Posology : מינונים

4.2   Posology and method of administration

Ramucirumab therapy must be initiated and supervised by physicians experienced in oncology.
Posology

Gastric cancer and gastro-oesophageal junction (GEJ) adenocarcinoma

Cyramza in combination with paclitaxel
The recommended dose of ramucirumab is 8 mg/kg on days 1 and 15 of a 28 day cycle, prior to paclitaxel infusion. The recommended dose of paclitaxel is 80 mg/m2 administered by intravenous infusion over approximately 60 minutes on days 1, 8 and 15 of a 28 day cycle. Prior to each paclitaxel infusion, patients should have a complete blood count and blood chemistry performed to evaluate hepatic function. Criteria to be met prior to each paclitaxel infusion are provided in Table 1.

Table 1: Criteria to be met prior to each paclitaxel administration

Criteria
Neutrophils                      Day 1: ≥ 1.5 x 109/L
Days 8 and 15: ≥ 1.0 x 109/L
Platelets                        Day 1: ≥ 100 x 109/L
Days 8 and 15: ≥ 75 x 109/L
Bilirubin                        < 1.5 x upper limit of normal value (ULN) Aspartate aminotransferase       No liver metastases: ALT/AST ≤ 3 x ULN (AST) /Alanine
Liver metastases: ALT/AST ≤ 5 x ULN aminotransferase (ALT)

Cyramza as a single agent
The recommended dose of ramucirumab as a single agent is 8 mg/kg every 2 weeks.



Colorectal cancer
The recommended dose of ramucirumab is 8 mg/kg every 2 weeks administered by intravenous infusion, prior to FOLFIRI administration. Prior to chemotherapy, patients should have a complete blood count. Criteria to be met prior to FOLFIRI are provided in Table 2.


Table 2: Criteria to be met prior to FOLFIRI administration
Criteria
Neutrophils                      ≥ 1.5 x 109/L
Platelets                        ≥ 100 x 109/L
Chemotherapy-related gastro-     ≤ Grade 1 (National Cancer Institute Common intestinal toxicity              Terminology Criteria for Adverse Events [NCI CTCAE])

Non-small cell lung cancer (NSCLC)

Cyramza in combination with erlotinib for the treatment of non-small cell lung adenocarcinoma with activating EGFR mutations
The recommended dose of ramucirumab in combination with erlotinib is 10 mg/kg every two weeks.

EGFR mutation status should be determined prior to initiation of treatment with ramucirumab and erlotinib using a validated test method. See erlotinib prescribing information for the posology and method of administration of erlotinib.

Cyramza in combination with docetaxel for the treatment of NSCLC after platinum-based chemotherapy
The recommended dose of ramucirumab is 10 mg/kg on day 1 of a 21 day cycle, prior to docetaxel infusion. The recommended dose of docetaxel is 75 mg/m2 administered by intravenous infusion over approximately 60 minutes on day 1 of a 21 day cycle. For East Asian patients, a reduced docetaxel starting dose of 60 mg/m2 on day 1 of a 21 day cycle should be considered. See docetaxel prescribing information for specific dosing advice.

Hepatocellular carcinoma (HCC)

The recommended dose of ramucirumab as a single agent is 8 mg/kg every 2 weeks.
Alpha fetoprotein (AFP) testing in HCC

Patients with HCC should be selected based on a serum AFP concentration of ≥ 400 ng/ml with a validated AFP test prior to ramucirumab treatment (see section 5.1).

Duration of treatment

It is recommended that treatment be continued until disease progression or until unacceptable toxicity has occurred.

Premedication

Premedication is recommended with a histamine H1 antagonist (for example diphenhydramine) prior to infusion of ramucirumab. If a patient experiences a Grade 1 or 2 infusion-related reaction premedication must be given for all subsequent infusions. If a patient experiences a second Grade 1 or 
2 infusion-related reaction (IRR) administer dexamethasone (or equivalent); then, for subsequent infusions, premedicate with the following or equivalent medicinal products: an intravenous histamine H1 antagonist (for example diphenhydramine hydrochloride), paracetamol and dexamethasone.

See prescribing information for paclitaxel, for components of FOLFIRI and for docetaxel, as applicable, for premedication requirements and additional information.

Posology adjustments for ramucirumab

Infusion-related reactions
The infusion rate of ramucirumab should be reduced by 50% for the duration of the infusion and all subsequent infusions if the patient experiences a grade 1 or 2 IRR. Ramucirumab should be immediately and permanently discontinued in the event of a grade 3 or 4 IRR (see section 4.4).

Hypertension
The blood pressure of patients should be monitored prior to each ramucirumab administration and treated as clinically indicated. Ramucirumab therapy should be temporarily discontinued in the event of severe hypertension, until controlled with medical management. If there is medically significant hypertension that cannot be controlled safely with antihypertensive therapy, ramucirumab therapy should be permanently discontinued (see section 4.4).

Proteinuria
Patients should be monitored for the development or worsening of proteinuria during ramucirumab therapy. If the urine protein is ≥ 2+ on a dipstick, a 24 hour urine collection should be performed.
Ramucirumab therapy should be temporarily discontinued if the urine protein level is ≥ 2 g/24 hours.
Once the urine protein level returns to < 2 g/24 hours, treatment should be resumed at a reduced dose level (see Table 3). A second dose reduction (see Table 3) is recommended if a urine protein level ≥2 g/24 hours reoccurs.

Ramucirumab therapy should be permanently discontinued if the urine protein level is >3 g/24 hours or in the event of nephrotic syndrome.

Table 3: Ramucirumab dose reductions for proteinuria

Initial ramucirumab dose       First dose reduction to        Second dose reduction to 8 mg/kg                        6 mg/kg                        5 mg/kg 10 mg/kg                       8 mg/kg                        6 mg/kg 
Elective surgery or impaired wound healing
Ramucirumab therapy should be temporarily discontinued for at least 4 weeks prior to elective surgery. Ramucirumab therapy should be temporarily discontinued if there are wound healing complications, until the wound is fully healed (see section 4.4).

Permanent discontinuation
Ramucirumab therapy should be permanently discontinued in the event of: Severe arterial thromboembolic events (see section 4.4).
Gastrointestinal perforations (see section 4.4).
Severe bleeding: NCI CTCAE Grade 3 or 4 bleeding (see section 4.4).
Spontaneous development of fistula (see section 4.4).
Hepatic encephalopathy or hepatorenal syndrome (see section 4.4).



Paclitaxel dose adjustments

Paclitaxel dose reductions may be applied based upon the grade of toxicity experienced by the patient.
For NCI CTCAE Grade 4 hematological toxicity or Grade 3 paclitaxel-related non-hematological toxicity, it is recommended to reduce the paclitaxel dose by 10 mg/m2 for all following cycles. A second reduction of 10 mg/m2 is recommended if these toxicities persist or reoccur.

FOLFIRI dose adjustments

Dose reductions for individual components of FOLFIRI may be made for specific toxicities. Dose modifications of each component of FOLFIRI should be made independently and are provided in Table 4. Table 5 provides details of dose delays or dose reductions of components of FOLFIRI at the next cycle based on maximum grade of specific adverse drug reactions.

Table 4: FOLFIRI dose reductions

FOLFIRI                                              Dose level componenta              Initial dose            -1                  -2               -3 Irinotecan              180 mg/m2          150 mg/m 2
120 mg/m2         100 mg/m2
5-FU bolus              400 mg/m2          200 mg/m 2
0 mg/m2          0 mg/m2
5-FU infusion            2,400 mg/m2        2,000 mg/m  2
1,600 mg/m2       1,200 mg/m2 over 46-48 hours   over 46-48 hours over 46-48 hours    over 46-48 hours a
5-FU = 5-fluorouracil.

Table 5: Dose modification of FOLFIRI components due to specific adverse drug reactions (ADRs)

ADR                         NCI   Dose modification at day 1 of cycle subsequent to ADR CTCAE grade
Diarrhea                    2     If diarrhea has recovered to Grade ≤1, reduce by 1 dose level for 5-FU.
For recurrent Grade 2 diarrhea, reduce by 1 dose level for
5-FU and irinotecan.
3     If diarrhea has recovered to Grade ≤1, reduce by 1 dose level for 5-FU and irinotecan.
4     If diarrhea has recovered to Grade ≤1, reduce by 2 dose levels for 5-FU and irinotecan.
If Grade 4 diarrhea does not resolve to Grade ≤1, withhold
5-FU and irinotecan for a maximum of 28⃰ days until resolution to Grade ≤1.
Neutropenia or                    Hematological criteria in        Hematological criteria in Thrombocytopenia                  Table 2 are met                  Table 2 are not met 2          No dose modification.         Reduce by 1 dose level for
5-FU and irinotecan.
3          Reduce by 1 dose level for    Delay 5-FU and irinotecan for 5-FU and irinotecan.          a maximum of 28* days until resolution to Grade ≤1, then dose reduce by 1 level for
5-FU and irinotecan.
4          Reduce by 2 dose levels for   Delay 5-FU and irinotecan for 5-FU and irinotecan.          a maximum of 28* days until resolution to Grade ≤1, then

                                                                         dose reduce by 2 levels for
5-FU and irinotecan.
Stomatitis/Mucositis       2           If stomatitis/mucositis has recovered to Grade ≤1, reduce by 1 dose level for 5-FU.
For recurrent Grade 2 stomatitis, reduce by 2 dose levels for
5-FU.
3           If stomatitis/mucositis has recovered to Grade ≤1, reduce by 1 dose level for 5-FU.
If Grade 3 mucositis/stomatitis does not resolve to Grade ≤1,
delay 5-FU for a maximum of 28* days until resolution to
Grade ≤1, then dose reduce by 2 levels for 5-FU.
4           Withhold 5-FU for a maximum of 28* days until resolution to Grade ≤1, then dose reduce by 2 dose levels for 5-FU.
Febrile neutropenia                    Hematological criteria in        Hematological criteria in Table 2 are met and fever        Table 2 are not met and fever resolved                         resolved
Reduce by 2 dose levels for   Delay 5-FU and irinotecan for
5-FU and irinotecan.          a maximum of 28* days until resolution to Grade ≤1, then dose reduce by 2 levels for
5-FU and irinotecan.
Consider use of colony- stimulating factor prior to next cycle.
*The 28 day time period begins on day 1 of the cycle subsequent to the ADR.

Docetaxel dose adjustments

Docetaxel dose reductions may be applied based upon the grade of toxicity experienced by the patient.
Patients who experience either febrile neutropenia, neutrophils < 500 cells/mm3 for more than 1 week, severe or cumulative cutaneous reactions, or other Grade 3 or 4 non-hematological toxicities during docetaxel treatment should have treatment withheld until resolution of the toxicity. It is recommended to reduce the docetaxel dose by 10 mg/m2 for all following cycles. A second reduction of 15 mg/m2 is recommended if these toxicities persist or reoccur. In this case, East Asian patients with a starting dose of 60 mg/m² should have docetaxel treatment discontinued (see Posology).

Special populations

Elderly
In the pivotal studies there is limited evidence that patients 65 years of age or older are at increased risk of adverse events compared to patients younger than 65 years old. No dose reductions are recommended (see sections 4.4 and 5.1).

Renal impairment
There have been no formal studies with Cyramza in patients with renal impairment. Clinical data suggest that no dose adjustments are required in patients with mild, moderate or severe renal impairment (see sections 4.4 and 5.2). No dose reductions are recommended.

Hepatic impairment
There have been no formal studies with Cyramza in patients with hepatic impairment. Clinical data suggest that no dose adjustments are required in patients with mild or moderate hepatic impairment.
There are no data regarding ramucirumab administration in patients with severe hepatic impairment (see sections 4.4 and 5.2). No dose reductions are recommended.

Pediatric population
Cyramza is not indicated in children and adolescents below 18 years old.
The safety and efficacy of Cyramza in children and adolescents (< 18 years) has not been established.

There is no relevant use of ramucirumab in the pediatric population for the indications of advanced gastric cancer or gastro-oesophageal adenocarcinoma, adenocarcinoma of the colon and rectum, lung carcinoma, and hepatocellular carcinoma.

Method of administration

Cyramza is for intravenous use. After dilution, Cyramza is administered as an intravenous infusion over approximately 60 minutes. It should not be administered as an intravenous bolus or push. To achieve the required infusion duration of approximately 60 minutes, the maximum infusion rate of 25 mg/minute should not be exceeded, instead the infusion duration should be increased. The patient should be monitored during infusion for signs of infusion-related reactions (see section 4.4) and the availability of appropriate resuscitation equipment should be ensured.

For instructions on dilution of the medicinal product before administration, see section 6.6.