Posology : מינונים

3.        DOSAGE AND ADMINISTRATION

3.1       Recommended Dose and Schedule
•   When used in combination with fulvestrant, tamoxifen, or a non-steroidal aromatase inhibitor, the recommended dose of VERZENIO is 150 mg taken orally twice daily. Refer to the Full Prescribing Information for the recommended dose of the fulvestrant, tamoxifen or non-steroidal aromatase inhibitor being used.
•   Pre/perimenopausal women and men treated with the combination of VERZENIO plus an aromatase inhibitor should be treated with a gonadotropin-releasing hormone agonist (GnRH) according to current clinical practice standards.
•   Pre/perimenopausal women treated with the combination of VERZENIO plus fulvestrant should be treated with a GnRH according to current clinical practice standards.
•   When used as monotherapy, the recommended dose of VERZENIO is 200 mg taken orally twice daily.
•   For early breast cancer, continue VERZENIO until completion of 2 years of treatment or until disease recurrence, or unacceptable toxicity.
•   For advanced or metastatic breast cancer, continue treatment until disease progression or unacceptable toxicity.
VERZENIO may be taken with or without food [see Clinical Pharmacology (12.3)].
Instruct patients to take their doses of VERZENIO at approximately the same times every day.

If the patient vomits or misses a dose of VERZENIO, instruct the patient to take the next dose at its scheduled time.
Instruct patients to swallow VERZENIO tablets whole and not to chew, crush, or split tablets before swallowing. Instruct patients not to ingest VERZENIO tablets if broken, cracked, or otherwise not intact.

3.2    Dose Modification
Dose Modifications for Adverse Reactions
The recommended VERZENIO dose modifications for adverse reactions are provided in Tables 1-7. Discontinue VERZENIO for patients unable to tolerate 50 mg twice daily.


Table 1: VERZENIO Dose Modification —Adverse Reactions
Dose Level                                          VERZENIO Dose                               VERZENIO Dose for in Combination with Fulvestrant,                     Monotherapy
Tamoxifen or a Non-steroidal
Aromatase Inhibitor
Recommended starting dose                             150 mg twice daily                         200 mg twice daily First dose reduction                                  100 mg twice daily                         150 mg twice daily Second dose reduction                                 50 mg twice daily                          100 mg twice daily Third dose reduction                                    not applicable                            50 mg twice daily 

Table 2: VERZENIO Dose Modification and Management — Hematologic Toxicitiesa 
Monitor complete blood counts prior to the start of VERZENIO therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated.
CTCAE Grade                                            VERZENIO Dose Modifications Grade 1 or 2                                                  No dose modification is required.
Grade 3                                               Suspend dose until toxicity resolves to ≤Grade 2.
Dose reduction is not required.
Grade 3 recurrent, or                                 Suspend dose until toxicity resolves to ≤Grade 2.
Grade 4                                                        Resume at next lower dose.
Abbreviation: CTCAE = Common Terminology Criteria for Adverse Events.
a
If blood cell growth factors are required, suspend VERZENIO dose for at least 48 hours after the last dose of blood cell growth factor and until toxicity resolves to ≤Grade 2. Resume at next lower dose unless already performed for the toxicity that led to the use of the growth factor. Growth factor use as per current treatment guidelines.
Table 3: VERZENIO Dose Modification and Management — Diarrhea

At the first sign of loose stools, start treatment with antidiarrheal agents and increase intake of oral fluids.
CTCAE Grade                                             VERZENIO Dose Modifications Grade 1                                                                         No dose modification is required.
Grade 2                                                             If toxicity does not resolve within 24 hours to ≤Grade 1, suspend dose until resolution. No dose reduction is required.
Grade 2 that persists or recurs after resuming the same                 Suspend dose until toxicity resolves to ≤Grade 1.
dose despite maximal supportive measures                                         Resume at next lower dose.
Grade 3 or 4 or requires hospitalization                                Suspend dose until toxicity resolves to ≤Grade 1.
Resume at next lower dose.
Table 4: VERZENIO Dose Modification and Management — Hepatotoxicity Monitor ALT, AST, and serum bilirubin prior to the start of VERZENIO therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated.
CTCAE Grade for ALT and AST                                     VERZENIO Dose Modifications Grade 1 (>ULN-3.0 x ULN)
Grade 2 (>3.0-5.0 x ULN),                                                 No dose modification is required.
WITHOUT increase in total bilirubin above 2 x ULN
Persistent or Recurrent Grade 2, or Grade 3 (>5.0-           Suspend dose until toxicity resolves to baseline or Grade 1.
20.0 x ULN), WITHOUT increase in total bilirubin above 2 x ULN                                                              Resume at next lower dose.

Elevation in AST and/or ALT >3 x ULN WITH total
Discontinue VERZENIO.
bilirubin >2 x ULN, in the absence of cholestasis
Grade 4 (>20.0 x ULN)                                                          Discontinue VERZENIO.
Abbreviations: ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit of normal.

Table 5: VERZENIO Dose Modification and Management — Interstitial Lung Disease/Pneumonitis 
CTCAE Grade                                           VERZENIO Dose Modifications Grade 1 or 2                                                                 No dose modification is required.
Persistent or recurrent Grade 2 toxicity that does not              Suspend dose until toxicity resolves to baseline or resolve with maximal supportive measures within 7 days to                              ≤Grade 1.
baseline or Grade 1                                                          Resume at next lower dose.
Grade 3 or 4                                                                      Discontinue VERZENIO.

Table 6: VERZENIO Dose Modification and Management — Venous Thromboembolic Events (VTEs) 
CTCAE Grade                                           VERZENIO Dose Modifications Early Breast Cancer
Any Grade                                                        Suspend dose and treat as clinically indicated. Resume VERZENIO when the patient is clinically stable.
Advanced or Metastatic Breast Cancer
Grade 1 or 2                                                                 No dose modification is required.
Grade 3 or 4                                                     Suspend dose and treat as clinically indicated. Resume VERZENIO when the patient is clinically stable.


Table 7: VERZENIO Dose Modification and Management — Other Toxicitiesa 
CTCAE Grade                                           VERZENIO Dose Modifications Grade 1 or 2                                                                 No dose modification is required.
Persistent or recurrent Grade 2 toxicity that does not              Suspend dose until toxicity resolves to baseline or resolve with maximal supportive measures within 7 days to                              ≤Grade 1.
baseline or Grade 1                                                          Resume at next lower dose.
Grade 3 or 4                                                        Suspend dose until toxicity resolves to baseline or ≤Grade 1.
Resume at next lower dose.
a
Excluding diarrhea, hematologic toxicity, hepatotoxicity ILD/pneumonitis, and VTEs.

Refer to the Full Prescribing Information for coadministered fulvestrant, tamoxifen or a non-steroidal aromatase inhibitor for dose modifications and other relevant safety information.


Dose Modification for Use with Strong and Moderate CYP3A Inhibitors
Avoid concomitant use of the strong CYP3A inhibitor ketoconazole.
With concomitant use of strong CYP3A inhibitors other than ketoconazole, in patients with recommended starting doses of 200 mg twice daily or 150 mg twice daily, reduce the VERZENIO dose to 100 mg twice daily. In patients who have had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the VERZENIO dose to 50 mg twice daily. If a patient taking VERZENIO discontinues a CYP3A inhibitor, increase the VERZENIO dose (after 3-5 half-lives of the inhibitor) to the dose that was used before starting the strong inhibitor [see Drug Interactions (8.1) and Clinical Pharmacology (12.3)].

With concomitant use of moderate CYP3A inhibitors, monitor for adverse reactions and consider reducing the VERZENIO dose in 50 mg decrements as demonstrated in Table 1, if necessary.


Dose Modification for Patients with Severe Hepatic Impairment
For patients with severe hepatic impairment (Child Pugh-C), reduce the VERZENIO dosing frequency to once daily [see Use in Specific Populations (9.7) and Clinical Pharmacology (12.3)].

Refer to the Full Prescribing Information for the coadministered fulvestrant, tamoxifen or a non-steroidal aromatase inhibitor for dose modification requirements for severe hepatic impairment.

4      DOSAGE FORMS AND STRENGTHS
50 mg tablets: oval beige tablet with “Lilly” debossed on one side and “50” on the other side.
100 mg tablets: oval white to practically white tablet with “Lilly” debossed on one side and “100” on the other side.
150 mg tablets: oval yellow tablet with “Lilly” debossed on one side and “150” on the other side.