Krazati · 4.3 Contraindications · 1

HOS-100379 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile The most common adverse reactions are diarrhoea (65.2%), nausea (59.9%), fatigue (54.3%), vomiting (50.3%), decreased appetite (32.9%), anaemia (32.4%), blood creatinine increased (31.7%), AST increased (29.0%), ALT increased (28.3%), peripheral oedema (23.0%), blood alkaline phosphatase increased (18.1%), dizziness (17.1%) and hyponatraemia (17.1%). The most common severe adverse reactions (NCI CTCAE Grade ≥ 3) are fatigue (9.0%), anaemia (7.2%), ALT increased (6.6%), increased lipase (4.8%), AST increased (4.6%), hyponatraemia (4.0%), lymphocyte count decreased (3.7%) and electrocardiogram QT prolonged (3.4%). The most common serious adverse reactions are vomiting (2.8%), nausea (2.1%), acute kidney injury (2.2%), diarrhoea (1.3%) and ALT increased (1.0%). 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 (14.7%), diarrhoea (13.3%), vomiting (13.4%), fatigue (10.2%), ALT increased (10.2%), AST increased (7.3%), blood creatinine increased (6.9%), anaemia (3.5%) and electrocardiogram QT prolonged (3.4%). 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 821 patients exposed at adagrasib 600 mg twice-daily for a median duration of 5.2 months in pooled clinical studies involving patients with KRAS G12C mutation-positive, for all solid tumours. 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. 7 Table 3: Adverse reactions reported i

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HOS-100375 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Concomitant use of CYP3A substrates with a narrow therapeutic index (see sections 4.4 and 4.5).

HOS-100374 · has-indication-information · PDF-Seite 2

KRAZATI as monotherapy is indicated for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) with KRAS G12C mutation and disease progression after at least one prior systemic therapy.

HOS-100377 · has-interaction-information · PDF-Seite 5

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 Cmax by 88% and AUC by 95% in healthy subjects. Concomitant use of strong CYP3A inducers should be avoided. Strong CYP3A inhibitors Adagrasib Cmax 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: Co-administration 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 5 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: Co-administration 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) Cmax and AUC by 1.1-fold and 1.4-fold, respectively, in he

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HOS-100378 · has-pregnancy-information · PDF-Seite 6

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. 6

HOS-100376 · has-warning-information · PDF-Seite 4

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. 4 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 perman

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