Posology : מינונים

4.2    Posology and method of administration

Treatment with LUMYKRAS must be initiated by a physician experienced in the use of anticancer medicinal products.

The presence of a KRAS G12C mutation must be confirmed using a validated test prior to initiation of LUMYKRAS therapy.

Posology

The recommended dose is 960 mg sotorasib (eight 120 mg tablets) once daily, at the same time each day.

Duration of treatment
Treatment with LUMYKRAS is recommended until disease progression or unacceptable toxicity.

Missed doses or vomiting
If less than 6 hours have passed since the scheduled time of dosing, the patient should take the dose as normal. If more than 6 hours have passed since the scheduled time of dosing, the patient must not take the dose. Treatment should be continued as prescribed the next day.

If vomiting occurs after taking LUMYKRAS, the patient must not take an additional dose on the same day, and treatment must be continued as prescribed the next day.


Dose modifications
Dosing should be modified based on LUMYKRAS toxicity. The dose reduction rules outlined in section 4.2 are based on clinical data. Pharmacokinetic (PK) data do suggest a similar exposure at lower sotorasib doses. Dose reduction levels are summarised in table 1. Dose modifications for adverse reactions are provided in table 2 (see section 5.2).

If toxicity events occur, a maximum of two dose reductions are permitted. LUMYKRAS must be discontinued if patients are unable to tolerate the minimum dose of 240 mg once daily.

Table 1. Recommended sotorasib dose reduction levels

Dose reduction level                                 Dose
Starting dose                                        960 mg (eight 120 mg tablets) once daily First dose reduction                                 480 mg (four 120 mg tablets) once daily Second dose reduction                                240 mg (two 120 mg tablets) once daily 
Table 2. Recommended dose modifications for sotorasib

Adverse reaction                 Severitya                        Dose modification Hepatotoxicity                   Grade 2 AST or ALT with          •    Stop treatment until symptoms                              recovered to ≤ grade 1 or to baseline grade or                               •    After recovery, resume treatment at the next dose
Grade ≥ 3 AST or ALT                  reduction level
AST or ALT > 3 × ULN with        •    Permanently discontinue total bilirubin > 2 × ULN, in         treatment the absence of alternative causes
Interstitial Lung Disease        Any grade                        •      Stop treatment if (ILD)/pneumonitis                                                        ILD/pneumonitis is suspected
•      Permanently discontinue treatment if ILD/pneumonitis is confirmed
Nausea, vomiting, or             Grade ≥ 3                        •      Stop treatment until diarrhoea persisting despite                                             recovered to ≤ grade 1 or to supportive care (including                                               baseline grade anti-emetic or anti-diarrhoeal                                    •      After recovery, resume therapy)                                                                 treatment at the next dose reduction level
Other medicinal product-         Grade ≥ 3                        •      Stop treatment until related toxicity                                                         recovered to ≤ grade 1 or to baseline grade
•      After recovery, resume treatment at the next dose reduction level
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal a
Grading defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0

Co-administration of LUMYKRAS with acid-reducing agents

Co-administration of proton pump inhibitors (PPIs) or H2 receptor antagonists with LUMYKRAS is not recommended. If treatment with an acid-reducing agent is required a local antacid may be used, 

LUMYKRAS should be taken either 4 hours before or 10 hours after administration of a local antacid (see section 4.5).

Special populations

Elderly
The limited data on the safety and efficacy of LUMYKRAS in patients aged 75 years and older do not suggest that a dose adjustment is required in elderly patients (see sections 4.8 and 5.2).

Hepatic impairment
No dose adjustment is recommended for patients with mild hepatic impairment (AST or ALT< 2.5 × ULN or total bilirubin < 1.5 × ULN). Administration of sotorasib in subjects with moderate and severe hepatic impairment is not recommended.

Renal impairment
No dose adjustment is recommended for patients with mild renal impairment (creatine clearance, CrCL ≥ 60 mL/min). LUMYKRAS has not been studied in patients with moderate or severe renal impairment (CrCL < 60 mL/min). Therefore, caution should be exercised when treating patients with moderate, severe and end stage renal impairment (see section 5.2).

Paediatric population
The safety and efficacy of LUMYKRAS in children and adolescents under the age of 18 years have not yet been established.

Method of administration

LUMYKRAS is for oral use. The tablets must be swallowed whole. There are no data to support the administration of LUMYKRAS if the tablets are chewed, crushed, or split but the tablets can be dispersed in water (see below). The tablets can be taken with or without food.

Administration to patients who have difficulty swallowing solids
Patients should disperse tablets in 120 mL of non-carbonated, room-temperature water, without crushing them. Other liquids must not be used. Patients should stir until the tablets are dispersed into small pieces (the tablet will not dissolve completely) and drink it immediately. The appearance of the mixture may range from pale to bright yellow. The container must be rinsed with an additional 120 mL of water, which should be drunk immediately. If it is not drunk immediately, patients must stir again to ensure that the tablets are dispersed. The dispersion must be discarded if it is not drunk within 2 hours.