Catumaxomab

Patients with moderate to severe renal impairment have not been studied. Treatment of these patients with catumaxomab should only be considered after a thorough evaluation of benefit/risk.

Patients with severe hepatic impairment 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. Patients should be monitored for signs and symptoms of infection, before and after catumaxomab administration and treated appropriately.

Appropriate medical management of ascites drainage is a prerequisite for catumaxomab 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.

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.

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.

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.

Women of childbearing potential

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

Fertility

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

Catumaxomab has minor 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

The most commonly reported adverse reactions were pyrexia (62%), abdominal pain (42%), nausea (41%), and vomiting (38%). The most serious adverse reactions are systemic inflammatory response syndrome and hepatic failure.

Tabulated list of adverse reactions

Adverse reactions are derived from an integrated safety analysis of 11 studies including 4 studies in patients with malignant ascites and 7 studies in patients with various other cancers. This includes data from the randomised, controlled main study period from pivotal study IP-REM-AC-01. Of 517 patients included in the analysis, 293 patients received catumaxomab intraperitoneally as 6-hour infusion and 224 patients received catumaxomab intraperitoneally as 3-hour infusion.

In the following table, adverse reactions are listed by MedDRA system 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). Within each frequency grouping the adverse reactions are presented in the order of decreasing seriousness.

Adverse reactions reported from patients receiving catumaxomab treatment:

^* Adverse reaction terms indicated by asterisk are included due to the inclusion of n=7 studies in indications other than malignant ascites (e.g. in cancer subjects undergoing curative surgery and intraoperative administration of catumaxomab)
^** n=7 events of cytokine release syndrome (CRS) were specifically reported as event terms in 6 of 517 subjects each treated with catumaxomab in the 11 studies included in the analysis (frequency category "common"). However, the frequency of CRS displayed in the above table is based on the retrospective, algorithm-based analysis of CRS that was used in the pivotal study IP-REM-AC-01 where the algorithm took into consideration diagnoses of CRS as well as a combination of symptoms such as fever, hypotension, gastrointestinal symptoms, headache, myalgia, arthralgia, tachycardia, chills, respiratory symptoms, skin symptoms and fatigue.
^*** n=3 events of cytolytic hepatitis were reported in 3 subjects; however, 2 events were of mild intensity and one was of moderate intensity, and all 3 events were assessed as non-serious.
^**** n=5 events of hepatic failure were reported in 3 subjects; all events were of moderate intensity and assessed as non-serious. Most of these events consisted of increased hepatic/hepatobiliary laboratory values.

Description of selected adverse reactions

Cytokine release syndrome

Cytokine release syndrome (CRS), identified based on occurrence of hallmark symptoms for CRS (fever, hypotension, gastrointestinal symptoms, headache, myalgia, arthralgia, tachycardia, chills, respiratory symptoms, skin symptoms, and fatigue) in close temporal relationship (fever and at least 2 additional adverse reactions within a 4 day time window). At the time of the conduct of the pivotal study, 72% of catumaxomab exposed patients (ISS2) experienced at least one adverse event counted as hallmark symptoms of CRS during or within 1 day after a catumaxomab infusion. As the analysis was highly unspecific, data from the pivotal study were reanalysed according to an algorithm based on current CRS definitions and guidelines. Based on this re-analysis, 23% of patients treated with catumaxomab experienced CRS in the main study period or the crossover period of the pivotal clinical phase II/III study.

In the majority of cases, CRS was of CTCAE grade 1 or 2. Of 41 suspected CRS episodes, 3 were of grade 1, 27 were of grade 2, 10 were of grade 3, and 1 was of grade 4. Symptoms of cytokine release can be ameliorated or avoided by pre-medication.

Systemic inflammatory response syndrome (SIRS)

SIRS (with concurrent fever, increased heart rate and respiratory rate, and abnormal leukocyte count) was reported in 2 patients out of 203 patients exposed to catumaxomab in the pivotal study (157 in the main study period, 46 after crossover from control to catumaxomab). In both patients, SIRS was of Grade 4, required hospitalisation/prolongation of hospitalisation, and led to discontinuation of the treatment.

Abdominal pain

In 38.9% of patients in the main study period of the pivotal study, abdominal pain was reported as an adverse reaction, reaching grade 3 or higher in 8.9% of patients, but it resolved under symptomatic treatment.

Hepatic laboratory values

Transient increases in hepatic enzymes (alanine transaminase [ALT], aspartate transaminase [AST], alkaline phosphatase [ALP], gamma-glutamyl transferase [GGT]) and total bilirubin were 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. In the pivotal clinical phase II/III study, 12 patients (5.6%) treated with catumaxomab experienced elevations of ALT of >3 × upper limit of normal (ULN) in conjunction with bilirubin >2 × ULN. In 2 of 12 patients, values continued to increase after end of infusion whereas in 10 of 12 patients, the increased values were reversible and showed a trend to improve shortly after the last catumaxomab infusion. Only in case of clinically relevant or persisting increase further diagnostics or therapy should be considered.

Duration of infusion

Data on a 3-hour infusion duration of catumaxomab are available from studies in malignant ascites and studies in other oncological indications, mainly ovarian cancer and gastric cancer. The safety profile of catumaxomab using a 3 hour versus a 6-hour infusion time is in general comparable with regards to nature, frequency and severity of adverse reactions. An increased frequency of some adverse reactions was seen in relation to 3-hour administration including chills and hypotension (grades 1 or 2), diarrhoea (all grades) fatigue (grade 1 or 2), anaemia (all grades), and pleural effusion (grades 1 or 2).