Bevacizumab (Concentrate) Instructions for Use

Marketing Authorization Holder

NANOLEK LLC (Russia)

Manufactured By

Universal Pharma, S.L. (Spain)

Quality Control Release

GH GENHELIX, S.A. (Spain)

ATC Code

L01FG01 (Bevacizumab)

Active Substance

Bevacizumab (Rec.INN registered by WHO)

Dosage Forms

	Bevacizumab	Concentrate for solution for infusion 25 mg/1 ml: vial 4 ml
		Concentrate for solution for infusion 25 mg/1 ml: vial 16 ml

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion is a clear to opalescent, colorless to yellowish or brownish liquid.

Excipients: α,α-trehalose dihydrate, sodium dihydrogen phosphate monohydrate, anhydrous disodium hydrogen phosphate, polysorbate 20 (tween 20), water for injections.

4 ml – colorless glass vials (type I) with a capacity of 8 ml (1) – cardboard packs with a holder.

Concentrate for solution for infusion is a clear to opalescent, colorless to yellowish or brownish liquid.

Excipients: α,α-trehalose dihydrate, sodium dihydrogen phosphate monohydrate, anhydrous disodium hydrogen phosphate, polysorbate 20 (tween 20), water for injections.

16 ml – colorless glass vials (type I) with a capacity of 20 ml (1) – cardboard packs with a holder.

Clinical-Pharmacological Group

Antitumor drug. Monoclonal antibodies

Pharmacotherapeutic Group

Antineoplastic agents; other antineoplastic agents; monoclonal antibodies

Pharmacological Action

Antineoplastic agent. It is a recombinant humanized monoclonal antibody that selectively binds to and neutralizes 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 mass 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

The pharmacokinetic parameters of bevacizumab were dose-linear in clinical studies (over a dose range of 1 to 10 mg/kg).

Evaluation 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. The recommended dose is 5 mg/kg, 7.5 mg/kg, 10 mg/kg, or 15 mg/kg, depending on the specific indication and chemotherapy regimen.

For metastatic colorectal cancer, administer 5 mg/kg, 7.5 mg/kg, or 10 mg/kg every 2 weeks; or 7.5 mg/kg every 3 weeks in combination with fluoropyrimidine-based chemotherapy.

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

For non-small cell lung cancer, administer 7.5 mg/kg or 15 mg/kg every 3 weeks in addition to platinum-based chemotherapy.

For 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.

For ovarian, fallopian tube, and primary peritoneal cancer, administer 15 mg/kg every 3 weeks or 10 mg/kg every 2 weeks in combination with chemotherapy, depending on the treatment line.

Administer the first infusion over 90 minutes. If well tolerated, administer the second infusion over 60 minutes. If the 60-minute infusion is well tolerated, administer all subsequent infusions 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, grade 4 venous thromboembolism, hypertensive crisis, or reversible posterior leukoencephalopathy syndrome.

Withhold bevacizumab for severe hypertension, proteinuria (≥2 g/24 hours), or severe hemorrhage until controlled. Resume based on clinical judgment.

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 NSCLC patients; 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.

From the body as a whole 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 products 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 prior to initiation of 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 carried out 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 occurs.

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.

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

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 radiation therapy, atherosclerosis, central tumor location, cavitation before or during treatment are possible risk factors for the development of pulmonary hemorrhages/hemoptysis, while a statistically significant association of these symptoms with the development of bleeding has been proven only for squamous cell lung cancer.

In patients with colorectal cancer, tumor-related gastrointestinal bleeding, including rectal bleeding and melena, may occur.

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

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

Bevacizumab therapy should be discontinued if arterial or venous thromboembolism occurs.

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 previously received anthracycline therapy and/or chest radiation therapy, as well as with other risk factors for congestive heart failure, such as coronary artery disease or concomitant therapy with cardiotoxic drugs. Both asymptomatic left ventricular ejection fraction reduction 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. Cases of fistulas at other sites (bronchopleural, urogenital, biliary) have been rarely reported. Fistula formation is more frequently observed during the first 6 months of bevacizumab therapy, but can occur as early as 1 week and up to 1 year or more after initiation of therapy. Bevacizumab therapy should be discontinued if a tracheoesophageal fistula or a fistula of any location of grade 4 severity 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 may present 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.