Removab - summary of medicine characteristics

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One pre-filled syringe contains 10 micrograms of catumaxomab* in 0.1 ml solution, corresponding to 0.1 mg/ml.

*rat-mouse hybrid IgG2 monoclonal antibody produced in a rat-mouse hybrid-hybridoma cell line

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Concentrate for solution for infusion.

Clear and colourless solution.

4.1 Therapeutic indications

Removab is indicated for the intraperitoneal treatment of malignant ascites in adults with EpCAM-positive carcinomas where standard therapy is not available or no longer feasible.

4.2 Posology and method of administration

Removab must be administered under the supervision of a physician experienced in the use of anti-neoplastic medicinal products.

Posology             * Xy

Prior to the intraperitoneal infusion, pre-medication with analgesic / antipyretic / non-steroidal products is recommended (see section 4.4).

le comprises the following four intraperitoneal infusions:

icrograms on day 0

20 micrograms on day 3

50 micrograms on day 7

150 micrograms on day 10

Removab has to be administered as constant rate intraperitoneal infusion with an infusion time of at least 3 hours. In clinical studies infusion times of 3 hours and 6 hours were investigated. For the first of the four doses an infusion time of 6 hours may be considered depending on the patient’s health condition.

An interval of at least two infusion free calendar days must elapse between infusion days. The interval between the infusion days can be prolonged in case of relevant adverse reactions. The overall treatment period should not exceed 20 days.

Monitoring

Adequate monitoring of the patient after end of Removab infusion is recommended. In the pivotal study patients were monitored for 24 h after each infusion.

Special populations

Hepatic impairment

Patients with hepatic impairment of a higher severity grade than moderate and / or with more than 70% of the liver metastasised and / or portal vein thrombosis / obstruction have not been investigated. Treatment of these patients with Removab should only be considered after a thorough evaluation of benefit / risk (see section 4.4).

Renal impairment

Patients with renal impairment of a higher severity grade than mild have not been investigated.

Treatment of these patients with Removab should only be considered after a thorough evaluation of benefit / risk (see section 4.4).

Paediatric population

There is no relevant use of Removab in the paediatric population in the granted indication.

Method of administration

Removab must be administered as an intraperitoneal infusion only.

Removab must not be administered by intraperitoneal bolus or by any other route of administration.

For information on the perfusion system to be used see section 4.4.

Precautions to be taken before administering the medicinal product

Before administration of Removab the concentrate for solution for infusion is diluted in sodium chloride 9 mg/ml (0.9%) solution for injection. The diluted Removab solution for infusion is administered intraperitoneally as constant rate infusion using an adequate pump system.

For instructions on dilution of the medicinal

4.3 Contraindicationsinistration, see section 6.6.

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

Hypersensitivity to murine

4.4 Special warnings and

Removab must not be admini

Cytokine release related symptoms

As release of pro-inflammatory and cytotoxic cytokines is initiated by the binding of catumaxomab to immune and tumour cells, cytokine release related clinical symptoms such as fever, nausea, vomiting and chills have been very commonly reported during and after the Removab administration (see section 4.8). Dyspnoea and hypo-/ hypertension are commonly observed. In the clinical studies in patients with malignant ascites, 1,000 mg paracetamol intravenously was routinely administered prior to Removab infusion for pain and pyrexia control. Despite this premedication, patients experienced the adverse reactions described above with an intensity of up to grade 3, according to the Common Terminology Criteria for Adverse Events (CTCAE) of the US National Cancer Institute, version 3.0. Other or additional standard pre-medication with analgesic / antipyretic / nonsteroidal antiphlogistic medicinal products is recommended.

Systemic Inflammatory Response Syndrome (SIRS), which may also occur commonly due to the mechanism of action of catumaxomab, develops, in general, within 24 hours after Removab infusion, showing symptoms of fever, tachycardia, tachypnoea and leucocytosis (see section 4.8). Standard therapy or premedication, e.g. analgesic / antipyretic / nonsteroidal antiphlogistic is appropriate to limit the risk.

Abdominal pain

Abdominal pain was commonly reported as an adverse reaction. This transient effect is considered partially a consequence of the intraperitoneal route of administration.

Performance status and BMI

A solid performance status expressed as Body Mass Index (BMI) > 17 (to be assessed after drainage of ascites fluid) and Karnofsky Index > 60 is required prior to Removab therapy.

Acute infections

In presence of factors interfering with the immune system, in particular acute infections, the administration of Removab is not recommended.

Ascites drainage

Appropriate medical management of ascites drainage is a prerequisite for Removab treatment in order to assure stable circulatory and renal functions. This must at least include ascites drainage until stop of spontaneous flow or symptom relief, and, if appropriate, supportive replacement therapy with crystalloids and / or colloids.

Patients with hemodynamic insufficiency, oedema or hypoproteinaemia

Blood volume, blood protein, blood pressure, pulse and renal function should be assessed before each Removab infusion. Conditions such as hypovolaemia, hypoproteinaemia, hypotension, circulatory decompensation and acute renal impairment must be resolved prior to each Removab infusion.

Hepatic impairment or portal vein thrombosis / obstruction

Patients with hepatic impairment of a higher severity grade than moderate and / or with more than 70% of the liver metastasised and / or portal vein thrombosis / obstruction have not been investigated. Treatment of these patients with Removab should only be considered after a thorough evaluation of benefit / risk.

Renal impairment

Patients with renal impairment of a higher severity grade than mild have not been investigated. Treatment of these patients with Removab should only be considered after a thorough evaluation of benefit / risk.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of catumaxomab in pregnant women.

Animal studies are insufficient with respect to reproductive toxicity (see section 5.3).

Removab is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

It is unknown whether catumaxomab/me­tabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue / abstain from Removab therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

No data on the effect of catumaxomab on fertility are available.

4.7 Effects on ability to drive and use machines Removab has minor to moderate influence on the ability to drive and use machines.

Patients experiencing infusion-related symptoms should be advised not to drive and use machines until symptoms abate.

4.8 Undesirable effects

Summary of the safety profile

Adverse reactions are derived from an integrated safety analysis including 12 clinical studies. 728 patients received catumaxomab intraperitoneally, 293 patients as 6 hour – and 435 patients as 3 hour infusions.

The overall safety profile of Removab is characterised by cytokine-release related symptoms and gastrointestinal reactions.

Cytokine-release related reactions: SIRS a potentially life-threatening combination of tachycardia, fever and/or dyspnoea, can develop within 24 hours after a catumaxomab infusion and resolves under symptomatic treatment. Other cytokine-release related reactions such as fever, chills, nausea, and vomiting are very commonly reported reactions in intensity of CTCAE grade 1 and 2 (US National Cancer Institute, version 4.0). These symptoms reflect the mechanism of action of catumaxomab and are in general fully reversible.

Gastrointestinal reactions like abdominal pain, nausea, vomiting and diarrhoea are very common and occur mostly with CTCAE grade 1 or 2, but were also observed in higher grades, and respond to adequate symptomatic treatment.

The safety profile of catumaxomab using a 3h versus a 6h infusion time is in general comparable in regards to nature, frequency and severity. An increased frequency of some adverse reactions was seen in relation to 3h administration including chills and hypotension (grades 1 / 2), diarrhoea (all grades) and fatigue (grade 1 / 2).

Tabulated list of adverse reactions        Q

In Table 1, adverse reactions are listed by organ class. Frequency groupings are defined as follows: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100).

Table 1 Adverse reactions reported from patients receiving catumaxomab treatment

Infections and infestations

were also reported as serious adverse reactions

underlined : see section ‘Description of selected adverse reactions’

Description of selected adverse reactions K

The following definitions of CTCAE criteria of the US National Cancer Institute (version 4.0) apply: CTCAE grade 1 = mild, CTCAE grade 2 = moderate, CTCAE grade 3 = severe, CTCAE grade 4 = life-threatening

Cytokine release related symptoms with higher intensities

In 5.1% of patients pyrexia reached an intensity of CTCAE grade 3 as it was the case with cytokine release syndrome (1.0%), chills (0.8%), nausea (3.4%), vomiting (4.4%), dyspnoea (1.6%) and hypo-/hypertension (2.1% / 0.8%). In one patient (0.1%) dyspnoea and in 3 patients (0.4%) hypotension was reported in CTCAE grade 4 intensity. Symptoms of pain and pyrexia can be ameliorated or avoided by pre-medication (see sections 4.2 and 4.4).

Systemic Inflammatory Response Syndrome (SIRS)

In 3.8% of the patients symptoms of SIRS were observed within 24 hours after catumaxomab infusion. In three patients (0.4%) an intensity of CTCAE grade 4 was observed. These reactions resolved under symptomatic treatment.

Abdominal pain

In 43.7% of patients abdominal pain was reported as an adverse reaction reaching grade 3 in 8.2 % of patients, but it resolved under symptomatic treatment.

Hepatic enzymes

Transient increase in hepatic enzymes was commonly observed after the administration of Removab. In general, the changes in laboratory parameters were not clinically relevant and mostly returned to baseline after end of treatment.

Only in case of clinically relevant or persisting increase further diagnostics or therapy should be considered.

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

No case of overdose has been reported. Patients receiving a higher than recommended dose of catumaxomab experienced more severe (grade 3) adverse reactions.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC09

Mechanism of action

Catumaxomab is a trifunctional rat-mouse hybrid monoclonal antibody that is specifically directed against the epithelial cell adhesion molecule (EpCAM) and the CD3 antigen.

The EpCAM antigen is overexpressed on most carcinomas (Table 2). CD3 is expressed on mature T-cells as a component of the T-cell receptor. A third functional binding site in the Fc-region of catumaxomab enables interaction with accessory immune cells via Fcy receptors.

Due to catumaxomab’s bin­ding properties, tumour cells, T-cells and accessory immune cells come in close proximity. Thereby, a concerted immunoreaction against tumour cells is induced which includes different mechanisms of action such as T-cell activation, antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and phagocytosis. This results in destruction of tumour cells.

Table 2 EpCAM expression in most relevant ascites causing cancer types

*= lobular breast cancer

Pharmacodynamic effects

The anti-tumour activity of catumaxomab has been demonstrated in vitro and in vivo. Effective catumaxomab-mediated killing of tumour cells in vitro was observed for target cells with low and high expression of the EpCAM antigen, independent of the primary tumour type. The in vivo anti-tumour activity of catumaxomab was confirmed in an immunologically compromised mouse model of ovarian carcinoma, where tumour development was delayed by an intraperitoneal treatment with catumaxomab and human peripheral blood mononuclear cells.

Clinical efficacy

The efficacy of catumaxomab was demonstrated in two phase III clinical studies. Patients of nonCaucasian origin have not been included in these clinical studies.

IP-REM-AC-01

A pivotal, two-arm, randomised, open-label, phase II/III clinical trial in 258 patients with symptomatic malignant ascites due to EpCAM-positive carcinomas of whom 170 were randomised to catumaxomab treatment. This study compared paracentesis plus catumaxomab versus paracentesis alone (control).

Catumaxomab was applied in patients where standard therapy was not available or no longer feasible and who had a Karnofsky performance status of at least 60. Catumaxomab was administered as four intraperitoneal infusions with increased doses of 10, 20, 50 and 150 micrograms on day 0, 3, 7 and 10, respectively (see section 4.2). In the pivotal study IP-REM-AC-01 98.1% of patients were hospitalised for a median of 11 days.

In this study, the primary efficacy endpoint was puncture-free survival, which was a composite endpoint defined as the time to first need for therapeutic ascites puncture or death, whichever occurred first. The results for puncture-free survival and time to first need for therapeutic ascites puncture in terms of medians and hazard ratios are presented in Table 3. Kaplan Meier estimates for time to first need for therapeutic ascites puncture are given in Figure 1.

Table 3 Efficacy results (puncture-free survival and time to first need for therapeutic

ascites puncture) of study IP-REM-AC-01 _____________­______________

Figure 1 Kaplan-Meier estimates of time to first need for therapeutic ascites puncture of

study IP-REM-AC-01

Estimated Probability of Being Puncture-free (%)

Altogether 45 out of 88 (51%) patients in the control arm crossed-over to achieve active treatment with catumaxomab.

IP-CAT-AC-03

This confirmatory two-arm, randomized, open label, phase IIIb study in 219 epithelial cancer patients with symptomatic malignant ascites requiring therapeutic ascites puncture investigated treatment with catumaxomab plus 25 mg prednisolone premedication vs. catumaxomab alone. Catumaxomab was administered as four 3-hour constant-rate i.p. infusions in doses of 10, 20, 50 and 150 micrograms on day 0, 3, 7 and 10, respectively, in both groups. The patient population was comparable to the pivotal study.

In order to assess the impact of prednisolone premedication on safety and efficacy the primary safety endpoint “composite safety score” and the co-primary efficacy endpoint “puncture-free survival” were investigated.

The composite safety score evaluated the frequency and severity of the main known adverse reactions pyrexia, nausea, vomiting and abdominal pain in both treatment groups. Administration of prednisolone as premedication did not result in a reduction of these adverse reactions.

The primary efficacy endpoint, puncture-free survival, was a composite endpoint defined as the time to first need for therapeutic ascites puncture or death, whichever occurred first (identical to the pivotal study).

Table 5 Efficacy results (puncture-free survival and time to first need for therapeutic

ascites puncture) of study IP-CAT-AC-03

As secondary efficacy endpoint overall survival (Table 6) was assessed.

Table 6 Overall survival of study IP-CAT-AC-03 in post study phase

Immunogenicity

The induction of human anti-murine (rat and / or mouse) antibodies (HAMAs/HARAs) is an intrinsic effect of murine monoclonal antibodies. Current data on catumaxomab derived from the pivotal study show that only 5.6% of patients (7/124 patients) were HAMA positive before the 4th infusion.

HAMAs were present in 94% of patients one month after the last catumaxomab infusion. No hypersensitivity reactions were observed.

Patients who developed HAMAs 8 days after catumaxomab treatment showed better clinical outcome, as measured by puncture-free survival, time to next puncture and overall survival, compared with HAMA-negative patients.

In a feasibility study evaluating a second i.p. infusion cycle consisting of 10, 20, 50 and 150 micrograms of catumaxomab in 8 patients with malignant ascites due to carcinoma (IP-CAT-AC-04) ADA was detectable in all available ascites and plasma samples at screening. The patients remained ADA positive during treatment phase and follow-up. Despite pre-existing ADA values all patients received all 4 catumaxomab infusions. The median puncture-free survival time was 47.5 days, median time to first therapeutic puncture 60.0 days and median overall survival 406.5 days. All patients experienced symptoms related to catumaxomab mode of action with a safety profile comparable in nature to the first i.p. treatment cycle. No hypersensitivity reactions were observed.

5.2 Pharmacokinetic properties

Pharmacokinetics of catumaxomab during and after four intraperitoneal infusions of 10, 20, 50 and 150 micrograms catumaxomab were investigated in 13 patients with symptomatic malignant ascites due to EpCAM-positive carcinomas.

The variability between subjects was high. The geometric mean plasma Cmax was approximately 0.5 ng/ml (range 0 to 2.3), and the geometric mean plasma AUC was approximately 1.7 day* ng/ml (range < LLOQ (lower limit of quantification) to 13.5). The geometric mean apparent terminal plasma elimination half-life (t1/2) was approximately 2.5 days (range 0.7 to 17).

Catumaxomab was detectable in the ascites fluid and in plasma. The concentrations increased with the number of infusions and the doses applied in most patients. Plasma levels tended to decline after achieving a maximum after each dose.

Special populations

No studies have been conducted.

5.3 Preclinical safety data

Administration of catumaxomab in animal models did not result in any signs of abnormal or drug-related acute toxicity or signs of local intolerance at the injection/infusion site. However, these findings are of limited value due to t

Repeated-dose toxicity, genotoxicity, carcinogenicity, reproductive and developmental toxicity studies have not been performed.

ARTICULARS

6.1

Sodium citrate

Citric acid monohydrate

Polysorbate 80

Water for injections

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

2 years

After dilution

The prepared solution for infusion is physically and chemically stable for 48 hours at 2°C to 8°C and for 24 hours at a temperature not above 25°C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use 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

6.5 Nature and contents of container

6.6 Special precautions for disposal and other handling

Disposal

No special requirements.

Material and equipment required

The following components must be used for the dilution an is only compatible with:

• • 50 ml polypropylene syringes
• • polyethylene perfusion tubings with an inner diameter of 1 mm and a length of 150 cm
• • polycarbonate infusion valves / Y connections
• • polyurethane, polyurethane silicon coated catheters

In addition the following is required:

• • Sodium chloride 9 mg/ml (0.9%) solution for injection
• • Precision perfusion pump

Instructions for dilution prior to administration

Removab should be prepared by a healthcare professional using appropriate aseptic technique.

The outer surface of the pre-filled syringe is not sterile.

Based on the dose, the appropriate amount of sodium chloride 9 mg/ml (0.9%) solution for injection is extracted with a 50 ml syringe (Table 7).

An additional air buffer of at least 3 ml is included in the 50 ml syringe.

The tip cap from the Removab pre-filled syringe is removed with the tip pointing up.

The enclosed cannula is attached to the Removab pre-filled syringe. For each syringe a new cannula is used.

The pre-filled syringe cannula is inserted through the 50 ml syringe opening so that the cannula is immersed in the sodium chloride 9 mg/ml (0.9%) solution for injection (Figure 2).

The entire content of the syringe (Removab concentrate plus air buffer) is injected from the pre-filled syringe directly into the sodium chloride 9 mg/ml (0.9%) solution for injection.

The plunger rod MUST NOT be drawn back to rinse the pre-filled syringe, in order to avoid contamination and to ensure that the correct volume is ejected.

The 50 ml syringe is closed with a cap and shaken gently to mix the solution. Any air bubble(s) from the 50 ml syringe is eliminated.

The peelable sticker, which is provided on the inner side of the Removab carton box, displaying the text “Diluted Removab. Intraperitoneal use only.” must be attached to the 50 ml syringe containing the diluted Removab solution for intraperitoneal infusion. This is a precautionary measure to ensure that Removab is infused only via the intraperitoneal route of administration. The 50 ml syringe is inserted in the infusion pump.

infusion

Table 7

of Removab solution for i

Pre-filled syringe

Sodium Chloride 9 mg/ml (0.9%)

Method of administration

The catheter for intraperitoneal administration should be placed under ultrasound guidance by a physician experienced in intraperitoneal administration procedures. The catheter is used for ascites drainage and infusion of diluted Removab and sodium chloride 9 mg/ml (0.9%) solution for injection. It is recommended that the catheter remains in the abdominal cavity during the entire treatment period. It can be removed the day after the last infusion.

Prior to each Removab administration the ascites fluid must be drained until stop of spontaneous flow or symptom relief (see section 4.4). Subsequently, prior to each Removab administration 500 ml sodium chloride 9 mg/ml (0.9%) solution for injection shall be infused to support distribution of the antibody in the abdominal cavity.

Removab must be administered intraperitoneally over an infusion time of at least 3 hours via a constant infusion pump system as described below:

• • The 50 ml syringe containing the diluted Removab solution for infusion is installed in the precision pump.
• • The connected perfusion tubing equipment of the precision pump is prefilled with the diluted Removab solution for infusion. A perfusion tubing of an inner diameter of 1 mm and a length of 150 cm must be used.

The perfusion tubing is connected to the Y-connection.

Parallel to each Removab application 250 ml sodium chloride 9 mg/ml (0.9%) solution for injection are infused via an infusion valve / Y connection in the perfusion lead of the catheter. The pump speed is adjusted according to the volume to be administered and the scheduled infusion time.

When the 50 ml syringe containing the diluted Removab solution for infusion is empty it is replaced with a 50 ml syringe containing 20 ml sodium chloride 9 mg/ml (0.9%) solution for injection until the end of the scheduled infusion time to clear the dead volume in the perfusion lead (approximately 2 ml) under unchanged conditions. The remaining sodium chloride 9 mg/ml (0.9%) solution for injection can be discarded.

The catheter is kept closed until the next infusion.

Removab solution for i.p. infusion

Perfusion Tubing (1 mm inner diameter, 150 cm length)

Infusion valve

Perfusion Lead

6 Catheter

7. MARKETING AUTHORISATION HOLDER

Neovii Biotech GmbH

Am Haag 6–7

82166 Graefelfing

Germany

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/09/512/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 20 April 2009

Date of latest renewal: 18 December 2013

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines

Agency:.