TheraCIM

TheraCIM

nimotuzumab

Manufacturer:

Innogene Kalbiotech

Distributor:

Alliance Pharma
Full Prescribing Info
Contents
Nimotuzumab.
Description
Each 10 mL also contains the following excipients: Dibasic sodium phosphate 18 mg, monobasic sodium phosphate 4.5 mg, sodium chloride 86 mg, polysorbate 80 2 mg and water for injection to make 10 mL.
TheraCIM is a recombinant humanized monoclonal antibody that binds to the extracellular domain of human epidermal growth factor receptor (EGFR). The humanized antibody (IgG1) was obtained by transplanting the complementarity determining regions (CDRs) of the murine IgG2a monoclonal antibody (ior egf/r3) to a human framework assisted by computer modeling. A reshaped antibody was constructed using the light and heavy chains (REI and Eu, respectively) as human immunoglobulin framework for CDR-grafting. TheraCIM is produced through mammalian cell culture of nonsecreting NSO cells and has a molecular weight of 151 KD.
Action
Pharmacology: Nimotuzumab binds with intermediate affinity and high specificity to the extracellular domain of epidermal growth factor receptor (EGFR, HER1, c-Erb-1). Nimotuzumab blocks the binding of the EGF and other ligands eg, transforming growth factor α, etc, to its receptor and inhibits in vivo and in vitro tumor cell growth. Nimotuzumab has a potent anti-angiogenic, antiproliferative and pro-apoptotic effects, and also decreases motility, cell invasion and metastasis in those tumors that overexpress the EGFR.
EGFR is expressed in cells from all 3 embryonic layer cells especially in cells of epithelial origin (skin; respiratory, gastrointestinal and urinary tract; and liver). EGFR is present in a wide diversity of human tumors of epithelial origin eg, non-small cell lung cancer (NSCLC), head and neck, pancreatic, colon, breast, kidney, ovarian and bladder carcinomas. It is also overexpressed in glioma and uterine cervical cancers.
Pharmacokinetics: Nimotuzumab administered in combination with concomitant chemotherapy or radiotherapy exhibits nonlinear pharmacokinetics. Following a 30-min infusion, the area under the concentration time curve (AUC) increased in a greater than dose-proportional manner as the dose increased from 50-400 mg. Evidence from an animal pharmacokinetic study indicates that the concentration of the antibody in tumors is highest at 24 hrs after injection. In humans, the volume of the central compartment (Vc) for nimotuzumab ranged from 2.3-7.2 L and maximal concentration (Cmax) was 27-57 ng/mL for 50-400 mg doses, respectively. Nimotuzumab is mainly distributed in liver, spleen, heart, kidney and bladder. Most of the antibodies uptake were by the liver.
Nimotuzumab clearance (CL) decreased from 1.08 to 0.34 mL/hr/kg as the dose increased from 50-200 mg and at doses >200 mg, it appeared to plateau. Pharmacokinetic analysis of plasma clearance curves showed terminal half-life times (t½β) for 50-, 100-, 200- and 400-mg doses of 62, 82, 302 and 304 hrs, respectively. Under normal physiological conditions, the percentage of injected dosage discharged through the urinary tract are 21.1%, 28.2%, 27.36% and 33.57% for 50 mg, 100 mg, 200 mg and 400 mg, respectively.
Indications/Uses
Treatment of relapsed high-grade gliomas in children and adolescents, relapsed high grade glioma in adults in combination with radiation therapy, advanced squamous cell carcinoma of the head and neck (SCCHN) with concurrent radiotherapy or chemoradiotherapy.
Dosage/Direction for Use
Relapsed High-Grade Glioma: Children and Adolescents: Monotherapy in 2 consecutive phases. Induction Phase: 150 mg/m2 body surface area (BSA) weekly for 6 weeks. Consolidation Phase: After induction phase, patients without progressive disease upon 8th week evaluation will be given with 150 mg/m2 BSA every 3 weeks until disease progression.
Relapsed High-Grade Glioma In Combination with Radiation Therapy: Adults: 200 mg weekly for 6 weeks with radiation and maintenance with 200 mg every 21 days for 1 year.
SCCHN: 200 mg once weekly for 6-8 weeks in combination with standard radiotherapy or chemoradiotherapy by continuous IV infusion.
Administration: TheraCIM is administered as continuous IV infusions as monotherapy for relapsed glioma in pediatric/adolescent. Nimotuzumab is diluted in 250 mL of sodium chloride 0.9% solution and administered IV within 30 min. Pre-treatment with diphenhydramine is recommended to minimize possible infusion reaction.
Overdosage
A phase I study conducted in Canada has demonstrated that doses up to 800 mg/week are safe and well tolerated in humans.
Contraindications
No contraindications have been reported to date.
Special Precautions
TheraCIM should be administered with caution in patients who have previously received treatment with the murine monoclonal antibody ior egf/r3, patients with previous notification of having hypersensitivity to nimotuzumab or other products derived from NSO mammalian cells or any component of TheraCIM. TheraCIM should be used with caution in patients with chronic diseases in decompensate phase eg, cardiac dysfunction, diabetes mellitus or arterial hypertension or in patients with history of severe allergic reaction.
TheraCIM should be applied under the supervision of skilled clinical doctors.
Use in pregnancy: Effects of nimotuzumab on pregnancy have not been studied. However, animal studies have shown that at the embryonic stage, lack of EGFR can cause lack of maturation of the epithelium and postnatal death. EGFR has been implicated in the control of prenatal development and hence may be essential for normal organogenesis, proliferation and differentiation in the developing embryo. Human IgG1 is known to cross the placental barrier; therefore, the antibody has the potential to be transmitted from the mother to the developing fetus. The use of nimotuzumab during pregnancy is not recommended. The antibody should only be given to a pregnant woman or any woman not employing adequate contraception if the potential benefit outweighs the potential risks to the fetus. If the patient becomes pregnant while receiving nimotuzumab, the patient should be informed of the potential hazard to the fetus and/or the potential risk of loss of the pregnancy.
Use in lactation: Nimotuzumab is secreted in human milk, therefore, it is not recommended for use in lactating women. No recommendation is made on the potential benefit versus risk of administering nimotuzumab to nursing mothers.
Use in children: A phase II clinical study in pediatric patients with brain tumors was done and showed no significant adverse events related to nimotuzumab. Efficacy in heavily pre-treated relapsed high grade gliomas in children and adolescents has been demonstrated in the phase II study. The repeated application of nimotuzumab as monotherapy was well tolerated and safe. The clinical deteriorations were mostly associated with complications of the tumor disease, tumor progressions or rarely, with another concomitant disease. In particular, no allergic reactions or severe skin or gastrointestinal toxicity were observed. No safety concerns arose from laboratory tests, vital signs or physical examination findings. No severe hematological or nonhematological side effects associated with the nimotuzumab monoclonal antibody were seen. A phase III study of newly diagnosed diffuse intrinsic pontine glioma in pediatric/adolescent is currently ongoing.
Use In Pregnancy & Lactation
Use in pregnancy: Effects of nimotuzumab on pregnancy have not been studied. However, animal studies have shown that at the embryonic stage, lack of EGFR can cause lack of maturation of the epithelium and postnatal death. EGFR has been implicated in the control of prenatal development and hence may be essential for normal organogenesis, proliferation and differentiation in the developing embryo. Human IgG1 is known to cross the placental barrier; therefore, the antibody has the potential to be transmitted from the mother to the developing fetus. The use of nimotuzumab during pregnancy is not recommended. The antibody should only be given to a pregnant woman or any woman not employing adequate contraception if the potential benefit outweighs the potential risks to the fetus. If the patient becomes pregnant while receiving nimotuzumab, the patient should be informed of the potential hazard to the fetus and/or the potential risk of loss of the pregnancy.
Use in lactation: Nimotuzumab is secreted in human milk, therefore, it is not recommended for use in lactating women. No recommendation is made on the potential benefit versus risk of administering nimotuzumab to nursing mothers.
Adverse Reactions
Common adverse events with recommended dose reported following administration of nimotuzumab that are at least possibly related to nimotuzumab include chills, fatigue, headache, nausea, pyrexia, tremors and vomiting. In the pediatric trial, nonserious adverse events considered at least possibly related to nimotuzumab included erythema, fatigue, headache, leucopenia, nausea and vomiting. Rare adverse events reported were myalgia, somnolence, disorientation, hematuria and elevated liver function enzymes. In clinical experience, potentially fatal allergic reaction was very rarely reported. This event includes rapid and severe hypotension and urticaria.
Drug Interactions
The interaction of nimotuzumab with other cytostatic drugs has not been widely evaluated to date. The combination of nimotuzumab with various chemotherapy agents (docetaxel, carboplatin and capecitabine) were explored in 19 patients with malignant gliomas or squamous cell carcinoma of head and neck and found acceptable toxicity. Synergistic effects and potentiation of the anti-tumor activity had been already shown when other EGFR inhibitors have been used in combination with chemotherapy.
Caution For Usage
Preparation for Administration: Do not shake the content of the vial. A vigorous shaking could denature the protein and affect the biological activity of TheraCIM. TheraCIM should be inspected visually for particulates and discoloration prior to administration. If these are present, do not use the product. Use a sterile syringe and appropriate aseptic technique. Remove the cap from the vial containing TheraCIM and clean the top of the vial with antibacterial solution and insert the needle into the vial to extract the content. TheraCIM at the selected dosage should be diluted in 250 mL of sodium chloride 0.9%.
Storage
Store in a refrigerator at 2-8°C. The biological activity of the antibody may be lost after freezing and thawing. Do not freeze or shake.
The antibody diluted in the saline buffer is physically and chemically stable for up to 72 hrs when stored at room temperature (25±3°C). Nimotuzumab diluted in saline buffer may not be active beyond these conditions, the solution should be discarded and fresh solution should be prepared for infusion.
ATC Classification
L01XC - Monoclonal antibodies ; Used in the treatment of cancer.
Presentation/Packing
Vial 50 mg/10 mL (colorless, sterile) x 2's.
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