Krazati

Treatment with KRAZATI should be initiated by a physician experienced in the use of anti-cancer medicinal products. The presence of a KRAS G12C mutation must be confirmed using a validated test prior to initiation of therapy with KRAZATI.

Posology The recommended dose of KRAZATI is 600 mg (three 200 mg tablets) twice daily. Duration of treatment Treatment with KRAZATI is recommended until disease progression or unacceptable toxicity. Delayed or missed doses Patients should be advised that if less than 4 hours have passed since the scheduled time of dosing, the patient should take the dose as normal.

If a dose is missed by more than 4 hours, the dose should be skipped, and dosing should resume at the next scheduled dose. If vomiting occurs after taking a dose, patients should be advised not to take an additional dose. The next dose should be taken as prescribed.

Dose adjustments during treatment The recommended dose reduction levels for the management of adverse reactions are outlined in Table 1. 3 Table 1: Recommended dose reduction levels for adverse reactions Dose reduction level Reduced dosage First dose reduction Two 200 mg tablets (400 mg) twice daily Second dose reduction Three 200 mg tablets (600 mg) once daily The recommended dose modifications for adverse reactions are provided in Table 2.

, Grade 3) or intolerable adverse reactions require interruption of KRAZATI until sufficient improvement is observed before dosing is resumed. 0 Special populations Elderly population No clinically relevant difference was observed among patients older and younger than 65 years of age.

There are limited safety and efficacy data in patients 75 years or older. 8). Hepatic impairment No clinically significant differences in the pharmacokinetics of adagrasib are expected in patients with mild to severe hepatic impairment (Child-Pugh classes A to C).

2). 2). Paediatric population The safety and efficacy of adagrasib in children aged 0 to 18 years have not been established. 1). Method of administration KRAZATI is for oral use. The tablets can be taken with or without food and should be swallowed whole with water.

Administration with food may improve tolerability. Administration to patients who have difficulty swallowing solids Patients may disperse tablets in 120 mL of non-carbonated, room-temperature water, without crushing them. Other liquids must not be used.

1%). 4%). 0%). Adverse reactions leading to treatment discontinuation are pneumonitis (< 1%), nausea (< 1%), fatigue (< 1%), ALT increased (< 1%) and AST increased (< 1%). 4%). Tabulated list of adverse reactions Adverse reactions reported in clinical studies are listed by system organ class, preferred terms and by frequency.

2 months in pooled clinical studies involving patients with KRAS G12C mutation-positive, for all solid tumours. 1 for information on the characteristics of participants in the main clinical study. The adverse reaction frequencies from clinical studies are displayed as all-cause adverse event frequencies; a proportion of the events included in the frequency estimate for an adverse reaction may have other causes, such as the disease being treated, concomitant medicinal products, or other unrelated causes.

Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

3%). These events may lead to potential consequences such as dehydration, hyponatraemia, blood creatinine increased, and acute kidney injury. 4% of patients respectively. 1%. 3% (Grade ≥ 3) of patients treated with adagrasib. 0% of patients.

6% of patients, respectively. Liver injury has been reported in < 1% of patients. Median time to first onset of adverse reactions was 22 days for ALT and AST increased, 63 days for blood bilirubin increased and 22 days for blood alkaline phosphatase increased, with a median duration of 22, 13 and 35 days, respectively.

3% of patients. 5% respectively. 9% of patients. 2% of patients. The median time to first onset of QT interval prolongation reported as a severe adverse event (CTCAE grade 3 and above) was 13 days with a median duration of 7 days. 4). No QT […]

8). Patients should be monitored and managed using supportive care, including anti-diarrhoeals, antiemetics, or fluid replacement, as indicated. 2). 8). Liver laboratory tests, including AST, ALT, alkaline phosphatase, and blood bilirubin should be monitored prior to the start of treatment and monthly for 3 months after starting treatment with KRAZATI and as clinically indicated, with more frequent testing in patients who develop transaminase and/or alkaline phosphatase elevations.

Based on the severity of the adverse reaction, the adagrasib dose should either be reduced, temporarily withheld until a return to ≤ Grade 1 or return to baseline then resumed at a reduced dose or permanently discontinued. 2. 8). It is recommended that a baseline electrocardiogram (ECG) prior to treatment initiation be performed in all patients and repeated during treatment.

5 When possible, the use of KRAZATI should be avoided in patients with congenital long QT syndrome, in patients with concurrent QTc prolongation and in patients who have experienced torsades de pointes arrhythmia in the past. Periodic monitoring with electrocardiograms and electrolytes should be considered in patients with congestive heart failure, electrolyte abnormalities, or those who are taking medicinal products that are known to prolong the QTc interval.

Based on the severity of the adverse reaction, and after correction of any possible electrolyte disturbances, treatment with KRAZATI can be continued with a reduced dose or temporarily discontinued followed by resumption at a reduced dose after a return to ≤ Grade 1 or return to baseline.

8). 5). CYP3A substrates Adagrasib is a strong CYP3A4 inhibitor. , alfuzosin, amiodarone, cisapride, pimozide, quinidine, ergotamine, dihydroergotamine, quetiapine, lovastatin, simvastatin, sildenafil, sirolimus, midazolam, triazolam, ticagrelor and tacrolimus).

Severe cutaneous adverse reactions (SCARs) Severe cutaneous adverse reactions (SCARs) including Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported in association with KRAZATI.

1. 5).