Korjuny 10 mcg Concentrate for Solution for infusion

4.1. Therapeutic indications

Korjuny is indicated for the intraperitoneal treatment of malignant ascites in adults with epithelial cellular adhesion molecule (EpCAM)-positive carcinomas, who are not eligible for further systemic anticancer therapy.

4.2. Posology and method of administration

Korjuny must be administered under the supervision of a physician experienced in the use of anti-cancer medicinal products EpCAM testing EpCAM expression in the clinical studies was determined using a validated immunocytochemical assay applied to malignant ascites samples, with a positivity threshold of ≥ 400 EpCAM-positive cells per 10⁶ analysed ascites cells. Where a CE-marked in vitro diagnostic device with the appropriate intended purpose is not available, alternative assays used in clinical practice should be validated and demonstrate appropriate analytical performance characteristics for this intended use. Posology Prior to the intraperitoneal infusion, medication for the prophylactic treatment of cytokine release symptoms, including analgesic, antipyretic and non-steroidal antiphlogistic medicinal products is recommended (see sections 4.4 and 5.1). Side effects of catumaxomab treatment should be treated as medically indicated and according to the current standard of care. Korjuny dosing schedule comprises the 4 intraperitoneal infusions listed in table 1. Table 1 Korjuny dosing schedule Infusion number Dose Day 1 10 micrograms 0 2 20 micrograms 3 3 50 micrograms 7 4 150 micrograms 10 Patients should remain under close medical supervision for at least 24 hours after the first infusion of Korjuny. For the remaining doses, patients may be hospitalised for at least 6 hours or for a longer time after infusions of Korjuny at the discretion of the treating physician to safeguard patient safety. The interval between the infusion days can be prolonged at the discretion of the treating physician if needed in order to minimise the risk of adverse reactions. The overall treatment period should not exceed 21 days. Special populations Hepatic impairment No dose adjustment is needed for patients with mild to moderate hepatic impairment. 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 Korjuny should only be considered after a thorough evaluation of benefit/risk (see sections 4.4 and 5.2). Renal impairment No dose adjustment is needed for patients with mild renal impairment. Patients with moderate to severe renal impairment have not been studied. Treatment of these patients with Korjuny should only be considered after a thorough evaluation of benefit/risk (see sections 4.4 and 5.2). Paediatric population The safety and efficacy of Korjuny in children aged less than 18 years have not been established. No data are available. Method of administration Korjuny must be administered as an intraperitoneal infusion only. Korjuny 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 6.5. Korjuny 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 4 doses, an infusion time of 6 hours may be considered depending on the patient's health condition. Precautions to be taken before administering the medicinal product Before administration of Korjuny, the concentrate for solution for infusion is diluted in sodium chloride 9 mg/mL (0.9%) solution for injection. The diluted KORJUNY 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

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/m 2 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. 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.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

4.6. Fertility, pregnancy and lactation

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.

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

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 System Organ Class Frequency Adverse reactions Infections and infestations Common Infection Uncommon Oral candidiasis, Skin infection, Erythema induratum*, Herpes simplex*, Localised infection*, Pneumonia*, Urinary tract infection* Blood and lymphatic system disorders Common Anaemia, Leukocytosis, Lymphopenia Uncommon Coagulopathy*, Leukopenia*, Neutropenia*, Thrombocytopenia*, Thrombocythaemia Immune system disorders Very common Cytokine release syndrome** Common Systemic inflammatory response syndrome, Hypersensitivity* Metabolism and nutrition disorders Common Decreased appetite, Dehydration, Hypokalaemia, Hyponatraemia, Hypoalbuminaemia, Hyperglycaemia*, Hypocalcaemia*, Hypoproteinaemia* Uncommon Fluid retention*, Hypoglycaemia, Polydipsia, Hypomagnesaemia* Psychiatric disorders Common Anxiety* Uncommon Agitation, Depression* Nervous system disorders Common Dizziness Uncommon Syncope, Tremor, Paraesthesia, Convulsion*, Lethargy, Peripheral sensory neuropathy*, Polyneuropathy*, Dysgeusia* Eye disorders Uncommon Vision blurred* Ear and labyrinth disorders Uncommon Vertigo* Cardiac disorders Common Tachycardia Uncommon Sinus tachycardia, Palpitations*, Arrhythmia*, Cardiac failure* Vascular disorders Common Hypertension, Hypotension, Flushing, Hot flush* Respiratory, thoracic and mediastinal disorders Common Dyspnoea*, Hypoxia, Pleural effusion* Uncommon Pulmonary embolism, Acute respiratory distress syndrome*, Bronchospasm*, Cough*, Hiccups*, Lung infiltration*, Pharyngolaryngeal pain, Respiratory distress*, Respiratory failure*, Tachypnoea*, Wheezing* Gastrointestinal disorders Very common Abdominal pain, Nausea, Vomiting, Diarrhoea Common Abdominal discomfort, Abdominal distension, Upper abdominal pain, Gastrooesophageal reflux disease, Sub-ileus, Flatulence* Uncommon Abdominal cramps, Dry mouth, Ileus paralytic, Impaired gastric emptying, Abdominal rigidity*, Ascites*, Duodenogastric reflux*, Gastric disorder*, Gastrointestinal hypomotility*, Heartburn*, Peritonitis*, Retching*, Small intestinal obstruction*, Stomach discomfort*, Lower abdominal pain, Haematemesis*, Stomatitis* Hepatobiliary disorders Common Hyperbilirubinaemia, Cholangitis* Uncommon Cytolytic hepatitis***, Hepatic failure****, Cholestasis*, Hepatic function abnormal*, Hepatitis toxic*, Jaundice* Skin and subcutaneous tissue disorders Common Dermatitis allergic, Rash, Erythema, Hyperhidrosis, Pruritis Uncommon Night sweats, Urticaria, Palmar erythema*, Rash pruritic*, Skin reaction Musculoskeletal and connective tissue disorders Common Back pain, Myalgia, Arthralgia* Uncommon Bone pain, Flank pain*, Musculoskeletal pain*, Pain in extremity* Renal and urinary disorders Common Haematuria, Proteinuria* Uncommon Dysuria*, Leukocyturia, Oliguria*, Renal failure*, Renal failure acute*, Renal pain* Reproductive system and breast disorders Uncommon Pelvic pain General disorders and administration site conditions Very common Pyrexia, Chills, Fatigue, Pain Common Asthenia*, Inflammation, Oedema, Chest pain, Influenza-like illness*, Malaise*, Oedema peripheral* Uncommon Application site inflammation, Catheter site pain, Early satiety*, Extravasation, Feeling cold*, Feeling hot*, Injection site reaction*, Mucosal inflammation*, Thirst, Catheter site erythema*, General physical health deterioration* Investigations Very common C-reactive protein increased Common Alanine aminotransferase increased, Aspartate aminotransferase increased, Blood alkaline phosphatase increased, Body temperature increased, Gamma-glutamyltransferase increased, Haemoglobin decreased, Neutrophil count increased, Protein total decreased, Weight decreased, White blood cell count increased, Blood creatinine increased*, Blood potassium decreased*, Hepatic enzyme increased*, Procalcitonin increased*, Blood urea increased, Blood amylase increased*, Blood creatinine phosphokinase increased*, Platelet count increased* Uncommon Bilirubin conjugated increased, Body temperature decreased, Oxygen saturation decreased, Transaminases increased, Blood fibrinogen increased*, Blood iron decreased*, Blood lactate dehydrogenase increased*, Blood pressure increased*, Cells in urine*, Elevated liver enzymes, Haematocrit decreased, Lipase increased*, Liver function test abnormal*, Red blood cell count decreased*, Urobilin urine present, White blood cells urine positive*, Activated thromboplastin time prolonged*, Blood chloride decreased*, Blood sodium decreased*, Blood uric acid increased*, International normalised ratio increased* Injury, poisoning and procedural complications Uncommon Anastomotic complication*, Procedural pain*, Wound dehiscence* * 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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms Higher planned doses of catumaxomab were investigated in dose escalation studies, up to single treatment courses of catumaxomab 10-20-50-200-200 micrograms. Overall, effects observed with catumaxomab doses higher than the proposed dose were in line with known adverse reactions associated with catumaxomab administration and its mechanism of action. Laboratory values, notably changes in liver parameters, showed transient increases that were dose-dependent and showed tendency to accumulate. Treatment No antidote for catumaxomab is available. In case of overdose, symptomatic treatment should be initiated at the physician's discretion.