Zirabev
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZIRABEV (ZIRABEV)
Composition:
Active substance: bevacizumab;
1 ml of concentrate for solution for infusion contains 25 mg of bevacizumab;
1 vial (4 ml concentrate) contains 100 mg of bevacizumab or
1 vial (16 ml concentrate) contains 400 mg of bevacizumab;
Excipients: sucrose, succinic acid, disodium edetate dihydrate, sodium hydroxide, polysorbate 80, water for injections.
Pharmaceutical form. Concentrate for solution for infusion.
Main physicochemical properties: clear or slightly opalescent, colorless or pale brown liquid.
Pharmacotherapeutic group
Antineoplastic and immunomodulating agents. 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
Zirabeve is a similar biological medicinal product (biosimilar). Bevacizumab is a recombinant humanized monoclonal antibody produced by recombinant 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-affected blood vessels, and inhibition of new blood vessel formation within the tumor, thereby suppressing tumor growth.
Pharmacodynamic effects
Administration of bevacizumab or its original murine antibody in xenograft models of malignant tumors in nude mice resulted in potent antitumor activity against human tumors, including colorectal, breast, pancreatic, and prostate cancers. Progression of metastatic disease was inhibited, and microvascular permeability was reduced.
Clinical efficacy
| Clinical study |
Comparison groups |
Overall survival, months (median) |
Progression-free survival, months (median) |
| Metastatic colorectal cancer (mCRC), in combination with chemotherapy (CT) based on fluoropyrimidine derivatives |
|||
| First-line treatment of mCRC* |
Bevacizumab 5 mg/kg every 2 weeks + IFL, n = 402 |
20.3 (HR 0.660; p-value = 0.00004) |
10.6 (HR 0.54; p-value < 0.0001) |
| Placebo + IFL, n = 411 |
15.6 |
6.2 |
|
| Second-line treatment of mCRC* |
Bevacizumab 10 mg/kg every 2 weeks + FOLFOX-4, n = 293 |
13.0 (HR 0.751; p-value = 0.0012) |
7.5 (HR 0.518; p-value < 0.0001) |
| FOLFOX-4, n = 292 |
10.8 |
4.5 |
|
| Continuation of bevacizumab treatment after first progression in mCRC* |
Bevacizumab + fluoropyrimidine-based CT + irinotecan/oxaliplatin, n = 409 |
11.2 (HR 0.81; p-value = 0.0062) |
5.7 (HR 0.68; p-value < 0.0001) |
| Fluoropyrimidine-based CT + irinotecan/oxaliplatin, n = 410 |
9.8 |
4.1 |
|
| First-line treatment of metastatic breast cancer (mBC) |
|||
| In combination with paclitaxel** |
Bevacizumab 10 mg/kg every 2 weeks + paclitaxel, n = 368 |
26.5 (HR 0.869; p-value = 0.1374) |
11.4 (HR 0.421; p-value < 0.0001) |
| Paclitaxel, n = 354 |
24.8 |
5.8 |
|
| In combination with capecitabine** |
Bevacizumab 15 mg/kg every 3 weeks + capecitabine, n = 409 |
HR 0.88; p-value = 0.33 |
8.6 (HR 0.69; p-value = 0.0002) |
| Placebo + capecitabine, n = 206 |
5.7 |
||
| Treatment of unresectable, advanced, metastatic or recurrent non-squamous non-small cell lung cancer (NSCLC) in combination with platinum-based chemotherapy |
|||
| First-line treatment* |
Bevacizumab 15 mg/kg every 3 weeks + carboplatin/paclitaxel, n = 434 |
12.3 (HR 0.80; p-value = 0.003) |
6.4 (HR 0.65; p-value < 0.0001) |
| Carboplatin/paclitaxel, n = 444 |
10.3 |
4.8 |
|
| Treatment of unresectable, advanced, metastatic or recurrent non-squamous non-small cell lung cancer (NSCLC) with EGFR-activating mutations (EGFR — epidermal growth factor receptor) |
|||
| First-line treatment in combination with erlotinib** |
Bevacizumab 15 mg/kg IV every 3 weeks + erlotinib 150 mg/day orally, n = 75 |
47.0 (HR 0.81; p-value = 0.3267) |
16.0 (HR 0.54; p-value = 0.0015) |
| Erlotinib (150 mg/day orally), n = 77 |
47.4 |
9.7 |
|
| Treatment of advanced and/or metastatic renal cell carcinoma (mRCC) |
|||
| First-line treatment in combination with interferon alfa-2a* |
Bevacizumab 10 mg/kg every 2 weeks + interferon alfa-2a, n = 327 |
23.3 (HR 0.91; p-value = 0.3360) |
10.2 (HR 0.63; p-value < 0.0001) |
| Placebo + interferon alfa-2a, n = 322 |
21.3 |
5.4 |
|
| Treatment of advanced and/or metastatic epithelial ovarian, fallopian tube, and primary peritoneal cancer |
|||
| First-line treatment in combination with carboplatin and paclitaxel** |
Carboplatin/paclitaxel 6 cycles + bevacizumab 15 mg/kg every 3 weeks until 15 months/progression, n = 623 |
43.8 (HR 0.88; p-value = 0.0641) |
14.7 (HR 0.70; p-value < 0.0001) |
| 6 cycles: carboplatin/paclitaxel + placebo until 15 months, n = 625 |
40.6 |
10.6 |
|
| First-line treatment in combination with carboplatin and paclitaxel** |
Carboplatin/paclitaxel 6 cycles + bevacizumab 7.5 mg/kg every 3 weeks until 12 months/progression, n = 764 |
57.4 (HR 0.99; p-value = 0.8910) |
19.3 (HR 0.86; p-value = 0.0185) |
| Carboplatin/paclitaxel 6 cycles, n = 764 |
58.0 |
16.9 |
|
| Treatment of first recurrence, under platinum-sensitive conditions** |
Gemcitabine/carboplatin 6–10 cycles + bevacizumab 15 mg/kg every 3 weeks until progression, n = 242 |
33.6 (HR 0.952; p-value = 0.6479) |
12.4 (HR 0.52; p-value < 0.0001) |
| Gemcitabine/carboplatin 6–10 cycles + placebo until progression, n = 242 |
32.9 |
8.4 |
|
| Treatment of recurrence, under platinum-resistant conditions** |
Topotecan or pegylated liposomal doxorubicin + bevacizumab 10 mg/kg every 2 weeks (or bevacizumab 15 mg/kg every 3 weeks when combined with alternative-dose topotecan), n = 179 |
16.6 (HR 0.870; p-value = 0.2711) |
6.7 (HR 0.379; p-value < 0.0001) |
| Topotecan or pegylated liposomal doxorubicin, n = 182 |
13.3 |
3.4 |
|
| Treatment of persistent, recurrent or metastatic cervical cancer |
|||
| In combination with paclitaxel and cisplatin, or alternatively with paclitaxel and topotecan in adult patients who cannot receive platinum-based therapy* |
Paclitaxel and cisplatin or paclitaxel and topotecan + bevacizumab 15 mg/kg every 3 weeks until progression, n = 227 |
16.8 (HR 0.74; p-value = 0.0132) |
8.3 (HR 0.66; p-value < 0.0001) |
| Paclitaxel and cisplatin or paclitaxel and topotecan, n = 225 |
12.9 |
6.0 |
|
* Primary endpoint – overall survival.
** Primary endpoint – progression-free survival.
HR – hazard ratio.
IFL – irinotecan, 5-fluorouracil, leucovorin.
FOLFOX-4 – leucovorin, 5-fluorouracil, oxaliplatin.
n – number of patients.
Pharmacokinetics
Pharmacokinetic data on bevacizumab were obtained from 10 clinical studies in patients with solid tumors. In all clinical studies, bevacizumab was administered as an intravenous infusion. The infusion rate was based on tolerability, with an initial infusion duration of 90 minutes. The pharmacokinetics of bevacizumab were linear over the dose range of 1 to 10 mg/kg.
Distribution
The typical value of central volume (Vc) is 2.73 L and 3.28 L in women and men, respectively, which corresponds to levels described for IgG and other monoclonal antibodies. The peripheral volume of distribution (Vp) is 1.69 L and 2.35 L in women and men, respectively, when bevacizumab is administered with other antineoplastic agents. After dose adjustment based on body weight, Vc in men is 20% higher than in women.
Biological transformation
After a single intravenous administration of 125I-bevacizumab to rabbits, its metabolic characteristics were similar to those of a natural IgG molecule that does not bind VEGF. The metabolism and elimination of bevacizumab are similar to those of endogenous IgG, primarily occurring via proteolytic catabolism in all cells of the body, including endothelial cells, rather than solely through renal and hepatic excretion. Binding of IgG to FcRn receptors protects it from cellular metabolism and ensures a prolonged elimination half-life.
Elimination
The clearance of bevacizumab averages 0.188 L/day in women and 0.220 L/day in men. After dose adjustment based on body weight, the clearance of bevacizumab in men is 17% higher than in women. According to the two-compartment model, the typical elimination half-life is 18 days in women and 20 days in men.
Low albumin levels and high tumor burden generally indicate disease severity. The clearance of bevacizumab is approximately 30% faster in patients with low serum albumin levels and 7% faster in patients with high tumor burden compared to a typical patient with average albumin levels and average tumor burden.
Special patient groups
A population pharmacokinetic analysis was performed to evaluate the impact of demographic characteristics in adult and pediatric patients. In adults, results showed no significant differences in bevacizumab pharmacokinetics based on patient age.
Renal impairment
The pharmacokinetics of bevacizumab have not been studied in clinical trials in patients with renal impairment, as the kidneys are not the primary organ for metabolism and elimination of bevacizumab.
Hepatic impairment
The pharmacokinetics of bevacizumab have not been studied in clinical trials in patients with hepatic impairment, as the liver is not the primary organ for metabolism and elimination of bevacizumab.
Children
The pharmacokinetics of bevacizumab were evaluated in 152 children, adolescents, and young adults (from 7 months to 21 years, weighing 5.9 to 125 kg) across 4 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 by body weight, with a trend toward decreased exposure as body weight decreases. These data indicate no effect of patient age on bevacizumab pharmacokinetics when adjusted for body weight.
The pharmacokinetics of bevacizumab were well characterized using a pediatric population pharmacokinetic model in 70 patients in study BO20924 (aged 1.4 to 17.6 years; weight 11.6 to 77.5 kg) and 59 patients in clinical study BO25041 (aged 1 to 17 years; weight 11.2 to 82.3 kg). In clinical study BO20924, bevacizumab exposure was mostly lower compared to that in a typical adult patient after administration of the same dose. In clinical study BO25041, bevacizumab exposure was similar to that of a typical adult patient after administration of 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 adult patients in combination with fluoropyrimidine-based chemotherapy.
Treatment of metastatic breast cancer in adult patients:
- 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 previous 12 months in the adjuvant setting should not receive Zirabeve in combination with capecitabine.
Treatment in adult patients of unresectable advanced, metastatic, or recurrent non-squamous non-small cell lung cancer, excluding predominantly squamous histology:
- first-line treatment in combination with platinum-based chemotherapy.
Treatment in adult patients of unresectable advanced, metastatic, or recurrent non-squamous non-small cell lung cancer with EGFR-activating mutations (EGFR — epidermal growth factor receptor):
- first-line treatment in combination with erlotinib.
Treatment of advanced and/or metastatic renal cell carcinoma in adult patients:
- first-line treatment in combination with interferon alfa-2a.
Treatment of advanced (stages III B, III C, and IV according to the International Federation of Gynecology and Obstetrics (FIGO)) epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer in adult patients:
- first-line treatment in combination with carboplatin and paclitaxel.
Treatment of first recurrence of epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer, platinum-sensitive, in combination with carboplatin and gemcitabine or in combination with carboplatin and paclitaxel in adult patients who have not previously received therapy with bevacizumab or other VEGF inhibitors or agents targeting the VEGF receptor.
Treatment of recurrent epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer, platinum-resistant, 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.
Contraindications
Hypersensitivity to bevacizumab or to any other component of the medicinal product. Hypersensitivity to products derived from Chinese hamster ovary cells or to other recombinant human or humanized antibodies.
Pregnancy (see section "Use during pregnancy or breastfeeding").
Interaction with other medicinal products and other forms of interaction
Effect of anticancer agents on the pharmacokinetics of bevacizumab
According to population pharmacokinetic analysis, no clinically significant interaction was observed when chemotherapy was administered concomitantly, with no impact on the pharmacokinetics of bevacizumab. There was no statistically or clinically significant difference in the clearance of bevacizumab between patients receiving Zirabeve as monotherapy compared to patients receiving Zirabeve 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 anticancer 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. It is not possible to draw conclusions regarding the effect of bevacizumab on the pharmacokinetics of gemcitabine.
Combination of bevacizumab and malate of sunitinib
In two clinical studies of metastatic renal cell carcinoma, microangiopathic hemolytic anemia was reported in 7 out of 19 patients receiving treatment with bevacizumab (10 mg/kg every 2 weeks) in combination with malate of sunitinib (50 mg daily).
Microangiopathic hemolytic anemia is a hemolytic disorder characterized by erythrocyte fragmentation, anemia, and thrombocytopenia. Additionally, some of these patients experienced hypertension (including hypertensive crises), elevated creatinine levels, and neurological symptoms. All these symptoms were reversible upon discontinuation of treatment with bevacizumab and malate of sunitinib (see section "Special precautions for use").
Combination with platinum-based or taxane-based therapy (see sections "Special 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.
Radiation therapy
The safety and efficacy of concomitant use of radiation therapy and Zirabeve 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 plus chemotherapy alone.
Special precautions for use
Traceability
To improve traceability of biological medicinal products, the trade name and batch number of the administered medicinal product should be clearly documented (or stated) in the patient's medical records.
Gastrointestinal (GI) perforation and fistula (see section "Adverse reactions")
Patients receiving treatment with Zirabeve have an increased risk of developing gastrointestinal and gallbladder perforation. Intra-abdominal inflammatory processes may be a risk factor for GI perforation in patients with metastatic colorectal cancer; therefore, caution is advised when treating such patients. Prior radiotherapy is a risk factor for GI perforation in patients receiving Zirabeve for persistent, recurrent, or metastatic cervical cancer; all patients who developed GI perforation had a history of radiotherapy. Treatment should be permanently discontinued in patients who develop gastrointestinal perforation.
Gastrointestinal-vaginal fistula in the GOG-0240 study
Patients receiving Zirabeve 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 the main risk factor for gastrointestinal-vaginal fistulae; all patients with gastrointestinal-vaginal fistulae had a history of radiotherapy. Recurrent cancer in the 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 treatment with Zirabeve have an increased risk of developing fistulae. Zirabeve treatment should be discontinued in patients with tracheoesophageal fistula or any grade 4 fistula. Information regarding continuation of Zirabeve treatment in patients with other fistulae is limited.
In case of development of internal fistula not involving the gastrointestinal tract, discontinuation of Zirabeve should be considered.
Wound healing complications (see section "Adverse reactions")
Zirabeve may negatively affect wound healing. Serious wound healing complications, including anastomotic leakage with fatal outcomes, have been reported. Bevacizumab treatment 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, Zirabeve therapy should be temporarily discontinued until complete wound healing. Treatment must be discontinued if planned surgical intervention is required.
Necrotizing fasciitis, including fatal cases, has been rarely reported in patients receiving Zirabeve. This condition usually arises secondary to wound healing complications, gastrointestinal perforation, or fistula formation. Therefore, Zirabeve 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 Zirabeve. Clinical safety data suggest that the frequency of arterial hypertension is dose-dependent for bevacizumab. Zirabeve may only be administered to patients with previously well-controlled arterial hypertension. There are no data on the effect of Zirabeve in patients with uncontrolled hypertension at the start of treatment.
Blood pressure monitoring is recommended during Zirabeve 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. Zirabeve should be discontinued if medically significant arterial hypertension is not adequately controlled with antihypertensive therapy or if hypertensive crisis or hypertensive encephalopathy develops.
Aneurysms and arterial dissections
The use of VEGF inhibitors in patients with or without hypertension may promote the development of aneurysms and/or arterial dissections. This risk should be carefully considered before initiating Zirabeve treatment in patients with risk factors such as arterial hypertension or a history of aneurysm.
Posterior reversible encephalopathy syndrome (PRES) (see section "Adverse reactions")
Symptoms suggestive of posterior reversible encephalopathy syndrome have been rarely observed in patients receiving Zirabeve. PRES is a rare neurological disorder characterized by symptoms such as seizures, headache, mental status changes, visual disturbances, cortical blindness, with or without associated arterial hypertension. Diagnosis of PRES can be confirmed by brain imaging techniques, with magnetic resonance imaging (MRI) being preferred.
In case of PRES development, treatment of specific symptoms, including control of arterial hypertension, should be initiated, and Zirabeve therapy should be discontinued. The safety of re-initiating Zirabeve 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 (according to National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 [NCI-CTCAE v.3]) may be dose-related. Monitoring for proteinuria is recommended before and during Zirabeve therapy. Grade 4 proteinuria (nephrotic syndrome) was observed in nearly 1.4% of patients receiving Zirabeve. Zirabeve must 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 Zirabeve in combination with chemotherapy compared to those receiving chemotherapy alone.
A history of arterial thromboembolism, diabetes, or age over 65 years is associated with an increased risk of arterial thromboembolism during treatment with Zirabeve plus chemotherapy. Caution is required when treating such patients.
Zirabeve 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 treatment with Zirabeve.
Patients receiving Zirabeve in combination with paclitaxel and cisplatin for persistent, recurrent, or metastatic cervical cancer may have an increased risk of venous thromboembolic events.
Zirabeve treatment must be discontinued if life-threatening (grade 4) thromboembolic events occur, including pulmonary embolism (NCI-CTCAE v.3). In case of thromboembolic events of grade ≤3, careful patient monitoring is required (NCI-CTCAE v.3).
Bleeding
Patients receiving Zirabeve have an increased risk of bleeding, particularly tumor-related bleeding. Zirabeve should be discontinued in case of grade 3 or 4 bleeding (NCI-CTCAE v.3) (see section "Adverse reactions").
Patients with signs and symptoms of untreated central nervous system (CNS) metastases were excluded from clinical trials of Zirabeve 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. Zirabeve treatment should be discontinued in case of intracranial hemorrhage.
There is no information on the safety profile of Zirabeve in patients with congenital hemorrhagic diathesis, acquired coagulopathy, or patients receiving full-dose anticoagulants for thromboembolism prior to starting Zirabeve, as such patients were excluded from clinical trials. Therefore, caution should be exercised when prescribing Zirabeve to such patients. However, in patients with venous thrombosis receiving Zirabeve and warfarin concomitantly at full dose due to venous thrombosis, no increased incidence of grade 3 or higher bleeding events was observed.
Pulmonary hemorrhage / hemoptysis
Patients with non-small cell lung cancer receiving Zirabeve have an increased risk of serious, and in some cases fatal, pulmonary hemorrhages/hemoptysis. Zirabeve should not be administered to patients who have recently experienced bleeding/hemoptysis (more than 2.5 ml of blood).
Heart failure (see section "Adverse reactions")
In clinical trials, events consistent with heart failure have been reported. Both asymptomatic left ventricular ejection fraction reduction and symptomatic heart failure requiring therapy or hospitalization have been observed. Zirabeve should be used with caution in patients with clinically significant cardiovascular disease, such as ischemic heart disease or heart failure, in their medical history.
In most cases, heart failure occurred in patients with metastatic breast cancer who had previously received anthracycline therapy, radiotherapy to the left side of the chest, and other risk factors for heart failure.
In the AVF3694g study, no increased incidence of heart failure of all grades 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. Grade 3 or higher heart failure was slightly more frequent 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 (NCI-CTCAE v.3).
Neutropenia and infections (see section "Adverse reactions")
When Zirabeve is used in combination with certain myelotoxic chemotherapy regimens, an increased incidence of severe neutropenia, febrile neutropenia, or infections with or without severe neutropenia (including fatal cases) has been observed compared to chemotherapy alone. These events were mainly observed with Zirabeve use in combination with platinum-based or taxane-based chemotherapy for 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/hypersensitivity reactions (including anaphylactic shock) is observed during Zirabeve therapy. As with any humanized monoclonal antibody, careful patient monitoring is recommended during Zirabeve treatment. Infusion should be stopped and appropriate treatment initiated if reactions occur. Systemic premedication is not justified.
Osteonecrosis of the jaw (ONJ) (see section "Adverse reactions")
Cases of ONJ have been reported in cancer patients receiving Zirabeve. Most cases occurred in patients who had previously or concurrently received intravenous bisphosphonates, which are known to carry a risk of ONJ. Caution is advised when prescribing Zirabeve concomitantly with intravenous bisphosphonates or sequentially with bisphosphonates.
Invasive dental procedures are a known risk factor for ONJ. Before starting Zirabeve treatment, patients should undergo a dental examination and, if necessary, preventive dental procedures. If possible, invasive dental procedures should be avoided in patients who have previously received or are receiving intravenous bisphosphonates.
Intravitreal use
Zirabeve is not indicated for intravitreal use.
Ocular disorders
Individual cases and clusters of serious ocular disorders have been reported following unlicensed intravitreal administration of bevacizumab obtained from vials intended for intravenous use in patients with malignancies. These reactions included infectious endophthalmitis; intraocular inflammation, including sterile endophthalmitis, uveitis, and vitritis; retinal detachment; retinal pigment epithelium tear; increased intraocular pressure; intraocular hemorrhage, including vitreous hemorrhage and retinal hemorrhage; and conjunctival hemorrhage. Some of these ocular disorders led to vision loss of varying severity, including permanent blindness.
Systemic effects after intravitreal use
Reduced levels of circulating vascular endothelial growth factor (VEGF) have been demonstrated after intravitreal administration of VEGF inhibitors. Systemic reactions, including bleeding outside the eye and arterial thromboembolic events, have been reported after intravitreal injection of VEGF inhibitors.
Ovarian function / fertility
Bevacizumab may impair fertility in women (see sections "Use during pregnancy or breastfeeding", "Adverse reactions"). Therefore, fertility preservation strategies should be discussed with female patients of reproductive age before initiating Zirabeve treatment.
Information on excipients
This medicinal product contains 3.0 mg sodium per 4 ml concentrate vial, equivalent to 0.15% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
This medicinal product contains 12.1 mg sodium per 16 ml concentrate vial, equivalent to 0.61% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Use during pregnancy or breastfeeding
Women of reproductive potential
Women of reproductive potential should use reliable contraception during treatment and for 6 months after completion of treatment.
Pregnancy
There are no clinical data on the use of bevacizumab in pregnant women. Animal studies have demonstrated reproductive toxicity, including potential congenital malformations. It is known that IgG crosses the placental barrier, and bevacizumab may inhibit fetal angiogenesis. Therefore, there is a suspicion that bevacizumab may cause severe fetal abnormalities when used during pregnancy. Cases of fetal abnormalities have been observed in the post-marketing period in women who received bevacizumab either as monotherapy or in combination with chemotherapeutic agents known to have embryotoxic effects (see section "Adverse reactions"). Bevacizumab is contraindicated during pregnancy (see section "Contraindications").
Breastfeeding
It is unknown whether bevacizumab is excreted in human breast milk. Since maternal IgG is excreted in breast milk and bevacizumab may impair infant growth and development, women should be advised to discontinue breastfeeding during treatment and for at least 6 months after receiving the last dose of bevacizumab.
Fertility
Animal toxicity studies 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 impairment was observed in the bevacizumab group compared to the control group. Ovarian function recovered in most patients after discontinuation of bevacizumab treatment. The long-term impact of bevacizumab treatment on fertility is unknown.
Ability to influence the ability to drive and use machines
Bevacizumab has no effect or a negligible effect on the ability to drive and use machines. Symptoms such as somnolence and syncope have been observed with bevacizumab use (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 Zirabeve must only be conducted under the supervision of a physician experienced in the use of anticancer therapies.
Dosage
Metastatic Colorectal Cancer (mCRC)
The recommended dose of Zirabeve is 5 mg/kg or 10 mg/kg body weight administered once every 2 weeks, or 7.5 mg/kg or 15 mg/kg body weight administered once every 3 weeks as an intravenous infusion.
Treatment should be continued until disease progression or the development of unacceptable toxicity.
Metastatic Breast Cancer (mBC)
The recommended dose of Zirabeve is 10 mg/kg body weight administered once every 2 weeks, or 15 mg/kg body weight administered once every 3 weeks as an intravenous infusion.
Treatment should be continued until disease progression or the development of unacceptable toxicity.
Non-Small Cell Lung Cancer (NSCLC)
First-line treatment of non-squamous NSCLC in combination with platinum-based chemotherapy
Zirabeve is used in combination with platinum-based chemotherapy for up to 6 treatment cycles, followed by continued administration of the drug as monotherapy until signs of disease progression.
The recommended dose of Zirabeve is 7.5 mg/kg or 15 mg/kg body weight administered once every 3 weeks as an intravenous infusion.
Clinical benefit in patients with NSCLC has been demonstrated with both doses – 7.5 mg/kg and 15 mg/kg.
Treatment should be continued until disease progression or the development of unacceptable toxicity.
First-line treatment of non-squamous NSCLC with EGFR-activating mutations in combination with erlotinib
Testing for EGFR mutation should be performed prior to initiating combination therapy with Zirabeve and erlotinib. It is important to use a validated and reliable method to avoid false results.
The recommended dose of Zirabeve when used in combination with erlotinib is 15 mg/kg body weight administered once every 3 weeks as an intravenous infusion.
Combination therapy with Zirabeve and erlotinib should be continued until disease progression.
For information on the dosage and administration of erlotinib, refer to the erlotinib prescribing information.
Advanced and/or Metastatic Renal Cell Carcinoma (mRCC)
The recommended dose of Zirabeve is 10 mg/kg body weight administered once every 2 weeks as an intravenous infusion.
Treatment should be continued until disease progression or the development of unacceptable toxicity.
Epithelial Ovarian Cancer, Fallopian Tube Cancer, and Primary Peritoneal Cancer
First-line treatment. Zirabeve is administered in combination with carboplatin and paclitaxel for up to 6 treatment cycles, followed by continued administration of Zirabeve as monotherapy until disease progression or for a maximum of 15 months, or until the development of unacceptable toxicity, whichever occurs first.
The recommended dose of Zirabeve is 15 mg/kg body weight administered once every 3 weeks as an intravenous infusion.
Treatment of disease recurrence. Zirabeve 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 administration of Zirabeve as monotherapy until disease progression. The recommended dose of Zirabeve is 15 mg/kg body weight administered once every 3 weeks as an intravenous infusion.
Treatment of platinum-resistant recurrent disease. Zirabeve is administered in combination with one of the following agents: paclitaxel, topotecan (administered weekly), or pegylated liposomal doxorubicin. The recommended dose of Zirabeve in these cases is 10 mg/kg body weight administered once every 2 weeks as an intravenous infusion. When Zirabeve is prescribed in combination with topotecan (on days 1–5 every 3 weeks), the recommended dose is 15 mg/kg body weight administered once every 3 weeks as an intravenous infusion. Treatment should be continued until disease progression or the development of unacceptable toxicity.
Cervical Cancer
Zirabeve is administered in combination with one of the following chemotherapy regimens: paclitaxel and cisplatin, or paclitaxel and topotecan.
The recommended dose of Zirabeve is 15 mg/kg body weight administered once every 3 weeks as an intravenous infusion.
Treatment should be continued until disease progression or the development of unacceptable toxicity.
Special Patient Populations
Elderly patients. Dose adjustment is not required for patients aged 65 years and older.
Renal impairment. The safety and efficacy of bevacizumab in patients with renal impairment have not been studied (see section "Pharmacological Properties").
Hepatic impairment. The safety and efficacy of bevacizumab in patients with hepatic impairment have not been studied (see section "Pharmacological Properties").
Administration
Zirabeve is intended for intravenous administration. The initial dose should be administered over 90 minutes as an intravenous infusion. If the first infusion is well tolerated, the second infusion may be administered over 60 minutes. If the 60-minute infusion is well tolerated, all subsequent infusions may be administered over 30 minutes.
Zirabeve must not be administered as an intravenous bolus or by rapid push injection!
It is not recommended to reduce the dose of bevacizumab due to adverse reactions. If necessary, therapy should be completely or temporarily discontinued (see section "Special Warnings and Precautions for Use").
Precautions for Preparation and Administration of Zirabeve
Do not shake the vial.
Zirabeve must be prepared by healthcare professionals under aseptic conditions to ensure sterility of the prepared solution. A sterile needle and syringe should be used for preparation.
Zirabeve infusion solution must not be mixed with or administered using glucose-containing solutions. The drug must not be mixed with other medicinal products except 0.9% sodium chloride injection solution.
The appropriate amount of bevacizumab should be withdrawn and diluted to the required volume using 0.9% (9 mg/mL) sodium chloride injection solution. The concentration of bevacizumab in the prepared solution should be between 1.4 and 16.5 mg/mL. In most cases, the required amount of Zirabeve can be diluted with 0.9% sodium chloride injection solution to a total volume of 100 mL.
Parenteral medicinal products should be inspected visually for particulate matter and discoloration prior to administration.
No incompatibility has been observed between Zirabeve and polyvinyl chloride or polyolefin bags, or infusion systems.
Zirabeve from a single vial 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.
Chemical and physical stability of the prepared solution (in 0.9% (9 mg/mL) sodium chloride injection solution) is maintained for 35 days at 2–8°C and for 48 hours at temperatures not exceeding 30°C after dilution. From a microbiological standpoint, the product should be used immediately. If not used immediately, the storage duration and conditions of the prepared solution are the responsibility of the user. The prepared solution may be stored for no more than 24 hours at 2–8°C, provided dilution was not performed under controlled and validated aseptic conditions.
Children
The safety and efficacy of bevacizumab in children (under 18 years of age) have not been established. Available data are presented in the sections "Adverse Reactions" and "Pharmacological Properties," but they do not allow for any dosage recommendations.
Appropriate data on the use of bevacizumab in children for the treatment of colorectal cancer, breast cancer, lung cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer, cervical cancer, and renal cancer are lacking.
Overdose
In several patients receiving the maximum dose of 20 mg/kg body weight intravenously every 2 weeks, severe migraine was reported.
Adverse Reactions
Safety profile summary
The overall safety profile of bevacizumab is based on data from administration to more than 5,700 patients with various malignant tumours who received treatment predominantly with bevacizumab in combination with chemotherapy in clinical trials.
The most serious adverse reactions were gastrointestinal perforation; haemorrhage, including pulmonary haemorrhage/haemoptysis, which occurred more frequently 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 bevacizumab were hypertension, weakness or asthenia, diarrhoea, and abdominal pain.
Analysis of clinical safety data suggests that hypertension and proteinuria development during bevacizumab therapy are likely to be dose-dependent.
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 the available data).
The adverse reactions listed below are associated with bevacizumab use in combination with various chemotherapy regimens across different indications, classified by system organ classes according to the MedDRA dictionary.
Adverse reactions identified during the post-marketing surveillance period are included in the relevant subsections "Adverse reactions by frequency" and "Serious adverse reactions by frequency". Detailed information on reactions documented during the post-marketing period is provided below in the subsection "Adverse reactions reported during the post-marketing period".
The adverse reactions listed below are assigned to the appropriate frequency category based on the highest frequency observed for any indication.
Within each frequency group, adverse reactions are listed in order of decreasing severity.
Some of these adverse reactions are typically observed with chemotherapy; however, bevacizumab 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.
Adverse reactions by frequency
Below are all adverse reactions for which a causal relationship with bevacizumab administration has been established, listed by frequency of occurrence:
- in clinical trials, when comparing the frequency of adverse reactions observed in 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% compared to the control group for grade 3–5 reactions according to NCI-CTCAE);
- in post-marketing safety studies;
- from spontaneous reports;
- in epidemiological/non-interventional or observational studies;
- based on evaluation of individual clinical cases.
Infections and infestations
Common: sepsis, abscessb,d, cellulitis, infections, urinary tract infections.
Rare: necrotizing fasciitisa.
Blood and lymphatic system disorders
Very common: febrile neutropenia, leucopenia, neutropenia, thrombocytopenia.
Common: anaemia, lymphopenia.
Immune system disorders
Common: hypersensitivity, infusion reactionsa,b,d.
Rare: anaphylactic shocka,d.
Metabolism and nutrition disorders
Very common: anorexia, hypomagnesaemia, hyponatraemia.
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, haemorrhageb,d, deep vein thrombosis.
Frequency not known: aneurysms and arterial dissections, renal thrombotic microangiopathya,b.
Respiratory, thoracic and mediastinal disorders
Very common: dyspnoea, rhinitis, epistaxis, cough.
Common: pulmonary haemorrhage/haemoptysisb,d, pulmonary embolism, hypoxia, dysphoniaa.
Frequency not known: pulmonary hypertensiona, nasal septum perforationa.
Gastrointestinal disorders
Very common: rectal haemorrhage, stomatitis, constipation, diarrhoea, 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 colour changes.
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.
General disorders and administration site conditions
Very common: asthenia, weakness, pyrexia, pain, mucosal inflammation.
Common: lethargy.
Investigations
Very common: weight decreased.
When adverse reactions of all grades, including grades 3–5, were recorded during clinical trials, the highest frequency of adverse reactions was also recorded. Data are not adjusted for differing treatment durations.
a See also the subsection "Adverse reactions reported during the post-marketing period" below.
b Terms represent a group of events describing a medical concept, not just a single condition or preferred term in 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 ischaemic attack, and other arterial thromboembolic events).
c Based on a sub-study conducted within NSABP C-08 (National Surgical Adjuvant Breast and Bowel Project) involving 295 patients.
d See also the subsection "Description of selected serious adverse reactions".
e Rectovaginal fistulae are the most common among gastrointestinal-vaginal fistulae.
f Observed only in children.
Serious adverse reactions by frequency
Below are serious adverse reactions listed by frequency of occurrence. Serious 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 (NCI-CTCAE) classification. Also included are adverse reactions considered by the marketing authorization holder to be clinically significant or serious.
Infections and infestations
Common: sepsis, abscessa,b, cellulitis, infections, urinary tract infections.
Frequency not known: necrotizing fasciitisc.
Blood and lymphatic system disorders
Very common: febrile neutropenia, leucopenia, neutropeniaa, thrombocytopenia.
Common: anaemia, lymphopenia.
Immune system disorders
Common: hypersensitivity, infusion reactionsa,b,c.
Rare: anaphylactic shockb,c.
Metabolism and nutrition disorders
Common: dehydration, hyponatraemia.
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, haemorrhagea,b, thromboembolism (venous)a,b, deep vein thrombosis.
Frequency not known: aneurysms and arterial dissections, renal thrombotic microangiopathyc,b.
Respiratory, thoracic and mediastinal disorders
Common: pulmonary haemorrhage/haemoptysisa,b, pulmonary embolism, epistaxis, dyspnoea, hypoxia.
Frequency not known: pulmonary hypertensionc, nasal septum perforationc.
Gastrointestinal disorders
Very common: diarrhoea, 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 haemorrhage.
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, weakness.
Common: pain, lethargy, mucosal inflammation.
The section presents serious adverse reactions by frequency of occurrence. Serious 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 (NCI-CTCAE) classification. Also included are adverse reactions considered by the marketing authorization holder to be clinically significant or serious. 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 also include clinically significant adverse reactions observed only during the post-marketing period, so the frequency and NCI-CTCAE grade are unknown. Therefore, these clinically significant reactions were included in the "frequency not known" category.
a Terms represent a group of events describing a medical concept, not just a single condition or preferred term in 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 ischaemic attack, and other arterial thromboembolic events).
b See also the subsection "Description of selected serious adverse reactions".
c See also the subsection "Adverse reactions reported during the post-marketing period".
d Rectovaginal fistulae are the most common among gastrointestinal-vaginal fistulae.
Description of selected serious adverse reactions
Gastrointestinal fistulae (see section "Special warnings and precautions for use")
Treatment with bevacizumab has been associated with severe cases of gastrointestinal 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 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 prior pelvic irradiation in their medical history. The manifestations ranged from free air on abdominal X-ray, which resolved without treatment, to intestinal perforation with fatal intra-abdominal abscess. In some cases, intra-abdominal inflammation occurred due to peptic ulcer disease, tumour necrosis, diverticulitis, or chemotherapy-associated colitis.
Approximately one-third of serious gastrointestinal perforations were fatal, corresponding to 0.2–1% of all patients receiving bevacizumab.
In clinical trials of bevacizumab use, gastrointestinal fistula (all grades) was reported in up to 2% of patients with metastatic colorectal cancer and ovarian cancer, and less frequently in patients with other cancer types.
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 bevacizumab treatment and 0.9% in the control group, all of whom had prior pelvic irradiation in their medical history. The incidence of gastrointestinal-vaginal fistulae was higher in the bevacizumab + chemotherapy group among patients with recurrence in the previously irradiated area (16.7%) compared to those with recurrence outside the previously irradiated area (3.6%). Corresponding incidence 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, including stoma formation.
Fistulae not involving the gastrointestinal tract (see section "Special warnings and precautions for use")
Treatment with bevacizumab 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 (GOG-0240), fistulae of the vagina, bladder, or female genital tract not involving the gastrointestinal tract were reported in 1.8% of patients receiving bevacizumab treatment and in 1.4% of patients in the control group.
Uncommonly (from ≥ 0.1% to < 1%), fistulae involving other body sites (e.g., bronchopleural fistulae, biliary fistulae) were reported during use for various indications. Fistulae have also been reported during the post-marketing period.
Fistulae have been reported at various times during treatment—both one week and one year or later after initiation of bevacizumab treatment, with most reactions occurring within the first 6 months of therapy.
Wound healing (see section "Special warnings and precautions for use")
Since bevacizumab 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 haemorrhage or impaired wound healing was observed in patients who underwent major surgery within the previous 28–60 days before starting bevacizumab treatment. However, an increased frequency of postoperative haemorrhage or wound healing complications within 60 days after major surgery was observed when patients received bevacizumab treatment during surgery. The frequency of these serious adverse events ranged from 10% (4 out of 40) to 20% (3 out of 15).
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 bevacizumab compared to 0.9% in control groups (NCI-CTCAE v.3).
In clinical trials of ovarian cancer, wound healing complications of grade 3–5 were observed in 1.8% of patients in the bevacizumab treatment group compared to 0.1% in the control group (NCI-CTCAE v.3).
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 bevacizumab-containing regimens compared to 14% in control groups. The overall frequency of grade 3–4 arterial hypertension according to NCI-CTC classification in patients receiving bevacizumab ranged from 0.4% to 17.9%. Grade 4 arterial hypertension (hypertensive crisis) was observed in nearly 1% of patients receiving bevacizumab 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 bevacizumab 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 bevacizumab 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 bevacizumab treatment or hospitalization.
Very rarely, cases of hypertensive encephalopathy have been reported, some of which were fatal. The risk of arterial hypertension associated with bevacizumab use did not correlate with baseline patient characteristics, underlying disease, or concomitant therapy.
Reversible posterior encephalopathy syndrome (see section "Special warnings and precautions for use")
In patients receiving bevacizumab, symptoms suggestive of reversible posterior encephalopathy syndrome (RPES) have been rarely observed. RPES 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 RPES are often non-specific, and diagnosis is confirmed by brain imaging, preferably magnetic resonance imaging.
In case of RPES development, early recognition and prompt treatment of specific symptoms, including control of arterial hypertension (in cases of severe uncontrolled hypertension), and discontinuation of bevacizumab therapy are recommended. Symptoms usually resolve or improve within days after discontinuation of treatment, although some neurological sequelae may persist in some patients. The safety of re-administering bevacizumab to patients with a history of RPES is unknown.
Eight cases of RPES were recorded in clinical trials. 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 reported in 0.7–54.7% of patients receiving bevacizumab.
Proteinuria severity ranged from clinically asymptomatic transient detection of trace protein in urine to nephrotic syndrome, with most cases being grade 1 proteinuria. Grade 3 proteinuria was observed in 10.9% of patients. Grade 4 proteinuria (nephrotic syndrome) was observed in 1.4% of patients receiving treatment. Before initiating treatment with Zirabeve, urine analysis for proteinuria should be performed. In most clinical trials, proteinuria ≥ 2 g/24 hours led to discontinuation of bevacizumab therapy until proteinuria decreased to < 2 g/24 hours.
Haemorrhage (see section "Special warnings and precautions for use")
In clinical trials, the overall frequency of grade 3–5 haemorrhage according to NCI-CTCAE v.3 classification across all indications was 0.4–6.9% in patients receiving bevacizumab compared to 4.5% in the chemotherapy control group.
In a clinical trial (GOG-0240) involving patients with persistent, recurrent, or metastatic cervical cancer, grade 3–5 haemorrhage was reported in 8.3% of patients receiving bevacizumab in combination with paclitaxel and topotecan compared to 4.6% of patients receiving paclitaxel and topotecan alone.
The most commonly observed haemorrhages in clinical trials were tumour-related or minor mucocutaneous bleeding (e.g., epistaxis).
Haemorrhage associated with tumour (see section "Special warnings and precautions for use")
Significant or massive pulmonary haemorrhage/haemoptysis in trials occurred predominantly in patients with non-squamous non-small cell lung cancer. Possible risk factors for pulmonary haemorrhage/haemoptysis include squamous cell histology, treatment with anti-rheumatic/anti-inflammatory agents, anticoagulants, prior radiotherapy, bevacizumab therapy, history of atherosclerosis, central tumour location, and pre-existing or treatment-induced tumour cavitation. However, a statistically significant association with haemorrhage during bevacizumab use 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 trials, while patients with unknown tumour histology were included in the trials.
In patients with non-squamous non-small cell lung cancer (excluding predominantly squamous histology), events of all severity grades occurred in up to 9.3% of patients treated with bevacizumab in combination with chemotherapy compared to 5% of patients receiving chemotherapy alone. Grade 3–5 events occurred in 2.3% of patients receiving bevacizumab in combination with chemotherapy compared to < 1% of patients receiving chemotherapy alone. Significant or massive pulmonary haemorrhage/haemoptysis may occur suddenly, and up to two-thirds of serious pulmonary haemorrhages were fatal.
In patients with colorectal cancer, gastrointestinal tract bleeding associated with tumour, including rectal haemorrhage and melena, was reported.
Tumour-associated haemorrhage was rarely observed in other tumour types and locations and included CNS bleeding in patients with CNS metastases (see section "Special warnings and precautions for use").
The frequency of CNS haemorrhage 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 tumour types, CNS haemorrhage (all grade 4) developed 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), one case of grade 2 CNS haemorrhage was reported among 83 individuals receiving bevacizumab (1.2%) based on interim safety analysis (NCI-CTCAE v.3).
In all clinical trials, mucosal and skin bleeding was observed in nearly 50% of patients receiving bevacizumab. Most commonly observed were grade 1 epistaxis according to NCI-CTCAE v.3 lasting less than 5 minutes, which resolved without medical intervention and did not require changes in Zirabeve treatment regimen. Clinical safety data suggest that the frequency of minor mucosal and skin bleeding (e.g., epistaxis) may be dose-dependent.
Less frequent were minor skin and mucosal bleeding at other sites, such as gingival bleeding or vaginal bleeding.
Thromboembolism (see section "Special warnings and precautions for use")
Arterial thromboembolism
An increased frequency of arterial thromboembolic events, including stroke, myocardial infarction, transient ischaemic attack, etc., was observed in patients receiving bevacizumab for various indications.
In clinical trials, the overall frequency of arterial thromboembolic events ranged from 3.8% in bevacizumab-containing treatment groups to 2.1% in chemotherapy control groups. Fatal outcomes occurred in 0.8% of patients receiving bevacizumab in combination with chemotherapy compared to 0.5% of patients receiving chemotherapy alone. Stroke (including transient ischaemic attack) was recorded in 2.7% of patients receiving bevacizumab in combination with chemotherapy compared to 0.5% of patients receiving chemotherapy alone. Myocardial infarction was reported in 1.4% of patients receiving bevacizumab in combination with chemotherapy compared to 0.7% of patients receiving chemotherapy alone.
In one clinical trial evaluating bevacizumab 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 occurred 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 bevacizumab 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 bevacizumab-containing treatment group compared to 3.2–15.6% in control groups.
Grade 3–5 venous thromboembolic events (NCI-CTCAE v.3) 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 (GOG-0240), grade 3–5 venous thromboembolic events were recorded in nearly 15.6% of patients receiving bevacizumab in combination with paclitaxel and cisplatin compared to 7.0% of patients receiving paclitaxel and cisplatin.
Patients who develop venous thromboembolism may have an increased risk of recurrence when treated with Zirabeve and chemotherapy compared to chemotherapy alone.
Congestive heart failure (CHF)
Congestive heart failure (CHF) has occurred with bevacizumab use across all cancer indications to date, 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 CHF occurred in 3.5% of patients receiving bevacizumab in combination with chemotherapy compared to 0.9% in control groups. In patients participating in the AVF3694g trial who received anthracyclines concomitantly with bevacizumab, the frequency of grade 3 or higher CHF in bevacizumab and control groups was comparable to that in other metastatic breast cancer trials: 2.9% in the anthracycline + bevacizumab group and 0% in the anthracycline + placebo group. Additionally, in the AVF3694g trial, the frequency of all-grade CHF was similar in the anthracycline + bevacizumab (6.2%) and anthracycline + placebo (6.0%) treatment groups.
In most patients who developed CHF during the metastatic breast cancer trial, symptoms improved and/or left ventricular function improved after appropriate medical treatment.
Patients with existing NYHA (New York Heart Association) class II–IV CHF were excluded from most bevacizumab clinical trials. Therefore, there is no information on the risk of CHF in these patients.
Prior anthracycline therapy and/or prior radiotherapy to the chest area may be potential risk factors for CHF development.
An increased frequency of CHF was observed in clinical trials in patients with diffuse large B-cell lymphoma receiving bevacizumab with a cumulative doxorubicin dose exceeding 300 mg/m². In this Phase III clinical trial, rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP) + bevacizumab was compared to R-CHOP without bevacizumab. The frequency of CHF in both groups was higher than previously observed with doxorubicin therapy, and the frequency was higher 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 reactions (see section "Special warnings and precautions for use" and the subsection "Post-marketing experience" below)
In some clinical trials, anaphylactic reactions and anaphylactoid-type reactions were reported more frequently in patients receiving bevacizumab in combination with chemotherapy compared to patients receiving chemotherapy alone. The occurrence of these reactions in some clinical trials is common (up to 5% of patients receiving bevacizumab).
Infections
In a clinical trial involving patients with persistent, recurrent, or metastatic cervical cancer (GOG-0240), grade 3–5 infections were recorded in 24% of patients receiving bevacizumab in combination with paclitaxel and topotecan compared to 13% of patients receiving paclitaxel and topotecan.
Ovarian failure/fertility (see sections "Special warnings and precautions for use" and "Use in pregnancy or lactation")
In the Phase III NSABP C-08 trial of bevacizumab use in adjuvant therapy for patients with colon cancer, the incidence of new cases of ovarian failure, defined as amenorrhoea for 3 months or more, follicle-stimulating hormone ≥ 30 IU/mL, and negative pregnancy test by β-human chorionic gonadotropin measurement, was studied in 295 premenopausal women. New cases of ovarian failure were reported in 2.6% of patients in the mFOLFOX-6 group compared to 39% 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 abnormalities
Decreased neutrophil and leukocyte counts and presence of protein in urine may be associated with bevacizumab treatment.
In clinical trials, the following grade 3 and 4 laboratory abnormalities (NCI-CTCAE v.3) were observed with at least a 2% difference in patients receiving bevacizumab treatment compared to control group patients: hyperglycaemia, decreased haemoglobin, hypokalaemia, hyponatraemia, decreased leukocyte count, increased international normalized ratio (INR).
Clinical trials have demonstrated bevacizumab-associated transient increases in serum creatinine levels (1.5–1.9 times above baseline), both with and without proteinuria. This increase was not associated with a higher frequency of clinical manifestations of renal dysfunction in patients receiving bevacizumab 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 ischaemic attack, and myocardial infarction. In patients over 65 years of age, leucopenia grade 3–4 and thrombocytopenia (NCI-CTCAE v.3), as well as neutropenia (all grades), diarrhoea, nausea, headache, and weakness were also observed more frequently compared to patients under 65 years of age receiving bevacizumab treatment (see "Thromboembolism" in 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 trial involving patients with recurrent platinum-resistant ovarian cancer, alopecia, mucositis, peripheral sensory neuropathy, proteinuria, and arterial hypertension were also observed at frequencies at least 5% higher in the bevacizumab + chemotherapy treatment group among patients aged ≥ 65 years compared to patients under 65 years of age receiving bevacizumab.
The frequency of other adverse reactions, including gastrointestinal perforation, wound healing complications, congestive heart failure, and haemorrhage, in elderly patients (over 65 years) receiving bevacizumab was comparable to that in patients aged ≤ 65 years.
Paediatric population
The safety and efficacy of bevacizumab in children (under 18 years of age) have not been established.
In the BO25041 trial, in which bevacizumab was added to postoperative radiotherapy with concomitant and adjuvant temozolomide therapy in children with newly diagnosed supratentorial, infratentorial, cerebellar, or peduncular high-grade glioma, the safety profile in children was comparable to that observed in adults with other tumour types receiving bevacizumab.
In the BO20924 trial, in which bevacizumab was used with standard therapy for rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma, the safety profile in children receiving bevacizumab was comparable to that observed in adults receiving bevacizumab.
Bevacizumab is not approved for use in patients under 18 years of age. Published data report cases of osteonecrosis at sites other than the jaw in patients under 18 years of age receiving bevacizumab treatment.
Post-marketing experience
Adverse reactions reported during the post-marketing period
Infections and infestations
Necrotizing fasciitis, usually secondary to wound healing complications, gastrointestinal perforation, or fistula formation (rare) (see section "Special warnings and precautions for use").
Immune system disorders
Hypersensitivity reactions, infusion reactions (common), with possible accompanying symptoms: dyspnoea/respiratory distress, flushing/erythema/rash, arterial hypotension or hypertension, oxygen desaturation, chest pain, chills, nausea/vomiting (see section "Special warnings and precautions for use" and "Hypersensitivity reactions, infusion reactions" above); anaphylactic shock (rare) (see also section "Special warnings and precautions for use").
Neurological disorders
Hypertensive encephalopathy (very rare) (see section "Special warnings and precautions for use" and "Adverse reactions, Hypertension"); reversible posterior encephalopathy syndrome (rare) (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 "Proteinuria" in sections "Special warnings and precautions for use" and "Adverse reactions").
Respiratory, thoracic and mediastinal disorders
Nasal septum perforation (frequency not known), pulmonary hypertension (frequency not known), dysphonia (common).
Gastrointestinal disorders
Gastrointestinal ulceration (frequency not known).
Hepatobiliary disorders
Gallbladder perforation (frequency not known).
Musculoskeletal and connective tissue disorders
Cases of osteonecrosis of the jaw have been reported in patients receiving bevacizumab treatment. Most cases occurred in patients with known risk factors for ONJ, particularly those 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 have been observed in children receiving bevacizumab treatment (see section "Adverse reactions. Paediatric population").
Congenital, familial and genetic disorders
Cases of fetal abnormalities have been observed in women receiving bevacizumab as monotherapy or in combination with chemotherapeutic agents with known embryotoxic effects (see section "Use in pregnancy or lactation").
If frequency is specified, data were obtained from clinical trials.
Reporting suspected adverse reactions
Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of this medicinal product. Healthcare professionals, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.
Shelf life. 3 years.
Storage conditions
Store in a refrigerator at 2–8 °C. Store in the original cardboard packaging to protect from light. Do not freeze. Keep out of reach of children.
Incompatibilities
The medicinal product must not be mixed with other medicinal products except 0.9% sodium chloride solution for injection. A concentration-dependent degradation profile of bevacizumab was observed when diluted with 5% glucose solution.
Packaging
100 mg/4 mL or 400 mg/16 mL in a vial. 1 vial in a cardboard box.
Prescription status. Prescription only.
Manufacturer
Pfizer Service Company BV / Pfizer Service Company BV.
Manufacturer's location and address of place of business
Hoge Wei 10, Zaventem, 1930, Belgium / Hoge Wei 10, Zaventem, 1930, Belgium.
or ٭
Manufacturer
Pharmacia & Upjohn Company LLC / Pharmacia & Upjohn Company LLC.
Manufacturer's location and address of place of business
7000 Portage Road, Kalamazoo, Michigan (MI) 49001, USA / 7000 Portage Road, Kalamazoo, Michigan (MI) 49001, USA.
٭ The package insert contains information on only one manufacturer (the one involved in the batch release).