Removab (Concentrate) Instructions for Use

Marketing Authorization Holder

RaiPharm, LLC (Russia)

Manufactured By

Vetter Pharma-Fertigung, GmbH & Co. KG (Germany)

Labeled By

FRESENIUS BIOTECH, GmbH (Germany)

ATC Code

L01FX03 (Catumaxomab)

Active Substance

Catumaxomab (Rec.INN registered by WHO)

Dosage Form

Removab

Concentrate for preparation of solution for intraperitoneal administration 0.1 mg/ml: 100 µl or 500 µl syringes

Dosage Form, Packaging, and Composition

Concentrate for preparation of solution for intraperitoneal administration transparent, colorless.

Excipients: sodium citrate dihydrate 24.4 mg, citric acid monohydrate to pH 5.6, polysorbate 80 0.216 mg, water for injections to 1 ml.

100 µl – syringes (1) made of borosilicate glass – blister packs (1) made of PVC/paper complete with a cannula – cardboard boxes.
500 µl – syringes (1) made of borosilicate glass – blister packs (1) made of PVC/paper complete with a cannula – cardboard boxes.

Clinical-Pharmacological Group

Antitumor drug. Monoclonal antibodies

Pharmacotherapeutic Group

MIBP-monoclonal antibodies

Pharmacological Action

Catumaxomab is a hybrid monoclonal trifunctional bispecific antibody against epithelial cell adhesion molecules (EpCAM) and the CD3 antigen.

EpCAM antigen expression is pronounced on the surface of most malignant tumor cells. CD3 expression is carried out predominantly on mature T-lymphocytes and is a component of T-lymphocyte receptors. The third binding site is the Fc fragment of catumaxomab, which interacts with accessory immune cells carrying the Fcy receptor on their surface.

Due to the binding ability of catumaxomab, tumor cells, T-lymphocytes, and accessory immune cells are brought into close proximity. Thus, a coordinated immune response against tumor cells is induced, which includes mechanisms such as T-lymphocyte activation, antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and phagocytosis. As a result of the combined action of these mechanisms, tumor cell death occurs.

The antitumor activity of catumaxomab was studied in in vitro and in vivo studies. The efficacy of catumaxomab was confirmed in an in vitro study against tumor cells with low and high EpCAM antigen expression, regardless of tumor type. The activity of catumaxomab was confirmed in vivo in models of immunologically induced ovarian cancer in mice; tumor development ceased after treatment with intraperitoneal administration of catumaxomab and human mononuclear cells.

Immunogenicity

Induction of human anti-mouse (rat and/or mouse) antibodies (HAMAs/HARAs) is characteristic of murine monoclonal antibodies. In a conducted study, it was found that 5.6% of patients (7 out of 124) had HAMA antibodies detected before the 4th administration of the drug. Anti-mouse HAMA antibodies were detected in 94% of patients one month after the last administration of catumaxomab. Hypersensitivity reactions were not observed.

In patients whose blood had detectable HAMA antibodies 8 days after catumaxomab administration, unlike patients who did not develop antibodies, a positive effect of antibody detection on treatment efficacy was noted, as confirmed by overall survival rates, time to first paracentesis, and time to next paracentesis.

Pharmacokinetics

The geometric mean value of the maximum concentration (C_max) of catumaxomab in blood plasma is 0.5 ng/ml (range from 0 to 2.3), the geometric mean value of the area under the concentration-time curve (AUC) is 1.7 day×ng/ml (range from below the lower limit of quantification to 13.5). The geometric mean value of the half-life (T_1/2) is about 2.5 days (from 0.7 to 17 days). Interindividual variability of pharmacokinetic parameters in patients is significant.

Catumaxomab is detected in ascitic fluid and blood plasma. The concentration of the drug increases proportionally with increasing drug dose and number of administrations.

The concentration of the drug in blood plasma tends to decrease after reaching the maximum concentration after each drug dose administration. Studies on the pharmacokinetics of catumaxomab in special patient groups have not been conducted.

Indications

• Treatment of carcinomatous ascites in patients with EpCAM-positive malignant tumors when standard therapy is ineffective or inappropriate.

ICD codes

Dosage Regimen

Intraperitoneally.

Treatment should be prescribed and monitored by a surgeon experienced in the diagnosis and treatment of patients with malignant neoplasms. Adequate monitoring of the patient’s condition after administration of Removab is necessary. In pivotal studies, patient monitoring continued for 24 hours after drug administration. Premedication with non-narcotic analgesics and NSAIDs is administered before Removab administration.

Dosage regimen of Removab

The drug is administered as 4 intraperitoneal infusions

Process of infusion administration of the drug

The procedure is performed by an experienced physician. The catheter for intraperitoneal administration is inserted under ultrasound guidance. The catheter is used for drainage of the abdominal cavity, removal of ascitic fluid, as well as for administration of the diluted Removab concentrate and 0.9% sodium chloride solution. The catheter remains in the abdominal cavity for the entire treatment period. The catheter is removed the day after the last infusion of the drug. Before each drug administration, ascitic fluid is removed through the catheter until spontaneous discharge ceases or symptoms (e.g., dyspnea, nausea, abdominal pain, or bloating) disappear. Also, 500 ml of 0.9% sodium chloride solution is preliminarily administered through the catheter to ensure uniform distribution of antibodies in the abdominal cavity. Removab is administered intraperitoneally over 3 or more hours at a constant rate using an infusion pump system.

A 50 ml syringe containing the infusion solution with Removab is placed in the pump.

The perfusion tube connected to the pump is pre-filled with the solution containing Removab. The use of a perfusion tube with an internal diameter of 1 mm and a length of 150 cm is recommended.

The perfusion tube is connected to a Y-connector.

Simultaneously with the administration of Removab, 250 ml of 0.9% sodium chloride solution is administered through the infusion valve/Y-connector and the perfusion catheter guide.

The pump rate is adjusted depending on the volume of the drug required for administration over the intended infusion time.

When the contents of the 50 ml syringe containing Removab are finished, it is replaced with a 50 ml syringe containing 20 ml of 0.9% sodium chloride solution, its contents are administered over the remaining intended infusion time to flush the unused volume of the drug solution in the perfusion guide (about 2 ml) under unchanged conditions. The remaining amount of sodium chloride solution can be discarded.

The catheter is left closed until the next drug administration.

One day after the last drug dose administration, final drainage of the abdominal cavity is performed until spontaneous discharge of ascitic fluid ceases, after which the catheter is removed.

Adverse Reactions

Characterization of the safety profile

The safety profile of Removab is generally characterized by symptoms due to cytokine release, as well as those related to gastrointestinal disorders.

Reactions due to cytokine release, such as increased body temperature, chills, nausea, and vomiting, occur very often with intensity of grade 1-2 (according to version 3 of the Common Terminology Criteria for Adverse Events of the National Cancer Institute (CTCAE), USA). The occurring symptoms are related to the mechanism of action of catumaxomab and are generally completely reversible.

Systemic inflammatory response syndrome, including tachycardia, increased body temperature and/or dyspnea, and having life-threatening intensity for the patient, is observed less frequently, occurs within 24 hours after Removab administration, and ceases with symptomatic therapy. Gastrointestinal reactions, such as abdominal pain, nausea, vomiting, and diarrhea, occur often, in most cases have intensity of grade 1 or 2, but can be more severe, and cease in response to adequate symptomatic therapy.

The safety profile of catumaxomab when administered over 3 and 6 hours was generally comparable in nature, frequency, and severity of adverse reactions. With three-hour drug administration, chills and decreased blood pressure (grade 1/2), diarrhea (various intensities), and increased fatigue (grade 1/2) were most frequently observed.

Adverse reactions are grouped by frequency of occurrence: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, <1/100); rare (≥ 1/10,000, <1/1000); very rare (<1/10,000), including isolated reports. Separately (*) adverse reactions classified as serious are marked.

Infections and infestations common – infections, urinary tract infections; uncommon – inflammatory skin lesions (indurative erythema)*, catheter-related infections*.

Blood and lymphatic system disorders common – anemia, lymphopenia, leukocytosis, neutrophilic leukocytosis, thrombocytosis; uncommon – thrombocytopenia*.

Immune system disorders common – cytokine release reactions*, hypersensitivity reactions.

Metabolism and nutrition disorders common – decreased appetite*/anorexia, dehydration*, hypokalemia, hyponatremia, hypocalcemia, hypoproteinemia, hyperglycemia, hypoalbuminemia.

Psychiatric disorders common – insomnia, anxiety.

Nervous system disorders common – headache, dizziness; uncommon – seizures*.

Ear and labyrinth disorders common – vertigo.

Cardiac disorders common – tachycardia*, including sinus tachycardia, decreased blood pressure*, increased blood pressure*, hot flush, facial flushing.

Respiratory, thoracic and mediastinal disorders common – dyspnea*, pleural effusion*, hypoxia*, cough; uncommon – pulmonary embolism*.

Gastrointestinal disorders very common – abdominal pain*, nausea*, vomiting*, diarrhea*; common – constipation*, abdominal distension, dyspepsia, flatulence, obstruction of jejunum and ileum*, ulcerative lesion of gastric mucosa, reflux esophagitis; uncommon – gastrointestinal hemorrhage*, intestinal obstruction*.

Hepatobiliary disorders common – cholangitis, hyperbilirubinemia.

Skin and subcutaneous tissue disorders common – skin rash, erythema, pruritus, hyperhidrosis, allergic dermatitis*; uncommon – skin reactions*.

Musculoskeletal and connective tissue disorders common – back pain, myalgia, arthralgia.

Renal and urinary disorders common – proteinuria, hematuria, leukocyturia; uncommon – acute renal failure*.

General disorders and administration site conditions very common – pyrexia*, fatigue*, chills*, pain; common – systemic inflammatory response syndrome*, asthenia, edema, including peripheral, chest pain, influenza-like illness, malaise, redness at the catheter insertion site; uncommon – extravasation*, inflammation at the administration site*, general health deterioration*.

*serious adverse reactions

Description of selected adverse reactions

Criteria for assessing the severity of adverse reactions according to the CTCAE classification of the National Cancer Institute, USA (version 3): grade 1 – mild, grade 2 – moderate; grade 3 – severe, grade 4 – life-threatening.

Severe symptoms due to cytokine release

In 4.4% of patients, increased body temperature reached grade 3, the same severity grade was noted for cytokine release syndrome (1.2%), and for symptoms such as chills (1.0%), nausea (3.7%), vomiting (5.6%), dyspnea (1.4%), and decreased and increased blood pressure (1.9%/1.2%). One patient (0.2%) had grade 4 dyspnea, and 3 patients (0.6%) had grade 4 decreased blood pressure. The use of symptomatic therapy reduces the severity of pain and fever syndrome.

Systemic inflammatory response syndrome

In 4.6% of patients, systemic inflammatory response syndrome is observed within 24 hours after Removab administration. In 3 patients (0.6%), grade 4 severity was noted. Symptomatic therapy reduces the severity of the clinical manifestations of the syndrome.

Abdominal pain

In 48.4% of patients, abdominal pain occurs, in 9.9% its intensity reaches grade 3 severity, symptomatic therapy may reduce the severity of the pain syndrome.

Contraindications

• Severe general condition of the patient (body mass index <17, Karnofsky index <60);
• Acute infectious processes;
• Pregnancy;
• Lactation;
• Age under 18 years;
• Hypersensitivity to catumaxomab, proteins of murine (rat and/or mouse) origin, as well as to other components of the drug, severe general condition of the patient (body mass index <17, Karnofsky index <60).

With caution.

Due to insufficient clinical experience with the use of Removab in patients with severe hepatic impairment and metastatic liver involvement of more than 70%, in patients with thrombosis of the central and portal veins of the liver, with severe obstruction of the hepatic veins; with severe renal impairment, the decision to use Removab may be made after mandatory consideration of the possible risk to the patient.

Use in Pregnancy and Lactation

Contraindicated during pregnancy and lactation.

Use in Hepatic Impairment

Due to insufficient clinical experience with the use of Removab in patients with severe hepatic impairment and metastatic liver involvement of more than 70%, in patients with thrombosis of the central and portal veins of the liver, the decision to use Removab may be made after mandatory consideration of the possible risk to the patient.

Use in Renal Impairment

Due to insufficient clinical experience in severe renal impairment, the decision to use Removab may be made after mandatory consideration of the possible risk to the patient.

Pediatric Use

Contraindicated in children under 18 years of age.

Special Precautions

Removab should not be mixed with other drugs and it is prohibited to administer it as a bolus or by any other method except the intraperitoneal infusion method described above.

Women of childbearing potential should use effective and reliable methods of contraception during treatment with Removab.

Symptoms due to cytokine release

Since the binding of catumaxomab to immune system cells and tumor cells initiates the release of inflammatory mediators and cytokines with cytotoxic activity, patients experience clinical symptoms such as increased body temperature, nausea, vomiting, chills. Dyspnea, decreased or increased blood pressure often occur. To prevent severe pain syndrome and significant increase in body temperature in patients, it is recommended to administer 1000 mg of paracetamol intravenously before infusion administration of Removab. Despite premedication, the occurrence of the listed symptoms of grade 3 severity is possible. In such cases, other drugs should be used to enhance premedication.

A systemic inflammatory response to the cytotoxic activity of catumaxomab is often noted, it develops within 24 hours after Removab administration and is manifested by increased body temperature, palpitations, increased respiratory rate, and leukocytosis is noted in the blood count. The use of non-narcotic analgesics and non-steroidal anti-inflammatory drugs may reduce the risk of occurrence and severity of the syndrome.

Abdominal pain

The occurrence of abdominal pain is often observed, is short-term, and is probably due, first of all, to the method of drug administration – administration as an intraperitoneal infusion.

General condition of patients and body mass index

Before starting treatment with Removab, the general condition of the patient should be assessed, after drainage of the abdominal cavity and removal of ascitic fluid, determine the body mass index (>17) and the Karnofsky index (> 60).

Acute infectious diseases

In the presence of factors affecting the immune system, for example, acute infectious diseases, the use of Removab is not recommended.

Drainage of the abdominal cavity for removal of ascitic fluid

For the administration of Removab, it is recommended to use only the following equipment

• Polypropylene syringes with a volume of 50 ml
• Polyethylene perfusion tubes with an internal diameter of 1 mm and a length of 150 cm
• Polycarbonate infusion valves/Y-connectors
• Catheters made of uncoated polyurethane or with silicone coating

Store the syringe in the consumer packaging to protect from light.

Storage of the Ready-to-Use Solution of Removab

The ready-to-use solution is physically and chemically stable for 48 hours at a temperature of 2 to 8°C (46.4°F) and for 24 hours at a temperature not exceeding 25°C (77°F).

According to the requirements for microbiological sterility, the drug should be used immediately after dilution.

If the administration of the drug is delayed, the timing of its use and the compliance with storage conditions are the responsibility of the user, but should not exceed 24 hours at a temperature of 2 to 8°C (46.4°F), provided that the drug was diluted under the necessary sterile conditions.

Effect on the Ability to Drive Vehicles and Operate Machinery

During treatment with Removab, a number of symptoms associated with the infusion of the drug may occur, which may adversely affect the ability to drive a car and operate complex machinery; therefore, until the symptoms subside, patients should refrain from activities requiring concentration and high speed of psychomotor reactions.

Overdose

No cases of overdose have been reported. Unintentional administration of doses exceeding the recommended ones resulted in an increased severity of adverse reactions (up to grade 3).

Drug Interactions

No studies on drug interactions have been conducted.

Storage Conditions

In a light-protected place at a temperature of 2 to 8°C (46.4°F). Keep out of reach of children.

Shelf Life

Shelf life – 2 years.

Dispensing Status

By prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.