Posology : מינונים

4.2     Posology and method of administration

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

Posology

The recommended dose of Tevimbra is 200 mg administered by intravenous infusion once every 3 weeks.

Duration of treatment
Patients should be treated with Tevimbra until disease progression or unacceptable toxicity.

Dose delay or discontinuation (see also section 4.4)
No dose reductions of Tevimbra as monotherapy are recommended. Tevimbra should be withheld or discontinued as described in Table 1.

Detailed guidelines for the management of immune-related adverse reactions are described in section 4.4.

Table 1      Recommended treatment modifications for Tevimbra

Immune-related adverse             Severity1                         Tevimbra treatment modification reaction
Grade 2                           Withhold2,3
Pneumonitis
Recurrent grade 2; grade 3 or 4   Permanently discontinue3
ALT or AST >3 to 8 x ULN or       Withhold2,3 total bilirubin >1.5 to 3 x ULN
Hepatitis
ALT or AST >8 x ULN or total      Permanently discontinue3 bilirubin >3 x ULN
Grade 3                           Withhold2,3
Rash
Grade 4                           Permanently discontinue3
Withhold2,3
For suspected SJS or TEN, do not
Suspected SCARs, including SJS resume unless SJS/TEN has been
Severe cutaneous adverse           or TEN ruled out in consultation with reactions (SCARs) appropriate specialist(s).
Confirmed SCARs, including SJS    Permanently discontinue or TEN
Grade 2 or 3                      Withold2,3
Colitis
Recurrent grade 3; grade 4        Permanently discontinue3
Grade 2 or 3                      Withhold2,3
Myositis/rhabdomyolysis
Recurrent grade 3; grade 4        Permanently discontinue3
Hypothyroidism may be managed
Hypothyroidism                     Grade 2, 3 or 4                   with replacement therapy without treatment interruption.
Withhold2
For grade 3 or 4 that has improved to grade ≤2 and is controlled with anti-thyroid therapy, if indicated
Hyperthyroidism                    Grade 3 or 4 continuation of Tevimbra may be considered after corticosteroid taper. Otherwise, treatment should be discontinued.


Consider withholding treatment
Grade 2 until controlled by HRT.
Withhold3
For grade 3 or 4 that has improved
Adrenal insufficiency                                                       to grade ≤2 and is controlled with Grade 3 or 4                          HRT, if indicated continuation of Tevimbra may be considered after corticosteroid taper. Otherwise,
treatment should be discontinued.3
Consider withholding treatment
Grade 2 until controlled by HRT.
Withhold2,3
For grade 3 or 4 that has improved
Hypophysitis                                                                to grade ≤2 and is controlled with Grade 3 or 4                          HRT, if indicated continuation of Tevimbra may be considered after corticosteroid taper. Otherwise,
treatment should be discontinued.3
Withhold
Type 1 diabetes mellitus
For grade 3 or 4 that has improved associated with grade ≥3 to grade ≤2 with insulin therapy, if hyperglycaemia
Type 1 diabetes mellitus                                                    indicated continuation of Tevimbra (glucose >250 mg/dl may be considered once metabolic or >13.9 mmol/l) or associated control is achieved. Otherwise,
with ketoacidosis treatment should be discontinued.
Grade 2 (creatinine >1.5 to 3 x       Withhold2,3 baseline or >1.5 to 3 x ULN)
Nephritis with renal dysfunction      Grade 3 (creatinine >3 x baseline     Permanently discontinue3 or >3 to 6 x ULN) or grade 4
(creatinine >6 x ULN)
Myocarditis                           Grade 2, 3 or 4                       Permanently discontinue3 Grade 2                               Withhold2,3
Neurological toxicities
Grade 3 or 4                          Permanently discontinue3
Grade 3 pancreatitis or grade 3 or    Withhold2,3
4 serum amylase or lipase levels
Pancreatitis increased (>2 x ULN)
Grade 4                               Permanently discontinue3
Other immune-related adverse          Grade 3                               Withhold2,3 reactions                             Recurrent grade 3; grade 4            Permanently discontinue3 Other adverse drug reactions
Consider pre-medication for prophylaxis of subsequent infusion
Grade 1 reactions.
Slow the rate of infusion by 50%.
Infusion-related reactions                                                  Interrupt infusion.
Resume infusion if resolved or
Grade 2 decreased to grade 1, and slow rate of infusion by 50%.
Grade 3 or 4                         Permanently discontinue
ALT = alanine aminotransferase, AST = aspartate aminotransferase, HRT= hormone replacement therapy, SJS = Stevens-Johnson syndrome, TEN = toxic epidermal necrolysis, ULN = upper limit normal 1
Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0). Hypophysitis grade is in accordance with NCI-CTCAE v5.0.
2
Resume in patients with complete or partial resolution (grade 0 to 1) after corticosteroid taper over at least 1 month. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating corticosteroids or inability to reduce prednisone to ≤10 mg/day (or equivalent) within 12 weeks of initiating corticosteroids.
3
Initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a taper to ≤10 mg/day (or equivalent) over at least 1 month is recommended, except for pneumonitis, where initial dose of 2 to 4 mg/kg/day is recommended.

Special populations

Paediatric population
The safety and efficacy of Tevimbra in patients aged below 18 years have not been established. No data are available.

Elderly
No dose adjustment is needed for patients aged ≥65 years (see section 4.8).

Renal impairment
No dose adjustment is needed for patients with mild or moderate renal impairment. Data from patients with severe renal impairment are too limited to make dosing recommendations for this population (see section 5.2).

Hepatic impairment
No dose adjustment is needed for patients with mild or moderate hepatic impairment. Data from patients with severe hepatic impairment are too limited to make dosing recommendations for this population (see section 5.2).

Method of administration

Tevimbra is for intravenous use only. It is to be administered as an infusion and must not be administered as an intravenous push or single bolus injection. For instructions on dilution of the medicinal product before administration, see section 6.6.

The first infusion should be administered over a period of 60 minutes. If this is well tolerated, the subsequent infusions may be administered over a period of 30 minutes. The infusion should be given via an intravenous line containing a sterile, non-pyrogenic, low-protein-binding 0.2 or 0.22 micron in- line or add-on filter.

Other medicinal products must not be mixed or co-administered through the same infusion line.