Lextemy - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Lextemy 25 mg/mL concentrate for solution for infusion.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each mL of concentrate contains 25 mg of bevacizumab*.

Each 4 mL vial contains 100 mg of bevacizumab.

Each 16 mL vial contains 400 mg of bevacizumab.

For dilution and other handling recommendations, see section 6.6.

*Bevacizumab is a recombinant humanised monoclonal antibody produced by DNA technology in Chinese Hamster Ovary cells.

Excipient(s) with known effect

Each 4 mL vial contains 4.196 mg of sodium.

Each 16 mL vial contains 16.784 mg of sodium.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Concentrate for solution for infusion (sterile concentrate).

Clear to slightly opalescent, colourless to pale brown liquid with a pH of 5.70 to 6.40, an osmolality of 0.251 – 0.311 Osmol/kg and free of visible particles.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Lextemy in combination with fluoropyrimidine-based chemotherapy is indicated for treatment of adult patients with metastatic carcinoma of the colon or rectum.

Lextemy in combination with paclitaxel is indicated for first-line treatment of adult patients with metastatic breast cancer. For further information as to human epidermal growth factor receptor 2 (HER2) status, please refer to section 5.1.

Lextemy in combination with capecitabine is indicated for first-line treatment of adult patients with metastatic breast cancer in whom treatment with other chemotherapy options including taxanes or anthracyclines is not considered appropriate. Patients who have received taxane and anthracycline-containing regimens in the adjuvant setting within the last 12 months should be excluded from treatment with Lextemy in combination with capecitabine. For further information as to HER2 status, please refer to section 5.1.

Lextemy, in addition to platinum-based chemotherapy, is indicated for first-line treatment of adult patients with unresectable advanced, metastatic or recurrent non-small cell lung cancer other than predominantly squamous cell histology.

Lextemy, in combination with erlotinib, is indicated for first-line treatment of adult patients with unresectable advanced, metastatic or recurrent non-squamous non-small cell lung cancer with Epidermal Growth Factor Receptor (EGFR) activating mutations (see section 5.1).

Lextemy in combination with interferon alfa-2a is indicated for first line treatment of adult patients with advanced and/or metastatic renal cell cancer.

Lextemy, in combination with carboplatin and paclitaxel is indicated for the front-line treatment of adult patients with advanced (International Federation of Gynecology and Obstetrics [FIGO] stages III B, III C and IV) epithelial ovarian, fallopian tube, or primary peritoneal cancer. (see section 5.1).

Lextemy, in combination with paclitaxel and cisplatin or, alternatively, paclitaxel and topotecan in patients who cannot receive platinum therapy, is indicated for the treatment of adult patients with persistent, recurrent, or metastatic carcinoma of the cervix (see section 5.1).

4.2 Posology and method of administration

Lextemy must be administered under the supervision of a physician experienced in the use of antineoplastic medicinal products.

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Posology                                     v

Metastatic carcinoma of the colon or rectum (mCRC)

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The recommended dose of Lextemy, administered as an intravenous infusion, is either 5 mg/kg or

10 mg/kg of body weight (bw) given once every 2 weeks or 7.5 mg/kg bw or 15 mg/kg bw given once every 3 weeks.

It is recommended that treatment be continued until progression of the underlying disease or until unacceptable toxicity.

Metastatic breast cancer (mBC)

The recommended dose of Lextemy is 10 mg/kg bw given once every 2 weeks or 15 mg/kg bw given once every 3 weeks as an intravenous infusion.

It is recommended that treatment be continued until progression of the underlying disease or until unacceptable toxicity.

Non-small cell lung cancer (NSCLC)

First-line treatment of non-squamous NSCLC in combination with platinum-based chemotherapy

Lextemy is administered in addition to platinum-based chemotherapy for up to 6 cycles of treatment followed by Lextemy as a single agent until disease progression.

The recommended dose of Lextemy is 7.5 mg/kg or 15 mg/kg bw given once every 3 weeks as an intravenous infusion.

Clinical benefit in NSCLC patients has been demonstrated with both 7.5 mg/kg bw and 15 mg/kg bw doses (see section 5.1).

It is recommended that treatment be continued until progression of the underlying disease or until unacceptable toxicity.

First-line treatment of non-squamous NSCLC with EGFR activating mutations in combination with erlotinib

EGFR mutation testing should be performed prior to initiation of treatment with the combination of Lextemy and erlotinib. It is important that a well-validated and robust methodology is chosen to avoid false negative or false positive determinations.

The recommended dose of Lextemy when used in addition to erlotinib is 15 mg/kg bw given once every 3 weeks as an intravenous infusion.

It is recommended that the treatment with Lextemy in addition to erlotinib is continued until disease progression.

For the posology and method of administration of erlotinib, please refer to the full erlotinib prescribing information.

Advanced and/or metastatic renal cell cancer (mRCC)

The recommended dose of Lextemy is 10 mg/kg bw given once every 2 weeks as an intravenou infusion.

It is recommended that treatment be continued until progression of the underlying disease unacceptable toxicity.

Epithelial ovarian, fallopian tube and primary peritoneal cancer

Front-line treatment

Lextemy is administered in addition to carboplatin and paclitaxel for up t followed by continued use of Lextemy as single agent until disease progr 15 months or until unacceptable toxicity, whichever occurs earlier.

The recommended dose of Lextemy is 15 mg/kg bw given once every 3 weeks as an intravenous infusion.

Cervical cancer

Lextemy is administered in combination with one of the following chemotherapy regimens: paclitaxel and cisplatin or paclitaxel and topotecan.

The recommended dose of Lextemy is 15 mg/kg bw given once every 3 weeks as an intravenous infusion.

ontinued until progression of the underlying disease or until

ment

d efficacy have not been studied in patients with renal impairment (see section 5.2).

Hepatic impairment

The safety and efficacy have not been studied in patients with hepatic impairment (see section 5.2).

Paediatric population

The safety and efficacy of bevacizumab in children aged less than 18 years old have not been established. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.

There is no relevant use of bevacizumab in the paediatric population in the indications for treatment of cancers of the colon, rectum, breast, lung, ovarian, fallopian tube, peritoneum, cervix and kidney.

Method of administration

Lextemy is for intravenous use. The initial dose should be delivered 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.

It should not be administered as an intravenous push or bolus.

Dose reduction for adverse reactions is not recommended. If indicated, therapy should either be permanently discontinued or temporarily suspended as described in section 4.4.

Precautions to be taken before handling or administering the medicinal product

For instructions on dilution of the medicinal product before administration, see section 6. infusions should not be administered or mixed with glucose solutions. This medicinal not be mixed with other medicinal products except those mentioned in section 6.6.

4.3 Contraindications

4.4 Special warnings and precautions for use

persistent, recurrent, or metastatic cervical cancer with bevacizumab are at fistulae between the vagina and any part of the GI tract (Gastrointestinal-vaginal r radiation is a major risk factor for the development of GI-vaginal fistulae and all ith GI-vaginal fistulae had a history of prior radiation. Recurrence of cancer within the field of prior radiation is an additional important risk factor for the development of GI-vaginal fistulae.

Non-GI fistulae (see section 4.8)

Patients may be at increased risk for the development of fistulae when treated with bevacizumab.

Permanently discontinue bevacizumab in patients with tracheoesophageal (TE) fistula or any Grade 4 fistula [US National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE v.3)]. Limited information is available on the continued use of bevacizumab in patients with other fistulae. In cases of internal fistula not arising in the gastrointestinal tract, discontinuation of bevacizumab should be considered.

Wound healing complications (see section 4.8)

Bevacizumab may adversely affect the wound healing process. Serious wound healing complications, including anastomotic complications, with a fatal outcome have been reported. Therapy should not be initiated for at least 28 days following major surgery or until the surgical wound is fully healed. In patients who experienced wound healing complications during therapy, treatment should be withheld until the wound is fully healed. Therapy should be withheld for elective surgery.

Necrotising fasciitis, including fatal cases, has rarely been reported in patients treated with bevacizumab. This condition is usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Bevacizumab therapy should be discontinued in patients who develop necrotising fasciitis, and appropriate treatment should be promptly initiated.

Hypertension (see section 4.8)

An increased incidence of hypertension was observed in bevacizumab-treated patients. Clini data suggest that the incidence of hypertension is likely to be dose-dependent. Pre-existing

hypertension should be adequately controlled before starting bevacizumab treatment. information on the effect of bevacizumab in patients with uncontrolled hypertension

initiating therapy. Monitoring of blood pressure is generally recommended durin In most cases hypertension was controlled adequately using standard antihypert appropriate for the individual situation of the affected patient. The use of diureti hypertension is not advised in patients who receive a cisplatin-based chemotherapy regimen. Bevacizumab should be permanently discontinued if medically significant hypertension cannot be adequately controlled with antihypertensive therapy, or if the patient develops hypertensive crisis or hypertensive encephalopathy.

Posterior reversible encephalopathy syndrome (PRES) (see section 4.8)

There have been rare reports of bevacizumab-treated patients developing signs and symptoms that are consistent with PRES, a rare neurologic disorder, which can present with the following signs and symptoms among others: seizures, headache, altered mental status, visual disturbance, or cortical blindness, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). In patients developing PRES, treatment of specific symptoms including control of hypertension is recommended along with discontinuation of bevacizumab. The safety of reinitiating bevacizumab therapy in patients previously experiencing PRES is not known.

Proteinuria (see section 4.8)

Patients with a history of hypertension may be at increased risk for the development of proteinuria when treated with bevacizumab. There is evidence suggesting that all Grade (US National Cancer

logy Criteria for Adverse Events [NCI-CTCAE v.3]) proteinuria may be related to the dose. Monitoring of proteinuria by dipstick urinalysis is recommended prior to starting and during therapy. Grade 4 proteinuria (nephrotic syndrome) was seen in up to 1.4% of patients treated with bevacizumab. Therapy should be permanently discontinued in patients who develop nephrotic syndrome (NCI-CTCAE v.3).

Arterial thromboembolism (see section 4.8)

In clinical trials, the incidence of arterial thromboembolic reactions including cerebrovascular accidents (CVAs), transient ischaemic attacks (TIAs) and myocardial infarctions (MIs) was higher in patients receiving bevacizumab in combination with chemotherapy compared to those who received chemotherapy alone.

Patients receiving bevacizumab plus chemotherapy, with a history of arterial thromboembolism, diabetes or age greater than 65 years have an increased risk of developing arterial thromboembolic reactions during therapy. Caution should be taken when treating these patients with bevacizumab.

Therapy should be permanently discontinued in patients who develop arterial thromboembolic reactions.

Venous thromboembolism (see section 4.8)

Patients may be at risk of developing venous thromboembolic reactions, including pulmonary embolism under bevacizumab treatment.

Patients treated for persistent, recurrent, or metastatic cervical cancer with bevacizumab in combination with paclitaxel and cisplatin may be at increased risk of venous thromboembolic events. Bevacizumab should be discontinued in patients with life-threatening (Grade 4) thromboembolic reactions, including pulmonary embolism (NCI-CTCAE v.3). Patients with thromboembolic reactions < Grade 3 need to be closely monitored (NCI-CTCAE v.3).

Haemorrhage

Patients treated with bevacizumab have an increased risk of haemorrhage, especially tumour-associated haemorrhage. Bevacizumab should be discontinued permanently in patients who experience Grade 3 or 4 bleeding during bevacizumab therapy (NCI-CTCAE v.3) (see section 4.8).

Co

Patients with untreated CNS metastases were routinely excluded from clinical trials with bevacizumab, based on imaging procedures or signs and symptoms. Therefore, the risk of CNS haemorrhage in such patients has not been prospectively evaluated in randomised clinical trials (see section 4.8). Patients should be monitored for signs and symptoms of CNS bleeding, and bevacizumab treatment discontinued in cases of intracranial bleeding.

There is no information on the safety profile of bevacizumab in patients with congenital bleeding diathesis, acquired coagulopathy or in patients receiving full dose of anticoagulants for the treatment of thromboembolism prior to starting bevacizumab treatment, as s clinical trials. Therefore, caution should be exercised before initiat

However, patients who developed venous thrombosis while receiving therapy did not appear to have an increased rate of Grade 3 or above bleeding when treated with a full dose of warfarin and bevacizumab concomitantly (NCI-CTCAE v.3).

Pulmonary haemorrhage/ha­emoptysis

Patients with non-small cell lung cancer treated with bevacizumab may be at risk of serious, and in some cases fatal, pulmonary haemorrhage/ha­emoptysis. Patients with recent pulmonary haemorrhage/ haemoptysis (> 2.5 mL of red blood) should not be treated with bevacizumab.

Aneurysms and artery dissections

The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating bevacizumab, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.

Congestive heart failure (CHF) (see section 4.8)

Reactions consistent with CHF were reported in clinical trials. The findings ranged from asymptomatic declines in left ventricular ejection fraction to symptomatic CHF, requiring treatment or hospitalisation. Caution should be exercised when treating patients with clinically significant cardiovascular disease such as pre-existing coronary artery disease, or congestive heart failure with

Most of the patients who experienced CHF had metastatic breast cancer and had received previous treatment with anthracyclines, prior radiotherapy to the left chest wall or other risk factors for CHF were present.

In patients in AVF3694g who received treatment with anthracyclines and who had not received anthracyclines before, no increased incidence of all Grade CHF was observed in the anthracycline + bevacizumab group compared to the treatment with anthracyclines only. CHF Grade 3 or higher reactions were somewhat more frequent among patients receiving bevacizumab in combination with chemotherapy than in patients receiving chemotherapy alone. This is consistent with results in patients in other studies of metastatic breast cancer who did not receive concurrent anthracycline treatment (NCI-CTCAE v.3) (see section 4.8).

Neutropenia and infections (see section 4.8)

Increased rates of severe neutropenia, febrile neutropenia, or infection with or without severe neutropenia (including some fatalities) have been observed in patients treated with some myelotoxic chemotherapy regimens plus bevacizumab in comparison to chemotherapy alone. This has mainly been seen in combination with platinum- or taxane-based therapies in the treatment of NSCLC, mBC, and in combination with paclitaxel and topotecan in persistent, recurrent, or metastatic cervical cancer.

Hypersensitivity reactions/infusion reactions (see section 4.8)

Patients may be at risk of developing infusion/hyper­sensitivity reactions. Close observation of the patient during and following the administration of bevacizumab is recommended as expected for any infusion of a therapeutic humanised monoclonal antibody. If a reaction occurs, the infusion should be discontinued and appropriate medical therapies should be administered. A systematic premedication is not warranted.

itreal use

concentration has been demonstrated following intravitreal anti-VEGF therapy. Systemic adverse reactions including non-ocular haemorrhages and arterial thromboembolic reactions have been reported following intravitreal injection of VEGF inhibitors.

zility

impair female fertility (see sections 4.6 and 4.8). Therefore fertility preservation discussed with women of child-bearing potential prior to starting treatment with

Lextemy contains sodium.

This medicinal product contains 4.196 mg of sodium in each 4 mL vial, equivalent to 0.21% of the

WHO recommended maximum daily intake of 2 g of sodium for an adult.

This medicinal product contains 16.784 mg of sodium in each 16 mL vial, equivalent to 0.84% of the WHO recommended maximum daily intake of 2 g of sodium for an adult.

4.5 Interaction with other medicinal products and other forms of interaction

Effect of antineoplastic agents on bevacizumab pharmacokinetics

No clinically relevant interaction of co-administered chemotherapy on bevacizumab pharmacokinetics was observed based on the results of population pharmacokinetic analyses. There were neither statistically significant nor clinically relevant differences in bevacizumab clearance in patients receiving bevacizumab monotherapy compared to patients receiving bevacizumab in combination with interferon alfa-2a, erlotinib or chemotherapies (IFL, 5-FU/LV, carboplatin/pa­clitaxel, capecitabine, doxorubicin or cisplatin/gem­citabine).

Effect of bevacizumab on the pharmacokinetics of other antineoplastic agents

No clinically relevant interaction of bevacizumab was observed on the pharmacokinetics of co-administered interferon alpha 2a, erlotinib (and its active metabolite OSI-420), or the chemotherapies irinotecan (and its active metabolite SN38), capecitabine, oxaliplatin (as determined by measurement of free and total platinum), and cisplatin. Conclusions on the impact of bevacizumab on gemcitabine pharmacokinetics cannot be drawn.

Combination of bevacizumab and sunitinib malate

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

MAHA is a haemolytic disorder which can present with red cell fragmentation, anaemia, and thrombocytopenia. In addition, hypertension (including hypertensive crisis), elevated creatinine, and neurological symptoms were observed in some of these patients. All of these findings were reversible upon discontinuation of bevacizumab and sunitinib malate (see Hypertension, Proteinuria, PRES in section 4.4).

Combination with platinum- or taxane-based therapies (see sections 4.4 and 4.8)

Increased rates of severe neutropenia, febrile neutropenia, or infection with or without severe neutropenia (including some fatalities) have been observed mainly in patients treated with platinum- or taxane-based therapies in the treatment of NSCLC and mBC.

Radiotherapy

The safety and efficacy of concomitant administration of radiotherapy and bevacizumab has not been established.

EGFR monoclonal antibodies in combination with bevacizumab chemotherapy regimens

No interaction studies have been performed. EGFR monoclonal antibodies should not be administered for the treatment of mCRC in combination with bevacizumab-containing chemotherapy. Results from the randomised phase III studies, PACCE and CAIRO-2, in patients with mCRC suggest that the use of anti-EGFR monoclonal antibodies panitumumab and cetuximab, respectively, in combination with bevacizumab plus chemotherapy, is associated with decreased PFS and/or OS, and with increased toxicity compared with bevacizumab plus chemotherapy alone.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential have to use effective contraception during (and up to 6 months after) treatment.

Pregnancy

There are no clinical trial data on the use of bevacizumab in pregnant women. Studies in animals have shown reproductive toxicity including malformations (see section 5.3). IgGs are known to cross the placenta, and bevacizumab is anticipated to inhibit angiogenesis in the foetus, and thus is suspected to cause serious birth defects when administered during pregnancy. In the post-marketing setting, cases of foetal abnormalities in women treated with bevacizumab alone or in combination with known embryotoxic chemotherapeutics have been observed (see section 4.8). Bevacizumab is contraindicated in pregnancy (see section 4.3).

Breast-feeding

It is not known whether bevacizumab is excreted in human milk. As maternal IgG is excreted in milk and bevacizumab could harm infant growth and development (see section 5.3), women must discontinue breast-feeding during therapy and not breast-feed for at least six months following the last dose of bevacizumab.

Fertility

Repeat dose toxicity studies in animals have shown that bevacizumab may have an adverse effect on female fertility (see section 5.3). In a phase III trial in the adjuvant treatment of patients with co cancer, a substudy with premenopausal women has shown a higher incidence of new cases of o failure in the bevacizumab group compared to the control group. After discontinuation of bevaci treatment, ovarian function recovered in the majority of patients. Long term effects of the trea with bevacizumab on fertility are unknown.

4.7 Effects on ability to drive and use machines

Bevacizumab has minor influence on the ability to drive and use machines. er, somnolence and syncope have been reported with bevacizumab use (see table 1 in section 4. patients are experiencing symptoms that affect their vision or concentration, or their ability to react, they should be advised not to drive and use machines until symptoms abate.

4.8 Undesirable effects

Summary of the safety profile

The overall safety profile of bevacizumab is based on data from over 5,700 patients with various malignancies, predominantly treated with bevacizumab in combination with chemotherapy in clinical trials.

The most serious adverse reactions

e section 4.4).

monary haemorrhage/ha­emoptysis, which is more common in patients (see section 4.4).

(see section 4.4).

The most frequently observed adverse reactions across clinical trials in patients receiving bevacizumab were hypertension, fatigue or asthenia, diarrhoea and abdominal pain.

Analyses of the clinical safety data suggest that the occurrence of hypertension and proteinuria with bevacizumab therapy are likely to be dose-dependent.

Tabulated list of adverse reactions

The adverse reactions listed in this section fall into the following frequency categories: 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); not known (cannot be estimated from the available data). Within each frequency category, adverse reactions are presented in the order of decreasing seriousness.

Tables 1 and 2 list adverse reactions associated with the use of bevacizumab in combination with different chemotherapy regimens in multiple indications, by MedDRA system organ class.

Table 1 provides all adverse reactions by frequency that were determined to have a causal relationship with bevacizumab through:

• – comparative incidences noted between clinical trial treatment arms (with at least a 10% difference compared to the control arm for NCI-CTCAE Grade 1–5 reactions or at least a 2% difference compared to the control arm for NCI-CTCAE Grade 3–5 reactions,

• – post-authorisation safety studies,

• – spontaneous reporting,

• – epidemiological studies\non-interventional or observational studies,

• – or through an evaluation of individual case reports.

Table 2 provides the frequency of severe adverse reactions. Severe reactions are defined as adverse events with at least a 2% difference compared to the control arm in clinical studies for NCI-CTCAE Grade 3–5 reactions. Table 2 also includes adverse reactions which are considered by the MAH to be clinically significant or severe.

♦ Cor Post-marketing adverse reactions are included in both Tables 1 and 2, where applicable. Detailed information about these post-marketing reactions are provided in Table 3.

Adverse reactions are added to the appropriate frequency category in the tables below according to the highest incidence seen in any indication.

fir

Some of the adverse reactions are reactions commonly seen with chemotherapy; however, bevacizumab may exacerbate these reactions when combined with chemotherapeutic agents. Examples include palmar-plantar erythrodysaesthesia syndrome with pegylated liposomal doxorubicin or capecitabine, peripheral sensory neuropathy with paclitaxel or oxaliplatin, nail disorders or alopecia with paclitaxel, and paronychia with erlotinib.

Table 1: Adverse reactions by frequency

When events were noted as both all grade and grade 3–5 adverse drug reactions in clinical trials, the highest frequency observed in patients has been reported. Data are unadjusted for the differential time on treatment.

a For further information please refer to Table 3 ‚Adverse reactions reported in post-marketing setting.‘ b Terms represent a group of events that describe a medical concept rather than a single condition or MedDRA (Medical Dictionary for Regulatory Activities) preferred term. This group of medical terms may involve the same underlying pathophysiology (e.g. arterial thromboembolic reactions include cerebrovascular accident, myocardial infarction, transient ischaemic attack and other arterial thromboembolic reactions).

c Based on a substudy from NSABP C-08 with 295 patients

d For additional information refer below within section „Further information on selected serious adverse reactions.“

e Recto-vaginal fistulae are the most common fistulae in the GI-vaginal fistula category.

f Observed in pediatric population only

Table 2: Severe adverse reactions by frequency

Table 2 provides the frequency of severe adverse reactions. Severe reactions are defined as adverse events with at least a 2% difference compared to the control arm in clinical studies for NCI-CTCAE Grade 3–5 reactions. Table 2 also includes adverse reactions which are considered by the MAH to be clinically significant or severe. These clinically significant adverse reactions were reported in clinical trials but the grade 3–5 reactions did not meet the threshold of at least a 2% difference compared to the control arm. Table 2 also includes clinically significant adverse reactions that were observed only in

the postmarketing setting, therefore, the frequency and NCI-CTCAE grade is not known.These clinically significant reactions have therefore been included in Table 2 within the column entitled “Frequency Not Known.”

a Terms represent a group of events that describe a medical concept rather than a single condition or MedDRA (Medical Dictionary for Regulatory Activities) preferred term. This group of medical terms may involve the same underlying pathophysiology (e.g. arterial thromboembolic reactions include cerebrovascular accident, myocardial infarction, transient ischaemic attack and other arterial thromboembolic reactions).

b For additional information refer below within section „Further information on selected serious adverse reactions“

c For further information please refer to Table 3 ‚Adverse reactions reported in post-marketing setting.‘ d Recto-vaginal fistulae are the most common fistulae in the GI-vaginal fistula category.

Description of selected serious adverse reactions

Gastrointestinal (GI) perforations and fistulae (see section 4.4)

Bevacizumab has been associated with serious cases of gastrointestinal perforation.

Gastrointestinal perforations have been reported in clinical trials with an incide less than 1% in patients with non-squamous non-small cell lung cancer, up to 1.3% in patients with metastatic breast cancer, up to 2.0% in patients with metastatic renal cell cancer or in patients with ovarian cancer, and up to 2.7% (including gastrointestinal fistula and abscess) in patients with metastatic colorectal cancer. From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study GOG-0240), GI perforations (all grade) were reported in 3.2% of patients, all of whom had a history of prior pelvic radiation.

The occurrence of those events varied in type and severity, ranging from free air seen on the plain abdominal X-ray, which resolved without treatment, to intestinal perforation with abdominal abscess and fatal outcome. In some cases underlying intra-abdominal inflammation was present, either from gastric ulcer disease, tumour necrosis,

Fatal outcome was reported in approximately a third of serious cases of gastrointestinal perforations, which represents between 0.2%-1%

In bevacizumab clinical trials, gastrointestinal fistulae (all grade) have been reported with an incidence of up to 2% in patients with metastatic colorectal cancer and ovarian cancer, but were also reported less commonly in patients with other types of cancer.

Non-Gffistulae (see section 4.4)

Bevacizumab use has been associated with serious cases of fistulae including reactions resulting in death.

From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (GOG-240), 1.8% of bevacizumab-treated patients and 1.4% of control patients were reported to have had non-gastrointestinal vaginal, vesical, or female genital tract fistulae.

Uncommon (> 0.1% to < 1%) reports of fistulae that involve areas of the body other than the gastrointestinal tract (e.g. bronchopleural and biliary fistulae) were observed across various indications. Fistulae have also been reported in post-marketing experience.

Reactions were reported at various time points during treatment ranging from one week to greater than 1 year from initiation of bevacizumab, with most reactions occurring within the first 6 months of therapy.

Wound healing (see section 4.4)

As bevacizumab may adversely impact wound healing, patients who had major surgery within the last 28 days were excluded from participation in phase III clinical trials.

In clinical trials of metastatic carcinoma of the colon or rectum, there was no increased risk of post-operative bleeding or wound healing complications observed in patients who underwen surgery 28–60 days prior to starting bevacizumab. An increased incidence of post-operativ or wound healing complication occurring within 60 days of major surgery was observe was being treated with bevacizumab at the time of surgery. The incidence varied be and 20% (3/15).

Serious wound healing complications, including anastomotic complications, have been reported, some of which had a fatal outcome.                               w

In locally recurrent and metastatic breast cancer trials, Grade 3–5 wound healing complications were observed in up to 1.1% of patients receiving bevacizumab com with up to 0.9% of patients in the

control arms (NCI-CTCAE v.3).

In clinical trials of ovarian cancer, Grade 3–5 wound healing complications were observed in up to 1.8% of patients in the bevacizumab arm versus 0.1% in the control arm (NCI-CTCAE v.3).

Hypertension (see section 4.4)

In clinical trials, with the exception of study JO25567, the overall incidence of hypertension (all grades) ranged up to 42.1% in the bevacizumab containing arms compared with up to 14% in the control arms. The overall incidence of NCI-CTC Grade 3 and 4 hypertension in patients receiving bevacizumab ranged from 0.4% to 17.9%. Grade 4 hypertension (hypertensive crisis) occurred in up to 1.0% of patients treated with bevacizumab and chemotherapy compared to up to 0.2% of patients treated with the same chemo y alone.

hypertension was observed in 77.3% of the patients who received tion with erlotinib as first-line treatment for non-squamous NSCLC with ns, compared to 14.3% of patients treated with erlotinib alone. Grade 3 % in patients treated with bevacizumab in combination with erlotinib compared s treated with erlotinib alone. There were no grade 4 or 5 hypertension events.

Hypertension was generally adequately controlled with oral anti-hypertensives such as angiotensin-converting enzyme inhibitors, diuretics and calcium-channel blockers. It rarely resulted in discontinuation of bevacizumab treatment or hospitalisation.

Very rare cases of hypertensive encephalopathy have been reported, some of which were fatal.

The risk of bevacizumab-associated hypertension did not correlate with the patients’ baseline characteristics, underlying disease or concomitant therapy.

Posterior reversible encephalopathy syndrome (see section 4.4)

There have been rare reports of bevacizumab-treated patients developing signs and symptoms that are consistent with PRES, a rare neurological disorder. Presentation may include seizures, headache, altered mental status, visual disturbance, or cortical blindness, with or without associated hypertension. The clinical presentation of PRES is often nonspecific, and therefore the diagnosis of PRES requires confirmation by brain imaging, preferably MRI.

In patients developing PRES, early recognition of symptoms with prompt treatment of specific symptoms including control of hypertension (if associated with severe uncontrolled hypertension) is recommended in addition to discontinuation of bevacizumab therapy. Symptoms usually resolve or improve within days after treatment discontinuation, although some patients have experienced some neurologic sequelae. The safety of reinitiating bevacizumab therapy in patients previously experiencing PRES is not known.

Across clinical trials, 8 cases of PRES have been reported. Two of the eight cases did not have

radiological confirmation via MRI.

Proteinuria (see section 4.4)

In clinical trials, proteinuria has been reported within the range of 0.7% to 54.7% of patie bevacizumab.

Proteinuria ranged in severity from clinically asymptomatic, transient, trace proteinuria to nephrotic syndrome, with the great majority as Grade 1 proteinuria (NCI-CTCAE v.3).      3 proteinuria was

reported in up to 10.9% of treated patients. Grade 4 proteinuria (nephrotic syn e) was seen in up to 1.4% of treated patients. Testing for proteinuria is recommended prior to start of bevacizumab therapy. In most clinical trials urine protein levels of > 2g/24 hrs led to the holding of bevacizumab until recovery to < 2g/24 hrs.

Haemorrhage (see section 4.4)

In clinical trials across all indications the overall incide reactions ranged from 0.4% to 6.9% in bevacizumab tr patients in the chemotherapy control group.

From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study GOG-0240), grade 3–5 bleeding reactions have been reported in up to 8.3% of patients treated with bevacizumab in combination with paclit treated with paclitaxel and topotecan.

The haemorrhagic reactions that have been observed in clinical trials were predominantly tumour-associated haemorrhage (see below) and minor mucocutaneous haemorrhage (e.g. epistaxis).

hage (see section 4.4)

haemorrhage/ha­emoptysis has been observed primarily in trials in ell lung cancer (NSCLC). Possible risk factors include squamous cell ith antirheumatic/anti-inflammatory substances, treatment with anticoagulants, prior radiothe , bevacizumab therapy, previous medical history of atherosclerosis, central tumour location and cavitation of tumours prior to or during therapy. The only variables that showed statistically significant correlations with bleeding were bevacizumab therapy and squamous cell histology. Patients with NSCLC of known squamous cell histology or mixed cell type with predominant squamous cell histology were excluded from subsequent phase III trials, while patients with unknown tumour histology were included.

In patients with NSCLC excluding predominant squamous histology, all Grade reactions were seen with a frequency of up to 9.3% when treated with bevacizumab plus chemotherapy compared with up to 5% in the patients treated with chemotherapy alone. Grade 3–5 reactions have been observed in up to 2.3% of patients treated with bevacizumab plus chemotherapy as compared with < 1% with chemotherapy alone (NCI-CTCAE v.3). Major or massive pulmonary haemorrhage/ha­emoptysis can occur suddenly and up to two thirds of the serious pulmonary haemorrhages resulted in a fatal outcome.

Gastrointestinal haemorrhages, including rectal bleeding and melaena have been reported in colorectal cancer patients, and have been assessed as tumour-associated haemorrhages.

Tumour-associated haemorrhage was also seen rarely in other tumour types and locations, including cases of central nervous system (CNS) bleeding in patients with CNS metastases (see section 4.4).

The incidence of CNS bleeding in patients with untreated CNS metastases receiving bevacizumab has not been prospectively evaluated in randomised clinical trials. In an exploratory retrospective analysis of data from 13 completed randomised trials in patients with various tumour types, 3 patients out of 91 (3.3%) with brain metastases experienced CNS bleeding (all Grade 4) when treated with bevacizumab, compared to 1 case (Grade 5) out of 96 patients (1%) that were not exposed to bevacizumab. In two subsequent studies in patients with treated brain metastases (which included around 800 patients), one case of Grade 2 CNS haemorrhage was reported in 83 subjects treated with bevacizumab (1.2%) at the time of interim safety analysis (NCI-CTCAE v.3).                                     ­CrT

Across all clinical trials, mucocutaneous haemorrhage has been seen in up to 50% of bevacizumab–treated patients. These were most commonly NCI-CTCAE v.3 Grade 1 epistaxis that lasted less than 5 minutes, resolved without medical intervention and did not re      ny changes in

the bevacizumab treatment regimen. Clinical safety data suggest that the incide minor

mucocutaneous haemorrhage (e.g. epistaxis) may be dose-dependent.

There have also been less common reactions of minor mucocutaneous haemorrhage in other locations, such as gingival bleeding or vaginal bleeding.

Thromboembolism (see section 4.4)

Arterial thromboembolism

An increased incidence of arterial thromboembolic reactions was observed in patients treated with bevacizumab across indications, including cerebrovascular accidents, myocardial infarction, transient ischaemic attacks, and other arterial thromboembolic reactions.

In clinical trials, the overall incidence of arterial thromboembolic reactions ranged up to 3.8% in the bevacizumab containing arms compared with up to 2.1% in the chemotherapy control arms. Fatal outcome was reported in 0.8% of patients receiving bevacizumab compared to 0.5% in patients receiving chemotherapy alone. Cerebrovascular accidents (including transient ischaemic attacks) were reported in up to 2.7% of patients treated with bevacizumab in combination with chemotherapy compared to up to 0.5% of patients treated with chemotherapy alone. Myocardial infarction was reported in up to 1.4% tients treated with bevacizumab in combination with chemotherapy compared to up to 0. atients treated with chemotherapy alone.

aluating bevacizumab in combination with 5-fluorouracil/fo­linic acid, ents with metastatic colorectal cancer who were not candidates for treatment with included. In this trial arterial thromboembolic reactions were observed in 11%

atients compared to 5.8% (6/104) in the chemotherapy control group.

The incidence of venous thromboembolic reactions in clinical trials was similar in patients receiving bevacizumab in combination with chemotherapy compared to those receiving the control chemotherapy alone. Venous thromboembolic reactions include deep venous thrombosis, pulmonary embolism and thrombophlebitis.

In clinical trials across indications, the overall incidence of venous thromboembolic reactions ranged from 2.8% to 17.3% of bevacizumab-treated patients compared with 3.2% to 15.6% in the control arms.

Grade 3–5 (NCI-CTCAE v.3) venous thromboembolic reactions have been reported in up to 7.8% of patients treated with chemotherapy plus bevacizumab compared with up to 4.9% in patients treated with chemotherapy alone (across indications, excluding persistent, recurrent, or metastatic cervical cancer).

From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study GOG-0240), grade 3–5 venous thromboembolic events have been reported in up to 15.6% of patients treated with bevacizumab in combination with paclitaxel and cisplatin compared with up to 7.0% of patients treated with paclitaxel and cisplatin.

Patients who have experienced a venous thromboembolic reaction may be at higher risk for a recurrence if they receive bevacizumab in combination with chemotherapy versus chemotherapy alone.

Congestive heart failure (CHF)

In clinical trials with bevacizumab, congestive heart failure (CHF) was observed in all cance indications studied to date, but occurred predominantly in patients with metastatic breast four phase III trials (AVF2119g, E2100, BO17708 and AVF3694g) in patients with m cancer CHF Grade 3 (NCI-CTCAE v.3) or higher was reported in up to 3.5% of pat bevacizumab in combination with chemotherapy compared with up to 0.9% in

patients in study AVF3694g who received anthracyclines concomitan

incidences of Grade 3 or higher CHF for the respective bevacizumab and c arms were similar to those in the other studies in metastatic breast cancer: 2.9% in the anthracyc bevacizumab arm and 0% in the anthracycline + placebo arm. In addition, in study AVF3694g the incidences of all Grade CHF were similar between the anthracycline + bevacizuma 2%) and the anthracycline + placebo arms (6.0%).

Most patients who developed CHF during mBC trials sho ventricular function following appropriate medical the

In most clinical trials of bevacizumab, patients with pre-existing CHF of NYHA (New York Heart

Association) II-IV were excluded, therefore, no population.

Prior anthracyclines exposure and/or the development of CHF.

An increased incidence of CHF has been observed in a clinical trial of patients with diffuse large B-cell lymphoma when receiving bevacizumab with a cumulative doxorubicin dose greater than 300 mg/m2. This phase III clinical trial compared rituximab/cyclop­hosphamide/do­xorubicin/vin­cristine/pred­nisone (R-CHOP) plus bevacizumab to R-CHOP without bevacizumab. While the incidence of CHF was, in both arms, above that previously observed for doxorubicin therapy, the rate was higher in the R-CHOP plus bevacizumab arm. These results suggest that close clinical observation with appropriate cardiac assessments should be considered for patients exposed to cumulative doxorubicin doses greater than 300 mg/m2 when combined with bevacizumab.

Hypersensitivity reactions/infusion reactions (see section 4.4 and Post-marketing experience below) In some clinical trials anaphylactic and anaphylactoid-type reactions were reported more frequently in patients receiving bevacizumab in combination with chemotherapy than with chemotherapy alone. The incidence of these reactions in some clinical trials of bevacizumab is common (up to 5% in bevacizumab-treated patients).

Infections

From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study GOG-0240), grade 3–5 infections have been reported in up to 24% of patients treated with bevacizumab in combination with paclitaxel and topotecan compared with up to 13% of patients treated with paclitaxel and topotecan.

Ovarian failure/fertility (see sections 4.4 and 4.6)

In NSABP C-08, a phase III trial of bevacizumab in adjuvant treatment of patients with colon cancer, the incidence of new cases of ovarian failure, defined as amenorrhoea lasting 3 or more months, FSH level > 30 mIU/mL and a negative serum ß-HCG pregnancy test, has been evaluated in 295 premenopausal women. New cases of ovarian failure were reported in 2.6% 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 these evaluable women. Long term effects of the treatment with bevacizumab on fertility are unknown.

Laboratory abnormalities

Decreased neutrophil count, decreased white blood cell count and presence of urine protein may be associated with bevacizumab treatment.

Across clinical trials, the following Grade 3 and 4 (NCI-CTCAE v.3) laboratory abnormalities occurred in patients treated with bevacizumab with at least a 2% difference compared to the corresponding control groups: hyperglycaemia, decreased haemoglobin, hypokalaemia,

hyponatraemia, decreased white blood cell count, increased international normalise

Clinical trials have shown that transient increases in serum creatinine (ranging een 1.5–1.9 times baseline level), both with and without proteinuria, are associated with the use vacizumab. The observed increase in serum creatinine was not associated with a higher incidence of clinical manifestations of renal impairment in patients treated with bevaciz

Other special populations

Elderly

In randomised clinical trials, age > 65 years was associated with an increased risk of developing arterial thromboembolic reactions, including cerebrovascular accidents (CVAs), transient ischaemic attacks (TIAs) and myocardial infarctions (MIs). Other reactions with a higher frequency seen in patients over 65 were Grade 3–4 leucopenia and thrombocytopenia (NCI-CTCAE v.3); and all Grade neutropenia, diarrhoea, nausea, headache and fatigue as compared to those aged < 65 years when treated with bevacizumab (see sections 4.4 and 4.8 under Thromboembolism ). In one clinical trial, the incidence of hypertension of grade > 3 was two fold higher in patients aged > 65 years than in the younger age group (<65 years). In a study of platinum-resistant recurrent ovarian cancer patients, alopecia, mucosal inflammation, peripheral sensory neuropathy, proteinuria and hypertension were also reported and occurred at a rate at least 5% higher in the CT + BV arm for bevacizumab-treated patients > 65 years of age compared with bevacizumab-treated patients aged < 65 years.

No increase in the incidence of other reactions, including gastrointestinal perforation, wound healing complications, congestive heart failure, and haemorrhage was observed in elderly patients (> 65 years) receiving bevacizumab as compared to those aged < 65 years treated with bevacizumab.

n

fficacy of bevacizumab in children less than 18 years old have not been established.

O25041 of bevacizumab added to postoperative radiation therapy (RT) with concomitant and adjuvant temozolomide in paediatric patients with newly diagnosed supratentorial, infratentorial, cerebellar, or peduncular high-grade glioma, the safety profile was comparable with that observed in other tumour types in adults treated with bevacizumab.

In study BO20924 of bevacizumab with current standard of care in rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma, the safety profile of bevacizumab treated children was comparable with that observed in adults treated with bevacizumab.

Bevacizumab is not approved for use in patients under the age of 18 years. In published literature reports, cases of non-mandibular osteonecrosis have been observed in patients under the age of 18 years treated with bevacizumab.

Post-marketing experience

Table 3: Adverse reactions reported in post-marketing setting

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in

4.9 Overdose

The highest dose tested in humans (20 mg/kg bw, intravenous every 2 weeks) was associated with severe migraine in several patients.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

5.2  Pharmacokinetic properties

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

6.2 Incompatibilities

6.3 Shelf life

6.4 Special precautions for storage

6.6 Special precautions for disposal and other handling

Lextemy should be prepared by a healthcare professional using aseptic technique to ensure the sterility of the prepared solution. A sterile needle and syringe should be used to prepare Lextemy.

The necessary amount of bevacizumab should be withdrawn and diluted to the required administration volume with sodium chloride 9 mg/mL (0.9%) solution for injection. The concentration of the final bevacizumab solution should be kept within the range of 1.4 mg/mL to 16.5 mg/mL. In the majority of the occasions the necessary amount of Lextemy can be diluted with 0.9% sodium chloride solution for injection to a total volume of 100 mL.

Parenteral medicinal products should be inspected visually for particulate matter and discolouration prior to administration.

No incompatibilities between Lextemy and polyvinyl chloride or polyolefine bags or infusi have been observed.

Lextemy is for single-use only, as the product contains no preservatives.

Any unused medicinal product or waste material should be disposed in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Mylan IRE Healthcare Limited Unit 35/36 Grange Parade Baldoyle Industrial Estate Dublin, 13

Ireland

EU/1/20/1516/001

EU/1/20/1516/002

EU/1/20/1516/003

EU/1/20/1516/004

EU/1/20/1516/005

IRST AUTHORISATION/RE­NEWAL OF THE AUTHORISATION