Posology : מינונים

4.2    Posology and method of administration

Therapy must be initiated and supervised by specialist physicians experienced in the treatment of cancer.

The identification of dMMR/MSI-H tumour status should be determined using a validated testing method such as IHC, PCR or NGS* (see section 5.1 for information on assays used in the studies).
*IHC=immunohistochemistry; PCR=polymerase chain reaction; NGS=next-generation sequencing.
Posology
JEMPERLI in combination with carboplatin and paclitaxel

When JEMPERLI is administered in combination with carboplatin and paclitaxel, refer to the full Prescribing Information for the combination products (see also section 5.1).

The recommended dose is 500 mg dostarlimab every 3 weeks in combination with carboplatin and paclitaxel every 3 weeks for 6 cycles followed by 1000 mg dostarlimab as monotherapy every 6 weeks for all cycles thereafter.

The dosage regimen in combination with carboplatin and paclitaxel is presented in Table 1.

Table 1. Dosage regimen for JEMPERLI in combination with carboplatin and paclitaxel 500 mg once every 3 weeks                           1000 mg once every 6 weeks as in combination with carboplatin and paclitaxela        monotherapy until disease progression or (1 Cycle = 3 weeks)                       unacceptable toxicity (1 Cycle = 6 weeks) 
Cycle   Cycle 1   Cycle 2    Cycle 3   Cycle 4   Cycle 5   Cycle 6   Cycle 7   Cycle 8   Cycle 9    Continue dosing
Week      1          4          7        10        13           16     19        25        31         Q6W 

3 weeks between Cycle 6 and Cycle 7 a
Administer dostarlimab prior to carboplatin and paclitaxel on the same day.
Administration of dostarlimab should continue according to the recommended schedule until disease progression or unacceptable toxicity, or for a duration of up to 3 years (see section 5.1).

JEMPERLI monotherapy

The recommended dose as monotherapy is 500 mg dostarlimab every 3 weeks for 4 cycles followed by 1000 mg every 6 weeks for all cycles thereafter.

The dosage regimen as monotherapy is presented in Table 2.

Table 2. Dosage regimen for JEMPERLI as monotherapy



3 weeks between cycle 4 and cycle 5

Administration of dostarlimab should continue according to the recommended schedule until disease progression or unacceptable toxicity (see section 5.1).

Dose modifications
Dose reduction is not recommended. Dosing delay or discontinuation may be required based on individual safety and tolerability. Recommended modifications to manage adverse reactions are provided in Table 3.

Detailed guidelines for the management of immune-related adverse reactions and infusion-related reactions are described in section 4.4.
Table 3. Recommended dose modifications for JEMPERLI
Immune-related adverse       Severity gradea              Dose modification reactions


2 to 3             Withhold dose. Restart dosing when toxicity resolves to grade 0-1.
Colitis
4                     Permanently discontinue.
Grade 2 with ASTb or
ALTc > 3 and up to 5 × ULNd          Withhold dose. Restart dosing when or               toxicity resolves to grade 0 to 1.
total bilirubin > 1.5 and up to 3 × ULN
Hepatitis
Grade ≥ 3 with AST or
ALT > 5 × ULN               Permanently discontinue (see or                     exception below)e.
total bilirubin > 3 × ULN


Withhold dose. Restart dosing in
Type 1 diabetes mellitus
3 to 4 (hyperglycaemia)      appropriately managed, clinically
(T1DM) and metabolically stable patients.


Withhold dose. Restart dosing when toxicity resolves to grade 0 to 1.
Hypophysitis or adrenal             2 to 4
Permanently discontinue for insufficiency recurrence or worsening while on adequate hormonal therapy.

Hypothyroidism or                                    Withhold dose. Restart dosing when hyperthyroidism                  3 to 4              toxicity resolves to grade 0 to 1.

Withhold dose. Restart dosing when toxicity resolves to grade 0-1. If
2
Pneumonitis                                          grade 2 recurs, permanently discontinue.

3 to 4                  Permanently discontinue.

Withhold dose. Restart dosing when
2
Nephritis                                         toxicity resolves to grade 0-1.
3 to 4                  Permanently discontinue.

Withhold dose. Restart dosing when
Immune-mediated rash                  3 toxicity resolves to grade 0-1.


Table 3. Recommended dose modifications for JEMPERLI
Immune-related adverse             Severity gradea              Dose modification reactions


4                      Permanently discontinue.
Other immune-related adverse reactions (including but not                                   Withhold dose. Restart dosing when 3 limited to myositis,                                        toxicity resolves to grade 0-1.
myocarditis, encephalitis,
demyelinating neuropathy including Guillain Barré syndrome, sarcoidosis,
autoimmune haemolytic anaemia, pancreatitis,                    4                      Permanently discontinue.
iridocyclitis, uveitis, diabetic ketoacidosis, arthralgia, solid organ transplant rejection,
graft-versus-host disease)

Recurrence of immune-related adverse reactions after resolution to ≤ grade 1 (except for pneumonitis, see above)
3 to 4                   Permanently discontinue.



Other adverse reactions            Severity gradea              Dose modification 
Withhold dose. If resolved within 1 hour of stopping, may be restarted at
50 % of the original infusion rate, or
Infusion-related reactions                   2                restart when symptoms resolve with pre-medication. If grade 2 recurs with adequate premedication,
permanently discontinue.
3 to 4                    Permanently discontinue.
a
Toxicity graded per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
b
AST = aspartate aminotransferase c
ALT = alanine aminotransferase d
ULN = upper limit of normal e
For patients with liver metastases who begin treatment with grade 2 increase of AST or ALT, if AST or ALT increases by ≥ 50 % relative to baseline and lasts for at least 1 week, then treatment should be discontinued.

Patient Card

All prescribers of JEMPERLI should inform patients about the Patient Card, explaining what to do should they experience any symptom of immune-related adverse reactions. The physician will provide the Patient Card to each patient.

Special populations

Elderly
No dose adjustment is recommended for patients who are aged 65 years or over.
There are limited clinical data with dostarlimab in patients aged 75 years or over (see section 5.1).

Renal impairment
No dose adjustment is recommended for patients with mild or moderate renal impairment. There are limited data in patients with severe renal impairment or end-stage renal disease undergoing dialysis (see section 5.2).

Hepatic impairment
No dose adjustment is recommended for patients with mild hepatic impairment. There are limited data in patients with moderate hepatic impairment and no data in patients with severe hepatic impairment (see section 5.2).

Paediatric population
The safety and efficacy of JEMPERLI in children and adolescents aged under 18 years have not been established. No data are available.

Method of administration

JEMPERLI is for intravenous infusion only. JEMPERLI should be administered by intravenous infusion using an intravenous infusion pump over 30 minutes.

JEMPERLI must not be administered as an intravenous push or bolus injection.

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