KORJUNY Concentrate for solution for infusion Ref.[114664] Active ingredients: Catumaxomab

Korjuny must not be administered as a bolus or by any route other than intraperitoneally.

Cytokine release related symptoms (CRS)

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 have been reported during and after catumaxomab administration, including events of fever, hypotension, gastrointestinal symptoms, headache, myalgia, arthralgia, tachycardia, chills, respiratory symptoms, skin symptoms, and fatigue.

Despite pre-medication (see sections 4.2 and 5.1), patients may experience CRS as described above with an intensity of up to grade 4, (see section 4.8). Patients should be counselled to seek immediate medical attention if signs or symptoms of CRS occur at any time. CRS should be treated as medically indicated and according to the current standard of care.

Systemic inflammatory response syndrome (SIRS)

Isolated incidence of SIRS (with concurrent fever, increased heart rate and respiratory rate, and abnormal leukocyte count) have been reported during and after treatment with catumaxomab. Patients should be counselled to seek immediate medical attention if signs or symptoms of SIRS occur at any time. SIRS should be treated as medically indicated and according to the current standard of care.

Acute infections

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 Korjuny administration and treated appropriately.

Conditions affecting haemodynamic status of patients

Appropriate medical management of ascites drainage is a prerequisite for Korjuny 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 Korjuny infusion. Conditions such as hypovolaemia, hypoproteinaemia, hypotension, circulatory decompensation and acute renal impairment must be resolved prior to each Korjuny infusion.

Hepatic function

No dose adjustment is needed for patients with mild to moderate hepatic impairment. Transient elevations of liver parameters after catumaxomab infusions were observed in clinical studies which subsequently improved in the majority of patients shortly after completion of the last catumaxomab infusion. In rare cases, catumaxomab -drug induced liver injury (DILI) or hepatitis may occur, potentially leading to hepatic failure including fatal outcome. Patients treated with Korjuny should be closely monitored for signs of clinically significant elevated liver parameters.

Patients with severe hepatic impairment and/or with more than 70% of the liver volume involved by metastatic disease 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 (see section 5.2).

Renal impairment

Catumaxomab is not eliminated via the renal pathway. Patients with moderate to severe renal impairment have not been investigated. Treatment of these patients with Korjuny should only be considered after a thorough evaluation of benefit/risk (see section 5.2).

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.

Monitoring

Adequate monitoring of the patient after end of Korjuny infusion is recommended with close medical supervision for at least 24 hours after the first infusion of Korjuny and for at least 6 hours after subsequent infusions.

Performance status and Body Mass Index (BMI)

In the pivotal study IP-REM-AC-01, patients with a Karnofsky performance score of <60 and with a BMI of <17 or >40 kg/m² have not been investigated. Treating these patients with Korjuny is at the discretion of the treating physician.

Patient card

The prescriber must discuss the risks of Korjuny therapy with the patient. The patient should be provided with the patient card and instructed to carry it at all times. The patient card describes the common signs and symptoms of CRS and SIRS and provides instructions on when a patient should seek medical attention.

Excipient

This medicine contains 21.6 micrograms polysorbate 80 in each pre-filled syringe Korjuny 10 micrograms and 108 micrograms of polysorbate 80 in each pre-filled syringe Korjuny 50 micrograms. Polysorbates may cause allergic reactions.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose unit, that is to say essentially ‘sodium-free’. The amount of sodium administered per infusion is higher than that contained in the medicinal product due to the dilution of the concentrate with sodium chloride 9 mg/mL (0.9%) solution for injection. An additional 500 mL of sodium chloride 9 mg/mL (0.9%) solution for injection is given before each Korjuny administration and 250 mL of sodium chloride 9 mg/mL (0.9%) solution for injection is given in parallel with each Korjuny administration. See section 6.6.

No interaction studies have been performed.

Women of childbearing potential

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

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). Korjuny is not recommended during pregnancy.

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 Korjuny 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.

Korjuny 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 Table 2, 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.

Table 2. 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 (see sections 4.2 and 4.4).

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).

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.