Posology : מינונים

2   DOSAGE AND ADMINISTRATION

2.1 Important dosing information
Pretreatment Vitamin Supplementation
Folic Acid: Patients should take folic acid 1-1.25 mg orally once daily beginning 10 days before the first dose of Difolta. Continue folic acid during the full course of therapy and for 30 days after the last dose of Difolta [see Warnings and Precautions (5.1) (5.2)].

Vitamin B12: Administer vitamin B12 1 mg intramuscularly within 10 weeks prior to the first dose of Difolta and every 8-10 weeks thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with Difolta [see Warnings and Precautions (5.1) (5.2)].

Dosing and Administration
The recommended dose of Difolta is 30 mg/m2 administered as an intravenous push over 3-5 minutes via the side port of a free flowing 0.9% Sodium Chloride Injection intravenous line once weekly for 6 weeks in 7-week cycles until progressive disease or unacceptable toxicity. The calculated dose of Difolta should be aseptically withdrawn into a syringe for immediate use. Do not dilute Difolta.

For patients with severe renal impairment (eGFR 15 to < 30 mL/min/1.73 m2), the recommended dose of Difolta is 15 mg/m2.

Difolta is a clear, yellow solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use any vials exhibiting particulate matter or discoloration.

2.2 Monitoring and Dose Modifications for Adverse Reactions
Management of severe or intolerable adverse reactions may require dose omission, reduction, or discontinuation of Difolta therapy.

Monitoring
Monitor complete blood cell counts and severity of mucositis at baseline and weekly. Perform serum chemistry tests, including renal and hepatic function, prior to the start of the first and fourth dose of each cycle.

Recommended Dosage Modifications
Do not administer Difolta until:
• Mucositis should be Grade 1 or less.
• Platelet count should be 100,000/mcL or greater for first dose and 50,000/mcLor greater for all subsequent doses.
• Absolute neutrophil count (ANC) of 1,000/mcL or greater.

Doses may be omitted or reduced based on patient tolerance. Omitted doses will not be made up at the end of the cycle; once a dose reduction occurs for toxicity, do not re-escalate. For dose modifications and omissions, use the guidelines in Tables 1, 2, and 3.

For patients with severe renal impairment (eGFR 15 to < 30 mL/min/1.73 m2), the recommended starting dose of Difolta is 15 mg/m2 with dose modification to 10 mg/m2 for the toxicities specified in Tables 1, 2 and 3.

Dosage modification for adverse reactions are provided in Tables 1,2, and 3.

Table 1     Difolta Dosage Modifications for Mucositis
Mucositis Gradea on Day of Treatment           Action       Dose upon Recovery to  Grade 1          Dose Upon Recovery in Patients with Severe Renal Impairment
Grade 2                                       Omit dose           Continue prior dose                      Continue prior dose Grade 2 recurrence                            Omit dose                 20 mg/m2                               10 mg/m2 Grade 3                                       Omit dose                 20 mg/m2                               10 mg/m2 Grade 4                                      Stop therapy a
Based National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE, Version 3.0)

Table 2       Difolta Dose Modifications for Myelosuppression
Duration of                                                       Dose Upon Recovery Blood Count on Day of Treatment         Toxicity              Action              Dose upon Restart     in Patients with Severe Renal Impairment
1 week            Omit dose             Continue prior dose     Continue prior dose Platelet less than 50,000/mcL             2 weeks           Omit dose                 20 mg/m2                 10 mg/m2 3 weeks          Stop therapy
ANC 500 to 1,000/mcL and no fever         1 week            Omit dose             Continue prior dose     Continue prior dose Omit dose,            Continue prior dose     Continue prior dose give G-CSF or             with G-CSF or            with G-CSF or
1 week
GM-CSF support            GM-CSF support               GM-CSF
ANC 500 to 1,000/mcL with fever                                                                                 support or                                      2 weeks or          Omit dose,        20 mg/m2 with G-CSF        10 mg/m2 with G-CSF ANC less than 500/mcL                   recurrence        give G-CSF or        or GM-CSF support          or GM-CSF support GM-CSF support
3 weeks or
Stop therapy
2nd recurrence
G-CSF=granulocyte colony-stimulating factor; GM-CSF=granulocyte macrophage colony-stimulating factor 
Table 3     Difolta Dose Modifications for All Other Adverse reactions Toxicity Grade a on Day of Treatment           Action        Dose upon Recovery to  Grade 2        Dose Upon Recovery in Patients with Severe Renal Impairment
Grade 3                                       Omit dose                   20 mg/m2                            10 mg/m2 Grade 4                                      Stop therapy a
Per NCI CTCAE, Version 3.0

2.3 Preparation and Administration
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use any vials exhibiting particulate matter or discoloration.

Difolta is a hazardous drug. Follow applicable special handling and disposable procedures. If Difolta comes in contact with the skin, immediately and thoroughly wash with soap and water. If Difolta comes in contact with mucous membranes, flush thoroughly with water.

Aseptically withdraw the calculated dose from the appropriate number of vial(s) into a syringe for immediate use. Do not dilute Difolta
Administer undiluted Difolta intravenously over 3-5 minutes via the side port of a free-flowing 0.9% Sodium Chloride Injection.
After withdrawal of dose, discard vial(s) including any unused portion.