Cimaher Summary of Product CharacteristicsProduct Name: (Nimotuzumab) CIMAher ®
Pharmaceutical form: Injection IV.
Strength: 5 mg / ml
Presentation: Case with 4, 10ml bulbs
Holder of the Sanitary Registry, country: Center for Molecular Immunology, Cuba
Manufacturer Country: 1. Center for Molecular Immunology, Cuba
– Plant for the Production of Therapeutic Antibodies (ANTYTER).
Active Pharmaceutical Ingredient.
– Plant 3.
Formulation, filling and packaging.
– IFA production plant.
Active Pharmaceutical Ingredient.
Product Name: (Nimotuzumab) CIMAher ®
Pharmaceutical form: Injection IV.
Strength: 5 mg / ml
Presentation: Case with 4, 10ml bulbs
Holder of the Sanitary Registry, country: Center for Molecular Immunology, Cuba
Manufacturer Country: 1. Center for Molecular Immunology, Cuba
– Plant for the Production of Therapeutic Antibodies (ANTYTER).
Active Pharmaceutical Ingredient.
– Plant 3.
Formulation, filling and packaging.
– IFA production plant.
Active Pharmaceutical Ingredient.
Registration Date: February 19, 2002.
Composition Each bulb contains:
Substance : Quantity
Nimotuzumab 50.0 mg
Dibasic sodium phosphate
Monobasic sodium phosphate
Sodium chloride
Polysorbate 80
Water for injection csp
Validity period: 36 months.
Storage conditions: Temperature between 2 and 8 C. Protect from light. Do not freeze, or shake.
Therapeutic indications:
– Treatment of advanced head and neck tumors in combination with radiotherapy and / or
chemotherapy.
– Treatment of adult patients with glial tumors of high degree of malignancy: Glioblastoma multiforme and anaplastic astrocytoma, in combination with radiotherapy.
– Treatment of pediatric patients with high-grade glial tumors malignancy of new diagnosis in combination with radiotherapy and radiochemotherapy .
– Treatment of pediatric patients with recurrent or refractory glial tumors with nimotuzumab .
– Treatment of patients with malignant esophageal tumors of epithelial origin not operable in combination with radiochemotherapy .
– Treatment of patients with locally advanced adenocarcinoma or metastatic pancreas in combination with chemotherapy.
Contraindications:
Patients with a history of hypersensitivity to this or any other product derived from upper cells or other component of the formulation of this product.
Precautions:
CIMAher ® should be administered with caution in patients who have received treatment primer with the murine monoclonal antibody ior ® egf / r3.
CIMAher ® should be used with caution in patients with chronic diseases in decompensation such as ischemic heart disease, diabetes mellitus or arterial hypertension. Its use is not recommended during pregnancy and lactation.
Special warnings and precautions for use:
CIMAher ® does not contain any preservatives in the formulation, therefore CIMAher ® must be used to prepare the infusion immediately after opening the bulb.
CIMAher ® diluted in 0.9% saline infusion is physically and chemically stable for 72 hours at a temperature not exceeding 27° C. If these limits are exceeded, the infusion should be discarded.
Side effects:
The main adverse reactions that could occur after the administration of CIMAher ® consist of mild or moderate reactions such as:
– Tremors;
– Chills;
– Nausea;
– Headache;
– Vomiting;
– Anemia;
– Hypotension;
– Fever;
– Elevated phosphatase alkaline, TGP and TGO;
Other less frequent reactions that may occur include:
– Drowsiness;
– Disorientation;
– Myalgias;
– Motor dysphasia;
– Incoherent language;
– Dry mouth;
– Redness facial weakness;
– Weakness in the lower limbs;
– Phlebitis;
– Creatinine increase;
– Leucopenia;
– Hematuria;
– Chest pain; and
– Peribucal cyanosis
These adverse reactions are due to treatment with analgesics and antihistamines in conventional
doses.
Dosages (posology) and method of administration:
– Advanced head and neck tumors:
The recommended dose of CIMAher ® is 200 mg given once a week for 6 weeks concomitant with radiotherapy and / or chemoradiotherapy. Subsequently, dose of 200 mg every 15 days (maintenance dose) until the general condition of the patient allows it.
– Pediatric recurrent astrocytomas with high grade of malignancy and new diagnosis:
The recommended dose of CIMAher ® is 150 mg / m 2, given once a week for 6 weeks in monotherapy. Subsequently, a dose of 150 mg / m 2 every 15 days (maintenance dose) until the general condition of the patient allows it.
– Multiform glioblastomas and anaplastic astrocytomas in adults:
The recommended dose of CIMAher ® is 200 mg given once a week for 6 weeks concomitant with radiotherapy. Subsequently, a dose of 200 mg every 15 days (maintenance dose) until the general condition of the patient allows it.
– Malignant neoplasms of esophagus of non-operable epithelial origin in combination with radio chemotherapy:
The recommended dose of CIMAher ® is 200mg, administered once a week for 6 weeks concomitant with radiotherapy. Subsequently, a dose of 200 mg every 15 days (maintenance dose) until the general condition of the patient allows it.
– Locally advanced or metastatic adenocarcinoma of the pancreas, in combination with
chemotherapy:
The recommended dose of CIMAher ® is 400 mg administered once a week, in combination with chemotherapy. CIMAher ® will be given to progressive disease or unacceptable toxicity. In all clinical indications, CIMAher ® will be administered intravenously in 250 mL of rapidly infused saline solution (30 minutes). Interactions with other medicinal products and other forms of interaction: The interaction of CIMAher ® with other cytostatic drugs is being evaluated. Synergism or potentiation of antitumor ,activity has been demonstrated when used other EGFR inhibitory agents in combination with radiotherapy.
Use in pregnancy and lactation:
CIMAher ® is not recommended during pregnancy and lactation.
Effects on the driving of vehicles / machinery:
The effects of CIMAher ® on driving vehicles / machinery are unknown.
Overdose:
The effects of overdose with CIMAher ® are not known.
Pharmacodynamic properties:
CIMAher ® is a humanized antibody that recognizes the growth factor receptor epidermal (EGF-R) with high affinity.
EGF-R is a 170 kDa membrane glycoprotein. Its intracellular domain is associated to specific protein tyrosine kinase activity and its overexpression by tumor cells alters the regulation of the cell cycle (increasing proliferation), blocks apoptosis, promotes angiogenesis, increases motility, adhesiveness and invasiveness.
CIMAher ® blocks ligand binding to EGF-R and works by inhibiting tyrosine activity receptor kinase interfering with the cellular signaling pathway involved in the cell proliferation. CIMAher ® has anti angiogenic, anti-proliferative and pro-apoptotic effect in those tumors that verexpress EGF-R, thus inhibiting the growth of cells tumor cells of epithelial origin in vitro and in vivo.
Mode of actions of CIMAher ®
– Patients with head and neck tumors in advanced stages:
In patients with tumor lesions in stages III and IV the oncoespecific treatment consists of radiotherapy or chemoradiotherapy. The percentage of objective response (referrals complete and partial) to standard therapy is 30-40% and 50-60% respectively. The use of CIMAher ® concomitant with radiotherapy and / or chemoradiotherapy increases the percentage of objective response to values between 70 (radiotherapy and nimotuzumab) and 100% (chemoradiotherapy and nimotuzumab), while the overall survival rate of patients treated with the combination nimotuzumab and chemoradiotherapy is 70% after of 30 months of follow-up.
– Pediatric patients with recurrent and / or refractory high-grade astrocytomas:
In patients with recurrent brain tumors, refractory to surgery, irradiation and cytostatic therapy, the life expectancy is approximately 1 month. The median survival rate in this type of pediatric patients receiving monotherapy with CIMAher ® at a dose of 150 mg / m 2 is 8.9 months. The control and stabilization of disease is remarkable in this group of patients.
– Pediatric patients with glial tumors with a high grade of newly diagnosed malignancy in combination with radiotherapy and radiochemotherapy:
In pediatric patients with diffuse, newly diagnosed brain stem glioma, the combination of nimotuzumab with radiotherapy and vinorelbine (20 mg / m 2). The primary objective of study was the response rate, which was observed in 96% of patients. The combination was well tolerated without acute adverse events. Eleven of 16 patients presented local relapse and were re-irradiated. Progression-free survival rates and overall survival were 8.5 and 15 months respectively. The survival rate progression-free in re irradiated patients (11) was 8.3 months as compared to 8.5 months in the rest (14). The median survival for this group in relapse irradiated was 13.3 months, whereas for those patients who in relapse were not
irradiated, was 12 months (p = 0.03).
– Adult patients with multiform glioblastomas and anaplastic astrocytomas:
In patients with astrocytic tumors of high grade of malignancy, the expected survival with radiant therapy alone corresponds to 12 months for tumors classified as multifome glioblastoma and 24 months for grade III or anaplastic astrocytomas. In patients treated with CIMAher ® combined with radiotherapy, carriers of glioblastoma multiforme values of median and mean survival attained are 16.30 and 20.45 months respectively. For the case of patients with anaplastic astrocytoma receiving the combination, the mean survival attained is 30.03 months.
In post-marketing study it was observed that median progression-free survival and median intention-to-treat survival for this type of patients was 8.6 months and 12.23 months respectively. According to histological grade, for patients with Glioblastoma, the median survival was 10.56 months and for the anaplastic Astrocytoma of 28.26 months. The 24- month survival rate was 21.6% and 57.1%.
– Patients with malignant esophageal tumors of epithelial origin not operable in combination with radiotherapy chemotherapy:
In patients with malignant tumors of the esophagus, who receive standard therapy, expected survival is 3 months, whereas in patients treated with CIMAher ® in combination with radium and chemotherapy results in a median survival of 8.1 months.
Clinical control of the disease is achieved in patients treated with CIMAher ® plus chemoradiotherapy in 60.9%, while in patients receiving chemotherapy only reach 26.9%. CIMAher ® combined with chemoradiotherapy increases the occurrence of serious adverse events over standard treatment.
– Patients with locally advanced or metastatic adenocarcinoma of the pancreas, in combination with chemotherapy:
Patients with locally advanced or metastatic pancreatic adenocarcinoma showed an increase in survival time after combined treatment with nimotuzumab and gemcitabine. The median overall survival increased from 6.0 months in the control arm (gemcitabine plus placebo) at 8.6 months in the experimental arm (nimotuzumab plus gemcitabine). The year-to-year survival rate was also higher for patients received nimotuzumab and gemcitabine compared to the control group (34.4% vs 19.2%).
Patients with tumors with the non-mutated KRAS oncogene showed a increased survival time. Median survival increased from 5.7 months in the arm of gemcitabine / placebo at 11.6 months in the group treated with nimotuzumab and gemcitabine.
Patients treated with nimotuzumab and gemcitabine also had an increase significant difference in progression-free survival (4.47 months) compared to the group treated with gemcitabine and placebo (3.23 months).
Pharmacokinetic properties (absorption, distribution, biotransformation, elimination):
Pharmacokinetic data show that CIMAher ® shows a behavior pharmacokinetics between doses of 50 and 200 mg. Increasing values of the product are obtains an increase in the average life
time of distribution, disposal and volume of distribution.
Pharmacokinetic analysis in patients receiving CIMAher ® infusions between 50 and 400 mg, showed that the elimination half-lives corresponded to 62.91 ± 61.81 hrs, 82.6 ± 7.89, 302.94 ± 44.13, 304.51 ± 50.7 hrs for the doses of 50, 100, 200 and 400 mg, respectively. The mean elimination half-life was increased linearly with the dose up to the 200-mg dose. The clearance values reported for CIMAher ® were 1.22 ± 0.46 mL / min, 0.69 ± 0.08 mL / min, 0.41 ± 0.17 mL / min and 0.74 ± 0.40 mL / min for all 4 doses respectively.
The liver, heart, spleen, kidneys, and urinary bladder were identified as white organs, observing
significant incorporation into the liver and mild to moderate incorporation into others organs.
Instructions for use, handling and destruction of the unusable remainder of the product:
Method of Preparation:
1. Verify that the bulbs are within the period of validity stated on the label and that the product has been stored at a temperature of 2 to 8 ° C.
2. Place a sterile needle in a sterile syringe.
3. Remove the flip off cover from the bulb containing the CIMAher ® and wipe the top with a disinfectant.
4. Insert the needle into the rubber stopper and remove the contents of the bulb.
5. Inoculate the contents of the 4 bulbs in 250 mL of 0.9% sodium chloride solution.
6. Administer by intravenous route (antecubital vein) the saline solution in rapid injection (30 minutes).