Avastin®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Avastin® (Avastin®)

Composition:

Active substance: 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; anhydrous sodium hydrogen phosphate; polysorbate 20; water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

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

Pharmacotherapeutic group.

Antineoplastic agents. Monoclonal antibodies and antibody-drug conjugates. Inhibitors of vascular endothelial growth factor / vascular endothelial growth factor receptors.

ATC 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 mediator of 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 reduced tumor vascularization, normalization of tumor-free vessels, and inhibition of new blood vessel formation within tumors, thereby suppressing tumor growth.

Administration of bevacizumab or its original murine antibody in xenograft models of malignant tumors in athymic mice resulted in potent antitumor activity against human tumors, including colorectal, breast, brain, pancreatic, and prostate tumors. Progression of metastatic disease was inhibited, and microvascular permeability was reduced.

Clinical efficacy

*Primary endpoint — overall survival.

**Primary endpoint — progression-free survival.

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

1Upper confidence limit cannot be determined.

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

HR — hazard ratio.

IFL — irinotecan, 5-fluorouracil, leucovorin.

FOLFOX4 — leucovorin, 5-fluorouracil, oxaliplatin.

CT — chemotherapy.

mCRC — 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. Bevacizumab pharmacokinetics were linear over the dose range of 1 to 10 mg/kg.

Distribution

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

Biotransformation

After a single intravenous administration of 125I-bevacizumab to rabbits, its metabolic profile was similar to that of a natural IgG molecule not binding VEGF. The metabolism and elimination of bevacizumab follow the same pathway as endogenous IgG, primarily via proteolytic catabolism in cells throughout the body, including endothelial cells, rather than renal or hepatic excretion. Binding of IgG to FcRn receptors protects it from cellular degradation and contributes to its long half-life.

Elimination

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

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

Special patient populations

A population pharmacokinetic analysis was performed to evaluate the impact of demographic characteristics in adult and pediatric patients. In adults, 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 impaired renal function, as the kidneys are not the primary route of metabolism or elimination of bevacizumab.

Patients with hepatic impairment. The pharmacokinetics of bevacizumab have not been studied in clinical trials in patients with impaired liver function, as the liver is not the primary route of metabolism or elimination of bevacizumab.

Children. Bevacizumab pharmacokinetics were evaluated in 152 children, adolescents, and young adults (aged 7 months to 21 years, weighing 5.9 to 125 kg) across four clinical studies using a population pharmacokinetic model. Pharmacokinetic study results showed that clearance and volume of distribution of bevacizumab are comparable in pediatric and young adult patients after normalization for body weight, with a trend toward decreased exposure as body weight decreases. Data indicate no effect of age, when adjusted for body weight, on bevacizumab pharmacokinetics.

Bevacizumab pharmacokinetics were well characterized using a pediatric population pharmacokinetic model in 70 patients in study BO20924 (aged 1.4 to 17.6 years; 11.6 to 77.5 kg) and 59 patients in clinical study BO25041 (aged 1 to 17 years; 11.2 to 82.3 kg). In clinical study BO20924, bevacizumab exposure was mostly lower compared to that in a typical adult patient receiving the same dose. In clinical study BO25041, bevacizumab exposure was nearly equivalent to that in a typical adult patient receiving the same dose. In both studies, a trend toward decreased exposure with decreasing body weight was observed.

Clinical characteristics.

Indications.

Treatment of metastatic colorectal cancer:

• in combination with fluoropyrimidine-based chemotherapy.

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 within the last 12 months in the adjuvant setting should not be given Avastin**®** in combination with capecitabine.

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

• 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, metastatic, or recurrent renal cell carcinoma in adult patients:

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

Treatment of advanced (FIGO stages III B, III C, and IV) 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 platinum-sensitive epithelial ovarian, fallopian tube, and primary peritoneal cancer:

• in combination with carboplatin and gemcitabine or in combination with carboplatin and paclitaxel in adult patients who have not previously received bevacizumab or other VEGF inhibitors or agents targeting 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 previously received 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 grade IV):

• as monotherapy following prior treatment with temozolomide.

Contraindications.

Hypersensitivity to bevacizumab or to any other component of the medicinal product, to products derived from Chinese hamster ovary cells, or to other recombinant human or humanized antibodies. Pregnancy.

Interaction with other medicinal products and other forms of interaction.

Effect of antineoplastic agents on the pharmacokinetics of bevacizumab

According to population pharmacokinetic analysis, no clinically significant interaction was observed when chemotherapy was administered concomitantly with bevacizumab, and no clinically significant effect on the pharmacokinetics of bevacizumab was noted. There was no statistically or clinically significant difference in the clearance of bevacizumab 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 agents

No clinically significant effect of bevacizumab on the pharmacokinetics of concurrently administered interferon alfa-2a, erlotinib (and its active metabolite OSI-420), or the chemotherapeutic agents irinotecan (and its active metabolite SN38), capecitabine, oxaliplatin (measured as free and total platinum levels), or cisplatin was observed. The effect of bevacizumab on the pharmacokinetics of gemcitabine cannot be concluded.

Combination of bevacizumab and malate salt of sunitinib

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

Microangiopathic hemolytic anemia is a hemolytic disorder characterized by erythrocyte fragmentation, anemia, and thrombocytopenia. In addition, some of these patients experienced hypertension (including hypertensive crises), elevated creatinine levels, and neurological symptoms. All these symptoms were reversible upon discontinuation of bevacizumab and malate salt of sunitinib (see section "Special warnings and precautions for use").

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

Increased incidence of severe neutropenia, febrile neutropenia, and infections with or without severe neutropenia (including fatal cases) was mainly observed in patients receiving platinum-based or taxane-based therapy for non-small cell lung cancer and metastatic breast cancer.

Radiotherapy

The safety and efficacy of concomitant use of radiotherapy and Avastin**®** have not been established.

Monoclonal antibodies to EGFR receptors in combination with chemotherapy containing bevacizumab

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

Special precautions for use.

To ensure improved traceability of medicinal biological products, the name and batch number of the administered medicinal product should be clearly documented.

Gastrointestinal perforation and fistulae (see section "Adverse reactions")

Patients receiving Avastin**®** have an increased risk of gastrointestinal and gallbladder perforation. Intrabdominal inflammatory conditions are risk factors for gastrointestinal perforation in patients with metastatic colorectal cancer; therefore, caution is advised when treating such patients.

Prior radiotherapy is a risk factor for gastrointestinal perforation in patients receiving Avastin**®** for persistent, recurrent, or metastatic cervical cancer; all patients who developed gastrointestinal perforation had a history of radiotherapy. Treatment should be permanently discontinued in patients who develop gastrointestinal perforation.

Gastrointestinal-vaginal fistulae in study GOG-0240

Patients receiving Avastin**®** for persistent, recurrent, or metastatic cervical cancer have an increased risk of developing fistulae between the vagina and any part of the gastrointestinal tract (gastrointestinal-vaginal fistulae). Prior radiotherapy is a major risk factor for gastrointestinal-vaginal fistulae; all patients with gastrointestinal-vaginal fistulae had a history of radiotherapy. Recurrent cancer in an area previously irradiated is an additional important risk factor for gastrointestinal-vaginal fistulae.

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

Patients receiving Avastin**®** have an increased risk of developing fistulae.

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

Information regarding continuation of Avastin**®** in patients with other fistulae is limited.

In the event of an internal fistula not involving the gastrointestinal tract, discontinuation of Avastin**®** should be considered.

Wound healing complications (see section "Adverse reactions")

Avastin**®** may impair wound healing. Serious wound healing complications, including anastomotic leakage with fatal outcomes, have been reported. Bevacizumab therapy should not be initiated within less than 28 days after major surgery or until surgical wounds are fully healed. If wound healing complications occur during treatment, Avastin**®** therapy should be temporarily discontinued until complete wound healing. Treatment must be discontinued if elective surgery is planned.

Rare cases of necrotizing fasciitis, including fatal cases, have been reported in patients receiving 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 immediately.

Arterial hypertension (see section "Adverse reactions")

An increased incidence of arterial hypertension has been observed in patients receiving Avastin**®. Clinical safety data suggest that the frequency of arterial hypertension is dose-dependent for bevacizumab. Avastin®** should only be administered to patients with previously controlled arterial hypertension. There are no data on the effect of Avastin**®** in patients with uncontrolled hypertension at the start of treatment. Blood pressure monitoring is recommended during Avastin**®** therapy.

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

Reversible posterior encephalopathy syndrome (see section "Adverse reactions")

Symptoms suggestive of reversible posterior encephalopathy syndrome have been rarely observed in patients receiving Avastin**®**. Reversible posterior encephalopathy syndrome is a rare neurological disorder characterized by symptoms such as seizures, headache, mental status changes, visual disturbances, and cortical blindness, with or without hypertension. Diagnosis of reversible posterior encephalopathy syndrome can be confirmed by brain imaging techniques, preferably magnetic resonance imaging (MRI).

In case of reversible posterior encephalopathy syndrome, treatment of specific symptoms, including control of arterial hypertension, should be initiated, and Avastin**®** therapy should be discontinued. The safety of reinitiating Avastin**®** therapy in such patients has not been established.

Proteinuria (see section "Adverse reactions")

The risk of proteinuria is increased in patients with a history of arterial hypertension. Available data indicate that proteinuria of all grades (Common Terminology Criteria for Adverse Events, National Cancer Institute, version 3.0) may be dose-related. Monitoring of proteinuria is recommended before and during Avastin**®** therapy. Grade 4 proteinuria (nephrotic syndrome) was observed in nearly 1.4% of patients receiving Avastin**®. Avastin®** should be discontinued if nephrotic syndrome develops.

Arterial thromboembolism (see section "Adverse reactions")

In clinical trials, the incidence of arterial thromboembolic events, including stroke, transient ischemic attack, and myocardial infarction, was higher in patients receiving Avastin**®** in combination with chemotherapy compared to those receiving chemotherapy alone.

A history of arterial thromboembolism or age over 65 years is associated with an increased risk of arterial thromboembolism during Avastin**®** treatment. Caution is advised when treating such patients.

Avastin**®** should be discontinued if arterial thromboembolism occurs.

Venous thromboembolism (see section "Adverse reactions")

An increased risk of venous thromboembolism, including pulmonary embolism, is observed during Avastin**®** treatment.

Patients receiving Avastin**®** in combination with paclitaxel and cisplatin for persistent, recurrent, or metastatic cervical cancer have an increased risk of venous thromboembolic events.

Avastin**®** treatment should be discontinued in the event of life-threatening (grade 4) thromboembolic events, including pulmonary embolism (Common Terminology Criteria for Adverse Events, National Cancer Institute, version 3.0). For thromboembolic events of grade ≤ 3, careful patient monitoring is recommended (Common Terminology Criteria for Adverse Events, National Cancer Institute, version 3.0).

Bleeding (see section "Adverse reactions")

Patients receiving Avastin**®** have an increased risk of bleeding, particularly tumor-related bleeding. Avastin**®** should be discontinued in the event of grade 3 or 4 bleeding.

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

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

Pulmonary hemorrhage/hemoptysis

Patients with non-squamous non-small cell lung cancer receiving Avastin® have an increased risk of serious, and in some cases fatal, pulmonary hemorrhage/hemoptysis. Avastin**®** should not be administered to patients who have recently experienced bleeding/hemoptysis (more than 2.5 mL of blood).

Aortic dissection and aneurysms

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

Congestive heart failure (see section "Adverse reactions")

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

Congestive heart failure most commonly occurred in patients with metastatic breast cancer who had previously received anthracycline therapy, radiotherapy to the left chest wall, and other risk factors for congestive heart failure.

In study AVF3694g, no increased incidence of congestive heart failure of any grade was observed in patients receiving anthracyclines or in those who had not previously received anthracyclines in the anthracycline + bevacizumab treatment group compared to anthracycline monotherapy. However, grade 3 or higher congestive heart failure occurred slightly more frequently in patients receiving bevacizumab in combination with chemotherapy compared to those receiving chemotherapy alone. Similar results were observed in other metastatic breast cancer studies in patients not receiving concomitant anthracycline therapy.

Neutropenia and infections (see section "Adverse reactions")

Treatment with Avastin**®** in combination with certain myelotoxic chemotherapy regimens, compared to chemotherapy alone, has been associated with an increased incidence of severe neutropenia, febrile neutropenia, or infections with or without severe neutropenia (including fatal cases). These events were primarily observed when Avastin**®** was used in combination with platinum- or taxane-based chemotherapy for non-squamous non-small cell lung cancer, metastatic breast cancer, and in combination with paclitaxel and topotecan for persistent, recurrent, or metastatic cervical cancer.

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

An increased risk of infusion reactions and hypersensitivity reactions (including anaphylactic shock) has been observed during Avastin**®** therapy. As with any humanized monoclonal antibody, careful monitoring of patients is recommended during Avastin**®** treatment. Infusion should be stopped and appropriate treatment initiated if reactions occur. Systemic premedication is not justified.

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

Cases of osteonecrosis of the jaw have been reported in cancer patients receiving Avastin**®. Most cases occurred in patients who had previously or concurrently received intravenous bisphosphonates, which are known to carry a risk of osteonecrosis of the jaw. Caution is advised when administering Avastin®** concomitantly with intravenous bisphosphonates or sequentially with bisphosphonates.

Invasive dental procedures are a known risk factor for osteonecrosis of the jaw. A dental examination and, if necessary, preventive dental procedures should be performed before starting Avastin**®** treatment. Invasive dental procedures should be avoided in patients who have previously received or are receiving intravenous bisphosphonates.

Intravitreal administration

Avastin**®** is not indicated for intravitreal administration.

Ocular disorders

Serious ocular disorders have been reported following off-label intravitreal administration of Avastin**®** for intravenous use in patients with malignant tumors: infectious endophthalmitis; intraocular inflammation, including sterile endophthalmitis, uveitis, vitritis; retinal detachment; retinal pigment epithelium tear; increased intraocular pressure; intraocular hemorrhage, including vitreous hemorrhage and retinal hemorrhage; conjunctival hemorrhage. Some of these ocular disorders were serious adverse reactions of varying degrees of visual loss, including permanent blindness.

Systemic effects after intravitreal administration of Avastin*®***

Reduction in circulating vascular endothelial growth factor (VEGF) concentration has been demonstrated after intravitreal injection of VEGF inhibitors. Systemic reactions, including non-ocular bleeding and arterial thromboembolic events, have been reported after intravitreal injection of VEGF inhibitors.

Ovarian function suppression/fertility

Avastin**®** may impair fertility in women (see sections "Use during pregnancy or breastfeeding", "Adverse reactions"). Therefore, fertility preservation strategies should be discussed with women of reproductive potential before initiating Avastin**®** treatment.

Sodium content

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

Immunogenicity

Patients in two phase III studies investigating adjuvant treatment of colorectal cancer were tested by immunoassay for antibodies to Avastin®. Of these 2233 patients, 14 (0.6%) tested positive, with neutralizing antibodies detected in three of them.

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

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

Use during pregnancy or breastfeeding.

Women of reproductive potential

Women of reproductive potential should use effective contraception during treatment and for 6 months after completion of treatment.

Pregnancy

There are no clinical data on the use of Avastin**®** in pregnant women. Animal studies have demonstrated reproductive toxicity, including potential for congenital malformations. IgG is known to cross the placental barrier, and Avastin**®** may inhibit fetal angiogenesis. Therefore, Avastin**®** is suspected to cause severe fetal malformations when used during pregnancy. Post-marketing reports have documented fetal abnormalities in women who received bevacizumab as monotherapy or in combination with chemotherapeutic agents known to have embryotoxic effects (see section "Adverse reactions"). Avastin**®** is contraindicated during pregnancy.

Breastfeeding

It is unknown whether bevacizumab is excreted in human milk. Since maternal IgG is excreted in breast milk and Avastin**®** may impair infant growth and development, women should be advised to discontinue breastfeeding during Avastin**®** therapy and for at least 6 months after the last dose of Avastin**®**.

Fertility

Toxicity studies in animals have shown that repeated doses of bevacizumab may adversely affect fertility in females. In a phase III adjuvant treatment study in premenopausal women with colorectal cancer, a higher incidence of new-onset ovarian function suppression was observed in the bevacizumab group compared to the control group. Ovarian function recovered in most patients after discontinuation of bevacizumab. The long-term impact of bevacizumab treatment on fertility is unknown.

Ability to drive and use machines.

Avastin**®** has no or negligible effect on the ability to drive and use machines. Symptoms such as somnolence and syncope have been observed with Avastin**®** (see section "Adverse reactions"). If patients experience symptoms affecting vision, concentration, or reaction ability, they should refrain from driving and operating machinery until symptoms resolve.

Administration and Dosage

Treatment with Avastin® must only be conducted under the supervision of a physician experienced in anti-cancer therapy.

Dose reduction of bevacizumab due to adverse reactions is not recommended. If necessary, treatment with Avastin® should be completely or temporarily discontinued (see section "Special Warnings and Precautions for Use").

Standard Dosing Regimen

Metastatic Colorectal Cancer

5 mg/kg or 10 mg/kg body weight every 2 weeks, or 7.5 mg/kg or 15 mg/kg body weight every 3 weeks as an intravenous infusion.

Treatment with Avastin® should be continued until disease progression or development of unacceptable toxicity.

Metastatic Breast Cancer

10 mg/kg body weight every 2 weeks or 15 mg/kg body weight every 3 weeks as an intravenous infusion.

Treatment with Avastin**®** should be continued until disease progression or development of unacceptable toxicity.

Non-Small Cell Lung Cancer

First-line treatment of non-squamous non-small cell lung cancer in combination with platinum-based chemotherapy

In combination with platinum-based chemotherapy for up to 6 cycles, followed by maintenance therapy with Avastin**®** as monotherapy until disease progression.

7.5 mg/kg or 15 mg/kg body weight every 3 weeks as an intravenous infusion.

Clinical benefit in patients with non-small cell lung cancer has been demonstrated with both doses — 7.5 mg/kg and 15 mg/kg.

Treatment with Avastin**®** should be continued until disease progression or development of unacceptable toxicity.

First-line treatment of non-squamous non-small cell lung cancer with EGFR-activating mutations in combination with erlotinib

Testing for EGFR mutation should be performed prior to initiating combination therapy with Avastin**®** and erlotinib. It is important to use a validated and reliable method to avoid false results.

The recommended dose of Avastin**®** when used in combination with erlotinib is 15 mg/kg body weight once every 3 weeks as an intravenous infusion.

Combination therapy with Avastin**®** and erlotinib should be continued until disease progression.

For information on dosing and administration of erlotinib, refer to the erlotinib prescribing information.

Advanced and/or Metastatic Renal Cell Carcinoma

10 mg/kg body weight every 2 weeks as an intravenous infusion.

Treatment with Avastin**®** should be continued until disease progression or development of unacceptable toxicity.

Epithelial Ovarian, Fallopian Tube, and Primary Peritoneal Cancer

First-line treatment: in combination with carboplatin and paclitaxel for up to 6 treatment cycles, followed by continued treatment with Avastin**®** as monotherapy until disease progression or for a maximum of 15 months, whichever occurs first, or until development of unacceptable toxicity.

The recommended dose of Avastin**®** is 15 mg/kg body weight every 3 weeks as an intravenous infusion.

Treatment of recurrent disease: Avastin**®** is administered in combination with carboplatin and gemcitabine for 6 to 10 treatment cycles, or in combination with carboplatin and paclitaxel for 6 to 8 treatment cycles, followed by long-term maintenance therapy with Avastin**®** as monotherapy until disease progression. The recommended dose of Avastin**®** is 15 mg/kg body weight once every 3 weeks as an intravenous infusion.

Treatment of platinum-resistant recurrent disease: Avastin**®** is used in combination with one of the following agents: paclitaxel, weekly topotecan, or pegylated liposomal doxorubicin. The recommended dose of Avastin**®** in these cases is 10 mg/kg body weight every 2 weeks as an intravenous infusion. When Avastin**®** is administered in combination with topotecan (on days 1–5 every 3 weeks), the recommended dose is 15 mg/kg body weight once every 3 weeks as an intravenous infusion. The recommended duration of treatment is until disease progression or development of unacceptable toxicity.

Cervical Cancer

Avastin**®** is used in combination with one of the following chemotherapy regimens: paclitaxel and cisplatin, or paclitaxel and topotecan.

The recommended dose of Avastin® is 15 mg/kg body weight, administered once every 3 weeks as an intravenous infusion.

Treatment should be continued until disease progression or development of unacceptable toxicity.

Recurrent Glioblastoma

The recommended dose of Avastin® is 10 mg/kg body weight every 2 weeks as an intravenous infusion. Treatment with Avastin® should be continued until disease progression. The use of a dose of 15 mg/kg every 3 weeks is not supported by available data.

Special Patient Populations

Elderly patients: dose adjustment is not required for elderly patients.

Renal impairment: the safety and efficacy of bevacizumab in patients with renal impairment have not been studied.

Hepatic impairment: the safety and efficacy of bevacizumab in patients with hepatic impairment have not been studied.

Paediatric Population

The safety and efficacy of bevacizumab in children (under 18 years of age) have not been established. Available data are presented in sections "Adverse Reactions" and "Pharmacological Properties", but they do not allow for any dosage recommendations.

There are no adequate data on the use of bevacizumab in children for the treatment of colorectal cancer, breast cancer, lung cancer, ovarian, fallopian tube, and primary peritoneal cancer, cervical cancer, or renal cancer.

Administration Instructions

The initial dose should be administered as an intravenous infusion over 90 minutes. If the first infusion is well tolerated, the second infusion may be given over 60 minutes. If the 60-minute infusion is well tolerated, all subsequent infusions may be administered over 30 minutes.

Avastin® must not be administered as an intravenous push or bolus injection!

Dose reduction due to adverse reactions is not recommended. If indicated, therapy should be permanently discontinued or temporarily suspended (see section "Adverse Reactions").

Precautions for Use and Administration of Avastin®

Avastin**®** must be prepared by healthcare professionals under aseptic conditions to ensure sterility of the prepared solution. Sterile needles and syringes should be used for preparing Avastin® for administration.

Avastin® infusion must not be mixed with or administered using glucose-containing solutions. The product must not be mixed with other medicinal products except 0.9% sodium chloride injection solution.

The required amount of bevacizumab should be withdrawn and diluted to the desired volume with 0.9% (9 mg/mL) sodium chloride injection solution. The final concentration of bevacizumab in the prepared solution should be between 1.4 and 16.5 mg/mL. In most cases, the required amount of Avastin® can be diluted with 0.9% sodium chloride injection solution to a total volume of 100 mL.

The solution should be inspected visually for particulate matter and discoloration prior to administration.

Avastin**®** is intended for single use only, as the product does not contain a preservative. Any unused product or waste material should be disposed of in accordance with local requirements.

No incompatibility has been observed between Avastin**®** and polyvinyl chloride or polyolefin bags, or infusion sets.

Chemical and physical stability of the prepared solution is maintained for 48 hours at 2 to 30 °C in 0.9% (9 mg/mL) sodium chloride injection solution. From a microbiological standpoint, the product should be used immediately. If not used immediately, the storage time and conditions prior to use are the responsibility of the user. The prepared solution may be stored for up to 24 hours at 2 to 8 °C, provided that dilution is performed under controlled and validated aseptic conditions.

Paediatric Population

The safety of Avastin® in children and adolescents has not been established.

Overdose

In several patients receiving the maximum dose of 20 mg/kg body weight intravenously every 2 weeks, severe migraine was reported. There is no specific antidote. Treatment is symptomatic.

Adverse Reactions.

The overall safety profile of Avastin**®** is based on data from more than 5,400 patients with various malignancies who received treatment predominantly with Avastin**®** in combination with chemotherapy in clinical trials.

The most serious adverse reactions were gastrointestinal perforations, hemorrhage including pulmonary hemorrhage/hemoptysis (more frequently observed in patients with non-squamous non-small cell lung cancer), and arterial thromboembolism (see section "Special Warnings and Precautions for Use").

In clinical trials, the most commonly observed adverse reactions in patients receiving Avastin**®** were hypertension, fatigue or asthenia, diarrhea, and abdominal pain.

Analysis of clinical safety data suggests that hypertension and development of proteinuria during treatment with Avastin**®** are likely to be dose-dependent.

The adverse reactions listed in this section are categorized by frequency as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); frequency not known (cannot be estimated from available data). Within each frequency category, adverse reactions are listed in order of decreasing severity.

Some of these adverse reactions are typically associated with chemotherapy; however, Avastin**®** may exacerbate these reactions when used in combination with chemotherapeutic agents. Examples of such adverse reactions include palmar-plantar erythrodysesthesia when used with pegylated liposomal doxorubicin or capecitabine, peripheral sensory neuropathy when used with paclitaxel or oxaliplatin, nail disorders or alopecia when used with paclitaxel, and paronychia when used with erlotinib.

The following adverse reactions are associated with the use of Avastin**®** in combination with various chemotherapy regimens across different indications.

Adverse reactions reported during the post-marketing period are included in the appropriate categories. Detailed information on reactions documented during the post-marketing period is provided below in the corresponding subsection.

Adverse Reactions by Frequency

Listed below are all adverse reactions identified as having a causal relationship with Avastin**®**, established:

• by comparing the frequency of adverse reactions observed in clinical trials between treatment groups (a difference of at least 10% compared to the control group for grade 1–5 reactions according to NCI-CTCAE [National Cancer Institute Common Terminology Criteria for Adverse Events], or at least 2% for grade 3–5 reactions);
• in post-marketing safety studies;
• from spontaneous reports;
• in epidemiological/non-interventional or observational studies;
• through evaluation of individual clinical cases.

Infections and infestations: common: sepsis, phlegmon, abscessb,d, cellulitis, infections, urinary tract infections; rare: necrotizing fasciitisc.

Blood and lymphatic system disorders: very common: febrile neutropenia, leukopenia, neutropeniab, thrombocytopenia; common: anemia, lymphopenia.

Immune system disorders: common: hypersensitivity, infusion-related reactionsa,b,d; rare: anaphylactic shock.

Metabolism and nutrition disorders: very common: anorexia, hypomagnesemia, hyponatremia; common: dehydration.

Nervous system disorders: very common: peripheral sensory neuropathyb, dysarthria, headache, dysgeusia; common: cerebrovascular accident, syncope, somnolence; rare: reversible posterior encephalopathy syndromea,b,d; very rare: hypertensive encephalopathya.

Eye disorders: very common: eye disorders, lacrimation increased.

Cardiac disorders: common: congestive heart failureb,d, supraventricular tachycardia.

Vascular disorders: very common: arterial hypertensionb,d, thromboembolism (venous)b,d; common: thromboembolism (arterial)b,d, hemorrhageb,d, deep vein thrombosis; frequency not known: renal thrombotic microangiopathya,b, arterial dissection and aneurysms.

Respiratory, thoracic and mediastinal disorders: very common: dyspnea, rhinitis, epistaxis, cough; common: pulmonary hemorrhage/hemoptysisb,d, pulmonary arterial embolism, hypoxia, dysphoniab,d; frequency not known: pulmonary hypertensiona, nasal septum perforationa.

Gastrointestinal disorders: very common: rectal hemorrhage, stomatitis, constipation, diarrhea, nausea, vomiting, abdominal pain; common: gastrointestinal perforationb,d, intestinal perforation, ileus, intestinal obstruction, rectovaginal fistulad,e, gastrointestinal disorders, proctalgia; frequency not known: gastrointestinal ulcerationa.

Hepatobiliary disorders: frequency not known: gallbladder perforationa,b.

Skin and subcutaneous tissue disorders: very common: wound healing complicationsb,d, exfoliative dermatitis, dry skin, skin discoloration; common: palmar-plantar erythrodysesthesia.

Musculoskeletal and connective tissue disorders: very common: arthralgia, myalgia; common: fistulab,d, muscle weakness, back pain; frequency not known: osteonecrosis of the jawa,b, osteonecrosis at sites other than the jawa,f.

Renal and urinary disorders: very common: proteinuriab,d.

Reproductive system and breast disorders: very common: ovarian failureb,c,d; common: pelvic pain.

Congenital, familial and genetic disorders: frequency not known: fetal abnormalitiesa,b.

Investigations: very common: weight decreased.

General disorders and administration site conditions: very common: asthenia, fatigue, pyrexia, pain, mucosal inflammation; common: lethargy.

When adverse reactions of all grades, including grades 3–5, were recorded during clinical trials, the highest frequency of occurrence was also documented. Data are not adjusted for differing treatment durations.

aSee also subsection "Adverse Reactions Reported in the Post-Marketing Period" below.

bTerms reflect a group of conditions describing a medical concept rather than a single condition or preferred term according to MedDRA (Medical Dictionary for Regulatory Activities). This group of medical terms may share the same underlying pathophysiology (e.g., arterial thromboembolic events including cerebrovascular accident, myocardial infarction, transient ischemic attack, and other arterial thromboembolic events).

cBased on a sub-study conducted within NSABP C-08 (National Surgical Adjuvant Breast and Bowel Project) involving 295 patients.

dSee also subsection "Serious Specific Adverse Reactions".

eRectovaginal fistulas are the most common type within the category of gastrointestinal-vaginal fistulas.

fObserved only in children.

Severe Adverse Reactions by Frequency

Severe reactions are defined as adverse events with a frequency difference of at least 2% compared to the control group in clinical trials and with severity grade 3–5 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE). This also includes adverse reactions considered by the marketing authorization holder to be clinically significant or severe. These clinically significant adverse reactions were recorded in clinical trials, but the frequency of grade 3–5 reactions did not reach a 2% difference compared to the control group. The data below also include clinically significant adverse reactions observed only during the post-marketing period; therefore, the frequency and grade of reactions according to NCI-CTCAE are unknown. Hence, these clinically significant reactions were included in the "frequency not known" category.

Infections and infestations: common: sepsis, cellulitis, abscessa,b, infections, urinary tract infections; frequency not known: necrotizing fasciitisc.

Blood and lymphatic system disorders: very common: febrile neutropenia, leukopenia, neutropeniaa, thrombocytopenia; common: anemia, lymphopenia.

Immune system disorders: common: frequency not known: hypersensitivity, infusion-related reactionsa,b,c; rare: anaphylactic shock.

Metabolism and nutrition disorders: common: dehydration, hyponatremia.

Nervous system disorders: very common: peripheral sensory neuropathya; common: cerebrovascular accident, syncope, somnolence, headache; frequency not known: reversible posterior encephalopathy syndromea,b,c, hypertensive encephalopathyc.

Cardiac disorders: common: congestive heart failurea,b, supraventricular tachycardia.

Vascular disorders: very common: hypertensiona,b; common: thromboembolism (arterial)a,b, hemorrhagea,b, thromboembolism (venous)a,b, deep vein thrombosis; frequency not known: renal thrombotic microangiopathyc,b, arterial dissection and aneurysms.

Respiratory, thoracic and mediastinal disorders: common: pulmonary hemorrhage/hemoptysisa,b, pulmonary arterial embolism, epistaxis, dyspnea, hypoxia; frequency not known: pulmonary hypertensionc, nasal septum perforationc.

Gastrointestinal disorders: very common: diarrhea, nausea, vomiting, abdominal pain; common: intestinal perforation, ileus, intestinal obstruction, rectovaginal fistulac,d, gastrointestinal disorders, stomatitis, proctalgia; frequency not known: gastrointestinal perforationa,b, gastrointestinal ulcerationc, rectal hemorrhages.

Hepatobiliary disorders: frequency not known: gallbladder perforationb,c.

Skin and subcutaneous tissue disorders: common: wound healing complicationsa,b, palmar-plantar erythrodysesthesia.

Musculoskeletal and connective tissue disorders: common: fistulaa,b, myalgia, arthralgia, muscle weakness, back pain; frequency not known: osteonecrosis of the jawb,c.

Renal and urinary disorders: common: proteinuriaa,b.

Reproductive system and breast disorders: common: pelvic pain; frequency not known: ovarian failurea,b.

Congenital, familial and genetic disorders: frequency not known: fetal abnormalitiesa,c.

General disorders and administration site conditions: very common: asthenia, fatigue; common: pain, lethargy, mucosal inflammation.

aTerms reflect a group of conditions describing a medical concept rather than a single condition or preferred term according to MedDRA (Medical Dictionary for Regulatory Activities). This group of medical terms may share the same underlying pathophysiology (e.g., arterial thromboembolic events including cerebrovascular accident, myocardial infarction, transient ischemic attack, and other arterial thromboembolic events).

bSee also subsection "Serious Specific Adverse Reactions".

cSee also subsection "Adverse Reactions Reported in the Post-Marketing Period".

dRectovaginal fistulas are the most common type within the category of gastrointestinal-vaginal fistulas.

Specific Serious Adverse Reactions

Gastrointestinal Fistulae (see section "Special Warnings and Precautions for Use")

Treatment with Avastin**®** has been associated with severe cases of gastrointestinal tract perforation.

In clinical trials, gastrointestinal perforations were observed in less than 1% of patients with non-squamous non-small cell lung cancer, approximately 1.3% of patients with metastatic breast cancer, approximately 2.0% of patients with metastatic renal cell carcinoma or patients with ovarian cancer receiving first-line treatment, and approximately 2.7% of patients with metastatic colorectal cancer (including gastrointestinal fistula and abscess). In a clinical trial involving patients with persistent, recurrent, or metastatic cervical cancer, gastrointestinal perforations (all grades) were reported in 3.2% of patients, all of whom had a history of prior pelvic radiation.

The manifestations ranged from free intraperitoneal gas on abdominal X-ray, which resolved without treatment, to intestinal perforation with fatal intra-abdominal abscess. In some cases, intra-abdominal inflammation occurred secondary to peptic ulcer, tumor necrosis, diverticulitis, or chemotherapy-associated colitis.

Approximately one-third of serious gastrointestinal perforations were fatal, occurring in 0.2–1% of all patients treated with Avastin**®**.

In clinical trials of Avastin**®**, gastrointestinal fistula (all grades) was reported in up to 2% of patients with metastatic colorectal cancer and ovarian cancer; it was observed less frequently in patients with other types of cancer.

Gastrointestinal-Vaginal Fistulae in the GOG-0240 Study

In a study involving patients with persistent, recurrent, or metastatic cervical cancer, the incidence of gastrointestinal-vaginal fistulae was 8.3% in patients receiving Avastin**®** compared to 0.9% in the control group, all of whom had a history of prior pelvic radiation. The incidence of gastrointestinal-vaginal fistulae was higher in the Avastin**®** + chemotherapy group among patients with recurrence within the prior radiation field (16.7%) compared to those with recurrence outside the prior radiation field (3.6%). The corresponding rates in the control group receiving chemotherapy alone were 1.1% versus 0.8%. Patients who developed gastrointestinal-vaginal fistulae may also experience intestinal obstruction and require surgical intervention along with stoma creation.

Fistulae Not Related to the Gastrointestinal Tract (see section "Special Warnings and Precautions for Use")

Treatment with Avastin**®** has been associated with serious cases of fistula formation, including fatal cases.

In a clinical trial involving patients with persistent, recurrent, or metastatic cervical cancer, vaginal, bladder, or female genital tract fistulae not related to the gastrointestinal tract were observed in 1.8% of patients receiving Avastin**®** and in 1.4% of patients in the control group.

Fistulae involving other body sites (e.g., bronchopleural fistulae, biliary fistulae) were infrequently reported (from ≥0.1% to <1%) during treatment across various indications. Fistulae have also been reported during the post-marketing period.

Fistulae have been reported at various times during treatment—within 1 week to 1 year or later after initiation of Avastin**®** treatment, with most reactions occurring within the first 6 months of therapy.

Wound Healing (see section "Special Warnings and Precautions for Use")

Since Avastin**®** may negatively affect wound healing, patients who underwent major surgery within the previous 28 days were excluded from Phase III clinical trials.

In clinical trials of metastatic colorectal cancer, no increased risk of postoperative hemorrhage or impaired wound healing was observed in patients who underwent major surgery 28–60 days prior to initiation of Avastin**®** treatment. However, an increased frequency of postoperative hemorrhage or wound healing complications within 60 days after major surgery was observed when patients received Avastin**®** treatment during surgery. The frequency of these serious adverse events ranged between 10% (4 out of 40 patients) and 20% (3 out of 15 patients).

Serious wound healing complications, including anastomotic complications, some of which were fatal, have been reported.

In studies of locally recurrent and metastatic breast cancer, wound healing complications of grade 3–5 were observed in 1.1% of patients receiving Avastin**®** compared to 0.9% in control groups.

In clinical trials of ovarian cancer, wound healing complications of grade 3–5 were observed in 1.2% of patients in the bevacizumab treatment group compared to 0.1% in the control group.

Arterial Hypertension (see section "Special Warnings and Precautions for Use")

In clinical trials, except for the JO25567 study, the overall frequency of arterial hypertension (all grades) reached 42.1% in treatment groups receiving Avastin**®-containing regimens compared to 14% in control groups. The overall frequency of grade 3–4 arterial hypertension (NCI-CTC [National Cancer Institute Common Toxicity Criteria]) in patients receiving Avastin®** ranged from 0.4% to 17.9%. Grade 4 arterial hypertension (hypertensive crisis) was observed in nearly 1% of patients receiving Avastin**®** and chemotherapy compared to 0.2% of patients receiving chemotherapy alone.

In the JO25567 study, arterial hypertension of all grades was observed in 77.3% of patients receiving Avastin**®** in combination with erlotinib as first-line treatment for non-squamous non-small cell lung cancer with EGFR-activating mutations, compared to 14.3% of patients receiving erlotinib alone. Grade 3 arterial hypertension was observed in 60% of patients receiving Avastin**®** in combination with erlotinib compared to 11.7% of patients receiving erlotinib alone. Grade 4 or 5 arterial hypertension was not observed.

Overall, arterial hypertension was adequately controlled with oral antihypertensive agents such as angiotensin-converting enzyme inhibitors, diuretics, and calcium channel blockers. Arterial hypertension rarely led to discontinuation of Avastin**®** treatment or hospitalization.

Very rarely, cases of hypertensive encephalopathy, some of which were fatal, have been reported. The risk of arterial hypertension associated with Avastin**®** treatment did not correlate with baseline patient characteristics, underlying disease, or concomitant therapy.

Reversible Posterior Encephalopathy Syndrome (see section "Special Warnings and Precautions for Use")

Reversible posterior encephalopathy syndrome symptoms were rarely observed in patients receiving Avastin**®**. Reversible posterior encephalopathy syndrome is a rare neurological disorder characterized by symptoms such as seizures, headache, altered mental status, visual disturbances, cortical blindness, which may or may not be accompanied by hypertension. Clinical manifestations of reversible posterior encephalopathy syndrome are often nonspecific; therefore, diagnosis can be confirmed by brain imaging, preferably magnetic resonance imaging.

In case of reversible posterior encephalopathy syndrome development, early recognition and prompt treatment of specific symptoms, including control of arterial hypertension (if severe uncontrolled hypertension is present), and discontinuation of Avastin**®** treatment are recommended. Symptoms usually resolve or improve within days after treatment discontinuation, although some neurological sequelae may persist in some patients. The safety of re-administering Avastin**®** to patients with a history of reversible posterior encephalopathy syndrome is unknown.

In clinical trials, 8 cases of reversible posterior encephalopathy syndrome were recorded. In two of the eight cases, radiological confirmation by magnetic resonance imaging was not obtained.

Proteinuria (see section "Special Warnings and Precautions for Use")

In clinical trials, proteinuria was observed in 0.7–54.7% of patients receiving Avastin**®**.

Proteinuria severity ranged from clinically asymptomatic transient detection of trace protein in urine to nephrotic syndrome, with most cases reported as grade 1 proteinuria. Grade 3 proteinuria was observed in 8.1% of patients. Grade 4 proteinuria (nephrotic syndrome) was observed in 1.4% of patients receiving treatment. Prior to initiation of Avastin**®** treatment, urine analysis for proteinuria is recommended. In most clinical trials, a urine protein level ≥2 g/24 hours required discontinuation of Avastin**®** treatment until proteinuria decreased to <2 g/24 hours.

Hemorrhage (see section "Special Warnings and Precautions for Use")

In clinical trials, the overall frequency of grade 3–5 hemorrhage according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTC) classification across all indications with Avastin**®** treatment ranged from 0.4% to 6.9% compared to 4.5% in the chemotherapy-only control group.

In a clinical trial involving patients with persistent, recurrent, or metastatic cervical cancer, grade 3–5 hemorrhage was reported in 8.3% of patients receiving Avastin**®** in combination with paclitaxel and topotecan compared to 4.6% of patients receiving paclitaxel and topotecan.

The most commonly observed hemorrhages in clinical trials were tumor-related or minor mucocutaneous bleeding (e.g., epistaxis).

Hemorrhage Associated with Tumor (see section "Special Warnings and Precautions for Use")

Significant or massive pulmonary hemorrhage/hemoptysis in studies occurred predominantly in patients with non-squamous non-small cell lung cancer. Possible risk factors for pulmonary hemorrhage/hemoptysis include squamous cell histology, treatment with anti-rheumatic/anti-inflammatory drugs, anticoagulants, prior radiotherapy, Avastin**®** treatment, history of atherosclerosis, central tumor location, and tumor cavitation before or during treatment. However, a statistically significant association with hemorrhage during Avastin**®** treatment has been demonstrated only for squamous cell histology. Patients with non-squamous non-small cell lung cancer with known predominantly squamous histology or mixed cell type with predominantly squamous histology were excluded from subsequent Phase III studies, while patients with unknown tumor histology were included in the studies.

In patients with non-squamous non-small cell lung cancer (excluding predominantly squamous histology), events of all severity grades were observed with a frequency of up to 9.3% with Avastin**®** in combination with chemotherapy compared to 5% in patients receiving chemotherapy alone. Grade 3–5 events were observed in 2.3% of patients receiving Avastin**®** in combination with chemotherapy compared to <1% of patients receiving chemotherapy alone. Significant or massive pulmonary hemorrhage/hemoptysis may occur suddenly, and up to two-thirds of serious pulmonary hemorrhages were fatal.

In patients with colorectal cancer, gastrointestinal tract hemorrhage associated with tumor, including rectal hemorrhage and melena, was reported.

Tumor-associated hemorrhage was rarely observed in other tumor types and locations and included CNS hemorrhage in patients with CNS metastases (see section "Special Warnings and Precautions for Use").

The frequency of CNS hemorrhage in patients with untreated CNS metastases receiving bevacizumab was not prospectively studied in randomized clinical trials. In a retrospective analysis of data from 13 completed randomized trials involving patients with various tumor types, CNS hemorrhage (all grades) occurred in 3 of 91 (3.3%) patients with brain metastases receiving bevacizumab compared to 1 case (grade 5) among 96 patients (1%) not receiving bevacizumab. In two subsequent trials involving patients with treated brain metastases (approximately 800 patients), there was one case of grade 2 CNS hemorrhage among 83 patients (1.2%) receiving bevacizumab according to interim safety analysis.

In all clinical trials of Avastin**®, mucosal and skin hemorrhage was observed in nearly 50% of patients receiving Avastin®. Most commonly observed were grade 1 NCI-CTC epistaxis lasting less than 5 minutes, which resolved without medical intervention and did not require changes in Avastin®** treatment regimen. Clinical safety data suggest that the frequency of minor mucosal and skin hemorrhage (e.g., epistaxis) may be dose-dependent.

Less frequent minor hemorrhages of skin and mucous membranes at other sites, such as gingival bleeding or vaginal bleeding, were also observed.

Thromboembolism (see section "Special Warnings and Precautions for Use")

Arterial Thromboembolism. An increased frequency of arterial thromboembolic events, including stroke, transient ischemic attack, myocardial infarction, etc., was observed in patients receiving Avastin**®** across various indications.

In clinical trials, the overall frequency of arterial thromboembolic reactions ranged from 3.8% in Avastin**®-containing treatment groups to 2.1% in chemotherapy-only control groups. Fatal outcomes were observed in 0.8% of patients receiving Avastin®** in combination with chemotherapy compared to 0.5% of patients receiving chemotherapy alone. Stroke (including transient ischemic attack) was reported in 2.7% of patients receiving Avastin**®** treatment compared to 0.5% of patients receiving chemotherapy alone. Myocardial infarction was observed in 1.4% of patients receiving Avastin**®** in combination with chemotherapy compared to 0.7% of patients receiving chemotherapy alone.

In one clinical trial evaluating Avastin**®** in combination with 5-fluorouracil/folic acid (AVF2192g), patients with metastatic colorectal cancer who were not candidates for irinotecan treatment were included. In this trial, arterial thromboembolism was observed in 11% (11 out of 100) of patients compared to 5.8% (6 out of 104) of patients in the chemotherapy control group.

Venous Thromboembolism. The frequency of venous thromboembolism in clinical trials was comparable in patients receiving Avastin**®** in combination with chemotherapy and patients in the control group receiving chemotherapy alone. Venous thromboembolism includes pulmonary embolism, deep vein thrombosis, and thrombophlebitis.

In clinical trials across various indications, the overall frequency of venous thromboembolic events ranged from 2.8% to 17.3% in the Avastin**®**-containing treatment group compared to 3.2%–15.6% in control groups.

Grade 3–5 venous thromboembolic events were recorded in 7.8% of patients receiving chemotherapy + bevacizumab compared to 4.9% of patients receiving chemotherapy alone (across all indications except persistent, recurrent, or metastatic cervical cancer).

In a clinical trial involving patients with persistent, recurrent, or metastatic cervical cancer, grade 3–5 venous thromboembolic events were recorded in nearly 15.6% of patients receiving Avastin**®** in combination with paclitaxel and cisplatin compared to 7.0% of patients receiving paclitaxel and cisplatin.

Patients who develop venous thromboembolism have an increased risk of recurrence during treatment with Avastin**®** and chemotherapy compared to chemotherapy alone.

Congestive Heart Failure

Congestive heart failure has occurred during clinical trials of Avastin**®** across all cancer indications, but primarily in metastatic breast cancer. In four Phase III trials (AVF2119g, E2100, B017708, and AVF3694g) in patients with metastatic breast cancer, grade 3 or higher congestive heart failure was observed in 3.5% of patients receiving Avastin**®** in combination with chemotherapy compared to 0.9% in control groups. In patients participating in the AVF3694g study who received anthracyclines concurrently with bevacizumab, the frequency of grade 3 or higher congestive heart failure in the bevacizumab and control groups was comparable to that in other metastatic breast cancer studies: 2.9% in the anthracycline + bevacizumab group and 0% in the anthracycline + placebo group. Additionally, in the AVF3694g study, the frequency of congestive heart failure of all severity grades was similar in the anthracycline + Avastin**®** (6.2%) and anthracycline + placebo (6.0%) treatment groups.

In most patients who developed congestive heart failure during the metastatic breast cancer study, improvement in symptoms and/or left ventricular function was observed after appropriate medical treatment.

Patients with existing New York Heart Association (NYHA) Class II–IV congestive heart failure were excluded from most Avastin**®** clinical trials. Therefore, there is no information on the risk of congestive heart failure in these patients.

Prior anthracycline therapy and/or prior thoracic radiation therapy are risk factors for the development of congestive heart failure.

An increased frequency of congestive heart failure was observed in clinical trials of patients with diffuse large B-cell lymphoma receiving bevacizumab with a cumulative doxorubicin dose exceeding 300 mg/m². In this Phase III clinical trial, R-CHOP (rituximab/cyclophosphamide/doxorubicin/vincristine/prednisolone) + bevacizumab was compared to R-CHOP without bevacizumab. The frequency of congestive heart failure in both groups was higher than previously observed with doxorubicin therapy alone, with a higher frequency in the R-CHOP + bevacizumab group. These results suggest that patients receiving a cumulative doxorubicin dose exceeding 300 mg/m² in combination with bevacizumab should be closely monitored and undergo appropriate cardiac evaluation.

Hypersensitivity Reactions (including anaphylactic shock)/Infusion-Related Reactions (see sections "Special Warnings and Precautions for Use", "Adverse Reactions Reported in the Post-Marketing Period")

In some clinical trials, the incidence of anaphylactic reactions and anaphylactoid-type reactions was higher in patients receiving Avastin**®** in combination with chemotherapy compared to patients receiving chemotherapy alone. By frequency, these reactions are common (up to 5% of patients receiving bevacizumab).

Infections

In a clinical trial involving patients with persistent, recurrent, or metastatic cervical cancer, grade 3–5 infections were recorded in 24% of patients receiving Avastin**®** in combination with paclitaxel and topotecan compared to 13% of patients receiving paclitaxel and topotecan.

Ovarian Function Suppression / Fertility (see sections "Special Warnings and Precautions for Use" and "Pregnancy and Lactation")

In the NSABP C-08 Phase III study evaluating Avastin**®** in adjuvant treatment of colon cancer patients, the incidence of new-onset ovarian function suppression, defined as amenorrhea for at least 3 months, follicle-stimulating hormone level ≥30 mIU/mL, and negative pregnancy test by β-human chorionic gonadotropin measurement, was studied in 295 premenopausal women. New-onset ovarian function suppression was observed in 2.6% of patients in the mFOLFOX-6 group compared to 39% of patients in the mFOLFOX-6 + bevacizumab group. After discontinuation of bevacizumab treatment, ovarian function recovered in 86.2% of women. The long-term impact of bevacizumab treatment on fertility is unknown.

Laboratory Test Abnormalities

Decreased neutrophil and leukocyte counts and presence of protein in urine may be associated with Avastin**®** treatment.

In clinical trials, the following grade 3–4 laboratory abnormalities (NCI-CTCAE v.3) were observed with at least a 2% higher frequency in patients receiving Avastin**®** treatment compared to control group patients: hyperglycemia, decreased hemoglobin, hypokalemia, hyponatremia, decreased leukocyte count, increased international normalized ratio (INR).

Clinical trials demonstrated transient increases in serum creatinine levels (1.5–1.9 times above baseline) associated with Avastin**®** treatment, both with and without proteinuria. Such increases were not associated with a higher frequency of clinical manifestations of renal dysfunction in patients receiving Avastin**®** treatment.

Special Patient Populations

Elderly Patients

In randomized clinical trials, patient age over 65 years was associated with an increased risk of arterial thromboembolism, including stroke, transient ischemic attack, and myocardial infarction. In patients over 65 years of age, grade 3–4 leukopenia and thrombocytopenia, as well as neutropenia (all grades), diarrhea, nausea, headache, and fatigue were also observed more frequently compared to patients under 65 years of age receiving Avastin**®** treatment (see sections "Special Warnings and Precautions for Use" and "Adverse Reactions"). In one clinical trial, the frequency of grade ≥3 arterial hypertension was twice as high in patients over 65 years of age compared to patients under 65 years of age. In a study involving patients with recurrent platinum-resistant ovarian cancer, alopecia, mucositis, peripheral sensory neuropathy, proteinuria, and arterial hypertension were also observed with at least a 5% higher frequency in the bevacizumab + chemotherapy treatment group among patients aged ≥65 years receiving bevacizumab compared to patients under 65 years of age receiving bevacizumab.

The frequency of other adverse reactions, including gastrointestinal perforation, wound healing complications, proteinuria, congestive heart failure, and hemorrhage, in elderly patients (over 65 years) receiving Avastin**®** was comparable to that in patients aged ≤65 years.

Pediatric Patients

The safety of Avastin® in children and adolescents has not been established. Avastin® is not approved for use in patients under 18 years of age. Published data indicate that patients under 18 years of age receiving Avastin® treatment experienced cases of osteonecrosis at sites other than the jaw.

Adverse Reactions Reported in the Post-Marketing Period

Infections and infestations: rare — necrotizing fasciitis, usually secondary to wound healing complications, gastrointestinal perforation, or fistula formation (see section "Special Warnings and Precautions for Use").

Immune system disorders: common: hypersensitivity reactions, infusion-related reactions (frequency not known) with possible accompanying symptoms: dyspnea/respiratory distress, flushing/erythema/rash, arterial hypotension or hypertension, oxygen desaturation, chest pain, chills, nausea/vomiting (see section "Special Warnings and Precautions for Use").

Rare: anaphylactic shock (see section "Special Warnings and Precautions for Use").

Neurological disorders: very rare — hypertensive encephalopathy (see section "Special Warnings and Precautions for Use"); rare — reversible posterior encephalopathy syndrome (see section "Special Warnings and Precautions for Use").

Vascular disorders: renal thrombotic microangiopathy, which may clinically present as proteinuria (frequency not known), with or without concomitant use of sunitinib (see sections "Special Warnings and Precautions for Use", "Adverse Reactions").

Respiratory, thoracic and mediastinal disorders: common — dysphonia; frequency not known — nasal septum perforation, pulmonary hypertension.

Hepatobiliary disorders: frequency not known — gallbladder perforation.

Gastrointestinal disorders: frequency not known — gastrointestinal ulceration.

Musculoskeletal and connective tissue disorders: cases of osteonecrosis of the jaw bones were observed in patients receiving Avastin**®** treatment. Most of these cases occurred in patients with known risk factors for osteonecrosis of the jaw bones, particularly patients receiving bisphosphonates and/or with a history of gingival pathology and requiring invasive dental procedures (see section "Special Warnings and Precautions for Use"). Cases of osteonecrosis at sites other than the jaw were observed in children receiving Avastin**®** treatment.

Congenital, hereditary and genetic disorders: fetal abnormalities were observed in women who received bevacizumab treatment as monotherapy or in combination with chemotherapeutic agents known to have embryotoxic effects (see section "Pregnancy and Lactation").

Reporting of adverse reactions after drug registration is important. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua/.

Shelf Life. 3 years.

Storage Conditions.

Store at 2–8°C in a light-protected place. Keep out of reach of children. Do not freeze.

Incompatibilities.

The medicinal product must not be mixed with other medicinal products except 0.9% sodium chloride solution for injection. Degradation of Avastin**®** dependent on concentration was observed when bevacizumab was diluted with 5% glucose solution.

No incompatibility was observed between Avastin**®** and polyvinyl chloride or polyolefin bags, or with infusion systems.

Packaging.

100 mg/4 mL or 400 mg/16 mL in a vial. 1 vial in a cardboard box.

Prescription Category. Prescription only.

Manufacturer.

F. Hoffmann-La Roche Ltd

Roche Diagnostics GmbH

Manufacturer's Address and Place of Business.

Wurmisweg, 4303 Kaiseraugst, Switzerland

Sandhofer Strasse 116, 68305 Mannheim, Germany