CIMAHER®

(NIMOTUZUMAB), Humanized monoclonal antibodies against the receptors for epidermal factor of growth

cimaherDescription:

CIMAher (nimotuzumab) are humanized monoclonal antibodies which recognize the receptor for epidermal factor of growth (EGF-R) with high affinity. The antibodies are obtained by cloning the changeable regions of murine antibodies ior egf/r3 to a human immunoglobulin frame (Eu for a denser/ heavier chain and the REI for a thinner/easier chain). These are the IgG1 antibodies of which the molecular mass is 150 KD.

CIMAher is manufactured of a cell culture of mammals from non-excreting NSO cells.

Pharmaceutical composition:

CIMAher is formulated as a colorless sterile solution in 10 ml of physiological buffer.

Each bottle contains 50 mg of CIMAher, 4.5 mg of monobasic sodium phosphate (NaH2PO4)  , 18.0 mg or dibasic sodium phosphate (Na2HPO4), 86.0 mg of sodium chloride, 2.0 mg of polysorbate 80 and the water for injections in the quantity for fill 10 ml.

Pharmacological properties:

EGF-R is a transmembrane glycoprotein of 170 KDa. Its intracellular domain is connected to the specific activity of tyrosine kinase of which the excessive expression to the cells of cancer changes the regulation of cell cycle ( increases the multiplication), blocks the apoptosis, stimulate angiogenesis, increases motility, invasion of cells and metastasis.

CIMAher blocks connecting of the EGF with its receptors and inhibits InVivo and InVitro cells of tumor and has a strong effect of anti-angiogenesis, as well as anti-proliferative and pro-apoptotic effect of those tumors of which the EGF-R is excessively expressed.

Pharmacological effect:

The patients in an advanced phase of the tumor of head and neck

In the patients whose degree of damage by the tumor III and IV, the oncology-specific treatment consists of radiotherapy and chemo radiotherapy. The percent of target responses (complete or partial remission) to radiotherapy and chemo radiotherapy in these phases is 30-40%, i.e. 50-60%.The use of CIMAher in the combination with radiotherapy and chemo radiotherapy increases the percent of the target response to even 70-80%. The average and average values of surviving were 24.19 and 15 months of the patients treated with CIMAher and the average and average values of surviving for the patients treated with placebo were 14.12 and 9.27 months (p=0.024).

Pediatric patients with the recurrent/persistent high degree of malign astrocytoma

With the pediatric patients with the astrocytoma of higher degree of malignity of recurrent or persistent to surgeries, radiotherapy or chemotherapy, none of the previous or currently used chemotherapy protocols is recommended as the therapy.

With the pediatric patients treated with CIMAher as a mono-therapy, the anti-tumor response was 37.8%.  The average value of surviving was 8.9 months for the patients who reacted to the therapy comparing to the 3.3 months for the patients who did not react to the therapy (p ≤ 0.05).

Adult patients with glioblasoma multiforme

With the patients with the glioblastoma multiforme, treated with CIMAher plus with radiotherapy, the average value of surviving was 16.3 months, comparing to the expected 12 months for the radiotherapy itself.

There were no serious undesired events during the treatments with CIMAher.

Indications:

The patients in an advanced phase of the tumor of head and neck

CIMAher is indicated for the application in treating the advanced phase of squamous cell cancer of head and neck in the same time with chemotherapy and/or radiotherapy.

Pediatric patients with the recurrent/persistent high degree of malign astrocytoma

CIMAher is indicated as a mono-therapy , for using in the treatment of astrocytoma of higher degree of malignity which is recurrent/persistent to surgeries, radiotherapy or chemotherapy of pediatric patients.

Adult patients with glioblasoma multiforme

CIMAher is indicated for the application in treating adult patients with glioblastoma multiforme, with the radiotherapy in the same time.

Contraindications:

No

MEASURES OF PRECAUTION:

CIMAher should be applied with precaution at the patients who were previously treated with murine monoclonal antibodies ior egf/r3; the patients with previously oversensitivity to this product or some other product derived from NSO cells of mammals or to any other component of this product. CIMAher should be used with precaution at the patients with chronic diseases in an uncontrolled phase, for example: heard dysfunction, diabetes mellitus or hypertension.

Using during pregnancy and lactation

It is not known whether the CIMAher causes damages of the fetus if given to pregnant women. The examinations to animals showed that in the embryonic stadium the deficiency of EGF-R cannot provoke the maturation of epithelium and postnatal death. The use of CIMAher during pregnancy is not recommended and it is not known whether the CIMAher is extracted in human milk, its use is not recommended during lactation.

Undesirable reactions

The greatest undesirable reactions which can appear after the use of the CIMAher consist of light and moderate reactions such as shivering, shuddering, nausea, vomiting, anemia, hypotension, or hypertension.

Less frequent undesirable reactions include drowsiness, disorientation, myalgia, motor dysfunction, dry mouth, blush, weakness in the lower extremities, increase in creatinine levels, leukopenia, anemia, chest pain and cyanosis of the mouth.

These undesirable reactions respond to anti-histamine treatment and treatment with analgesics, in conventional doses.

Interactions and incompatibilities:

The interactions of the CIMAher with other cytostatics have not been completely estimated so far. The synergetic effect has already been presented, as well as anti-tumor activities, when other anti EGF-R inhibitors are used in the combination with chemotherapy.

Dosing

The patients in an advanced phase of the tumor of head and neck

The recommended dose of CIMAher is 200 or 400 mg, and is applied once a week during the six weeks, in the combination with standard radiotherapy and/or chemotherapy for the cancer of head and neck. During the period of consolidation, the recommended dose is 200 or 400 mg on every 15 days to the progression of clinical deterioration.

Pediatric patients with the recurrent/persistent high degree of malign astrocytoma

The recommended dose of CIMAher is 150 mg/m2, which is given once a week during the six weeks as a mono-therapy.

During the period of consolidation the recommended dose is 150 mg/m2 on every 15 days to the progression of clinical deterioration.

Adult patients with glioblasoma multiforme

The recommended dose of CIMAher is 200 mg, and is applied once a week during the six weeks in the combination with the standard radiotherapy. During the period of consolidation, the recommended dose is 200 mg on every 15 days to the progression of clinical deterioration.

In all the indications, CIMAher should be applied as a continuous intravenous (IV) infusion, dissolute in 250 ml sodium chloride which is given for 30 minutes.

Duration of the therapy:

At all the Indications, the treatment with CIMAher has two phases, induction and consolidation. During the period of induction CIMAher is given once a week while the application of all the six doses is completed, in the same time with the recommended radiotherapy or chemo radiotherapy. When the radiotherapy or chemo radiotherapy is terminated by time, it will come to the discontinuity in treatment with CIMAher. The application is continued when the radiotherapy/chemo radiotherapy is renewed.

During the period of consolidation CIMAher will be applied every 15 days to the progression of clinical deterioration.

OVERDOSE:

There is no experience with the overdose with CIMAher in the clinical studies on humans.

Preparation for the administration

  1. Do not shake the content of the bottle. A strong shaking can denaturalize proteins and to influence the biological activity of the product.
  2. Any product which should be administrated by a parenteral infusion should be thoroughly checked visually before use.
  3. By using appropriate aseptic techniques, remove the plug from the bottle cap which contains CIMAher and clean the top of the bottle with an anti- bacteriostatic solution. Absorb the content of the bottle into a sterile syringe with the appropriate needle.
  4. The chosen dose of CIMAher should be diluted in 250 ml of sodium fluoride 9%.

Conditions of storage:

The bottles of CIMAher should be kept cooled on the temperatures 2 – 8°C. Do not freeze or shake the bottles.

How to order the medicine?

CIMAher is obtained for a single usage in the bottle of 10 ml which contains 50 mg of nimotuzumaba in the form of sterile, conserved, injection liquid in the salt buffer.