Posology : מינונים

4.2   Posology and method of administration
Kadcyla should only be prescribed by a physician and administered as an intravenous infusion under the supervision of a healthcare professional who is experienced in the treatment of cancer patients (i.e.
prepared to manage allergic/anaphylactic infusion reactions and in an environment where full resuscitation facilities are immediately available (see section 4.4)).

Patients treated with trastuzumab emtansine should have HER2 positive tumour status, defined as a score of 3 + by immunohistochemistry (IHC) or a ratio of ≥ 2.0 by in situ hybridization (ISH) or by fluorescence in situ hybridization (FISH).

In order to prevent medicinal product errors it is important to check the vial labels to ensure that the medicinal product being prepared and administered is Kadcyla (trastuzumab emtansine) and not another trastuzumab-containing product (e.g. trastuzumab or trastuzumab deruxtecan).

Posology

The recommended dose of trastuzumab emtansine is 3.6 mg/kg bodyweight administered as an intravenous infusion every 3 weeks (21-day cycle).

The initial dose should be administered as a 90 minute intravenous infusion. Patients should be observed during the infusion and for at least 90 minutes following the initial infusion for fever, chills, or other infusion-related reactions. The infusion site should be closely monitored for possible subcutaneous infiltration during administration. Cases of delayed epidermal injury or necrosis following extravasation have been observed in the post-marketing setting (see section 4.4 and 4.8).

If the prior infusion was well tolerated, subsequent doses of trastuzumab emtansine may be administered as 30 minute infusions. Patients should be observed during the infusion and for at least 30 minutes after infusion.

The infusion rate of trastuzumab emtansine should be slowed or interrupted if the patient develops infusion-related symptoms (see sections 4.4 and 4.8). Trastuzumab emtansine should be discontinued in case of life-threatening infusion reactions.

Duration of treatment

Early Breast Cancer (EBC)
Patients should receive treatment for a total of 14 cycles unless there is disease recurrence or unmanageable toxicity.

Metastatic Breast Cancer (MBC)
Patients should receive treatment until disease progression or unmanageable toxicity.
Dose modification
Management of symptomatic adverse reactions may require temporary interruption, dose reduction, or treatment discontinuation of trastuzumab emtansine as per guidelines provided in text and Tables 1 and 2.

Trastuzumab emtansine dose should not be re-escalated after a dose reduction is made.



Kadcyla PI Version 6
Table 1     Dose reduction schedule
Dose reduction schedule
Dose to be administered
(Starting dose is 3.6 mg/kg)
First dose reduction                        3 mg/kg
Second dose reduction                       2.4 mg/kg
Requirement for further dose reduction      Discontinue treatment


Table 2     Dose Modification Guidelines
Dose Modifications for Patients with EBC
Adverse reaction      Severity                 Treatment modification Thrombocytopenia      Grade 2-3 on day of      Do not administer trastuzumab emtansine until scheduled treatment      platelet count recovers to Grade 1 (≥ (25,000 to <             75,000/mm3), and then treat at the same dose level.
3
75,000/mm )              If a patient requires 2 delays due to thrombocytopenia, consider reducing dose by one level.
Grade 4 at any time      Do not administer trastuzumab emtansine until < 25,000/mm3             platelet count recovers to  Grade 1 (≥
75,000/mm3), and then reduce one dose level.
Increased Alanine     Grade 2-3                Do not administer trastuzumab emtansine until Transaminase (ALT) (> 3.0 to ≤ 20 ULN on ALT recovers to Grade ≤ 1, and then reduce one day of scheduled         dose level treatment)
Grade 4                  Discontinue trastuzumab emtansine
(> 20  ULN at any time)
Increased Aspartate   Grade 2                  Do not administer trastuzumab emtansine until Transaminase (AST) (> 3.0 to ≤ 5 ULN on AST recovers to Grade  1, and then treat at the day of scheduled         same dose level treatment)
Grade 3                  Do not administer trastuzumab emtansine until (> 5 to ≤ 20 ULN on     AST recovers to Grade ≤ 1, and then reduce one day of scheduled         dose level treatment)
Grade 4                  Discontinue trastuzumab emtansine
(> 20  ULN at any time)
Hyperbilirubinemia    TBILI                    Do not administer trastuzumab emtansine until total > 1.0 to ≤ 2.0the ULN bilirubin recovers to ≤ 1.0× ULN, and then reduce on day of scheduled      one dose level treatment
TBILI                    Discontinue trastuzumab emtansine
> 2 ULN at any time
Nodular Regenerative All Grades                Permanently discontinue trastuzumab emtansine Hyperplasia (NRH)
Peripheral Neuropathy Grade 3-4                Do not administer trastuzumab emtansine until resolution Grade 2


Kadcyla PI Version 6
Left Ventricular       LVEF < 45%               Do not administer trastuzumab emtansine .
Dysfunction                                     Repeat LVEF assessment within 3 weeks. If LVEF < 45% is confirmed, discontinue trastuzumab emtansine.
LVEF 45% to < 50%        Do not administer trastuzumab emtansine.
and decrease is ≥ 10%    Repeat LVEF assessment within 3 weeks. If the points from baseline*    LVEF remains < 50% and has not recovered to < 10% points from baseline, discontinue trastuzumab emtansine.
LVEF 45% to < 50%        Continue treatment with trastuzumab emtansine.
and decrease is < 10%    Repeat LVEF assessment within 3 weeks.
points from baseline*
LVEF ≥ 50%               Continue treatment with trastuzumab emtansine Heart Failure                                   Discontinue trastuzumab emtansine Symptomatic CHF,
Grade 3-4 LVSD or
Grade 3-4 heart failure,
or
Grade 2 heart failure accompanied by LVEF
<45%
Pulmonary Toxicity     Interstitial lung disease Permanently discontinue trastuzumab emtansine (ILD) or pneumonitis

Radiotherapy-Related Grade 2                    Discontinue trastuzumab emtansine if not resolving Pneumonitis                                     with standard treatment 
Grade 3-4                Discontinue trastuzumab emtansine

Dose Modifications for Patients with MBC
Adverse reaction       Severity                            Treatment modification Thrombocytopenia       Grade 3                  Do not administer trastuzumab emtansine until (25,000 to               platelet count recovers to  Grade 1 (≥
 50,000/mm3)            75,000/mm3), and then treat at the same dose level Grade 4                  Do not administer trastuzumab emtansine until  25,000/mm3)           platelet count recovers to  Grade 1 (≥ 75,000/mm3), and then reduce one dose level
Increased Transaminase Grade 2                 Treat at the same dose level (AST/ALT)              ( 2.5 to ≤ 5 the ULN)
Grade 3                  Do not administer trastuzumab emtansine until ( 5 to ≤ 20 the ULN)   AST/ALT recovers to Grade ≤ 2, and then reduce one dose level
Grade 4                  Discontinue trastuzumab emtansine
( 20 the ULN)



Kadcyla PI Version 6
Hyperbilirubinemia   Grade 2                  Do not administer trastuzumab emtansine until ( 1.5 to ≤ 3 the ULN) total bilirubin recovers to Grade ≤ 1, and then treat at the same dose level.
Grade 3                  Do not administer trastuzumab emtansine until ( 3 to ≤ 10 the ULN) total bilirubin recovers to Grade ≤ 1 and then reduce one dose level.
Grade 4                  Discontinue trastuzumab emtansine
( 10 the ULN)
Drug Induced Liver   Serum transaminases > 3 Permanently discontinue trastuzumab emtansine Injury (DILI)        x ULN and concomitant total bilirubin > 2 ULN
Nodular Regenerative All Grades               Permanently discontinue trastuzumab emtansine Hyperplasia (NRH)
Left Ventricular     Symptomatic CHF          Discontinue trastuzumab emtansine Dysfunction
LVEF <40%                Do not administer trastuzumab emtansine.
Repeat LVEF assessment within 3 weeks. If LVEF
<40% is confirmed, discontinue trastuzumab emtansine
LVEF 40% to ≤ 45%        Do not administer trastuzumab emtansine.
and decrease is ≥ 10%    Repeat LVEF assessment within 3 weeks. If the points from baseline     LVEF has not recovered to within 10% points from baseline, discontinue trastuzumab emtansine.
LVEF 40% to ≤ 45%        Continue treatment with trastuzumab emtansine.
and decrease is < 10%    Repeat LVEF assessment within 3 weeks.
points from baseline
LVEF > 45%               Continue treatment with trastuzumab emtansine.
Peripheral Neuropathy Grade 3-4                             Do not administer trastuzumab emtansine until resolution Grade 2
Pulmonary Toxicity            Interstitial lung disease     Permanently discontinue trastuzumab emtansine (ILD) or pneumonitis

ALT  alanine transaminase; AST  aspartate transaminase, CHF = congestive heart failure, LVEF  left ventricular ejection fraction, LVSD  left ventricular systolic dysfunction, TBILI = Total Bilirubin, ULN  upper limit of normal * Prior to starting trastuzumab emtansine treatment.

Delayed or missed dose
If a planned dose is missed, it should be administered as soon as possible; without waiting until the next planned cycle. The schedule of administration should be adjusted to maintain a 3-week interval between doses. The next dose should be administered in accordance with the dosing recommendations above.

Peripheral neuropathy
Trastuzumab emtansine should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until resolution to ≤ Grade 2. At retreatment a dose reduction may be considered according to the dose reduction schedule (see Table 1).

Special populations

Elderly patients
No dose adjustment is required in patients aged ≥ 65 years. There are insufficient data to establish the safety and efficacy in patients ≥ 75 years due to limited data in this subgroup. However, for patients Kadcyla PI Version 6
≥65 years, subgroup analysis of 345 patients from study MO28231 shows a tendency of higher incidences of grade 3, 4 and 5 AE’s, SAE’s and AE’s leading to drug discontinuation/interruption, but with a similar incidence of AEs of grade 3 and above classified as drug related.

Population pharmacokinetic analysis indicates that age does not have a clinically meaningful effect on the pharmacokinetics of trastuzumab emtansine (see sections 5.1 and 5.2).

Renal impairment
No adjustment to the starting dose is needed in patients with mild or moderate renal impairment (see section 5.2). The potential need for dose adjustment in patients with severe renal impairment cannot be determined due to insufficient data and therefore patients with severe renal impairment should be monitored carefully.

Hepatic impairment
No adjustment to the starting dose is required for patients with mild or moderate hepatic impairment.
Trastuzumab emtansine has not been studied in patients with severe hepatic impairment. Treatment of patients with hepatic impairment should be undertaken with caution due to known hepatotoxicity observed with trastuzumab emtansine (see section 4.4 and 5.2).

Paediatric population
The safety and efficacy in children and adolescents below 18 years of age have not been established as there is no relevant use in the paediatric population for the indication of breast cancer.

Method of administration

Kadcyla is for intravenous use. Trastuzumab emtansine must be reconstituted and diluted by a healthcare professional and administered as an intravenous infusion. It must not be administered as an intravenous push or bolus.

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