Arvestio^® (Concentrate) Instructions for Use

Marketing Authorization Holder

R-Pharm JSC (Russia)

Manufactured By

Sputnik Technopolis, LLC (Russia)

ATC Code

L01FG01 (Bevacizumab)

Active Substance

Bevacizumab (Rec.INN registered by WHO)

Dosage Form

Arvestio®

Concentrate for solution for infusion 25 mg/ml

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion

16 ml – vials – cardboard packs – Prescription only
4 ml – vials – cardboard packs – Prescription only

Clinical-Pharmacological Group

Antitumor drug. Monoclonal antibodies

Pharmacotherapeutic Group

Antineoplastic agents, monoclonal antibodies and their drug conjugates; VEGF/VEGFR (vascular endothelial growth factor) inhibitors

Pharmacological Action

Bevacizumab is an antitumor agent. It represents recombinant humanized monoclonal antibodies that selectively bind to and neutralize the biological activity of human vascular endothelial growth factor (VEGF).

Bevacizumab contains human framework regions with the complementarity-determining regions of a humanized mouse antibody that binds to VEGF. Bevacizumab is produced by recombinant DNA technology in Chinese hamster ovary cells.

Bevacizumab consists of 214 amino acids and has a molecular weight of approximately 149,000 daltons.

It inhibits the binding of VEGF to its receptors, Flt-1 and KDR, on the surface of endothelial cells. Neutralization of the biological activity of VEGF reduces tumor vascularization, thereby inhibiting tumor growth.

Pharmacokinetics

In clinical studies, the pharmacokinetic parameters of bevacizumab were linearly dose-dependent (in the dose range from 1 to 10 mg/kg).

An assessment of bevacizumab metabolism in experimental studies in rabbits after a single intravenous administration of ¹²⁵I-labeled bevacizumab showed that its metabolic profile was similar to that expected for a native IgG molecule that does not bind VEGF.

The clearance of bevacizumab was 0.207 L/day for women and 0.262 L/day for men.

Indications

Metastatic colorectal cancer: in combination with fluoropyrimidine-based chemotherapy.

Locally recurrent or metastatic breast cancer: as first-line therapy in combination with paclitaxel.

Advanced inoperable, metastatic or recurrent non-squamous non-small cell lung cancer: as first-line therapy in addition to platinum-based chemotherapy.

Advanced and/or metastatic renal cell carcinoma: as first-line therapy in combination with interferon alfa-2a.

Glioblastoma (WHO grade IV malignant glioma): in combination with radiotherapy and temozolomide in patients with newly diagnosed glioblastoma; as monotherapy or in combination with irinotecan for recurrent glioblastoma or disease progression.

Epithelial ovarian, fallopian tube, and primary peritoneal cancer: as first-line therapy in combination with carboplatin and paclitaxel for advanced (FIGO stage IIIB, IIIC, and IV) epithelial ovarian, fallopian tube, and primary peritoneal cancer; in combination with carboplatin and gemcitabine for recurrent platinum-sensitive epithelial ovarian, fallopian tube, and primary peritoneal cancer in patients who have not previously received bevacizumab or other VEGF inhibitors; in combination with paclitaxel, or topotecan, or pegylated liposomal doxorubicin for recurrent platinum-resistant epithelial ovarian, fallopian tube, and primary peritoneal cancer in patients who have received no more than two prior chemotherapy regimens.

ICD codes

Dosage Regimen

Administer as an intravenous infusion. Do not administer as an intravenous push or bolus. Calculate the dose based on the patient’s actual body weight.

For metastatic colorectal cancer, administer 5 mg/kg or 10 mg/kg every 2 weeks when combined with IV bolus-IFL; administer 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks when combined with FOLFOX4; administer 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks when combined with a fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin based chemotherapy.

For non-squamous non-small cell lung cancer, administer 15 mg/kg every 3 weeks in combination with carboplatin and paclitaxel.

For metastatic renal cell carcinoma, administer 10 mg/kg every 2 weeks in combination with interferon alfa-2a.

For glioblastoma, administer 10 mg/kg every 2 weeks as monotherapy.

For metastatic breast cancer, administer 10 mg/kg every 2 weeks in combination with paclitaxel.

For epithelial ovarian, fallopian tube, or primary peritoneal cancer, administer 15 mg/kg every 3 weeks in combination with carboplatin and paclitaxel, followed by 15 mg/kg every 3 weeks as a single agent; or administer 10 mg/kg every 2 weeks in combination with carboplatin and gemcitabine, followed by 15 mg/kg every 3 weeks as a single agent.

For cervical cancer, administer 15 mg/kg every 3 weeks in combination with paclitaxel and cisplatin, or paclitaxel and topotecan.

Dilute the calculated dose in 0.9% sodium chloride solution to a final volume of 100 ml. Do not mix with dextrose solutions.

Administer the first infusion over 90 minutes. If tolerated, administer the second infusion over 60 minutes. If well-tolerated, all subsequent infusions may be administered over 30 minutes.

Withhold bevacizumab for at least 28 days prior to elective surgery. Do not resume bevacizumab until the surgical wound is fully healed.

Permanently discontinue bevacizumab for gastrointestinal perforation, fistula formation involving an internal organ, wound dehiscence requiring medical intervention, severe hemorrhage, severe arterial thromboembolic events, nephrotic syndrome, or hypertensive crisis.

Temporarily suspend bevacizumab for severe hypertension not controlled with medication, proteinuria exceeding 2 grams per 24 hours, or severe infusion reactions.

Adverse Reactions

From the digestive system: diarrhea, nausea, abdominal pain, gastrointestinal perforation, small bowel obstruction, gastrointestinal disorders, constipation, stomatitis, rectal bleeding.

From the hematopoietic system: leukopenia, neutropenia, febrile neutropenia, anemia.

From the cardiovascular system: arterial hypertension, heart failure, supraventricular tachycardia, thromboembolism (arterial), deep vein thrombosis, bleeding.

From the urinary system: proteinuria, urinary tract infections.

From the blood coagulation system: bleeding, including pulmonary hemorrhage/hemoptysis, characteristic of patients with NSCLC; arterial thromboembolism.

From the CNS and peripheral nervous system: peripheral sensory neuropathy, ischemic stroke, syncope, drowsiness, headache, taste disorders, headache, lethargy, hypertensive encephalopathy (up to fatal outcome), reversible posterior leukoencephalopathy syndrome.

From the respiratory system: dyspnea, epistaxis, rhinitis, dyspnea, hypoxia, pulmonary embolism, nasal septum perforation.

From metabolism: dehydration, anorexia.

Dermatological reactions: palmar-plantar erythrodysesthesia syndrome, exfoliative dermatitis, dry skin, skin discoloration.

General disorders: frequently – fatigue or asthenia, sepsis, abscesses, infections, pain, fever.

Other: vision disorders, myasthenia.

Contraindications

CNS metastases, renal failure, hepatic failure, pregnancy, lactation (breastfeeding), children and adolescents under 18 years of age, hypersensitivity to bevacizumab, to drugs based on Chinese hamster ovary cells, or to other recombinant human or humanized antibodies.

Use in Pregnancy and Lactation

Contraindicated during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

Contraindicated: hepatic failure.

Use in Renal Impairment

Contraindicated: renal failure.

Pediatric Use

Contraindicated: pediatric age.

Geriatric Use

In elderly patients (over 65 years of age), the use of bevacizumab increases the risk of arterial thromboembolism (including stroke, transient ischemic attack, myocardial infarction), grade 3-4 leukopenia and thrombocytopenia, as well as neutropenia (all grades), diarrhea, nausea, headache, and asthenia.

Special Precautions

Use with caution in patients with a history of arterial thromboembolism; diabetes mellitus; in patients over 65 years of age; with congenital hemorrhagic diathesis and acquired coagulopathy; taking anticoagulants for thromboembolism treatment prior to initiating bevacizumab therapy; clinically significant cardiovascular disease (history of coronary artery disease or chronic heart failure); arterial hypertension; venous thromboembolism; during wound healing; bleeding/hemoptysis; history of gastrointestinal perforation; posterior reversible encephalopathy syndrome; neutropenia; proteinuria.

Treatment should only be administered under the supervision of a physician experienced in the use of anticancer therapy.

Bevacizumab may impair wound healing. Bevacizumab therapy should not be initiated earlier than 28 days after surgery or until the surgical wound is fully healed. If wound healing complications occur during treatment, Bevacizumab should be temporarily discontinued until complete healing. Bevacizumab therapy should also be temporarily discontinued in case of planned surgery.

Bevacizumab should only be used in patients with previously compensated arterial hypertension and under blood pressure control.

In patients with arterial hypertension, it is recommended to temporarily discontinue bevacizumab therapy until adequate blood pressure control is achieved. Normalization of blood pressure is achieved with ACE inhibitors, diuretics, and calcium channel blockers. Bevacizumab should be discontinued if blood pressure does not normalize, or if a hypertensive crisis or hypertensive encephalopathy develops.

The risk of proteinuria is increased in patients with a history of arterial hypertension.

Bevacizumab should be discontinued if grade 3 or 4 bleeding develops.

Caution is required when considering the use of bevacizumab in patients with congenital hemorrhagic diathesis, acquired coagulopathy, or those receiving full-dose anticoagulants for thromboembolism.

When using bevacizumab in patients with non-small cell lung cancer, there is an increased risk of serious, and in some cases, fatal pulmonary hemorrhages/hemoptysis.

Bevacizumab should not be used in patients with a history of bleeding/hemoptysis (more than 2.5 ml of blood). The use of antirheumatic/anti-inflammatory drugs, anticoagulants, prior radiotherapy, atherosclerosis, central tumor location, cavitation before or during treatment are possible risk factors for the development of pulmonary hemorrhages/hemoptysis, with a statistically significant association of these symptoms with the development of bleeding proven only for squamous cell lung cancer.

In patients with colorectal cancer, gastrointestinal bleeding associated with the tumor is possible, including rectal bleeding and melena.

Mucocutaneous bleeding was observed in 20-40% of patients. Epistaxis not exceeding grade 1 severity and lasting less than 5 minutes was most commonly observed. Less frequently, gingival bleeding or vaginal bleeding occurred.

When bevacizumab was used in combination with chemotherapy, the incidence of arterial thromboembolism, including stroke, transient ischemic attack, and myocardial infarction, was higher than with chemotherapy alone. A history of arterial thromboembolism or age over 65 years is associated with an increased risk of arterial thromboembolism during bevacizumab treatment. Particular caution is required when treating such patients.

If arterial or venous thromboembolism occurs, bevacizumab therapy should be discontinued.

In case of development of reversible posterior leukoencephalopathy, symptomatic therapy should be prescribed, blood pressure should be carefully controlled, and Bevacizumab should be discontinued. The safety of re-administration of bevacizumab in such patients has not been established.

In most cases, congestive heart failure occurred in patients with metastatic breast cancer who had a history of anthracycline therapy and/or chest radiotherapy, as well as other risk factors for congestive heart failure, such as coronary artery disease or concomitant therapy with cardiotoxic drugs. Both asymptomatic left ventricular ejection fraction decrease and congestive heart failure requiring therapy or hospitalization were observed. Caution should be exercised when prescribing bevacizumab to patients with clinically significant cardiovascular disease or a history of congestive heart failure.

Gastrointestinal fistulas occurred most frequently in patients with metastatic colorectal cancer, less frequently in other tumor locations. Rare cases of fistulas at other sites (bronchopleural, urogenital, biliary) have been reported. Fistula formation is more frequently observed during the first 6 months of bevacizumab therapy but can occur as early as 1 week or as late as 1 year or more after initiation of therapy. Bevacizumab therapy should be discontinued if a tracheoesophageal fistula or a grade 4 fistula of any location occurs. In case of an internal fistula not involving the gastrointestinal tract, the decision to discontinue bevacizumab should be made on an individual basis.

When bevacizumab was used as part of combination therapy with myelotoxic chemotherapeutic agents, an increased incidence of severe neutropenia, febrile neutropenia, or infections with severe neutropenia (including fatal cases) was observed.

In elderly patients (over 65 years of age), the use of bevacizumab increases the risk of arterial thromboembolism (including stroke, transient ischemic attack, myocardial infarction), grade 3-4 leukopenia and thrombocytopenia, as well as neutropenia (all grades), diarrhea, nausea, headache, and asthenia.

Drug Interactions

When bevacizumab was used in combination with sunitinib (50 mg, daily) in patients with metastatic renal cell carcinoma, cases of microangiopathic hemolytic anemia (belonging to a subgroup of hemolytic anemias that can manifest with red blood cell fragmentation, anemia, and thrombocytopenia) were reported. In some cases, neurological disorders, elevated creatinine levels, arterial hypertension, including hypertensive crisis, were also noted. These symptoms were reversible after discontinuation of bevacizumab and sunitinib therapy.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.