REMOVAB Concentrate for solution for infusion Ref.[27988] Active ingredients: Catumaxomab

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

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.

No interaction studies have been performed.

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.

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.

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:

^* 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.

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.

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