Removab

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Removab 10 micrograms concentrate for solution for infusion 
 
 
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. CLINICAL PARTICULARS 
 
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 
Prior to the intraperitoneal infusion, pre-medication with analgesic / antipyretic / non-steroidal 
antiphlogistic medicinal products is recommended (see section 4.4). 
Removab dosing schedule comprises the following four intraperitoneal infusions: 
1st dose  10 micrograms on day 0 
2nd dose  20 micrograms on day 3 
3rd dose  50 micrograms on day 7 
4th dose  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  

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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 product before administration, see section 6.6. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
Hypersensitivity to murine (rat and / or mouse) proteins. 
 
4.4 Special warnings and precautions for use 
 
Removab must not be administered as a bolus or by any route other than intraperitoneally. 
 
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 

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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 

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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 
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 
Common Infection. 
Uncommon Erythaema induratum*, device-related infection*. 
Blood and lymphatic system disorders 
Common Anaemia*, lymphopenia, leukocytosis, neutrophilia. 
Uncommon Thrombocytopenia*, coagulopathy*. 
Immune system disorders 
Common Cytokine release syndrome*, hypersensitivity*. 
Metabolism and nutrition disorders 
Common Decreased appetite* / anorexia, dehydration*, hypokalaemia, 

hypoalbuminaemia, hyponatraemia*, hypocalcaemia*, hypoproteinaemia. 
Psychiatric disorders 
Common Anxiety, insomnia. 
Nervous system disorders 
Common Headache, dizziness. 
Uncommon Convulsion*. 
Ear and labyrinth disorders 
Common Vertigo. 
Cardiac disorders 
Common Tachycardia*, incl. sinus tachycardia. 
Vascular disorders 
Common Hypotension*, hypertension*, flushing. 

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Respiratory, thoracic and mediastinal disorders 
Common Dyspnoea*, pleural effusion*, cough. 
Uncommon Pulmonary embolism*, hypoxia*. 
Gastrointestinal disorders 
Very common Abdominal pain*, nausea*, vomiting*, diarrhoea*. 
Common Constipation*, dyspepsia, abdominal distension, sub-ileus*, flatulence, 

gastric disorder, ileus*, gastroesophageal reflux disease, dry mouth. 
Uncommon Gastrointestinal haemorrhage*, intestinal obstruction*.  
Hepatobiliary disorders 
Common Cholangitis*, hyperbilirubinaemia. 
Skin and subcutaneous tissue disorders 
Common Rash*, erythaema*, hyperhidrosis, pruritus. 
Uncommon Skin reaction*, dermatitis allergic*. 
Musculoskeletal and connective tissue disorders 
Common Back pain, myalgia, arthralgia. 
Renal and urinary disorders 
Common Proteinuria. 
Uncommon Renal failure acute*. 
General disorders and administration site conditions 
Very common Pyrexia*, fatigue*, chills*. 
Common Pain, asthenia*, Systemic inflammatory response syndrome*, oedema 

incl. oedema peripheral*, general physical health deterioration*, chest 
pain, influenza-like illness, malaise*, catheter site erythema. 

Uncommon Extravasation*, application site inflammation*. 
* were also reported as serious adverse reactions 
underlined: see section ‘Description of selected adverse reactions’  
 
Description of selected adverse reactions  
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.  

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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 
 
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 Fcγ 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 

 Literature data  
 

Retrospective data from 
study 

IP-CAT-AC-03  
Cancer Type Percentage of tumors 

expressing EpCAM 
Percentage of EpCAM 

positive effusions 
Percentage of EpCAM 

positive effusions  
Ovarian 90-92 79-100 98 
Gastric 96 75-100 100 
Colon 100 87-100 100 
Pancreatic 98 83-100 80 
Breast 45*-81 71-100 86 
Endometrial 94 100 100 
*= 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 non-
Caucasian origin have not been included in these clinical studies. 

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http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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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  
Variable Paracentesis + catumaxomab 

(N=170) 
Paracentesis (control) 

(N=88) 
 Puncture free survival 
Median puncture-free survival (days) 44 11 
95% CI for median (days) [31; 49] [9; 16] 
p-value  
(log-rank test) 

< 0.0001 

Hazard ratio (HR) 0.310 
95% CI for HR [0.228; 0.423] 
Time to first need for therapeutic ascites puncture 
Median time to first need for therapeutic 
ascites puncture (days) 

77 13 

95% CI for median (days) [62;104] [9; 17] 
p-value  
(log-rank test) 

< 0.0001 

Hazard ratio (HR) 0.169 
95% CI for HR [0.114; 0.251] 
 

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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 (%) 

 
Time (days) to event 

Treatment: 
 

Catumaxomab (N=170) 
Control (N=88) 

N: number of patients in a treatment group. 
 
The efficacy of the treatment with paracentesis and catumaxomab in patients with malignant ascites 
due to EpCAM-positive carcinomas was statistically significantly superior to that with paracentesis 
alone in terms of puncture-free survival and time to first need for therapeutic ascites puncture. 
 
After completion of the study, patients were further observed until the end of their lifetime to assess 
overall survival (Table 4). 
 
Table 4 Overall survival of study IP-REM-AC-01 in post study phase  
 Paracentesis + catumaxomab 

(N=170) 
Paracentesis (control) 

(N=88) 
Hazard ratio (HR) 0.798 
95% CI for HR [0.606; 1.051] 
6 months survival rate 27.5% 17.1% 
1 year survival rate 11.4% 2.6% 
Median overall survival (days) 72 71 
95% CI for median (days) [61; 98] [54; 89] 
p-value (log-rank test) 0.1064 
 
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. 

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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  
Variable Catumaxomab + 

prednisolone 
(N=111) 

Catumaxomab  
(N=108) 

Pooled population 
(N=219) 

 Puncture free survival 
Median puncture-free survival (days) 30 37 35 
95% CI for median (days) [23; 67] [24; 61] [26; 59] 
p-value  
(log-rank test) 

0.402  

Hazard ratio (HR) (Catumaxomab 
versus Catumaxomab + Prednisolone) 

1.130  

95% CI for HR [0.845; 1.511]  
Time to first need for therapeutic ascites puncture 
Median time to first need for 
therapeutic ascites puncture (days) 

78 102 97 

95% CI for median (days) [30; 223] [69; 159] [67; 155] 
p-value  
(log-rank test) 

0.599  

Hazard ratio (HR) (Catumaxomab 
versus Catumaxomab + Prednisolone) 

0.901  

95% CI for HR [0.608; 1.335]  
 
As secondary efficacy endpoint overall survival (Table 6) was assessed. 
 
Table 6 Overall survival of study IP-CAT-AC-03 in post study phase  
 Catumaxomab + 

prednisolone 
(N=111) 

Catumaxomab  
(N=108) 

Pooled population 
(N=219) 

Median overall survival (days) 124 86 103 
95% CI for median (days) [97.0; 169.0] [72.0, 126.0] [82; 133] 
p-value (log-rank test) 0.186  
Hazard ratio (HR) 
(Catumaxomab versus 
Catumaxomab + Prednisolone) 

1.221  

95% CI for HR [0.907 ;1.645]  
 
 
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) 

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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 the high species-specificity of catumaxomab. 
 
Repeated-dose toxicity, genotoxicity, carcinogenicity, reproductive and developmental toxicity 
studies have not been performed. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
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 

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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 
 
Store in a refrigerator (2°C-8°C). Do not freeze. Store in the original package 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 
 
0.1 ml concentrate for solution for infusion in a pre-filled syringe (type I glass, siliconised) with 
plunger stopper (bromobutyl rubber) and luer lock system (polypropylene siliconised and 
polycarbonate) with tip cap (styrene butadiene rubber) with a cannula; pack size of 1. 
 
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 and administration of Removab as Removab 
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 

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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. 
 
Table 7 Preparation of Removab solution for intraperitoneal infusion 

Number of 
infusion / 

Dose 

Number of Removab pre-filled 
syringe(s)  

Total volume 
of Removab 

concentrate for 
solution for 

infusion 
 

Sodium 
chloride  
9 mg/ml 

(0.9%) solution 
for injection  

Final volume 
for 

administration 
 10 micrograms 

pre-filled 
syringe 

50 micrograms 
pre-filled 
syringe 

1st infusion 
10 micrograms 

1  0.1 ml 10 ml 10.1 ml 

2nd infusion 
20 micrograms 

2  0.2 ml 20 ml 20.2 ml 

3rd infusion 
50 micrograms 

 1 0.5 ml 49.5 ml 50 ml 

4th infusion 
150 micrograms 

 3 1.5 ml 48.5 ml 50 ml 

 
 
Figure 2 Illustration of the transfer of Removab from the pre-filled syringe to the 50 ml 
syringe 

Pre-filled syringe 

 

Air buffer 
 

Removab solution 
 

Air buffer 
 

Sodium Chloride 9 mg/ml (0.9%) 
 

50 ml Syringe 
 

 
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 

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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. 
• The day after the last infusion a drainage of ascites until stop of spontaneous flow is performed. 

Subsequently, the catheter can be removed. 
 
Figure 3 Schematic illustration of the infusion system 

 
  

1 250 ml Sodium Chloride 9 mg/ml (0.9%) 
2 Removab solution for i.p. infusion 
3 Perfusion Tubing (1 mm inner diameter, 150 cm length) 
4 Infusion valve 
5 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 
 
 

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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: http://www.ema.europa.eu. 
 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Removab 50 micrograms concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
One pre-filled syringe contains 50 micrograms of catumaxomab* in 0.5 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. CLINICAL PARTICULARS 
 
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 
Prior to the intraperitoneal infusion, pre-medication with analgesic / antipyretic / non-steroidal 
antiphlogistic medicinal products is recommended (see section 4.4). 
Removab dosing schedule comprises the following four intraperitoneal infusions: 
1st dose  10 micrograms on day 0 
2nd dose  20 micrograms on day 3 
3rd dose  50 micrograms on day 7 
4th dose  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  

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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 product before administration, see section 6.6. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
Hypersensitivity to murine (rat and / or mouse) proteins. 
 
4.4 Special warnings and precautions for use 
 
Removab must not be administered as a bolus or by any route other than intraperitoneally. 
 
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 

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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 

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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 
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 
Common Infection. 
Uncommon Erythaema induratum*, device-related infection*. 
Blood and lymphatic system disorders 
Common Anaemia*, lymphopenia, leukocytosis, neutrophilia. 
Uncommon Thrombocytopenia*, coagulopathy*. 
Immune system disorders 
Common Cytokine release syndrome*, hypersensitivity*. 
Metabolism and nutrition disorders 
Common Decreased appetite* / anorexia, dehydration*, hypokalaemia, 

hypoalbuminaemia, hyponatraemia*, hypocalcaemia*, hypoproteinaemia. 
Psychiatric disorders 
Common Anxiety, insomnia. 
Nervous system disorders 
Common Headache, dizziness. 
Uncommon Convulsion*. 
Ear and labyrinth disorders 
Common Vertigo. 
Cardiac disorders 
Common Tachycardia*, incl. sinus tachycardia. 
Vascular disorders 
Common Hypotension*, hypertension*, flushing. 

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Respiratory, thoracic and mediastinal disorders 
Common Dyspnoea*, pleural effusion*, cough. 
Uncommon Pulmonary embolism*, hypoxia*. 
Gastrointestinal disorders 
Very common Abdominal pain*, nausea*, vomiting*, diarrhoea*. 
Common Constipation*, dyspepsia, abdominal distension, sub-ileus*, flatulence, 

gastric disorder, ileus*, gastroesophageal reflux disease, dry mouth. 
Uncommon Gastrointestinal haemorrhage*, intestinal obstruction*.  
Hepatobiliary disorders 
Common Cholangitis*, hyperbilirubinaemia. 
Skin and subcutaneous tissue disorders 
Common Rash*, erythaema*, hyperhidrosis, pruritus. 
Uncommon Skin reaction*, dermatitis allergic*. 
Musculoskeletal and connective tissue disorders 
Common Back pain, myalgia, arthralgia. 
Renal and urinary disorders 
Common Proteinuria. 
Uncommon Renal failure acute*. 
General disorders and administration site conditions 
Very common Pyrexia*, fatigue*, chills*. 
Common Pain, asthenia*, Systemic inflammatory response syndrome*, oedema 

incl. oedema peripheral*, general physical health deterioration*, chest 
pain, influenza-like illness, malaise*, catheter site erythema. 

Uncommon Extravasation*, application site inflammation*. 
* were also reported as serious adverse reactions 
underlined: see section ‘Description of selected adverse reactions’  
 
Description of selected adverse reactions  
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.  

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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 
 
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 Fcγ 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 

 Literature data  
 

Retrospective data from 
study 

IP-CAT-AC-03  
Cancer Type Percentage of tumors 

expressing EpCAM 
Percentage of EpCAM 

positive effusions 
Percentage of EpCAM 

positive effusions  
Ovarian 90-92 79-100 98 
Gastric 96 75-100 100 
Colon 100 87-100 100 
Pancreatic 98 83-100 80 
Breast 45*-81 71-100 86 
Endometrial 94 100 100 
*= 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 non-
Caucasian origin have not been included in these clinical studies. 

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22 

 
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  
Variable Paracentesis + catumaxomab 

(N=170) 
Paracentesis (control) 

(N=88) 
 Puncture free survival 
Median puncture-free survival (days) 44 11 
95% CI for median (days) [31; 49] [9; 16] 
p-value  
(log-rank test) 

< 0.0001 

Hazard ratio (HR) 0.310 
95% CI for HR [0.228; 0.423] 
Time to first need for therapeutic ascites puncture 
Median time to first need for therapeutic 
ascites puncture (days) 

77 13 

95% CI for median (days) [62;104] [9; 17] 
p-value  
(log-rank test) 

< 0.0001 

Hazard ratio (HR) 0.169 
95% CI for HR [0.114; 0.251] 
 

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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 (%) 

 
Time (days) to event 

Treatment: 
 

Catumaxomab (N=170) 
Control (N=88) 

N: number of patients in a treatment group. 
 
The efficacy of the treatment with paracentesis and catumaxomab in patients with malignant ascites 
due to EpCAM-positive carcinomas was statistically significantly superior to that with paracentesis 
alone in terms of puncture-free survival and time to first need for therapeutic ascites puncture. 
 
After completion of the study, patients were further observed until the end of their lifetime to assess 
overall survival (Table 4). 
 
Table 4 Overall survival of study IP-REM-AC-01 in post study phase  
 Paracentesis + catumaxomab 

(N=170) 
Paracentesis (control) 

(N=88) 
Hazard ratio (HR) 0.798 
95% CI for HR [0.606; 1.051] 
6 months survival rate 27.5% 17.1% 
1 year survival rate 11.4% 2.6% 
Median overall survival (days) 72 71 
95% CI for median (days) [61; 98] [54; 89] 
p-value (log-rank test) 0.1064 
 
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. 

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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  
Variable Catumaxomab + 

prednisolone 
(N=111) 

Catumaxomab  
(N=108) 

Pooled population 
(N=219) 

 Puncture free survival 
Median puncture-free survival (days) 30 37 35 
95% CI for median (days) [23; 67] [24; 61] [26; 59] 
p-value  
(log-rank test) 

0.402  

Hazard ratio (HR) (Catumaxomab 
versus Catumaxomab + Prednisolone) 

1.130  

95% CI for HR [0.845; 1.511]  
Time to first need for therapeutic ascites puncture 
Median time to first need for 
therapeutic ascites puncture (days) 

78 102 97 

95% CI for median (days) [30; 223] [69; 159] [67; 155] 
p-value  
(log-rank test) 

0.599  

Hazard ratio (HR) (Catumaxomab 
versus Catumaxomab + Prednisolone) 

0.901  

95% CI for HR [0.608; 1.335]  
 
As secondary efficacy endpoint overall survival (Table 6) was assessed. 
 
Table 6 Overall survival of study IP-CAT-AC-03 in post study phase  
 Catumaxomab + 

prednisolone 
(N=111) 

Catumaxomab  
(N=108) 

Pooled population 
(N=219) 

Median overall survival (days) 124 86 103 
95% CI for median (days) [97.0; 169.0] [72.0, 126.0] [82; 133] 
p-value (log-rank test) 0.186  
Hazard ratio (HR) 
(Catumaxomab versus 
Catumaxomab + Prednisolone) 

1.221  

95% CI for HR [0.907 ;1.645]  
 
 
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) 

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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 the high species-specificity of catumaxomab. 
 
Repeated-dose toxicity, genotoxicity, carcinogenicity, reproductive and developmental toxicity 
studies have not been performed. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
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 

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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 
 
Store in a refrigerator (2°C-8°C). Do not freeze. Store in the original package 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 
 
0.5 ml concentrate for solution for infusion in a pre-filled syringe (type I glass, siliconised) with 
plunger stopper (bromobutyl rubber) and luer lock system (polypropylene siliconised and 
polycarbonate) with tip cap (styrene butadiene rubber) with a cannula; pack size of 1. 
 
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 and administration of Removab as Removab 
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 

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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. 
 
Table 7 Preparation of Removab solution for intraperitoneal infusion 

Number of 
infusion / 

Dose 

Number of Removab pre-filled 
syringe(s)  

Total volume 
of Removab 

concentrate for 
solution for 

infusion 
 

Sodium 
chloride  
9 mg/ml 

(0.9%) solution 
for injection  

Final volume 
for 

administration 
 10 micrograms 

pre-filled 
syringe 

50 micrograms 
pre-filled 
syringe 

1st infusion 
10 micrograms 

1  0.1 ml 10 ml 10.1 ml 

2nd infusion 
20 micrograms 

2  0.2 ml 20 ml 20.2 ml 

3rd infusion 
50 micrograms 

 1 0.5 ml 49.5 ml 50 ml 

4th infusion 
150 micrograms 

 3 1.5 ml 48.5 ml 50 ml 

 
 
Figure 2 Illustration of the transfer of Removab from the pre-filled syringe to the 50 ml 
syringe 

Pre-filled syringe 

 

Air buffer 
 

Removab solution 
 

Air buffer 
 

Sodium Chloride 9 mg/ml (0.9%) 
 

50 ml Syringe 
 

 
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 

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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. 
• The day after the last infusion a drainage of ascites until stop of spontaneous flow is performed. 

Subsequently, the catheter can be removed. 
 
Figure 3 Schematic illustration of the infusion system 

 
  

1 250 ml Sodium Chloride 9 mg/ml (0.9%) 
2 Removab solution for i.p. infusion 
3 Perfusion Tubing (1 mm inner diameter, 150 cm length) 
4 Infusion valve 
5 Perfusion Lead 
6 Catheter 

 
 
7. MARKETING AUTHORISATION HOLDER 
 
Neovii Biotech GmbH 
Am Haag 6-7 
82166 Graefelfing 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/09/512/002 
 
 

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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: http://www.ema.europa.eu. 
 

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ANNEX II 
 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE 
SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR 
BATCH RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE  
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 
 

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A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturer of the biological active substance 
 
Trion Pharma GmbH 
Frankfurter Ring 193a 
DE-80807 Munich 
Germany 
 
 
Name and address of the manufacturer responsible for batch release 
 
Neovii Biotech GmbH 
Am Haag 6-7 
82166 Graefelfing 
Germany 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic Safety Update Reports  
 
The marketing authorisation holder shall submit periodic safety update reports for this product 
in accordance with the requirements set out in the list of Union reference dates (EURD list) 
provided for under Article 107c(7) of Directive 2001/83/EC and published on the European 
medicines web-portal. 

 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT   

 
• Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in 
the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed 
subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency;  
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the 
same time. 
 

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ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 

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A. LABELLING 
 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Carton: Removab 10 micrograms 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Removab 10 micrograms concentrate for solution for infusion 
catumaxomab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One pre-filled syringe contains 10 micrograms catumaxomab in 0.1 ml solution, corresponding to 
0.1 mg/ml. 
 
 
3. LIST OF EXCIPIENTS 
 
Sodium citrate, citric acid monohydrate, polysorbate 80, water for injections 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion. 
1 pre-filled syringe. 
1 sterile cannula 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Intraperitoneal use only, after dilution. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. Do not freeze. Store in the original package in order to protect from light. 

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10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Neovii Biotech GmbH 
Am Haag 6-7 
82166 Graefelfing 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/09/512/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
Blister: Removab 10 micrograms 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Removab 10 micrograms concentrate for solution for infusion 
catumaxomab 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Neovii Biotech GmbH 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
1 pre-filled syringe. 
 
Intraperitoneal use only, after dilution. Read the package leaflet before use. 
 
Store in a refrigerator. Do not freeze. Store in the original package in order to protect from light. 
 

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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
Pre-filled syringe: Removab 10 micrograms 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Removab 10 micrograms concentrate for solution for infusion 
catumaxomab 
Intraperitoneal use only, after dilution. 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.1 ml 
 
 
6. OTHER 
 
Neovii Biotech GmbH 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Carton: Removab 50 micrograms 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Removab 50 micrograms concentrate for solution for infusion 
catumaxomab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One pre-filled syringe contains 50 micrograms catumaxomab in 0.5 ml solution, corresponding to 
0.1 mg/ml. 
 
 
3. LIST OF EXCIPIENTS 
 
Sodium citrate, citric acid monohydrate, polysorbate 80, water for injections 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion. 
1 pre-filled syringe. 
1 sterile cannula 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Intraperitoneal use only, after dilution. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. Do not freeze. Store in the original package in order to protect from light. 

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10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Neovii Biotech GmbH 
Am Haag 6-7 
82166 Graefelfing 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/09/512/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
Blister: Removab 50 micrograms 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Removab 50 micrograms concentrate for solution for infusion 
catumaxomab 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Neovii Biotech GmbH 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
1 pre-filled syringe. 
 
Intraperitoneal use only, after dilution. Read the package leaflet before use. 
 
Store in a refrigerator. Do not freeze. Store in the original package in order to protect from light. 
 

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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
Pre-filled syringe: Removab 50 micrograms 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Removab 50 micrograms concentrate for solution for infusion 
catumaxomab 
Intraperitoneal use only, after dilution. 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.5 ml 
 
 
6. OTHER 
 
Neovii Biotech GmbH 

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WARNING TEXT FOR PEELABLE STICKER TO BE ATTACHED TO 50ml SYRINGE 
CONTAINING THE DILUTED REMOVAB SOLUTION FOR INFUSION 
 
(Part of the Outer Carton) 
 
Diluted Removab. 
Intraperitoneal use only. 

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B. PACKAGE LEAFLET 
 

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Package leaflet: Information for the patient 
 
 

Removab 10 micrograms concentrate for solution for infusion 
catumaxomab 

 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or nurse. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or nurse. This includes any possible side effects 

not listed in this leaflet. See section 4. 
 
 
What is in this leaflet 
1. What Removab is and what it is used for 
2. What you need to know before you use Removab 
3. How to use Removab 
4. Possible side effects 
5. How to store Removab 
6. Contents of the pack and other information 
 
 
1. What Removab is and what it is used for  
 
Removab contains the active substance catumaxomab, a monoclonal antibody. It recognises a protein 
on the surface of cancer cells and recruits immune cells to destroy them. 
 
Removab is used to treat malignant ascites, when standard treatment is not available or no longer 
feasible. Malignant ascites is an accumulation of fluid in the abdominal space (peritoneal cavity) 
resulting from certain types of cancer. 
 
 
2. What you need to know before you use Removab 
 
Do not use Removab 
- if you are allergic to catumaxomab or any of the other ingredients of this medicine (listed in 

section 6) 
- if you are allergic to murine proteins (from rat and / or mouse) 
 
Warnings and precautions 
Talk to your doctor or nurse before using Removab. It is important to tell your doctor if you have any 
of the following: 
- undrained fluid in your abdominal cavity 
- cold hands and feet, light headedness, difficulty passing urine, increased heart rate, and 

weakness (symptoms of low blood volume) 
- weight gain, weakness, shortness of breath and fluid retention (symptoms of low blood protein 

levels) 
- feeling dizzy and faint (symptoms of low blood pressure) 
- problems with your heart and circulation 
- kidney or liver problems 
- an infection. 
 
 

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Before you start using Removab your doctor will check your: 
- Body Mass Index (BMI), which depends on your height and weight 
- Karnofsky Index, a measure of your general performance status.  
You are required to have a BMI above 17 (after drainage of the ascites fluid) and a Karnofsky Index 
above 60 to use this medicine. 
 
Infusion-related side effects and abdominal pain are very common (see section 4). You will be given 
other medicines to reduce fever, pain or inflammation caused by Removab (see section 3). 
 
Children and adolescents 
Removab should not be used in children and adolescents under 18 years of age. 
 
Other medicines and Removab 
Tell your doctor if you are taking, have recently taken or might take any other medicines. 
 
Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before taking this medicine.You should not use Removab if you are pregnant 
unless clearly necessary.  
 
Driving and using machines 
If you experience side effects such as dizziness or chills during or after administration, you should not 
drive or use machines until they disappear. 
 
 
3. How to use Removab 
 
You will be given Removab under the supervision of a doctor experienced in treating cancer. After 
the Removab infusion you will be observed as decided by your doctor. 
 
Before starting and during treatment, you will be given other medicines to reduce fever, pain or 
inflammation caused by Removab. 
 
Removab is given as 4 intraperitoneal infusions with increasing dose (10, 20, 50 and 
150 micrograms), separated at least by 2 infusion-free calendar days (for example you will receive 
infusion on day 0, 3, 7, 10). The infusion must be administered at constant rate with duration time of 
at least 3 hours. The overall treatment period should not exceed 20 days. 
 
A catheter will be placed in your abdominal space (intraperitoneal) for the whole treatment period, 
until the day after your last infusion. 
 
If you have any further questions on the use of this product, ask your doctor. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
The most common serious side effects of Removab are infusion-related side effects and side effects 
related to the gastrointestinal system (stomach and gut). 
 
Infusion-related side effects 
During and after infusion with Removab more than 1 in 10 patients (very common) will probably 
experience infusion-related side effects. The most common infusion-related side effects, which are 
mostly mild to moderate, are fever, chills, feeling sick and vomiting.  

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If such symptoms occur, please inform your doctor as soon as possible. Your doctor may consider 
reducing the infusion rate of Removab or giving you additional treatment to reduce these symptoms. 
 
A complex of symptoms including very fast heartbeat, fever and shortness of breath can develop in up 
to 4 out of 100 patients. These symptoms occur mainly within 24 hours after a Removab infusion and 
can become life-threatening, but can be treated well with additional therapy. 
If such symptoms occur, speak to a doctor immediately, as these side effects require immediate 
attention and treatment. 
 
Side effects related to the gastrointestinal system 
Gastrointestinal reactions like abdominal pain, feeling sick, vomiting and diarrhoea occur in more 
than 1 in 10 patients (very common), but are mostly mild to moderate and respond well to additional 
treatment. 
If such symptoms occur, please inform your doctor as soon as possible. Your doctor may consider 
reducing the infusion rate of Removab or giving you additional treatment to reduce these symptoms. 
 
Other serious side effects 
 Very common serious side effects (may affect more than 1 in 10 people): 

- Tiredness  
  
 Common serious side effects (may affect up to 1 in 10 people): 

- Loss of appetite 
- Dehydration 
- Reduction in red blood cells (anaemia) 
- Decreased blood levels of calcium and sodium 
- A very fast heart beat 
- High or low blood pressure 
- Abdominal pain accompanied by difficulty or blockage passing stools, constipation 
- Shortness of breath 
- Accumulation of fluid around the lungs which cause chest pain and breathlessness 
- Inflammation of the bile ducts 
- Skin redness, rash 
- Very fast heartbeat, fever, shortness of breath, feeling faint or light-headed  
- Complex of reactions due to the release of mediators of inflammation 
- Worsening of general state of health, generally feeling unwell and weak 
- Fluid retention 
- Hypersensitivity 

 
 Uncommon serious side effects (may affect up to 1 in 100 people): 

- Lumps under the skin on the back of the legs that may become sores and leave scars 
- Inflammation and pain or burning and stinging in the area around the catheter  
- Reduction in number of blood platelets, blood clotting problems 
- Bleeding in the stomach or gut, shown by the vomiting of blood or the passage of red or black 

stools 
- Skin reaction, severe allergic skin reaction (dermatitis) 
- Fits 
- Lung problems including blood clot in the lungs 
- Low blood oxygen levels 
- Severe kidney problems 
- Extravasation (inadvertent leakage of administered medicinal product from the intraperitoneal 

catheter system into surrounding tissue) 
 

If such symptoms occur, please inform your doctor as soon as possible. Some of these side effects 
may require medical treatment.  

 
Other side effects 

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 Common side effects (may affect up to 1 in 10 people): 
- Pain 
- Reduction or increase in number of white blood cells 
- Decreased blood levels of potassium 
- Decreased blood protein levels 
- Increase of bilirubin in blood 
- Spinning sensation 
- Indigestion, stomach problems, heartburn, feeling bloated, passing wind, dry mouth  
-  Flu-like symptoms 
-  Dizziness or headache 
-  Chest pain 
- Increased sweating 
- Infections  
-  Increased protein levels in urine 
- Back pain, aching muscles and joints 
- Feeling anxious and having difficulty sleeping 
- Itchy rash or hives 
- Redness of the skin in the area around the catheter 
- Flushing  
- Cough 

 
Reporting of side effects 
If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not 
listed in this leaflet. You can also report side effects directly via the national reporting system listed in 
Appendix V. By reporting side effects you can help provide more information on the safety of this 
medicine. 
 
 
5. How to store Removab 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton after EXP. The expiry date 
refers to the last day of that month. 
 
Store in a refrigerator (2°C – 8°C). Do not freeze. Store in the original package in order to protect 
from light. 
 
The prepared infusion solution should be used immediately. 
 
 
6. Contents of the pack and other information 
 
What Removab contains 
- The active substance is catumaxomab (10 micrograms in 0.1 ml, corresponding to 0.1 mg/ml). 
- The other ingredients are sodium citrate, citric acid monohydrate, polysorbate 80 and water for 

injections. 
 
What Removab looks like and contents of the pack 
Removab is presented as a clear and colourless concentrate for solution for infusion in a pre-filled 
syringe with a cannula. Pack size of 1. 
 
Marketing Authorisation Holder and Manufacturer 
Neovii Biotech GmbH 
Am Haag 6-7 

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48 

82166 Graefelfing 
Germany 
 
For any information about this medicine, please contact the Marketing Authorisation Holder. 
 
This leaflet was last revised in MM/YYYY. 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 
----------------------------------------------------------------------------------------------------------------------------- 
The following information is intended for healthcare professionals only: 
  
For information on dilution and administration of Removab please refer to section 6.6 of the Summary 
of Product Characteristics (SmPC) included in each package of Removab 10 micrograms and 
Removab 50 micrograms, respectively. 

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Package leaflet: Information for the patient 
 
 

Removab 50 micrograms concentrate for solution for infusion 
catumaxomab 

 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or nurse. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or nurse. This includes any possible side effects 

not listed in this leaflet. See section 4. 
 
 
What is in this leaflet 
1. What Removab is and what it is used for 
2. What you need to know before you use Removab 
3. How to use Removab 
4. Possible side effects 
5. How to store Removab 
6. Contents of the pack and other information 
 
 
1. What Removab is and what it is used for  
 
Removab contains the active substance catumaxomab, a monoclonal antibody. It recognises a protein 
on the surface of cancer cells and recruits immune cells to destroy them. 
 
Removab is used to treat malignant ascites, when standard treatment is not available or no longer 
feasible. Malignant ascites is an accumulation of fluid in the abdominal space (peritoneal cavity) 
resulting from certain types of cancer. 
 
 
2. What you need to know before you use Removab 
 
Do not use Removab 
- if you are allergic to catumaxomab or any of the other ingredients of this medicine (listed in 

section 6) 
- if you are allergic to murine proteins (from rat and / or mouse) 
 
Warnings and precautions 
Talk to your doctor or nurse before using Removab. It is important to tell your doctor if you have any 
of the following: 
- undrained fluid in your abdominal cavity 
- cold hands and feet, light headedness, difficulty passing urine, increased heart rate, and 

weakness (symptoms of low blood volume) 
- weight gain, weakness, shortness of breath and fluid retention (symptoms of low blood protein 

levels) 
- feeling dizzy and faint (symptoms of low blood pressure) 
- problems with your heart and circulation 
- kidney or liver problems 
- an infection. 
 
 

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Before you start using Removab your doctor will check your: 
- Body Mass Index (BMI), which depends on your height and weight 
- Karnofsky Index, a measure of your general performance status.  
You are required to have a BMI above 17 (after drainage of the ascites fluid) and a Karnofsky Index 
above 60 to use this medicine. 
 
Infusion-related side effects and abdominal pain are very common (see section 4). You will be given 
other medicines to reduce fever, pain or inflammation caused by Removab (see section 3). 
 
Children and adolescents 
Removab should not be used in children and adolescents under 18 years of age. 
 
Other medicines and Removab 
Tell your doctor if you are taking, have recently taken or might take any other medicines. 
 
Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before taking this medicine.You should not use Removab if you are pregnant 
unless clearly necessary.  
 
Driving and using machines 
If you experience side effects such as dizziness or chills during or after administration, you should not 
drive or use machines until they disappear. 
 
 
3. How to use Removab 
 
You will be given Removab under the supervision of a doctor experienced in treating cancer. After 
the Removab infusion you will be observed as decided by your doctor. 
 
Before starting and during treatment, you will be given other medicines to reduce fever, pain or 
inflammation caused by Removab. 
 
Removab is given as 4 intraperitoneal infusions with increasing dose (10, 20, 50 and 
150 micrograms), separated at least by 2 infusion-free calendar days (for example you will receive 
infusion on day 0, 3, 7, 10). The infusion must be administered at constant rate with duration time of 
at least 3 hours. The overall treatment period should not exceed 20 days. 
 
A catheter will be placed in your abdominal space (intraperitoneal) for the whole treatment period, 
until the day after your last infusion. 
 
If you have any further questions on the use of this product, ask your doctor. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
The most common serious side effects of Removab are infusion-related side effects and side effects 
related to the gastrointestinal system (stomach and gut). 
 
Infusion-related side effects 
During and after infusion with Removab more than 1 in 10 patients (very common) will probably 
experience infusion-related side effects. The most common infusion-related side effects, which are 
mostly mild to moderate, are fever, chills, feeling sick and vomiting.  

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If such symptoms occur, please inform your doctor as soon as possible. Your doctor may consider 
reducing the infusion rate of Removab or giving you additional treatment to reduce these symptoms. 
 
A complex of symptoms including very fast heartbeat, fever and shortness of breath can develop in up 
to 4 out of 100 patients. These symptoms occur mainly within 24 hours after a Removab infusion and 
can become life-threatening, but can be treated well with additional therapy. 
If such symptoms occur, speak to a doctor immediately, as these side effects require immediate 
attention and treatment. 
 
Side effects related to the gastrointestinal system 
Gastrointestinal reactions like abdominal pain, feeling sick, vomiting and diarrhoea occur in more 
than 1 in 10 patients (very common), but are mostly mild to moderate and respond well to additional 
treatment. 
If such symptoms occur, please inform your doctor as soon as possible. Your doctor may consider 
reducing the infusion rate of Removab or giving you additional treatment to reduce these symptoms. 
 
Other serious side effects 
 Very common serious side effects (may affect more than 1 in 10 people): 

- Tiredness  
  
 Common serious side effects (may affect up to 1 in 10 people): 

- Loss of appetite 
- Dehydration 
- Reduction in red blood cells (anaemia) 
- Decreased blood levels of calcium and sodium 
- A very fast heart beat 
- High or low blood pressure 
- Abdominal pain accompanied by difficulty or blockage passing stools, constipation 
- Shortness of breath 
- Accumulation of fluid around the lungs which cause chest pain and breathlessness 
- Inflammation of the bile ducts 
- Skin redness, rash 
- Very fast heartbeat, fever, shortness of breath, feeling faint or light-headed  
- Complex of reactions due to the release of mediators of inflammation 
- Worsening of general state of health, generally feeling unwell and weak 
- Fluid retention 
- Hypersensitivity 

 
 Uncommon serious side effects (may affect up to 1 in 100 people): 

- Lumps under the skin on the back of the legs that may become sores and leave scars 
- Inflammation and pain or burning and stinging in the area around the catheter  
- Reduction in number of blood platelets, blood clotting problems 
- Bleeding in the stomach or gut, shown by the vomiting of blood or the passage of red or black 

stools 
- Skin reaction, severe allergic skin reaction (dermatitis) 
- Fits 
- Lung problems including blood clot in the lungs 
- Low blood oxygen levels 
- Severe kidney problems 
- Extravasation (inadvertent leakage of administered medicinal product from the intraperitoneal 

catheter system into surrounding tissue) 
 

If such symptoms occur, please inform your doctor as soon as possible. Some of these side effects 
may require medical treatment.  

 
Other side effects 

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52 

 Common side effects (may affect up to 1 in 10 people): 
- Pain 
- Reduction or increase in number of white blood cells 
- Decreased blood levels of potassium 
- Decreased blood protein levels 
- Increase of bilirubin in blood 
- Spinning sensation 
- Indigestion, stomach problems, heartburn, feeling bloated, passing wind, dry mouth  
-  Flu-like symptoms 
-  Dizziness or headache 
-  Chest pain 
- Increased sweating 
- Infections  
-  Increased protein levels in urine 
- Back pain, aching muscles and joints 
- Feeling anxious and having difficulty sleeping 
- Itchy rash or hives 
- Redness of the skin in the area around the catheter 
- Flushing  
- Cough 

 
Reporting of side effects 
If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not 
listed in this leaflet. You can also report side effects directly via the national reporting system listed in 
Appendix V. By reporting side effects you can help provide more information on the safety of this 
medicine. 
 
 
5. How to store Removab 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton after EXP. The expiry date 
refers to the last day of that month. 
 
Store in a refrigerator (2°C – 8°C). Do not freeze. Store in the original package in order to protect 
from light. 
 
The prepared infusion solution should be used immediately. 
 
 
6. Contents of the pack and other information 
 
What Removab contains 
- The active substance is catumaxomab (50 micrograms in 0.5 ml, corresponding to 0.1 mg/ml). 
- The other ingredients are sodium citrate, citric acid monohydrate, polysorbate 80 and water for 

injections. 
 
What Removab looks like and contents of the pack 
Removab is presented as a clear and colourless concentrate for solution for infusion in a pre-filled 
syringe with a cannula. Pack size of 1. 
 
Marketing Authorisation Holder and Manufacturer 
Neovii Biotech GmbH 
Am Haag 6-7 

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http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


53 

82166 Graefelfing 
Germany 
 
For any information about this medicine, please contact the Marketing Authorisation Holder. 
 
This leaflet was last revised in MM/YYYY. 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 
----------------------------------------------------------------------------------------------------------------------------- 
The following information is intended for healthcare professionals only: 
  
For information on dilution and administration of Removab please refer to section 6.6 of the Summary 
of Product Characteristics (SmPC) included in each package of Removab 10 micrograms and 
Removab 50 micrograms, respectively. 

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54 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX IV 

 

GROUNDS FOR ONE ADDITIONAL RENEWAL 
 
  
 

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• Grounds for one additional renewal 

Based upon the data that have become available since the granting of the initial Marketing 
Authorisation, the CHMP considers that the benefit-risk balance of Removab remains positive, but 
considers that its safety profile is to be closely monitored for the following reasons: 

• Uncertainty in the knowledge about the rare unfavourable effects since the safety database is 
still very limited due to the low number of patients treated with Removab.  

Therefore, based upon the safety profile of Removab, which requires the submission of yearly PSURs, 
the CHMP concluded that the MAH should submit one additional renewal application in 5 years time. 

 

 

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	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT  
	A. LABELLING
	B. PACKAGE LEAFLET
	GROUNDS FOR ONE ADDITIONAL RENEWAL