VEGFR-1) and KDR (VEGFR-2) on the surface of endothelial cells. Neutralization of the biological activity of vascular endothelial growth factor leads to a decrease in tumor vascularization, normalizes non-tumor vessels, and inhibits the formation of new vessels in the tumor, thereby inhibiting tumor growth.

Administration of bevacizumab or its parent murine antibody to athymic mouse xenograft models of malignant tumors resulted in potent antitumor activity against human tumors, including colon, breast, brain, pancreatic, and prostate tumors. Metastatic disease progression was inhibited and microvascular permeability was reduced.

Clinical efficacy

6 cycles: carboplatin/paclitaxel +

placebo up to 15 months, n = 625

*Primary endpoint is overall survival.

**Primary endpoint is progression-free survival.

***Primary endpoints were 6-month progression-free survival and objective response rate (ORR) by independent review.

1An upper confidence limit cannot be established.

#A total of 154 patients were randomized (ECOG overall performance status 0 or 1).

VR is relative risk.

IFL — irinotecan, 5-fluorouracil, leucovorin.

FOLFOX4 — leucovorin, 5-fluorouracil, oxaliplatin.

HT is chemotherapy.

mCRC is metastatic colorectal cancer.

Pharmacokinetics.

Pharmacokinetic data for bevacizumab were obtained from 10 clinical studies in patients with solid tumors. In all clinical studies, bevacizumab was administered as an intravenous infusion. The infusion rate was based on tolerability, with an initial infusion duration of 90 minutes. The pharmacokinetics of bevacizumab were linear over the dose range of 1 to 10 mg/kg.

Distribution

Typical central volume of distribution (Vc) is 2.73 L and 3.28 L in women and men, respectively, which is consistent with the range described for IgG and other monoclonal antibodies. Peripheral volume of distribution (Vp) is 1.69 L and 2.35 L in women and men, respectively, when bevacizumab is administered with other antineoplastic agents. After dose adjustment for body weight, Vc is 20% higher in men than in women.

Biotransformation

Following a single intravenous administration of 125I-bevacizumab to rabbits, its metabolic profile was similar to that of the native IgG molecule that does not bind to VEGF. The metabolism and elimination of bevacizumab is consistent with that of endogenous IgG, i.e., it is primarily metabolized by proteolytic catabolism in all body cells, including endothelial cells, rather than by renal or hepatic excretion. Binding of IgG to FcRn receptors protects it from cellular metabolism and provides a long half-life.

Breeding

The clearance of bevacizumab averages 0.188 L/day in women and 0.220 L/day in men. After dose adjustment for body weight, the clearance of bevacizumab in men is 17% higher than in women. According to the two-compartment model, the typical half-life is 18 days in women and 20 days in men.

Low albumin levels and high tumor burden generally indicate disease severity. Bevacizumab clearance is approximately 30% faster in patients with low serum albumin levels and 7% faster in those with high tumor burden compared with a typical patient with average albumin levels and average tumor burden.

A population pharmacokinetic analysis was performed to assess the impact of demographic characteristics in adult and pediatric patients. In adults, the results showed no differences in bevacizumab pharmacokinetics based on age.

Patients with renal impairment: The pharmacokinetics of bevacizumab have not been studied in clinical trials in patients with renal impairment, as the kidneys are not the primary organ of metabolism and excretion of bevacizumab.

Patients with hepatic impairment: The pharmacokinetics of bevacizumab have not been studied in clinical trials in patients with hepatic impairment, as the liver is not the primary organ of metabolism and elimination of bevacizumab.

Children. The pharmacokinetics of bevacizumab were evaluated in 152 children, adolescents and young adults (7 months to 21 years, 5.9 to 125 kg) in 4 clinical studies using a population pharmacokinetic model. The results of the pharmacokinetic studies showed that the clearance and volume of distribution of bevacizumab were comparable in pediatric and young adult patients after normalization for body weight, with a trend for decreased exposure with decreasing body weight. The data suggest no effect of age on the pharmacokinetics of bevacizumab, adjusted for body weight.

The pharmacokinetics of bevacizumab were well studied using a paediatric population pharmacokinetic model in 70 patients in study BO20924 (1.4 to 17.6 years; 11.6 to 77.5 kg) and 59 patients in clinical study BO25041 (1 to 17 years; 11.2 to 82.3 kg). In clinical study BO20924, bevacizumab exposure was generally lower compared to that in a typical adult patient after administration of the same dose. In clinical study BO20924, bevacizumab exposure was approximately the same as that in a typical adult patient after administration of the same dose. In both studies, there was a trend for exposure to decrease with decreasing body weight.

Indication

Treatment of metastatic colorectal cancer:

in combination with chemotherapy based on fluoropyrimidine derivatives.

Treatment of metastatic breast cancer:

first-line treatment in combination with paclitaxel;

First-line treatment in combination with capecitabine (when treatment with other chemotherapy regimens, including taxanes or anthracyclines, is considered inappropriate). Patients who have received taxane- and anthracycline-based regimens in the adjuvant setting within the last 12 months should not be given Avastin® in combination with capecitabine.

Treatment of unresectable advanced, metastatic, or recurrent non-small cell lung cancer, excluding predominantly non-squamous cell lung cancer:

first-line treatment in combination with platinum-based chemotherapy.

Treatment of advanced unresectable, metastatic or recurrent non-squamous non-small cell lung cancer with EGFR-activating mutations (EGFR - epidermal growth factor receptor) in adult patients:

first-line treatment in combination with erlotinib.

Treatment of advanced and/or metastatic renal cell carcinoma in adult patients:

first-line therapy in combination with interferon alfa-2a.

Treatment of advanced (stages III B, III C and IV according to the International Federation of Gynecology and Obstetrics (FIGO) classification) epithelial ovarian, fallopian tube and primary peritoneal cancer in adult patients:

first-line therapy in combination with carboplatin and paclitaxel.

Treatment of first recurrence of epithelial ovarian, fallopian tube and primary peritoneal cancer sensitive to platinum-based therapy:

in combination with carboplatin and gemcitabine or in combination with carboplatin and paclitaxel in adult patients who have not received prior therapy with bevacizumab or other VEGF inhibitors or agents that target the VEGF receptor.

Treatment of recurrent epithelial ovarian, fallopian tube and primary peritoneal cancer resistant to platinum-based therapy:

in combination with paclitaxel, topotecan or pegylated liposomal doxorubicin in adult patients who have received no more than two prior chemotherapy regimens and who have not received prior therapy with bevacizumab or other VEGF inhibitors or agents targeting the VEGF receptor.

Treatment of persistent, recurrent or metastatic cervical cancer:

in combination with paclitaxel and cisplatin or, alternatively, paclitaxel and topotecan in adult patients who cannot receive platinum-based therapy.

Treatment of recurrent glioblastoma (WHO stage IV):

as monotherapy after prior therapy with temozolomide.

Contraindication

Hypersensitivity to bevacizumab or to any other component of the medicinal product, to Chinese hamster ovary cell preparations or to other recombinant human or humanized antibodies. Pregnancy.

Interaction with other medicinal products and other types of interactions

Based on population pharmacokinetic analysis, no clinically significant interaction was observed with concomitant chemotherapy and the effect on the pharmacokinetics of bevacizumab. No statistically significant or clinically relevant difference in bevacizumab clearance was observed in patients receiving Avastin® as monotherapy compared to patients receiving Avastin® in combination with interferon alfa-2a, erlotinib, or other chemotherapeutic agents (irinotecan, 5-fluorouracil, leucovorin; 5-fluorouracil/leucovorin; carboplatin/paclitaxel; capecitabine; doxorubicin or cisplatin/gemcitabine).

Effect of bevacizumab on the pharmacokinetics of other antineoplastic drugs

There was no clinically significant effect of bevacizumab on the pharmacokinetics of concomitantly administered interferon alfa-2a, erlotinib (and its active metabolite OSI-420) or the chemotherapeutic agent irinotecan (and its active metabolite SN38), capecitabine, oxaliplatin (as measured by free and total platinum levels) and cisplatin. No conclusions can be drawn regarding the effect of bevacizumab on the pharmacokinetics of gemcitabine.

Combination of bevacizumab and sunitinib malate

In two clinical trials of metastatic renal cell carcinoma, microangiopathic hemolytic anemia was reported in 7 of 19 patients treated with bevacizumab (10 mg/kg every 2 weeks) in combination with sunitinib malate (50 mg daily).

Microangiopathic hemolytic anemia is a hemolytic disorder characterized by red blood cell fragmentation, anemia, and thrombocytopenia. In addition, hypertension (including hypertensive crises), elevated creatinine, and neurological symptoms were observed in some of these patients. All of these symptoms were reversible upon discontinuation of bevacizumab and sunitinib malate (see section 4.4).

Combination with platinum-based or taxane-based therapy (see sections “Special warnings and precautions for use” and “Adverse reactions”)

An increased incidence of severe neutropenia, febrile neutropenia, and infections with or without severe neutropenia (including fatalities) was observed primarily in patients receiving platinum- or taxane-based therapies for the treatment of non-small cell lung cancer and metastatic breast cancer.

Radiation therapy

The safety and efficacy of concomitant use of radiation therapy and Avastin® have not been established.

Monoclonal antibodies to EGFR receptors in combination with chemotherapy, which includes bevacizumab

Interaction studies have not been conducted. EGFR monoclonal antibodies should not be used in combination with chemotherapy that includes bevacizumab for the treatment of metastatic colorectal cancer. Results from the randomized phase III trials PACCE and CAIRO-2 suggest that in patients with metastatic colorectal cancer, the use of the EGFR monoclonal antibodies panitumumab and cetuximab, respectively, in combination with bevacizumab and chemotherapy is associated with reduced progression-free survival and/or overall survival, and increased toxicity compared with bevacizumab and chemotherapy alone.

Application features

To ensure improved traceability of biological medicinal products, the name and number

The batches of the administered medicinal product must be clearly documented.

Gastrointestinal perforations and fistulas (see section "Adverse reactions")

Patients receiving Avastin® are at increased risk of gastrointestinal and gallbladder perforation. Intra-abdominal inflammation is a risk factor for gastrointestinal perforation in patients with metastatic colorectal cancer, and caution should be exercised when treating such patients.

Previous radiation is a risk factor for gastrointestinal perforation in patients treated with Avastin® for persistent, recurrent, or metastatic cervical cancer; all patients with gastrointestinal perforation had a history of radiation. Treatment should be permanently discontinued in patients who develop gastrointestinal perforation.

Gastrointestinal-vaginal fistulas in study GOG-0240

Patients treated with Avastin® for persistent, recurrent, or metastatic cervical cancer are at increased risk of developing fistulas between the vagina and any part of the gastrointestinal tract (gastrointestinal-vaginal fistulas). Previous radiation exposure is the major risk factor for developing gastrointestinal-vaginal fistulas; all patients with gastrointestinal-vaginal fistulas had a history of radiation exposure. Cancer recurrence in the area of prior radiation exposure is an additional important risk factor for developing gastrointestinal-vaginal fistulas.

Fistulas not related to the gastrointestinal tract (see section "Adverse reactions")

Patients treated with Avastin® are at increased risk of developing fistulas.

Avastin® treatment should be discontinued in patients with tracheoesophageal fistula or grade 4 fistula of any location.

If an internal fistula develops that does not penetrate the gastrointestinal tract, discontinuation of Avastin® should be considered.

Complications of the wound healing process (see section "Adverse reactions")

Avastin® may interfere with wound healing. Serious wound healing complications, including anastomotic fistula, with fatal outcomes, have been reported. Bevacizumab should not be initiated less than 28 days after major surgery or until the surgical wound is fully healed. If complications related to wound healing occur during treatment, Avastin® should be temporarily discontinued until the wound is fully healed. Treatment should be discontinued in the event of elective surgery.

Necrotizing fasciitis, including fatal cases, has been reported rarely in patients treated with Avastin®. This condition is usually secondary to wound healing complications, gastrointestinal perforation, or fistula formation. Therefore, Avastin® should be discontinued in patients who develop necrotizing fasciitis and appropriate treatment should be initiated promptly.

Arterial hypertension (see section "Adverse reactions")

An increased incidence of hypertension has been observed in patients receiving Avastin®. Clinical safety data suggest that the incidence of hypertension is dose-dependent. Avastin® should only be administered to patients with previously controlled hypertension. There are no data on the effects of Avastin® in patients with uncontrolled hypertension at the time of initiation of treatment. Monitoring of blood pressure is recommended during Avastin® therapy.

In most cases, normalization of blood pressure is achieved with standard antihypertensive therapy, depending on the specific clinical situation. Diuretics are not recommended for patients receiving cisplatin-based chemotherapy. Avastin® should be discontinued if medically significant hypertension is not adequately controlled with antihypertensive therapy or if hypertensive crisis or hypertensive encephalopathy develops.

Posterior reversible encephalopathy syndrome (see section "Adverse reactions")

Symptoms suggestive of posterior reversible encephalopathy syndrome have been rarely observed in patients treated with Avastin®. Posterior reversible encephalopathy syndrome is a rare neurological disorder that is characterized by, among others, the following symptoms: seizures, headache, mental status changes, visual disturbances, cortical blindness with or without hypertension. Posterior reversible encephalopathy syndrome can be confirmed by brain imaging, with magnetic resonance imaging being preferred.

If posterior reversible encephalopathy syndrome develops, specific symptomatic treatment, including control of hypertension, should be initiated and Avastin® therapy should be discontinued. The safety of re-treatment with Avastin® in such patients has not been established.

Proteinuria (see section "Adverse reactions")

The risk of proteinuria is increased in patients with a history of hypertension. Available data suggest that proteinuria of all grades (National Cancer Institute Common Adverse Event Criteria, version 3.0) may be dose-related. Monitoring of proteinuria is recommended prior to and during Avastin® therapy. Grade 4 proteinuria (nephrotic syndrome) has been observed in approximately 1.4% of patients treated with Avastin®. If nephrotic syndrome develops, Avastin® should be discontinued.

Arterial thromboembolism (see section "Adverse reactions")

In clinical trials, the incidence of arterial thromboembolism, including stroke, transient ischemic attack, and myocardial infarction, was higher in patients receiving Avastin® in combination with chemotherapy than in patients receiving chemotherapy alone.

A history of arterial thromboembolism or age over 65 years are associated with an increased risk of arterial thromboembolism during treatment with Avastin®. Caution should be exercised when treating such patients.

If arterial thromboembolism develops, Avastin® should be discontinued.

Venous thromboembolism (see section "Adverse reactions")

There is an increased risk of venous thromboembolism, including pulmonary embolism, during treatment with Avastin®.

Patients treated with Avastin® in combination with paclitaxel and cisplatin for persistent, recurrent, or metastatic cervical cancer are at increased risk of developing venous thromboembolic events.

Avastin® treatment should be discontinued for life-threatening thromboembolism (Grade 4), including pulmonary thromboembolism (National Cancer Institute Common Adverse Event Criteria, version 3.0). In the event of thromboembolism ≤ Grade 3, the patient should be closely monitored (National Cancer Institute Common Adverse Event Criteria, version 3. ).

Patients receiving Avastin® are at increased risk of bleeding, particularly tumour-related. Avastin® should be discontinued if Grade 3 or 4 bleeding occurs.

Patients with signs and symptoms of untreated central nervous system (CNS) metastases were excluded from clinical trials of Avastin® based on imaging findings. Therefore, the risk of CNS bleeding in these patients has not been prospectively studied in randomized clinical trials. It is recommended that patients be monitored for symptoms of CNS bleeding. Avastin® should be discontinued if intracranial bleeding occurs.

There is no information on the safety profile of Avastin® in patients with congenital bleeding diathesis, acquired coagulopathy, or patients receiving full-dose anticoagulants for thromboembolism prior to Avastin® treatment, as these patients were excluded from clinical trials. Therefore, caution should be exercised when prescribing Avastin® to such patients. However, in patients with venous thrombosis who received Avastin® and full-dose warfarin concomitantly for venous thrombosis, there was no increase in the incidence of Grade 3 or higher bleeding.

Pulmonary hemorrhage/hemoptysis

Patients with non-small cell lung cancer treated with Avastin® are at increased risk of serious and in some cases fatal pulmonary bleeding/hemoptysis. Patients with a recent history of bleeding/hemoptysis (greater than 2.5 mL of blood) should not receive Avastin®.

Arterial dissection and aneurysms

The use of vascular endothelial growth factor inhibitors in patients with or without hypertension may contribute to the formation of aneurysms and/or arterial dissection. This risk should be carefully considered before initiating Avastin® treatment in patients with risk factors such as hypertension or a history of aneurysm.

Congestive heart failure (see section "Adverse reactions")

Congestive heart failure has been reported in clinical trials. Both asymptomatic decreases in left ventricular ejection fraction and congestive heart failure requiring therapy or hospitalization have been observed. Avastin® should be used with caution in patients with a history of clinically significant cardiovascular disease, such as ischemic heart disease or congestive heart failure.

In most cases, congestive heart failure occurred in patients with metastatic breast cancer who had previously received anthracycline treatment, radiation therapy to the left side of the chest, and other risk factors for the development of congestive heart failure.

In study AVF3694g, in anthracycline-experienced and anthracycline-naïve patients, there was no increase in the incidence of all-grade congestive heart failure in the anthracycline + bevacizumab treatment group compared to anthracycline monotherapy. Congestive heart failure

Grade 3 or higher was slightly more common in patients receiving bevacizumab in combination with chemotherapy compared with patients receiving chemotherapy alone. Similar results have been observed in other studies of metastatic breast cancer in patients not receiving concomitant anthracycline therapy.

Neutropenia and infections (see section "Adverse reactions")

An increased incidence of severe neutropenia, febrile neutropenia, or infections with or without severe neutropenia (including fatal cases) has been observed with Avastin® in combination with some myelotoxic chemotherapy regimens compared to chemotherapy alone. These events have been observed primarily with Avastin® in combination with platinum- or taxane-based chemotherapy for the treatment of non-small cell lung cancer, metastatic breast cancer, and in combination with paclitaxel and topotecan for the treatment of persistent, recurrent, or metastatic cervical cancer.

Hypersensitivity reactions (including anaphylactic shock)/infusion reactions (see section "Adverse reactions")

There is an increased risk of infusion reactions and hypersensitivity reactions (including anaphylactic shock) during Avastin® therapy. As with any humanized monoclonal antibody, close monitoring of the patient is recommended during Avastin® treatment. If reactions occur, the infusion should be discontinued and appropriate treatment should be initiated. The use of systemic premedication is not warranted.

Osteonecrosis of the jaw (see section "Adverse reactions")

Invasive dental procedures are a known risk factor for osteonecrosis of the jaw. Patients should have an oral dental examination and, if necessary, preventive dental procedures before starting Avastin® treatment. Invasive dental procedures should be avoided if the patient has previously received or is receiving intravenous bisphosphonates.

Intravitreal application

Avastin® is not indicated for intravitreal use.

Visual impairment

Serious visual disturbances have been reported with the intravenous administration of Avastin® into the vitreous humor for an off-label indication in patients with malignancies: infectious endophthalmitis; intraocular inflammation, including sterile endophthalmitis, uveitis, vitreous inflammation; retinal detachment; retinal pigment epithelial tear; increased intraocular pressure; intraocular hemorrhage, including vitreous hemorrhage, retinal hemorrhage; conjunctival hemorrhage. Some of the visual disturbances were serious adverse reactions of varying severity with vision loss, including permanent blindness.

Systemic effects after intravitreal administration of Avastin®

A decrease in circulating vascular endothelial growth factor (VEGF) concentrations has been demonstrated following intravitreal injection of VEGF inhibitors. Systemic reactions, including non-ocular bleeding and arterial thromboembolism, have been reported following intravitreal injection of VEGF inhibitors.

Ovarian failure/fertility

Avastin® may impair female fertility (see sections “Use during pregnancy or lactation”, “Adverse reactions”). Therefore, fertility preservation strategies should be discussed with patients of reproductive age before initiating treatment with Avastin®.

Sodium content

This medicinal product contains less than 1 mmol (23 mg) sodium per vial, i.e. essentially 'sodium-free'.

Immunogenicity

Patients in two phase III studies in the adjuvant treatment of colon cancer were tested for antibodies to Avastin® by immunoassay. Of these 2,233 patients, 14 patients (0.6%) tested positive, three of whom had neutralizing antibodies.

The clinical significance of this immune response to Avastin® is unknown. However, no adverse event in any patient who developed antibodies to Avastin® was associated with a type I hypersensitivity reaction or a type III immune complex reaction.

Immunogenicity data are highly dependent on the sensitivity and specificity of the assay used and may also be affected by factors such as sample handling, timing of sample collection, drug interactions, concomitant medications, and underlying disease. Therefore, comparing the incidence of antibodies to Avastin® across indications or with the incidence of antibodies to other therapeutic proteins may be misleading.

Use during pregnancy or breastfeeding

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