Equidacent - summary of medicine characteristics

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each mL of concentrate contains 25 mg of bevacizumab*.

Each vial of 4 mL of concentrate contains 100 mg of bevacizumab.

Each vial of 16 mL of concentrate contains 400 mg of bevacizumab.

For dilution and other handling recommendations, see section 6.6.

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

Excipient(s) with known effect

Each vial of 4 mL of concentrate contains 191 mg sorbitol (E4

Each vial of 16 mL of concentrate contains 764 mg sorbitol (E

For the full list of excipients see section 6.1.

3. PHARMACEUTICAL FORM

Concentrate for solution for infusion.

Clear to opalescent, colourless to

4.1 Therapeutic indicationsBevacizum adult patien

bination with fluoropyrimidine-based chemotherapy is indicated for treatment of etastatic carcinoma of the colon or rectum.

b in combination with paclitaxel is indicated for first-line treatment of adult patients with ic breast cancer. For further information as to human epidermal growth factor receptor 2

Bevacizumab 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 Equidacent in combination with capecitabine. For further information as to HER2 status, please refer to section 5.1.

Bevacizumab, 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.

Bevacizumab, 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).

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

Bevacizumab, 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 IIIB, IIIC and IV) epithelial ovarian, fallopian tube, or primary peritoneal cancer (see section 5.1).

Bevacizumab, in combination with carboplatin and gemcitabine or in combination with carbopl and paclitaxel, is indicated for treatment of adult patients with first recurrence of platinum-s epithelial ovarian, fallopian tube or primary peritoneal cancer who have not received prio with bevacizumab or other VEGF inhibitors or VEGF receptor-targeted agents.

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

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4.2 Posology and method of administrationexperienced in the use of

Equidacent must be administered under the supervision of a p antineoplastic medicinal products.

Posology

Metastatic carcinoma of the colon or rectum (mC

The recommended dose of Equidacent, administered as an intravenous infusion, is either 5 mg/kg or 10 mg/kg of body weight given once every 2 weeks or 7.5 mg/kg or 15 mg/kg of body weight given once every 3 weeks.

It is recommended that treatme unacceptable toxicity.

of Equidacent is 10 mg/kg of body weight given once every 2 weeks or 15 iven 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

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

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

Clinical benefit in NSCLC patients has been demonstrated with both 7.5 mg/kg and 15 mg/kg 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 Equidacent 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 Equidacent when used in addition to erlotinib is 15 mg/kg of body weight given once every 3 weeks as an intravenous infusion.

It is recommended that the treatment with Equidacent in addition to erlotinib is continued progression.

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

Advanced and/or metastatic renal cell cancer (mRCC)

The recommended dose of Equidacent is 10 mg/kg of body weig intravenous infusion.

It is recommended that treatment be continued until progr unacceptable toxicity.

Epithelial ovarian,  fallopian tube and primary peritoneal cancer

Front-line treatment: Equidacent is administered in addition to carboplatin and paclitaxel for up to 6 cycles of treatment followed by continued use of Equidacent as single agent until disease progression or for a maximum of 15 months or until unacceptable toxicity, whichever occurs earlier.

t is 15 mg/kg of body weight given once every 3 weeks as an

recurrent disease: Equidacent is administered in combination with itabine for 6 cycles and up to 10 cycles or in combination with carboplatin es and up to 8 cycles, followed by continued use of Equidacent as single agent ion. The recommended dose of Equidacent is 15 mg/kg of body weight given s as an intravenous infusion.

cer

nt is administered in combination with one of the following chemotherapy regimens:

The recommended dose of Equidacent is 15 mg/kg of body weight 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 (see section 5.1).

Special populations

Elderly: No dose adjustment is required in the elderly.

Renal impairment : The safety and 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 less than 18 years old have not been esta Currently available data are described in sections 4.8, 5.1 and 5.2, but no recommendation on posology can be made.                                                   ­♦ &

There is no relevant use of bevacizumab in the paediatric population in the indicatio of cancers of the colon, rectum, breast, lung, ovarian, fallopian tube, peritoneu

Method of administration

Equidacent 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

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

4.3 Contraindicatio

y to the active substance or to any of the excipients listed in section 6.1.

y to Chinese Hamster Ovary (CHO) cell products or other recombinant human antibodies.

(see section 4.6).

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Gastrointestinal (GI) perforations and Fistulae (see section 4.8)

Patients may be at an increased risk for the development of gastrointestinal perforation and gall bladder perforation when treated with bevacizumab. Intra-abdominal inflammatory process may be a risk factor for gastrointestinal perforations in patients with metastatic carcinoma of the colon or rectum, therefore, caution should be exercised when treating these patients. Prior radiation is a risk factor for GI perforation in patients treated for persistent, recurrent or metastatic cervical cancer with Equidacent and all patients with GI perforation had a history of prior radiation. Therapy should be permanently discontinued in patients who develop gastrointestinal perforation.

Gl-vaginal Fistulae in study GOG-0240

Patients treated for persistent, recurrent, or metastatic cervical cancer with bevacizumab are at increased risk of fistulae between the vagina and any part of the GI tract (Gastrointestinal-vaginal fistulae). Prior radiation is a major risk factor for the development of GI-vaginal fistulae and all patients with 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 bevacizu Permanently discontinue Equidacent 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 Equidacent should be considered.

Wound healing complications (see section 4.8)

Bevacizumab may adversely affect the wound healing process. Seri including anastomotic complications, with a fatal outcome have

initiated for at least 28 days following major surgery or until patients who experienced wound healing complications duri until the wound is fully healed. Therapy should be wit

Necrotising fasciitis, including fatal cases, has ra

bevacizumab. This condition is usually secondary to wound healing complications, gastrointestinal rapy should be discontinued in patients who develop should be promptly initiated.

Hypertension (see section 4.8

nsion was observed in bevacizumab-treated patients. Clinical safety hypertension is likely to be dose-dependent. Pre-existing

hypertension should be adequately controlled before starting Equidacent treatment. There is no information on the effect of bevacizumab in patients with uncontrolled hypertension at the time of initiating therapy. Monitoring of blood pressure is generally recommended during therapy.

In most cases hypertension was controlled adequately using standard antihypertensive treatment or the individual situation of the affected patient. The use of diuretics to manage is not advised in patients who receive a cisplatin-based chemotherapy regimen.

Equidacent 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 Equidacent. 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 Institute-Common Terminology 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 cerebrov 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 Equidacent.

Therapy should be permanently discontinued in patients who reactions.

Venous thromboembolism (see section 4.8)

Patients treated for persistent, recurr r metastatic cervical cancer with bevacizumab in combination with paclitaxel and cis may be at increased risk of venous thromboembolic events.

Equidacent should be discontinue 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).

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

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 Equidacent 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 such patients were excluded from clinical trials. Therefore, caution should be exercised before initiating therapy in these patients. 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 Equidacent, 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 asymptomatic declines in left ventricular ejection fraction to symptomatic CHF hospitalisation. Caution should be exercised when treating patients with clinic cardiovascular disease such as pre-existing coronary artery disease, or congest bevacizumab.

Most of the patients who experienced CHF had metastatic breas treatment with anthracyclines, prior radiotherapy to the left c were present.

In patients in AVF3694g who received treatment with 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.

Osteonecrosis of the jaw (ONJ) (see section 4.8)

Cases of ONJ have been reported in cancer patients treated with bevacizumab, the majority of whom had received prior or concomitant treatment with intravenous bisphosphonates, for which ONJ is an identified risk. Caution should be exercised when bevacizumab and intravenous bisphosphonates are administered simultaneously or sequentially.

Invasive dental procedures are also an identified risk factor. A dental examination and appropriate preventive dentistry should be considered prior to starting the treatment with Equidacent. In patients who have previously received or are receiving intravenous bisphosphonates invasive dental procedures should be avoided, if possible.

Intravitreal use

Equidacent is not formulated for intravitreal use.

Eye disorders

Effect of antineoplastic agents on bevacizumab pharmacokinetics

evant 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 coadministered interferon alfa 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 sev 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 bevacizumal

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 lact

Women of childbearing potenti

l have to use effective contraception during (and up to 6 months after)

Pregnancy

al trial data on the use of bevacizumab in pregnant women. Studies in animals have e toxicity including malformations (see section 5.3). IgGs are known to cross the

bevacizumab is anticipated to inhibit angiogenesis in the foetus, and thus is suspected to c ious 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). Equidacent 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 colon cancer, a substudy with premenopausal women has shown a higher incidence of new cases of ovarian failure in the bevacizumab group compared to the control group. After discontinuation of bevacizumab treatment, ovarian function recovered in the majority of patients. Long term effects of the treatment with bevacizumab on fertility are unknown.

4.7 Effects on ability to drive and use machines

Bevacizumab has no or negligible influence on the ability to drive and use machines. However, somnolence and syncope have been reported with bevacizumab use (see table 1 in section 4.8). patients are experiencing symptoms that affect their vision or concentration, or their ability to r 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 were:

• • Gastrointestinal perforations (see section 4.4).
• • Haemorrhage, including pulmonary haemorrhage/haem

small cell lung cancer patients (see section 4.4).

• • Arterial thromboembolism (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.

ggest that the occurrence of hypertension and proteinuria with dose-dependent.

Tabulated list of adverse reactions ted in this section fall into the following frequency categories: Very common > 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < (< 1/10,000); not known (cannot be estimated from the available data).

Tables 1 and 2 list adverse reactions associated with the use of bevacizumab in combination with

hemotherapy regimens in multiple indications.

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.

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.

Within each frequency category, adverse reactions are presented in the order of decreasing seriousness.

( 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.

For further information please refer to table 3 “Adverse reactions reported in post-marketi setting”.

Terms represent a group of events that describe a medical concept rather than a single or MedDRA (Medical Dictionary for Regulatory Activities) preferred term. This grou 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).

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

For additional information refer below within section „Description of selected serious adverse reactions“.

Recto-vaginal fistulae are the most common fistulae in t Observed in paediatric population only.

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 post-marketing setting, therefore, the frequency and NCI-CTCAE grade is not known. Thes clinically significant reactions have therefore been included in table 2 within the column entitle “Frequency not known”.

Terms represent a group of events that describe a medical concept rather than a s or MedDRA (Medical Dictionary for Regulatory Activities) preferred term. medical terms may involve the same underlying pathophysiology (e.g. a reactions include cerebrovascular accident, myocardial infarction, transi

and other arterial thromboembolic reactions).

For additional information refer below within section „Description of selected serious adverse reactions“.

Bevacizumab has been associated with serious cases of gastrointestinal perforation.

Gastrointestinal perforations have been rted in clinical trials with an incidence of 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     in patients with persistent, recurrent, or metastatic cervical cancer (study

GOG- 0240), GI perfo     s (all grade) were reported in 3.2% of patients, all of whom had a history

of prior pelvic ra

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 e. In some cases underlying intra-abdominal inflammation was present, either from disease, tumour necrosis, diverticulitis, or chemotherapy-associated colitis.

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

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.

GI-vaginal Fistulae in study GOG-0240

In a trial of patients with persistent, recurrent or metastatic cervical cancer, the incidence of GI-vaginal fistulae was 8.3% in bevacizumab-treated patients and 0.9% in control patients, all of whom had a history of prior pelvic radiation. The frequency of GI-vaginal fistulae in the group treated with bevacizumab + chemotherapy was higher in patients with recurrence within the field of prior radiation (16.7%) compared with patients with no prior radiation and/or no recurrence inside the field of prior radiation (3.6%). The corresponding frequencies in the control group receiving chemotherapy alone were 1.1% vs. 0.8%, respectively. Patients who develop GI-vaginal fistulae may also have bowel obstructions and require surgical intervention as well as diverting ostomies.

Non-GIFistulae (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 nongastrointestinal vaginal, vesical, or female genital tract fistulae.

Uncommon (> 0.1% to < 1%) reports of fistulae that involve areas of the body other than th 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 than 1 year from initiation of bevacizumab, with most reactions occurrin therapy.

Wound healing (see section 4.4)

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

In clinical trials of metastatic carcinoma of the colon or rectum, there was no increased risk of postoperative bleeding or wound healing complications observed in patients who underwent major surgery 28–60 days prior to starting bevacizumab. An increased incidence of post-operative bleeding or wound healing complication occurring within 60 days of major surgery was observed if the patient was being treated with bevacizumab e time of surgery. The incidence varied between 10% (4/40) and 20% (3/15).

, including anastomotic complications, have been reported, some

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 compared with up to 0.9% of patients in the control arms (NCI-CTCAE v.3).

of ovarian cancer, grade 3–5 wound healing complications were observed in up to ents 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 chemotherapy alone.

In study JO25567, all grade hypertension was observed in 77.3% of the patients who received bevacizumab in combination with erlotinib as first-line treatment for non-squamous NSCLC with EGFR activating mutations, compared to 14.3% of patients treated with erlotinib alone. Grade 3 hypertension was 60.0% in patients treated with bevacizumab in combination with erlotinib compared to 11.7% in patients treated with erlotinib alone. There were no grade 4 or 5 hypertension events.

Hypertension was generally adequately controlled with oral anti-hypertensives such as angiotensincon­verting 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 sympt consistent with PRES, a rare neurological disorder. Presentation may include seizures, altered mental status, visual disturbance, or cortical blindness, with or without associa hypertension. The clinical presentation of PRES is often nonspecific, and there PRES requires confirmation by brain imaging, preferably MRI.

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)

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). Grade 3 proteinuria was reported in up to 10.9% of treated patients. Grade 4 proteinuria (nephrotic syndrome) was seen in up to 1.4% of treated patients. Testing for proteinuria is recommended prior to start of Equidacent therapy. In most clinical trials urine protein levels of > 2g/24 hrs led to stopping treatment with bevacizumab until recovery to < 2g/24 hrs.

In clinical trials across all indications the overall incidence of NCI-CTCAE v.3 grade 3–5 bleeding reactions ranged from 0.4% to 6.9% in bevacizumab-treated patients, compared with up to 4.5% of 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 paclitaxel and topotecan compared with up to 4.6% of patients 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).

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

mibolism (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% of patients treated with bevacizumab in combination with chemotherapy compared to up to 0.7% of patients treated with chemotherapy alone.

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

Venous thromboembolism: 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 reaction from 2.8% to 17.3% of bevacizumab-treated patients compared with 3.2% to 15.6% in the co 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 cancer indications studied to date, but occurred predominantly in patients with metastatic breast cancer. In

00, BO17708 and AVF3694g) in patients with metastatic breast cancer CHF grade 3 (NCI-CTCAE v.3) or higher was reported in up to 3.5% of patients treated with

with chemotherapy compared with up to 0.9% in the control arms. For who received anthracyclines concomitantly with bevacizumab, the

higher CHF for the respective bevacizumab and control arms were similar to

those in the other studies in metastatic breast cancer: 2.9% in the anthracycline + 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 + bevacizumab (6.2%) and the anthracycline +

Most patients who developed CHF during mBC trials showed improved symptoms and/or left ventricular function following appropriate medical therapy.

In most clinical trials of bevacizumab, patients with pre-existing CHF of NYHA (New York Heart Association) II-IV were excluded, therefore, no information is available on the risk of CHF in this population.

Prior anthracyclines exposure and/or prior radiation to the chest wall may be possible risk factors for 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 tr the incidence of new cases of ovarian failure, defined as ame level > 30 mIU/mL and a negative serum P-HCG pregna

premenopausal women. New cases of ovarian failure        orted in 2.6% patients in the

mFOLFOX-6 group compared to 39% in the mFOLF + 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, decreas associated with Equidacent treatmen

Ing 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 normalised ratio (INR).

s have shown that transient increases in serum creatinine (ranging between 1.5–1.9 times l), both with and without proteinuria, are associated with the use of bevacizumab. The rease in serum creatinine was not associated with a higher incidence of clinical

tions of renal impairment in patients treated with bevacizumab.

Other special populations

Elderly patients

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.

Paediatric population

The safety and efficacy of bevacizumab in children less than 18 years old have not been established.

In study BO25041 of bevacizumab added to post-operative radiation therapy (RT) with co and adjuvant temozolomide in paediatric patients with newly diagnosed supratentorial, i cerebellar, or peduncular high-grade glioma, the safety profile was comparable with tha other tumour types in adults treated with bevacizumab.

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

Equidacent is not approved for use in patients under the age of 18 reports, cases of non-mandibular osteonecrosis have been obse years treated with bevacizumab.

Post-marketing experience

Table 3. Adverse reactions reported in post-marketing setting

If specified, the frequency has been derived from clinical trial data.

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 Appendix V.

4.9 Overdose

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

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

15 mg/kg q 3 weeks

Patients were randomised to platinum-based chemotherapy, cisplatin 80 mg/m2 intravenous infusion on day 1 and gemcitabine 1,250 mg/m2 intravenous infusion on days 1 and 8 of every 3-week cycle for up to 6 cycles (CG) with placebo or CG with bevacizumab at a dose of 7.5 or 15 mg/kg IV infusion day 1 of every 3-week cycle. In the bevacizumab-containing arms, patients could receive bevacizumab as a single agent every 3 weeks until disease progression or unacceptable toxicity. Trial results show that 94% (277 / 296) of eligible patients went on to receive single agent bevacizumab at cycle 7. A high proportion of patients (approximately 62%) went on to receive a variety of nonprotocol specified anti-cancer therapies, which may have impacted the analysis of overall survival.

The efficacy results are presented in table 13.

Table 13. Efficacy results for trial BO17704

patients with measurable disease at baseline

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

JO25567

Study JO25567 was a randomised, open-label, multi-centre phase II study conducted in Japan to evaluate the efficacy and safety of bevacizumab used in addition to erlotinib in patients with non-squamous NSCLC with EGFR activating mutations (exon 19 deletion or exon 21 L858R mutation) who had not received prior systemic therapy for stage IIIB/IV or recurrent disease.

The primary endpoint was progression-free survival (PFS) based on independent review assessment. Secondary endpoints included overall survival, response rate, disease control rate, duration of response, and safety.

EGFR mutation status was determined for each patient prior to patient screening and 154 patients were randomised to receive either erlotinib + bevacizumab (erlotinib 150 mg oral daily + bevacizumab [15 mg/kg IV every 3 weeks]) or erlotinib monotherapy (150 mg oral daily) until disease progression (PD) or unacceptable toxicity. In the absence of PD, discontinuation of one component of study treatment in the erlotinib + bevacizumab arm did not lead to discontinuation of the other component of study treatment as specified in the study protocol.

The efficacy results of the study are presented in table 14.

Table 14. Efficacy results for study JO25567

# A total of 154 patients (ECOG Performance Status 0 or 1) were randomised. However two of

the randomised patients discontinued the study before receiving any study treatment.

ABlinded independent review (protocol-defined primary analysis).

* Exploratory analysis: final OS analysis at clinical cut off on 31 October 2017, approx. 59% of patients had died.

CI, confidence interval; HR, Hazard ratio from unstratified Cox regression analysis; NR, not reached.

Advanced and/or metastatic renal cell cancer (mRCC)

Bevacizumab in combination with interferon alfa-2a for the first-line treatment of advanced and/ or metastatic renal cell cancer (BO17705)

This was a phase III randomised double-blind trial conducted to evaluate the efficacy and safety of bevacizumab in combination with interferon (IFN) alfa-2a versus IFN alfa-2a alone as first-line treatment in mRCC. The 649 randomised patients (641 treated) had Karnofsky Performance Status (KPS) of > 70%, no CNS metastases and adequate organ function. Patients were nephrectomised for primary renal cell carcinoma. Bevacizumab 10 mg/kg was given every 2 weeks until disease progression. IFN alfa-2a was given up to 52 weeks or until disease progression at a recommended starting dose of 9 MIU three times a week, allowing a dose reduction to 3 MIU three times a week in 2 steps. Patients were stratified according to country and Motzer score and the treatment arms were shown to be well balanced for the prognostic factors.

The primary endpoint was overall survival, with secondary endpoints for the trial including progression-free survival. The addition of bevacizumab to IFN alfa-2a significantly increased PFS and objective tumour response rate. These results have been confirmed through an independent radiological review. However, the increase in the primary endpoint of overall survival by 2 months was not significant (HR = 0.91). A high proportion of patients (approximately 63% IFN/placebo; 55% bevacizumab/IFN) received a variety of non-specified post-trial anti-cancer therapies, including antineoplastic agents, which may have impacted the analysis of overall survival.

The efficacy results are presented in table 15.

Table 15. Efficacy results for trial BO17705

Interferon alfa-2a 9 MIU 3×/week.

b

Bevacizumab 10 mg/kg q 2 wk.

An exploratory multivariate Cox regression model using backward selection indicated that the following baseline prognostic factors were strongly associated with survival independent of treatment: gender, white blood cell count, platelets, body weight loss in the 6 months prior to trial entry, number of metastatic sites, sum of longest diameter of target lesions, Motzer score. Adjustment for these baseline factors resulted in a treatment hazard ratio of 0.78 (95% CI [0.63; 0.96], p = 0.0219), indicating a 22% reduction in the risk of death for patients in the bevacizumab + IFN alfa-2a arm compared to IFN alfa-2a arm.

Ninety-seven (97) patients in the IFN alfa-2a arm and 131 patients in the bevacizumab arm reduced the dose of IFN alfa-2a from 9 MIU to either 6 or 3 MIU three times a week as pre-specified in the protocol. Dose reduction of IFN alfa-2a did not appear to affect the efficacy of the combination of bevacizumab and IFN alfa-2a based on PFS event free rates over time, as shown by a subgroup analysis. The 131 patients in the bevacizumab + IFN alfa-2a arm who reduced and maintained the IFN alfa-2a dose at 6 or 3 MIU during the trial, exhibited at 6, 12 and 18 months PFS event free rates of 73, 52 and 21% respectively, as compared to 61, 43 and 17% in the total population of patients receiving bevacizumab + IFN alfa-2a.

AVF2938

This was a randomised, double-blind, phase II clinical trial investigating bevacizumab 10 mg/kg in a 2 weekly schedule with the same dose of bevacizumab in combination with 150 mg daily erlotinib, in patients with metastatic clear cell RCC. A total of 104 patients were randomised to treatment in this trial, 53 to bevacizumab 10 mg/kg every 2 weeks plus placebo and 51 to bevacizumab 10 mg/kg every 2 weeks plus erlotinib 150 mg daily. The analysis of the primary endpoint showed no difference between the bevacizumab + placebo arm and the bevacizumab + erlotinib arm (median PFS 8.5 versus 9.9 months). Seven patients in each arm had an objective response. The addition of erlotinib to bevacizumab did not result in an improvement in OS (HR = 1.764; p = 0.1789), duration of objective response (6.7 vs. 9.1 months) or time to symptom progression (HR = 1.172; p = 0.5076).

AVF0890

This was a randomised phase II trial conducted to compare the efficacy and safety of bevacizumab versus placebo. A total of 116 patients were randomised to receive bevacizumab 3 mg/kg every 2 weeks (n = 39), 10 mg/kg every 2 weeks; (n = 37), or placebo (n = 40). An interim analysis showed there was a significant prolongation of the time to progression of disease in the 10 mg/kg group as compared with the placebo group (hazard ratio, 2.55; p < 0.001). There was a small difference, of borderline significance, between the time to progression of disease in the 3 mg/kg group and that in the placebo group (hazard ratio, 1.26; p = 0.053). Four patients had objective (partial) response, and all of these had received the 10 mg/kg dose bevacizumab; the ORR for the 10 mg/kg dose was 10%.

Epithelial ovarian, fallopian tube and primary peritoneal cancer

Front-line treatment of ovarian cancer

The safety and efficacy of bevacizumab in the front-line treatment of patients with epithelial ovarian, fallopian tube or primary peritoneal cancer were studied in two phase III trials (GOG-0218 and BO17707) that evaluated the effect of the addition of bevacizumab to carboplatin and paclitaxel compared to the chemotherapy regimen alone.

GOG-0218

The GOG-0218 study was a phase III multicentre, randomised, double-blind, placebo-controlled, three arm study evaluating the effect of adding bevacizumab to an approved chemotherapy regimen (carboplatin and paclitaxel) in patients with advanced (stages IIIB, IIIC and IV according to FIGO staging version dated 1988) epithelial ovarian, fallopian tube or primary peritoneal cancer.

Patients who had received prior therapy with bevacizumab or prior systemic anti-cancer therapy for ovarian cancer (e.g. chemotherapy, monoclonal antibody therapy, tyrosine kinase inhibitor therapy, or hormonal therapy) or previous radiotherapy to the abdomen or pelvis were excluded from the study.

A total of 1,873 patients were randomised in equal proportions to the following three arms:

CPP arm: Five cycles of placebo (started cycle 2) in combination with carboplatin (AUC 6) and

paclitaxel (175 mg/m2) for 6 cycles followed by placebo alone, for a total of up to 15 months of therapy

• • CPB15 arm: Five cycles of bevacizumab (15 mg/kg q3w started cycle 2) in combination with carboplatin (AUC 6) and paclitaxel (175 mg/m2) for 6 cycles followed by placebo alone, for a total of up to 15 months of therapy
• • CPB15+ arm: Five cycles of bevacizumab (15 mg/kg q3w started cycle 2) in combination with carboplatin (AUC 6) and paclitaxel (175 mg/m2) for 6 cycles followed by continued use of bevacizumab (15 mg/kg q3w) as single agent for a total of up to 15 months of therapy.

The majority of patients included in the study were white (87% in all three arms); the median age was 60 years in CPP and CPB15 arms and 59 years in CPB15+ arm; and 29% of patients in CPP or CPB15 and 26% in CPB15+ were over 65 years of age. Overall approximately 50% of patients had a GOG PS of 0 at baseline, 43% a GOG PS score of 1, and 7% a GOG PS score of 2. Most patients had EOC (82% in CPP and CPB15, 85% in CPB15+) followed by PPC (16% in CPP, 15% in CPB15, 13% in CPB15+) and FTC (1% in CPP, 3% in CPB15, 2% in CPB15+). The majority of patients had serous adenocarcinoma histologic type (85% in CPP and CPB15, 86% in CPB15+). Overall approximately 34% of patients were FIGO stage III optimally debulked with gross residual disease, 40% stage III suboptimally debulked, and 26% were stage IV patients.

The primary endpoint was PFS based on investigator’s as­sessment of disease progression based on radiological scans or CA-125 levels, or symptomatic deterioration per protocol. In addition, a prespecified analysis of the data censoring for CA-125 progression events was conducted, as well as an independent review of PFS as determined by radiological scans.

The trial met its primary objective of PFS improvement. Compared to patients treated with chemotherapy (carboplatin and paclitaxel) alone in the front-line setting, patients who received bevacizumab at a dose of 15 mg/kg q3w in combination with chemotherapy and continued to receive bevacizumab alone (CPB15+), had a clinically meaningful and statistically significant improvement in PFS.

In patients who only received bevacizumab in combination with chemotherapy and did not continue to receive bevacizumab alone (CPB15), no clinically meaningful benefit in PFS was observed.

The results of this study are summarised in table 16.

Table 16. Efficacy results from study GOG-0218

Investigator assessed GOG protocol-specified PFS analysis (neither censored for CA-125 progressions nor censored for NPT prior to disease progression) with data cut-off date of 25 February, 2010.

Relative to the control arm; stratified hazard ratio.

One-sided log-rank p-value.

Subject to a p-value boundary of 0.0116.

Patients with measurable disease at baseline.

Final overall survival analysis performed when 46.9% of the patients had died.

Pre-specified PFS analyses were conducted, all with a cut-off date of 29 Sept of these pre-specified analyses are as follows:

The protocol-specified analysis of investigator assessed PFS ( progression or non-protocol therapy [NPT]) shows a stratifi 0.61–0.83, 1-sided log-rank p-value < 0.0001) when CPB

median PFS of 10.4 months in the CPP arm and 14.1 The primary analysis of investigator assessed PF NPT) shows a stratified hazard ratio of 0.62 (95

< 0.0001) when CPB15+ is compared with CPP, with a median PFS of 12.0 months in the CPP arm and 18.2 months in the CPB15+ arm.

• • The analysis of PFS as determined by the independent review committee (censoring for NPT) shows a stratified hazard ratio of 0.62 (95% CI: 0.50–0.77, 1-sided log-rank p-value < 0.0001) when CPB15+ is compared with CPP, with a median PFS of 13.1 in the CPP arm and 19.1 months in the CPB15+ arm.

PFS subgroup analyses by disease stage and debulking status are summarised in table 17. These results demonstrate robustness of the analysis of PFS as shown in table 16.

Table 17. PFS1 results by disease stage and debulking status from study GOG-0218

_____________­_______________|________­___________________|       (0.70, 1.16)       |      (0.49, 0.82)

Investigator assessed GOG protocol-specified PFS analysis (neither censored for CA-125 progressions nor censored for NPT prior to disease progression) with data cut-off date of 25 February, 2010.

With gross residual disease.

3.7% of the overall randomised patient population had stage IIIB disease.

Relative to the control arm.

BO17707 (ICON7)

BO17707 was a phase III, two-arm, multicentre, randomised, controlled, open-label study comparing the effect of adding bevacizumab to carboplatin plus paclitaxel in patients with FIGO stage I or IIA (grade 3 or clear cell histology only; n = 142), or FIGO stage IIB-IV (all grades and all histological types, n = 1,386) epithelial ovarian, fallopian tube or primary peritoneal cancer following surgery (NCI-CTCAE v.3). FIGO staging version dated 1988 was used in this trial.

Patients who had received prior therapy with bevacizumab or prior systemic anti-cancer therapy for ovarian cancer (e.g. chemotherapy, monoclonal antibody therapy, tyrosine kinase inhibitor therapy, or hormonal therapy) or previous radiotherapy to the abdomen or pelvis were excluded from the study.

A total of 1,528 patients were randomised in equal proportions to the following two arms:

s of this study are summarised in table 18.

Table 18. Efficacy results from study BO17707 (ICON7)

In patients with measurable disease at baseline.

Investigator assessed PFS analysis with data cut-off date of 30 November 2010.

Final overall survival analysis performed when 46.7% of the patients had died with data cut-off date of 31 March 2013.

The primary analysis of investigator assessed PFS with a data cut-off date of 28 February 2010 shows an unstratified hazard ratio of 0.79 (95% CI: 0.68–0.91, 2-sided log-rank p-value 0.0010) with a median PFS of 16.0 months in the CP arm and 18.3 months in the CPB7.5+ arm.

PFS subgroup analyses by disease stage and debulking status are summarised i results demonstrate robustness of the primary analysis of PFS as shown in tabl

Table 19. PFS1 results by disease stage and debulking status from study BO17707 (ICON7)

1 Investigator assessed PFS analysis with data cut-off date of 30 November 2010.

2 With or without gross residual disease.

3 % of the overall randomised patient population had stage IIIB disease.

4 ative to the control arm.

Recurrent ovarian cancer

The safety and efficacy of bevacizumab in the treatment of recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer was studied in phase III trials (AVF4095g and GOG-0213) with different patient populations and chemotherapy regimens.

AVF4095g evaluated the efficacy and safety of bevacizumab in combination with carboplatin and gemcitabine followed by bevacizumab as a single agent in patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer.

GOG-0213 evaluated the efficacy and safety of bevacizumab in combination with carboplatin and paclitaxel, followed by bevacizumab as a single agent in patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer.

AVF4095g

The safety and efficacy of bevacizumab in the treatment of patients with platinum-sensitive, recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who have not received prior chemotherapy in the recurrent setting or prior bevacizumab treatment, was studied in a phase III randomised, double-blind, placebo-controlled trial (AVF4095g). The study compared the effect of adding bevacizumab to carboplatin and gemcitabine chemotherapy and continuing bevacizumab as a single agent to progression, to carboplatin and gemcitabine alone.

Only patients with histologically documented ovarian, primary peritoneal, or fallopian tube carcinoma that had recurred > 6 months after platinum-based chemotherapy and who had not received chemotherapy in the recurrent setting and who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor-targeted agents were included in the study.

A total of 484 patients with measurable disease were randomised 1:1 to either:

• • Carboplatin (AUC 4, day 1) and gemcitabine (1,000 mg/m2 on days 1 and 8) and concurrent placebo every 3 weeks for 6 and up to 10 cycles followed by placebo (every 3 weeks) alone until disease progression or unacceptable toxicity.
• • Carboplatin (AUC 4, day 1) and gemcitabine (1,000 mg/m2 on days 1 and 8) and concurrent bevacizumab (15 mg/kg day 1) every 3 weeks for 6 and up to 10 cycles followed by bevacizumab (15 mg/kg every 3 weeks) alone until disease progression or unacceptable toxicity.

The primary endpoint was progression-free survival based on investigator assessment using modified RECIST 1.0. Additional endpoints included objective response, duration of response, overall survival and safety. An independent review of the primary endpoint was also conducted.

The results of this study are summarised in table 20.

Table 20. Efficacy results from study AVF4095g

PFS subgroup analyses depending on recurrence since last platinum therapy are summarised in table 21.

Table 21. Progression-free survival by time from last platinum therapy to recurren

GOG-0213

GOG-0213, a phase III randomised controlled open label trial, studied the safety and efficacy of bevacizumab in the treatment of patients with platinum-sensitive, recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who have not received prior chemotherapy in the recurrent setting. There was no exclusion criterion for prior anti-angiogenic therapy. The study evaluated the effect of adding bevacizumab to carboplatin+pa­clitaxel and continuing bevacizumab as a single agent until disease progression or unacceptable toxicity compared to carboplatin+pa­clitaxel alone.

A total of 673 patients were randomised in equal proportions to the following two treatment arms:

• • CP arm: Carboplatin (AUC5) and paclitaxel (175 mg/m2 IV) every 3 weeks for 6 and up to 8 cycles.
• • CPB arm: Carboplatin (AUC5) and paclitaxel (175 mg/m2 IV) and concurrent bevacizumab (15 mg/kg) every 3 weeks for 6 and up to 8 cycles, followed by bevacizumab (15 mg/kg every 3 weeks) alone until disease progression or unacceptable toxicity.

J

nts in both the CP arm (80.4%) and the CPB arm (78.9%) were white. The median age was in the CP arm and 59.0 years in the CPB arm. The majority of patients (CP: 64.6%; CPB: 68.8%) were in the age category < 65 years. At baseline, most patients in both treatment arms had a

GOG PS of 0 (CP: 82.4%: CPB; 80.7%) or 1 (CP: 16.7%: CPB; 18.1%). A GOG PS of 2 at baseline was reported in 0.9% of patients in the CP arm and in 1.2% of patients in the CPB arm.

The primary efficacy endpoint was overall survival (OS). The main secondary efficacy endpoint was progression-free survival (PFS). Results are presented in table 22.

Table 22. Efficacy results1,2 from study GOG-0213

1 Final analysis

2 Tumour assessments and response evaluations were determined by the investigators using the GOG RECIST criteria (Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228Y247).

a Hazard ratio was estimated from Cox proportional hazards models stratified by the duration of platinum free-interval prior to enrolling onto this study per eCRF (electronic case report form) and secondary surgical debulking status Yes/No (Yes = randomised to undergo cytoreduction or randomised to not undergo cytoreduction; No = not a candidate or did not consent to cytoreduction).

b stratified by the duration of treatment free-interval prior to enrolling onto this study per the registration form, and secondary surgical debulking status Yes/No.

The trial met its primary objective of OS improvement. Treatment with bevacizumab at 15 mg/kg every 3 weeks in combination with chemotherapy (carboplatin and paclitaxel) for 6 and up to 8 cycles, followed by bevacizumab until disease progression or unacceptable toxicity resulted, when data were derived from eCRF, in a clinically meaningful and statistically significant improvement in OS compared to treatment with carboplatin and paclitaxel alone.

< O

Cervical cancer

GOG-0240

The efficacy and safety of bevacizumab in combination with chemotherapy (paclitaxel and cisplatin or paclitaxel and topotecan) in the treatment for patients with persistent, recurrent or metastatic carcinoma of the cervix was evaluated in study GOG-0240, a randomised, four-arm, open label, multi-centre phase III trial.

A total of 452 patients were randomised to receive either:

Paclitaxel 135 mg/m2 IV over 24 hours on day 1 and cisplatin 50 mg/m2 IV on day 2, every 3 weeks (q3w); or

Paclitaxel 175 mg/m2 IV over 3 hours on day 1 and cisplatin 50 mg/m2 IV on day 2 (q3w); or

Paclitaxel 175 mg/m2 IV over 3 hours on day 1 and cisplatin 50 mg/m2 IV on day 1 (q3w)

Paclitaxel 135 mg/m2 IV over 24 hours on day 1 and cisplatin 50 mg/m2 IV on day 2 plus bevacizumab 15 mg/kg IV on day 2 (q3w); or

Paclitaxel 175 mg/m2 IV over 3 hours on day 1 and cisplatin 50 mg/m2 IV on day 2 plus bevacizumab 15 mg/kg IV on day 2 (q3w); or

Paclitaxel 175 mg/m2 IV over 3 hours on day 1 and cisplatin 50 mg/m2 IV on day 1 plus bevacizumab 15 mg/kg IV on day 1 (q3w)

Paclitaxel 175 mg/m2 IV over 3 hours on day 1 and topotecan 0.75 mg/m2 IV over 30 minutes on days 1–3 (q3w)

Paclitaxel 175 mg/m2 IV over 3 hours on day 1 and topotecan 0.75 mg/m2 IV over 30 minutes on days 1–3 plus bevacizumab 15 mg/kg IV on day 1 (q3w)

Eligible patients had persistent, recurrent or metastatic squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix which was not amenable to curative treatment with surgery and/or radiation therapy and who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor-targeted agents.

The median age was 46.0 years (range: 20–83) in the chemo alone group and 48.0 years (range: 22–85) in the chemo + bevacizumab group; with 9.3% of patients in the chemo alone group and 7.5% of patients in the chemo + bevacizumab group over the age of 65 years.

Of the 452 patients randomised at baseline, the majority of patients were white (80.0% in the chemo alone group and 75.3% in the chemo + bevacizumab group), had squamous cell carcinoma (67.1% in the chemo alone group and 69.6% in the chemo + bevacizumab group), had persistent/re­current disease (83.6% in the chemo alone group and 82.8% in the chemo + bevacizumab group), had 1–2 metastatic sites (72.0% in the chemo alone group and 76.2% in the chemo + bevacizumab group), had lymph node involvement (50.2% in the chemo alone group and 56.4% in the chemo + bevacizumab group), and had a platinum free interval > 6 months (72.5% in the chemo alone group and 64.4% in the chemo + bevacizumab group).

The primary efficacy endpoint was overall survival. Secondary efficacy endpoints included progression-free survival and objective response rate. Results from the primary analysis and the follow-up analysis are presented by bevacizumab treatment and by trial treatment in table 23 and 24, respectively.

Table 23. Efficacy results from stu

-0240 by bevacizumab treatment

Kaplan-Meier estimates.

Patients and percentage of patients with best overall response of confirmed CR or PR;

percentage calculated on patients with measurable disease at baseline.

95% CI for one sample binomial using Pearson-Clopper method.

Approximate 95% CI for difference of two rates using Hauck-Anderson method.

log-rank test (stratified).

Primary analysis was performed with a data cut-off date of 12 December 2012 and is considered the final analysis.

Follow-up analysis was performed with a data cut-off date of 07 March 2014.

p-value displayed for descriptive purpose only.

Paediatric population

ency has waived the obligation to submit the results of studies, in all ulation, in breast carcinoma, adenocarcinoma of the colon and rectum, and non-small cell carcinoma), kidney and renal pelvis carcinoma

toma, nephroblastoma­tosis, clear cell sarcoma, mesoblastic nephroma, renal

medullary carcinoma and rhabdoid tumour of the kidney), ovarian carcinoma (excluding  rhabdomyosarcoma and germ cell tumours), fallopian tube carcinoma (excluding rhabdomyosarcoma and germ cell tumours), peritoneal carcinoma (excluding blastomas and sarcomas) and cervix and corpus uteri carcinoma.

High-grade glioma

Anti-tumour activity was not observed in two earlier studies among a total of 30 children aged > 3 years old with relapsed or progressive high-grade glioma when treated with bevacizumab and irinotecan (CPT 11). There is insufficient information to determine the safety and efficacy of bevacizumab in children with newly diagnosed high-grade glioma.

• • In a single-arm study (PBTC-022), 18 children with recurrent or progressive non-pontine high-grade glioma (including 8 with glioblastoma [WHO grade IV], 9 with anaplastic astrocytoma [grade III] and 1 with anaplastic oligodendroglioma [grade III]) were treated with bevacizumab (10 mg/kg) two weeks apart and then with bevacizumab in combination with CPT-11 (125–350 mg/m2) once every two weeks until progression. There were no objective (partial or complete) radiological responses (MacDonald criteria). Toxicity and adverse reactions included arterial hypertension and fatigue as well as CNS ischaemia with acute neurological deficit.
• • In a retrospective single institution series, 12 consecutive (2005 to 2008) children with relapsed or progressive high-grade glioma (3 with WHO grade IV, 9 with grade III) were treated with bevacizumab (10 mg/kg) and irinotecan (125 mg/m2) every 2 weeks. There were no complete responses and 2 partial responses (MacDonald criteria).

In a randomised phase II study (BO25041) a total of 121 patients aged > 3 years to < 18 years with newly diagnosed supratentorial or infratentorial cerebellar or peduncular high-grade glioma (HGG) were treated with post-operative radiation therapy (RT) and adjuvant temozolomide (T) with and without bevacizumab: 10 mg/kg every 2 weeks IV.

The study did not meet its primary endpoint of demonstrating a significant improvement survival (EFS) (Central Radiology Review Committee (CRRC)-assessed) when bevacizumab was added to the RT/T arm compared with RT/T alone (HR = 1.44; 95% CI: 0.90, 2.30). These results were consistent with those from various sensitivity analyses and in clinically relevant subgroups. The results for all secondary endpoints (investigator assessed EFS, and ORR and OS) were consistent in showing no improvement associated with the addition of bevacizumab to the RT/T arm compared with the RT/T arm alone.

Addition of bevacizumab to RT/T did not demonstrate clinical be evaluable children patients with newly diagnosed supratentorial o peduncular high-grade glioma (HGG) (see section 4.2 for informa

Soft tissue sarcoma

In a randomised phase II study (BO20924) a total of 154 patients aged > 6 months to < 18 years with newly diagnosed metastatic rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma were treated with standard of care (Induction IVADO/IVA+/- local therapy followed by maintenance

vinorelbine and cyclophosphamide) with or without bevacizumab (2.5 mg/kg/week) for a total duration of treatment of approximately 18 months. At the time of the final primary analysis, the primary endpoint of EFS by independent central review did not show a statistically significant difference between the two treatment arms, with HR of 0.93 (95% CI: 0.61, 1.41; p-value = 0.72). The difference in ORR per independent central review was 18% (CI: 0.6%, 35.3%) between the two treatment arms in the few patients who had evaluable tumour at baseline and had a confirmed response prior to receiving any local therapy: 27/75 patients (36.0%, 95% CI: 25.2%, 47.9%) in the chemo arm and 34/63 patients (54.0%, 95% CI: 40.9%, 66.6%) in the BV + chemo arm. The final Overall Survival (OS) analyses showed no significant clinical benefit from addition of bevacizumab to chemotherapy in this patient population.

f bevacizumab to standard of care did not demonstrate clinical benefit in clinical trial in 71 evaluable children (from age 6 months to less than 18 years old) patients with rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma (see section 4.2 for information on paediatric use).

The incidence of adverse events, including grade > 3 adverse events and serious adverse events, was similar between the two treatment arms. No adverse events leading to death occurred in either treatment arm; all deaths were attributed to disease progression. Bevacizumab addition to multimodal standard of care treatment seemed to be tolerated in this paediatric population.

5.2 Pharmacokinetic properties

The pharmacokinetic data for bevacizumab are available from ten clinical trials in patients with solid tumours. In all clinical trials, bevacizumab was administered as an IV infusion. The rate of infusion was based on tolerability, with an initial infusion duration of 90 minutes. The pharmacokinetics of bevacizumab was linear at doses ranging from 1 to 10 mg/kg.

Distribution

The typical value for central volume (Vc) was 2.73 L and 3.28 L for female and male patients respectively, which is in the range that has been described for IgGs and other monoclonal antibodies. The typical value for peripheral volume (Vp) was 1.69 L and 2.35 L for female and male patients respectively, when bevacizumab is co-administered with anti-neoplastic agents. After correcting for body weight, male patients had a larger Vc (+ 20%) than female patients.

Biotransformation

Assessment of bevacizumab metabolism in rabbits following a single IV dose of 125I-bevaci indicated that its metabolic profile was similar to that expected for a native IgG molecule not bind VEGF. The metabolism and elimination of bevacizumab is similar to endogenou

primarily via proteolytic catabolism throughout the body, including endothelial cells, and rely primarily on elimination through the kidneys and liver. Binding of the IgG to the Fc results in protection from cellular metabolism and the long terminal half-life.

Elimination

The value for clearance is, on average, equal to 0.188 and 0.220 L/ for female and male patients, respectively. After correcting for body weight, male patients had a er bevacizumab clearance (+ 17%) than females. According to the two-compartmental model, the elimination half-life is 18 days for a typical female patient and 20 days for a typical male patient.

Low albumin and high tumour burden are generally indicative of disease severity. Bevacizumab clearance was approximately 30% faster in patients with low levels of serum albumin and 7% faster in subjects with higher tumour burden when compared with a typical patient with median values of albumin and tumour burden.

The population pharmacokinetics were analysed in adult and paediatric patients to evaluate the effects of demographic characteristics. In adults the results showed no significant difference in the pharmacokinetics of be umab in relation to age.

conducted to investigate the pharmacokinetics of bevacizumab in renally impaired idneys are not a major organ for bevacizumab metabolism or excretion.

atirment

No trials have been conducted to investigate the pharmacokinetics of bevacizumab in patients with hepatic impairment since the liver is not a major organ for bevacizumab metabolism or excretion.

Paediatric population

The pharmacokinetics of bevacizumab were evaluated in 152 children, adolescents and young adults (7 months to 21 years, 5.9 to 125 kg) across 4 clinical studies using a population pharmacokinetic model. The pharmacokinetic results show that the clearance and volume of distribution of bevacizumab were comparable between paediatric and young adult patients when normalised by body weight, with exposure trending lower as body weight decreased. Age was not associated with the pharmacokinetics of bevacizumab when body weight was taken into account.

The pharmacokinetics of bevacizumab was well characterised by the paediatric population PK model for 70 paediatric patients in study BO20924 (1.4 to 17.6 years; 11.6 to 77.5 kg) and 59 patients in study BO25041 (1 to 17 years; 11.2 to 82.3 kg). In study BO20924, bevacizumab exposure was generally lower compared to a typical adult patient at the same dose. In study BO25041, bevacizumab exposure was similar compared to a typical adult at the same dose. In both studies, bevacizumab exposure trended lower as body weight decreased.

5.3 Preclinical safety data

In studies of up to 26 weeks duration in cynomolgus monkeys, physeal dysplasia was observed in

young animals with open growth plates, at bevacizumab average serum concentrations below the expected human therapeutic average serum concentrations. In rabbits, bevacizumab was shown inhibit wound healing at doses below the proposed clinical dose. Effects on wound healing wer shown to be fully reversible.

Studies to evaluate the mutagenic and carcinogenic potential of bevacizumab have not performed.

No specific studies in animals have been conducted to evaluate the effect on fe An adverse effect on female fertility can however be expected as repeat dose toxicity studies in animals have shown inhibition of the maturation of ovarian follicles and a decrease/absence of corpora lutea and associated decrease in ovarian and uterus weight as well as a decrease in the number of menstrual cycles.

6.1 List of excipients

6.3 Shelf life

Unopened vial

3 years

Diluted medicinal product

Chemical and physical in-use stability has been demonstrated for 32 days at 2°C to 8°C plus an additional 48 hours at 2°C to 30°C in sodium chloride 9 mg/mL (0.9%) solution for injection. From a microbiological point of view, the product should be used immediately. If not used immediately, inuse storage times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

4 mL solution in a vial (Type I glass) with a stopper (butyl rubber) containing 100 mg of bevacizumab.

16 mL solution in a vial (Type I glass) with a stopper (butyl rubber) containing 400 mg of bevacizumab.

Pack of 1 vial.

6.6 Special precautions for disposal and other ha

Equidacent 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 Equidacent.

The necessary amount of bevacizumab should be withdrawn and diluted to the required administration

solution for injection. The concentration of the final e range of 1.4 mg/mL to 16.5 mg/mL. In the majority

unt of Equidacent can be diluted with 0.9% sodium chloride ume of 100 mL.

ould be inspected visually for particulate matter and discolouration ween Equidacent and polyvinyl chloride or polyolefin bags or infusion sets

Equidacent is for single-use only, as the product contains no preservatives. Any unused medicinal

r waste material should be disposed in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Centus Biotherapeutics Europe Limited

South Bank House, Barrow Street

Dublin 4

Ireland

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/20/1472/001

EU/1/20/1472/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 24 September 2020