For intravenous infusion.
Therapy with Cyramza ® can be prescribed and performed only under the supervision of a doctor who has experience in the use of antitumor drugs.
After dilution, the drug Ziramza® is administered by intravenous infusion over a period of about 60 minutes.
Do not administer the drug intravenously bolus or as a rapid intravenous injection.
To achieve the necessary duration of infusion, about 60 minutes, the maximum infusion rate should not exceed 25 mg / min, or the duration of infusion should be increased. During the infusion it is recommended to monitor the patient's condition to identify signs of infusion reactions. In addition, it is necessary to ensure the availability of appropriate resuscitation equipment.
Premedication
Before carrying out infusions of ramucirumab, it is recommended that premedication be carried out with antihistamines (for example, diphenhydramine). In the case of a patient developing an infusion reaction of 1 or 2 severity according to the NCI STAEE classification, premedication should be performed before all subsequent infusions of ramucirumab.In the case of repeated development of an infusion reaction of 1 or 2 degrees of severity, the patient should undergo premedication with glucocorticosteroids (for example, dexamethasone). In the future, before the subsequent infusions of ramucirumab, premedication should be performed using the following drugs or their analogues: antihistamines (for example, diphenhydramine) intravenously, paracetamol and dexamethasone.
Gastric cancer or adenocarcinoma of the gastroesophageal junction
Combination therapy with paclitaxel
The recommended dose of Cyramza® is 8 mg / kg in the first and the 15th days of the 28-day cycle before the infusion of paclitaxel. The recommended dose of paclitaxel is 80 mg / m2 in the form of intravenous infusion for about 60 minutes in the 1st, 8th and 15th days of the 28-day cycle. Before each infusion of paclitaxel, patients should undergo clinical and biochemical blood tests to assess the status of liver function. Before each infusion of paclitaxel, the criteria in table 1 should be observed.
Table 1. Necessary criteria for each infusion of paclitaxel.
| Criteria |
| Neutrophils | 1st day: ≥ 1.5 x 109/ l 8th and 15th days: ≥ 1.0 x 109/ l |
| Platelets | 1st day: ≥ 100 x 109/ l 8th and 15th days: ≥ 75 x 109/ l |
| Bilirubin | ≤ 1.5 x VGN |
| AST / Alanine aminotransferase (ALT) | Lack of metastases in the liver - ALT / AST ≤ 3 x ULN Metastases at liver - ALT / AST ≤ 5 x VLN |
Application of the drug Tsiramza® as a monotherapy
The recommended dose of Ciramza® for monotherapy is 8 mg / kg, every 2 weeks as an intravenous infusion for about 60 minutes, with a maximum infusion rate of 25 mg / min.
Locally or metastatic NSCLC
The recommended dose of Cyramza® is 10 mg / kg as an intravenous infusion for about 60 minutes on day 1 of the 21-day cycle before docetaxel infusion. Docetaxel in a dose of 75 mg / m2 must be administered as an intravenous infusion for about 60 minutes on day 1 of the 21-day cycle.
Metastatic colorectal cancer
The recommended dose of Cyramza® is 8 mg / kg as an intravenous infusion for about 60 minutes every two weeks before the combined chemotherapy according to the FOLFIRI regimen. Before starting chemotherapy, patients should undergo a clinical blood test.
Before the chemotherapy according to the FOLFIRI scheme, the criteria in Table 2 should be observed.
Table 2. Necessary criteria for chemotherapy according to the FOLFIRI scheme.
| Criteria |
| Neutrophils | ≥ 1.5 x 109/ l |
| Platelets | ≥ 100 x 109/ l |
| Toxic phenomena from the gastrointestinal tract on the background of chemotherapy | ≤ 1 degree (according to the NCI STCEE criteria) |
Duration of therapy
Therapy with Cyramza® should be continued until signs of disease progression or the development of unacceptable toxicity.
Recommendations for correcting the dosing regimen
Infusion reactions
If the patient develops an infusion reaction of 1 or 2 severity, reduce the rate of infusion of the drug Ziramza® by 50% for the ongoing, as well as for all subsequent infusions. In case of development of an infusion reaction of 3 or 4 degrees of severity, therapy with Cyramza® should be stopped immediately and completely. Arterial hypertension
Before each administration of the drug Tsiramza®, blood pressure should be monitored with therapy in accordance with clinical indications. In the case of severe arterial hypertensionTherapy with Cyramza® should be temporarily discontinued until adequate control is achieved against the background of drug therapy. If hypotensive therapy does not lead to a safe level of blood pressure, therapy with Cyramza® should be completely discontinued.
Proteinuria
During the treatment with Cirram®, patients should be monitored for signs of development or increase in proteinuria. If the level of protein in the urine is ≥2 +, a daily urine test should be performed. If the protein level in urine is ≥2 g / 24 hours, therapy with Cyramza® should be temporarily discontinued. After reducing the urinary protein level to <2 g / 24 hours, therapy should be resumed with a decrease in dose according to Table 3. If the protein level is repeatedly raised to ≥2 g / 24 hours, a repeated dose reduction according to Table 3 is recommended. Table 3. Dose Reduction drug Ziramza® for proteinuria.
| The recommended initial dose of Ziramza® | The first reduction in the dose of Ziramza® | Repeated dose reduction of Cirram ® |
| 8 mg / kg | 6 mg / kg | 5 mg / kg |
| 10 mg / kg | 8 mg / kg | 6 mg / kg |
If the level of protein in the urine is> 3 g / 24 hours, or if the nephrotic syndrome develops, the therapy with Cyramza® should be completely discontinued.
Planned operations or slowing down the process of wound healing
Therapy with Cyramza® should be temporarily discontinued at least 4 weeks before the scheduled operation. In case of complications related to delayed healing of wounds, therapy with Cyramza® should be temporarily stopped until the wound is completely healed.
Correction of the dosing regimen of paclitaxel
Based on the level of toxicity noted by the patient, the dose of paclitaxel can be reduced. With the development of hematologic toxicity of the 4th degree of severity or non-hematological toxicity of the 3rd degree of severity associated with paclitaxel therapy, it is recommended that in accordance with the NCI CACAE criteria, a dose of paclitaxel be reduced by 10 mg / m2 for the duration of all subsequent cycles of therapy. The following dose reduction of 10 mg / m2 It is recommended in case of preservation or repeated development of toxicity.
Correction of dosing regimen FOLFIRJ (irinotecan, calcium folinate and fluorouracil)
With the development of certain manifestations of dose toxicity of individual drugs, FOLFIRI regimens can be reduced. A change in the dose of each individual preparation of the FOLFIRI regimen should be carried out independently of each other according to the algorithm presented in Table 4. Table 5 provides detailed information on deferring the administration or dose reduction of FOLFIRI regimens during the next cycle based on the maximum severity of certain adverse events.
Table 4. Decrease in the dose of FOLFIRI regimens.
| The drug scheme FOLFIRI | Dose level |
| Initial dose | -1 | -2 | -3 |
| Irynotekan | 180 mg / m2 | 150 mg / m2 | 120 mg / m2 | 100 mg / m2 |
| 5-fluorouracil bolus | 400 mg / m2 | 200 mg / m2 | 0 mg / m2 | 0 mg / m2 |
| 5-fluorouracil infusion | 2400 mg / m2 for 46-48 hours | 2000 mg / m2 for 46-48 hours | 1600 mg / m2 for 46-48 hours | 1200 mg / m2 for 46-48 hours |
Table 5. Change in the dose of FOLFIRI regimens in the development of certain adverse events
| Unwanted phenomenon | Power NCI СТСАЕ | Dose change on the 1st day of the treatment cycle following the development of AE |
| Diarrhea | 2 | If the severity of diarrhea has decreased to ≤ 1 degree, the dose of 5-fluorouracil is reduced by 1 dose level. With the resumption of diarrhea 2 degrees of expression, the dose of 5-fluorouracil and irinotecan is reduced by 1 dose level. |
| 3 | If the severity of diarrhea has decreased to ≤ 1 degree, the dose of 5-fluorouracil and irinotecan is reduced by 1 dose level. |
| 4 | If the severity of diarrhea has decreased to ≤ 1 degree, the dose of 5-fluorouracil and irinotecan is reduced by 2 dose levels. If diarrhea 4 degrees of severity is not resolved to ≤ 1 degree, the administration of 5-fluorouracil and irinotecan is delayed no more than 28 days before the resolution of the phenomenon to ≤ 1 degree. |
| Neutropenia or thrombocytopenia |
| If the hematological criteria are met in Table 2 | When non-conformity hematological criteria in Table 2 |
| 2 | Correction of the dose is not required. | The dose of 5-fluorouracil and irinotecan is reduced by 1 dose level. |
| 3 | The dose of 5-fluorouracil and irinotecan is reduced by 1 dose level. | The administration of 5-fluorouracil and irinotecan is delayed no more than 28 days before the resolution of the phenomenon to ≤ 1 degree, then the dose of 5-fluorouracil and irinotecan is reduced by 1 dose level. |
| 4 | The dose of 5-fluorouracil and irinotecan is reduced by 2 dose levels. | The administration of 5-fluorouracil and irinotecan is delayed no more than 28 days before the resolution of the phenomenon to ≤ 1 degree, then the dose of 5-fluorouracil and irinotecan is reduced by 2 dose levels. |
| Stomatitis / inflammation of the oral mucosa | 2 | If the severity of stomatitis / inflammation of the oral mucosa decreased to ≤ 1 degree, the dose of 5-fluorouracil is reduced by 1 dose level. With the resumption of stomatitis / inflammation of the oral mucosa of the 2nd degree of severity, the dose of 5-fluorouracil is reduced by 2 dose levels. |
| 3 | If the severity of stomatitis / inflammation of the oral mucosa decreased to ≤ 1 degree, the dose of 5-fluorouracil is reduced by 1 dose level. If the degree of severity of stomatitis / inflammation of the oral mucosa did not decrease to ≤ 1 degree, the administration of 5-fluorouracil is delayed no more than 28 days before the resolution of the phenomenon to ≤ 1 degree, then the dose of 5-fluorouracil is reduced by 2 dose levels. |
| 4 | The administration of 5-fluorouracil is delayed no more than 28 days before the resolution of the phenomenon to ≤ 1 degree, then the dose of 5-fluorouracil is reduced by 2 dose levels. |
| Febrile neutropenia |
| If the hematologic criteria are met in Table 2 and the resolution of the fever | If there is a discrepancy between the hematological criteria in Table 2 and the resolution of fever |
| The dose of 5-fluorouracil and irinotecan is reduced by 2 dose levels. | The administration of 5-fluorouracil and irinotecan is delayed no more than 28 days before the resolution of the phenomenon to ≤ 1 degree, then the dose of 5-fluorouracil and irinotecan is reduced by 2 dose levels.
Before the next cycle, the use of colony-stimulating factors should be considered. |
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* - The 28-day period begins on the 1st day of the cycle following the development of the AE. Correction of the dosage regimen of docetaxel
Based on the toxicity level noted by the patient, the dose of docetaxel can be reduced. Patients who, during docetaxel treatment, develop febrile neutropenia, a decrease in the neutrophil count <500 cells / mm3 for more than 1 week, severe and cumulative skin reactions or other nonhematological manifestations of grade 3 or 4 toxicity, should stop docetaxel therapy before resolving these toxicity manifestations. It is recommended to reduce the dose of docetaxel by 10 mg / m2 for the duration of all subsequent cycles of therapy. The following dose reduction of 15 mg / m2 It is recommended in case of preservation or repeated development of toxicity.
Elderly patients
In clinical trials, there was no evidence of an increased risk of adverse events in patients 65 years of age or older compared with patients under the age of 65 years. There are no recommendations for reducing doses.
Patients with renal insufficiency
Studies of the use of the drug Ziramza® in patients with renal insufficiency have not been conducted. According to the available clinical data, it can be assumed that patients with renal insufficiency of mild, moderate or severe severity should not be required to adjust the dose. There are no recommendations for reducing doses.
Patients with hepatic insufficiency
Studies of the use of the drug Ziramza® in patients with hepatic insufficiency have not been conducted. According to clinical data, it can be assumed that patients with hepatic insufficiency of mild or moderate severity should not be required to adjust the dose. Data on the use of ramucirumab in patients with severe hepatic insufficiency are absent. There are no recommendations for reducing doses.
Children and teenagers under 18 years of age
The safety and efficacy of Cyramza® in children and adolescents under the age of 18 years are not established (see the section "Contraindications")
Instructions for the preparation and administration of an infusion solution
As a solvent, only 0.9% sodium chloride solution should be used. Cirram ® should not be administered or mixed with dextrose solutions.
Each bottle is intended for single use. Before breeding, the contents of the vial should be checked for mechanical inclusions and discoloration. In case of detection of mechanical inclusions or discoloration, the bottle should not be used.
In order to guarantee the sterility of the prepared infusion solution, it is necessary to observe aseptic methods.
In the case of pre-filled containers for intravenous infusion
Based on the calculated volume of ramucirumab, it is necessary to remove the corresponding volume of 0.9% sodium chloride solution from a pre-filled 250 ml intravenous infusion container. With observance of aseptic methods, enter the calculated volume of ramucirumab into a container for intravenous infusion.The total volume of the contents of the container should be 250 ml. Carefully turn the container over for even stirring. Solution for infusions Do not freeze or shake. Do not dilute with other solutions and do not use simultaneously with other electrolytes or medications.
In the case of using empty containers for intravenous infusions
With observance of aseptic methods, it is necessary to enter the calculated volume of ramucirumab into an empty container for intravenous infusions. Add the appropriate amount of 0.9% sodium chloride solution to a total volume of 250 ml. Carefully turn the container over for even stirring. Solution for infusions Do not freeze or shake. Do not dilute with other solutions and do not use simultaneously with other electrolytes or medications.
The unused solution of the drug should be disposed of in an appropriate way, as the preparation Ziramza® does not contain antimicrobial preservatives.
It is recommended to administer the drug using an infusion pump. For infusion, a separate infusion system with a built-in low-protein binding filter with a pore size of 0.22 μm should be used.At the end of the infusion, the system should be washed with 0.9% sodium chloride solution.
Prepared infusion solution
Solution for infusion Cyramza®, prepared in accordance with the instructions, does not contain antimicrobial preservatives.
Solution for infusion Cyramza® remains stable in terms of chemical and physical properties for 24 hours at a temperature of 2 to 8 ° C or for 4 hours at room temperature below 30 ° C. However, the solution should be used immediately after preparation to avoid microbiological contamination. If the resulting solution can not be used immediately, the user is responsible for storing it and for further use. Shelf life should not exceed 24 hours at a temperature of 2 to 8 ° C, except for cases when dilution was carried out in controlled and validated aseptic conditions.