Catumaxomab

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

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

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 catumaxomab should only be considered after a thorough evaluation of benefit/risk.

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

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

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 catumaxomab 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.

Catumaxomab 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 catumaxomab 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.

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 catumaxomab. 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.