Posology : מינונים

2         DOSAGE AND ADMINISTRATION
2.1 Patient Selection for Treatment of Urothelial Carcinoma, Triple-Negative Breast
Cancer, Non-Small Cell Lung Cancer and Melanoma
Select cisplatin-ineligible patients with previously untreated locally advanced or metastatic urothelial carcinoma for treatment with TECENTRIQ based on the PD-L1 expression on tumor- infiltrating immune cells [see Clinical Studies (14.1)].
Select patients with Stage II to IIIA non-small cell lung cancer for treatment with TECENTRIQ as a single agent based on PD-L1 expression on tumor cells [see Clinical Studies (14.2)].
Select patients with first-line metastatic non-small cell lung cancer for treatment with TECENTRIQ as a single agent based on the PD-L1 expression on tumor cells or on tumor infiltrating immune cells [see Clinical Studies (14.2)].
Select patients with locally advanced or metastatic triple-negative breast cancer for treatment with TECENTRIQ in combination with paclitaxel protein-bound based on the PD-L1 expression on tumor infiltrating immune cells [see Clinical Studies (14.3)].
Select patients with unresectable or metastatic melanoma for treatment with TECENTRIQ in combination with cobimetinib and vemurafenib after confirming the presence of a BRAF V600 mutation [see Clinical Studies (14.6)].
2.2       Recommended Dosage for Urothelial Carcinoma
The recommended dosage of TECENTRIQ is:
● 840 mg every 2 weeks or
● 1200 mg every 3 weeks or
● 1680 mg every 4 weeks administered intravenously over 60 minutes until disease progression or unacceptable toxicity. If the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes.
2.3       Recommended Dosage for NSCLC
Single Agent
Metastatic NSCLC
The recommended dosage of TECENTRIQ is:
● 840 mg every 2 weeks or
● 1200 mg every 3 weeks or
● 1680 mg every 4 weeks administered intravenously over 60 minutes until disease progression or unacceptable toxicity. If the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes.
Adjuvant Treatment of NSCLC
The recommended dosage of TECENTRIQ is:
•   840 mg every 2 weeks or
•   1200 mg every 3 weeks or
•   1680 mg every 4 weeks


administered intravenously over 60 minutes up to one year, unless there is disease recurrence or unacceptable toxicity. If the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes.


TECENTRIQ with Platinum-based Chemotherapy
The recommended dosage of TECENTRIQ is 1200 mg intravenously every 3 weeks until disease progression or unacceptable toxicity.
Administer TECENTRIQ prior to chemotherapy and bevacizumab when given on the same day.
Refer to the Prescribing Information for the chemotherapy agents or bevacizumab administered in combination with TECENTRIQ for recommended dosing information.
Following completion of 4-6 cycles of chemotherapy, and if bevacizumab is discontinued, the recommended dosage of TECENTRIQ is:
● 840 mg every 2 weeks or
● 1200 mg every 3 weeks or
● 1680 mg every 4 weeks administered intravenously until disease progression or unacceptable toxicity.
Administer the initial infusion of TECENTRIQ over 60 minutes. If the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes.
2.4      Recommended Dosage for Locally Advanced or Metastatic TNBC
The recommended dosage of TECENTRIQ is 840 mg administered intravenously over 60 minutes, followed by 100 mg/m2 paclitaxel protein-bound.
For each 28 day cycle, TECENTRIQ is administered on days 1 and 15, and paclitaxel protein- bound is administered on days 1, 8, and 15 until disease progression or unacceptable toxicity.
TECENTRIQ and paclitaxel protein-bound may be discontinued for toxicity independently of each other.
If the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes.
Refer to the Prescribing Information for paclitaxel protein-bound for recommended dosing information.
2.5      Recommended Dosage for SCLC
The recommended dosage of TECENTRIQ is 1200 mg intravenously every 3 weeks, when administered in combination with carboplatin and etoposide, until disease progression or unacceptable toxicity.
Administer TECENTRIQ prior to chemotherapy when given on the same day. Refer to the Prescribing Information for the chemotherapy agents administered in combination with TECENTRIQ for recommended dosing information.
Following completion of 4 cycles of carboplatin and etoposide, the recommended dosage of TECENTRIQ is 1200 mg every 3 weeks administered intravenously until disease progression or unacceptable toxicity.
Administer the initial infusion of TECENTRIQ over 60 minutes. If the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes.

2.6    Recommended Dosage for HCC
The recommended dosage of TECENTRIQ is 1,200 mg administered as an intravenous infusion over 60 minutes, followed by 15 mg/kg of bevacizumab on the same day, every 3 weeks until disease progression or unacceptable toxicity.
Refer to the Prescribing Information for bevacizumab prior to initiation.
If bevacizumab is discontinued for toxicity, the recommended dosage of TECENTRIQ is 1,200 mg every 3 weeks administered intravenously until disease progression or unacceptable toxicity.
If the first infusion of TECENTRIQ is tolerated, all subsequent infusions may be delivered over 30 minutes.
Tecentriq in combination with bevacizumab has not been studied in HCC patients with severe hepatic impairment (Child Pugh C) and is therefore not recommended for use in these patients.
2.7    Recommended Dosage for Melanoma
Prior to initiating TECENTRIQ, patients should receive a 28 day treatment cycle of cobimetinib 60 mg orally once daily (21 days on and 7 days off) and vemurafenib 960 mg orally twice daily from Days 1-21 and vemurafenib 720 mg orally twice daily from Days 22-28.
The recommended dose of TECENTRIQ is 840 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity, when administered with cobimetinib 60 mg orally once daily (21 days on and 7 days off) and vemurafenib 720 mg orally twice daily.
If the first infusion of TECENTRIQ is tolerated, all subsequent infusions may be delivered over 30 minutes.
Refer to the Prescribing Information for cobimetinib and vemurafenib prior to initiation.


2.8    Recommended Dosage for ASPS
ASPS (adult)
The recommended dosage of TECENTRIQ is 1200 mg every 3 weeks administered intravenously over 60 minutes, until disease progression or unacceptable toxicity.
If the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes.


ASPS (pediatric, 2 years of age and older)
The recommended dosage of TECENTRIQ is 15 mg/kg (up to a maximum 1200 mg) every 3 weeks administered intravenously over 60 minutes, until disease progression or unacceptable toxicity.
If the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes.



2.9    Dosage Modifications for Adverse Reactions
No dose reduction for TECENTRIQ is recommended.
In general, withhold TECENTRIQ for severe (Grade 3) immune-mediated adverse reactions.
Permanently discontinue TECENTRIQ for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating steroids.
Dosage modifications for TECENTRIQ for adverse reactions that require management different from these general guidelines are summarized in Table 1.
Table 1: Recommended Dosage Modifications for Adverse Reactions
Adverse Reaction          Severitya                Dosage Modification Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)] Pneumonitis               Grade 2                  Withholdb
Grades 3 or 4            Permanently discontinue
Colitis                   Grades 2 or 3            Withholdb
Grade 4                  Permanently discontinue
Hepatitis with no tumor   AST or ALT increases     Withholdb involvement of the liver  to more than 3 and up to
8 times ULN or Total bilirubin increases to more than 1.5 and up to
3 times ULN
AST or ALT increases     Permanently discontinue to more than 8 times
ULN or Total bilirubin increases to more than
3 times ULN

Hepatitis with tumor            Baseline AST or ALT is      Withholdb involvement of the liver c      more than 1 and up to 3 times ULN and increases to more than 5 and up to 10 times ULN or
Baseline AST or ALT is more than 3 and up to 5 times ULN and increases to more than 8 and up to 10 times ULN
AST or ALT increases        Permanently discontinue to more than 10 times
ULN or
Total bilirubin increases to more than 3 times
ULN

Adverse Reaction                     Severitya                        Dosage Modification Endocrinopathies                     Grades 3, or 4                   Withhold until clinically stable or permanently discontinue depending on severity.
Nephritis with Renal                 Grades 2 or 3 increased          Withholdb Dysfunction                          blood creatinine
Grade 4 increased blood          Permanently discontinue creatinine
Exfoliative Dermatologic             Suspected SJS, TEN, or           Withhold Conditions                           DRESS
Confirmed SJS, TEN, or           Permanently discontinue
DRESS
Myocarditis                          Grades 2, 3, or 4                Permanently discontinue Neurological Toxicities              Grade 2                          Withholdb Grades 3 or 4                    Permanently discontinue
Other Adverse Reactions
Infusion-Related Reactions           Grades 1 or 2                    Interrupt or slow the rate of [see Warnings and                                                     infusion Precautions (5.2)]                   Grades 3 or 4                    Permanently discontinue a
Based on Common Terminology Criteria for Adverse Events (CTCAE) version 4 b.
Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating steroids.
c.
If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue TECENTRIQ based on recommendations for hepatitis with no liver involvement.
ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit normal, DRESS = Drug Rash with Eosinophilia and Systemic Symptoms, SJS = Stevens Johnson syndrome, TEN = toxic epidermal necrolysis


2.10 Preparation and Administration
Preparation
Visually inspect drug product for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard the vial if the solution is cloudy, discolored, or visible particles are observed. Do not shake the vial.
Prepare the solution for infusion as follows:
● Select the appropriate vial(s) based on the prescribed dose.
● Withdraw the required volume of TECENTRIQ from the vial(s) using sterile needle and syringe.
● Dilute to a final concentration between 3.2 mg/mL and 16.8 mg/mL in a polyvinyl chloride (PVC), polyethylene (PE), or polyolefin (PO) infusion bag containing 0.9% Sodium Chloride Injection, USP.
● Dilute with only 0.9% Sodium Chloride Injection
● Mix diluted solution by gentle inversion. Do not shake.

● Discard used or empty vials of TECENTRIQ.
Storage of Infusion Solution
This product does not contain a preservative.
Administer immediately once prepared. If diluted TECENTRIQ infusion solution is not used immediately, store solution either:
● At ≤30°C for up to 24 hours from the time of preparation. This includes room temperature storage of the infusion in the infusion bag and time for administration of the infusion, or ● Under refrigeration at 2°C-8°C for up to 30 days from time of preparation.
●     From a microbiological point of view, the prepared solution for infusion should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 °C to 8 °C or 8 hours at ambient temperature (≤ 25 °C) unless dilution has taken place in controlled and validated aseptic conditions.
Do not freeze.
Do not shake.
Administration
Administer the initial infusion over 60 minutes through an intravenous line with or without a sterile, non-pyrogenic, low-protein binding in-line filter (pore size of 0.2–0.22 micron). If the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes.
Do not coadminister other drugs through the same intravenous line.
Do not administer as an intravenous push or bolus.

3.     DOSAGE FORMS AND STRENGTHS
Injection: 840 mg/14 mL (60 mg/mL) and 1200 mg/20 mL (60 mg/mL) colorless to slightly yellow solution in a single-dose vial.