KRAZATI Film-coated tablet Ref.[108847] Active ingredients: Adagrasib

Gastrointestinal adverse reactions

Gastrointestinal (GI) adverse reactions including diarrhoea, nausea, and vomiting can occur with adagrasib (see section 4.8).

Patients should be monitored and managed using supportive care, including anti-diarrhoeals, antiemetics, or fluid replacement, as indicated. Based on the severity of the adverse reaction, the dose of KRAZATI should either be reduced, temporarily withheld until a return to ≤ Grade 1 or return to baseline then resumed at a reduced dose (see section 4.2).

Hepatotoxicity

Increased transaminases occurred in patients treated with adagrasib (see section 4.8).

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. Specific guidance regarding dose management of KRAZATI in patients with increased transaminases is provided in section 4.2.

QT Prolongation

QTc interval prolongation can occur in patients treated with adagrasib (see section 4.8). It is recommended that a baseline electrocardiogram (ECG) prior to treatment initiation be performed in all patients and repeated during treatment.

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. In patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia, KRAZATI should be permanently discontinued (see sections 4.2, 4.5 and 4.8). The use of medicinal products known to prolong the QTc interval should be avoided (see section 4.5).

CYP3A substrates

Adagrasib is a strong CYP3A4 inhibitor. Co-administration of medicinal products that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated (e.g., alfuzosin, amiodarone, cisapride, pimozide, quinidine, ergotamine, dihydroergotamine, quetiapine, lovastatin, simvastatin, sildenafil, sirolimus, midazolam, triazolam, ticagrelor and tacrolimus).

In vitro studies showed that adagrasib is metabolised primarily by CYP3A4 and is a reversible inhibitor of CYP2B6, CYP2C9, CYP2D6 and CYP3A4, as well as a time-dependent inhibitor of CYP3A4. In vitro, adagrasib is a substrate of BCRP and inhibits P-gp, BCRP, MATE-1/MATE-2K, OATP1B1, and OCT1.

Effects of other medicinal products on adagrasib

Strong CYP3A inducers

Co-administration of multiple doses of rifampicin 600 mg QD (strong CYP3A4 inducer) with a single 600 mg dose of adagrasib decreased adagrasib C_max by 88% and AUC by 95% in healthy subjects. Concomitant use of strong CYP3A inducers should be avoided.

Strong CYP3A inhibitors

Adagrasib C_max increased by 2.4-fold and AUC increased by 4-fold following concomitant use of a single dose of 200 mg (0.33 times the approved recommended dose) with itraconazole (a strong CYP3A inhibitor). Concomitant use of strong CYP3A inhibitors should be avoided.

Effects of adagrasib on other medicinal products

Substrates of cytochrome P450 (CYP) enzymes

CYP3A4 substrates

Coadministration of oral midazolam (a sensitive CYP3A4 substrate) with multiple doses of adagrasib (400 mg BID) increased midazolam AUC by approximately 21-fold in healthy subjects. Administration of multiple doses of adagrasib at 600 mg BID in patients is predicted to increase oral midazolam AUC by 31-fold. Avoid concomitant use of adagrasib with sensitive CYP3A substrates unless otherwise recommended in the SmPC for these substrates.

CYP2C9 substrates

In vitro, adagrasib inhibits CYP2C9. Avoid concomitant use of adagrasib with sensitive CYP2C9 substrates where minimal concentration changes may lead to serious adverse reactions unless otherwise recommended in the SmPC for these substrates.

CYP2D6 substrates

Coadministration of dextromethorphan (a sensitive CYP2D6 substrate) with multiple doses of adagrasib (400 mg BID) increased dextromethorphan AUC by 1.8-fold in healthy subjects. Administration of adagrasib at 600 mg BID in patients is predicted to increase dextromethorphan AUC by 2.4-fold. Avoid concomitant use of adagrasib with sensitive CYP2D6 substrates where minimal concentration changes may lead to serious adverse reactions unless otherwise recommended in the SmPC for these substrates.

Transporter systems

P-glycoprotein (P-gp) substrates

Administration of adagrasib 600 mg single dose increased digoxin (a P-gp substrate) C_max and AUC by 1.1-fold and 1.4-fold, respectively, in healthy subjects. Avoid concomitant use of adagrasib with P-gp substrates where minimal concentration changes may lead to serious adverse reactions unless otherwise recommended in the SmPC for these substrates.

Breast cancer resistance protein (BCRP) or organic anion-transporting polypeptides 1B1 (OATP1B1) substrates

No clinically significant differences in the pharmacokinetics of rosuvastatin (a BCRP/OATP1B1 substrate) were observed when coadministered with adagrasib.

Medicinal products that prolong the QTc interval

The effect of co-administration of medicinal products known to prolong the QTc interval with adagrasib is unknown. The use of medicinal products known to prolong the QTc interval should be avoided. If concomitant administration of such medicinal products cannot be avoided, periodic ECG monitoring should be conducted (see section 4.4).

Women of childbearing potential/contraception

Use of adagrasib is not recommended in women of childbearing potential not using contraception. Female patients of childbearing potential receiving adagrasib must use an effective contraceptive method during treatment and for at least 5 days following the last dose of adagrasib.

Pregnancy

There are no data from the use of adagrasib in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Adagrasib is not recommended during pregnancy.

Breast-feeding

There are no data on the presence of adagrasib or its metabolites in human milk, effects of adagrasib on the breast-fed child, or on milk production. A risk to breast-fed newborns/infants cannot be excluded. Adagrasib should not be used during breast-feeding.

Fertility

No clinical data are available on the possible effects of adagrasib on fertility.

Adagrasib has minor influence on the ability to drive and use machines. Dizziness (including vertigo and fatigue) may occur following administration of adagrasib (see section 4.8).

Patients should be advised that dizziness may occur and that, if affected, they should not drive, use machines, or take part in other activities where this would put themselves or others at risk.

Summary of the safety profile

The most common adverse reactions are diarrhoea (71.5%), nausea (68.1%), vomiting (57.7%), fatigue (57.3%), anaemia (33.5%), blood creatinine increased (31.5%), decreased appetite (30.0%), peripheral oedema (30.0%), AST increased (28.5%), ALT increased (27.7%), dizziness (21.5%), hyponatraemia (21.2%) and blood alkaline phosphatase increased (20.0%).

The most common severe adverse reactions (NCI CTCAE Grade >3) are anaemia (11.2%), fatigue (8.8%), hyponatraemia (6.2%), increased lipase (5.8%), lymphocyte count decreased (5.0%), electrocardiogram QT prolonged (5.0%), ALT increased (5.0%) and AST increased (5.0%).

The most common serious adverse reactions are blood creatinine increased (2.7%), hyponatraemia (2.7%), and nausea (2.3%).

Adverse reactions leading to treatment discontinuation are pneumonitis (<1%), nausea (<1%), fatigue (<1%), ALT increased (<1%) and AST increased (<1%).

The most common adverse reactions leading to dose reduction or interruption are nausea (20.4%), fatigue (14.6%), diarrhoea (14.2%), vomiting (13.5%), ALT increased (11.2%), AST increased (9.2%), blood creatinine increased (6.2%), electrocardiogram QT prolonged (5.8%), and anaemia (5.0%).

Tabulated list of adverse reactions

Adverse reactions reported in clinical studies are listed by system organ class, preferred terms and by frequency. Adverse reaction frequency estimates are derived from 260 patients exposed at adagrasib 600 mg twice-daily for a median duration of 7.3 months in pooled clinical studies involving patients with KRAS G12C mutation-positive, locally advanced, or metastatic NSCLC (n=188), colorectal cancer (n=46), and other solid tumours (n=26). See section 5.1 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.

Table 3. Adverse reactions reported in patients treated with adagrasib:

¹ Includes lymphocyte count decreased and lymphocytopenia.
² Includes dizziness and vertigo.
³ Includes AST increased, ALT increased, blood alkaline phosphatase increased, blood bilirubin increased, Gammaglutamyltransferase increased, hepatic enzyme increased, liver function test increased and mixed liver injury.
⁴ Includes fatigue and asthenia.

Description of selected adverse reactions

Gastrointestinal adverse reactions

Gastrointestinal (GI) adverse reactions occur in 90.0% of patients taking adagrasib and include diarrhoea (71.5%, ≥ G3 4.6%), nausea (68.1%, ≥ G3 4.2%), and vomiting (57.7%, ≥ G3 1.9%). These events may lead to potential consequences such as dehydration, hyponatraemia, blood creatinine increased, and acute kidney injury. Diarrhoea, nausea and vomiting resulted in dose interruption or reduction in 14.2%, 20.4% and 13.5% of patients respectively. Discontinuations due to nausea was 0.4%. No treatment discontinuations due to diarrhoea or vomiting were reported.

Hepatotoxicity

Hepatotoxicity-related reactions were reported in 39.2% (all grades) and 7.7% (Grade ≥ 3) of patients treated with adagrasib. Elevations of ALT occurred in 27.7% of patients and elevations of AST in 28.5% of patients. Grade ≥3 elevations of ALT and AST each occurred in 5.0% of patients. 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, 39.5 days for blood bilirubin increased and 25.5 days for blood alkaline phosphatase increased, with a median duration of 17, 15, 7.5 and 22 days, respectively.

Elevations of ALT resulted in dose interruption and/or reduction in 11.2% of patients, and elevations of AST resulted in dose interruption and/or reduction in 9.2% of patients. Discontinuations due to elevations of AST or ALT was 0.4% each.

QT prolongation

Corrected QT interval prolongation (QTcF) greater than 500 msec occurred in 6.6% of 257 patients with both baseline and on-study ECG assessments. Increase in QTcF interval >60 msec from baseline occurred in 13.2% of patients. The median time to first onset of QT interval prolongation reported as a severe adverse event (CTCAE grade 3 and above) was 8 days with a median duration of 6 days.

QT interval prolongation resulted in dose interruption and/or reduction in 5.8% of patients (see sections 4.2 and 4.4). No QT interval prolongation leading to treatment discontinuation was observed.

Anaemia

Anaemia of any grade was reported in 33.5% of patients, with 11.2% of patients with grade ≥3 events. Median time to the first onset from first dose was 22 days, with a median duration of 31 days. Anaemia led to dose reduction or interruption in 5.0% of patients. No treatment discontinuation due to anaemia was reported.

Increased blood creatinine

Increased blood creatinine of any grade was reported 31.5% of patients, with <1% of patients with grade ≥3 events. Median time to the first onset from first dose was 10.5 days, with a median duration of 23.0 days. Most cases were laboratory findings that did require intervention, and it remains unknown if these increases reflect a decrease in glomerular filtration rate. Blood creatinine may have also resulted from gastrointestinal fluid losses that may also be associated with dehydration and/or hyponatraemia.

Blood creatinine increased led to dose reduction or interruption in 6.2% of patients. No blood creatinine increased leading to treatment discontinuation was observed.

Hyponatraemia

Hyponatraemia was reported in 21.2% (all grades) and 6.2% (grade ≥3) of patients treated with adagrasib. Hyponatraemia led to dose reduction or interruption in 3.1% of patients. Median time to the first onset from first dose was 24 days, with a median duration of 15 days. No hyponatraemia leading to treatment discontinuation was observed.

Special populations

Elderly

Adagrasib has been studied in 117 patients aged ≥65-year-old. When compared to those <65 years, no clinically relevant difference in safety profile was observed, except for fatigue (62.4% vs. 51.7%); decreased appetite (37.6% vs. 23.8%); and dizziness (27.4% vs. 15.4%).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.