DIQTA 1.0: Drug-Induced QT Prolongation Atlas

OSIMERTINIB

DIR Classification Postmarketing Surveillance Drug Property Information Reference

DIR Classification

Classification:Moderate-DIQT concern

Severity Score:3.0

Description in Drug Labeling: View Full Labeling: SPL in DailyMed | PDF

WARNINGS AND PRECAUTIONS
QTc Interval Prolongation
Heart rate-corrected QT (QTc) interval prolongation occurs in patients treated with TAGRISSO. Of the 1479 patients treated with TAGRISSO in clinical trials, 0.8% were found to have a QTc > 500 msec, and 3.1% of patients had an increase from baseline QTc > 60 msec [see CLINICAL PHARMACOLOGY (12.2)]. No QTc-related arrhythmias were reported.
Clinical trials of TAGRISSO did not enroll patients with baseline QTc of > 470 msec. Conduct periodic monitoring with ECGs and electrolytes in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval. Permanently discontinue TAGRISSO in patients who develop QTc interval prolongation with signs/symptoms of life-threatening arrhythmia [see DOSAGE AND ADMINISTRATION (2.4)].
DRUG INTERACTIONS
Drugs That Prolong the QTc Interval
The effect of co-administering medicinal products known to prolong the QTc interval with TAGRISSO is unknown. When feasible, avoid concomitant administration of drugs known to prolong the QTc interval with known risk of Torsades de pointes. If not feasible to avoid concomitant administration of such drugs, conduct periodic ECG monitoring [see WARNINGS AND PRECAUTIONS (5.2) and CLINICAL PHARMACOLOGY (12.3)].
DOSAGE AND ADMINISTRATION
ADVERSE REACTIONS
Clinical Trials Experience
The data described below reflect exposure to TAGRISSO (80 mg daily) in 337 patients with EGFR mutation-positive resectable NSCLC, and 558 patients with EGFR mutation-positive metastatic NSCLC in three randomized, controlled trials [ADAURA (n=337), FLAURA (n=279), and AURA3 (n=279)]. Patients with a history of interstitial lung disease, drug induced interstitial disease or radiation pneumonitis that required steroid treatment, serious arrhythmia or baseline QTc interval greater than 470 msec on electrocardiogram were excluded from enrollment in these studies.
linically relevant adverse reactions in ADAURA in <10% of patients receiving TAGRISSO were alopecia (6%), epistaxis (6%), interstitial lung disease (3%), palmar-plantar erythrodysesthesia syndrome (1.8%), keratitis (0.6%), QTc interval prolongation (0.6%), and erythema multiform (0.3%). QTc interval prolongation represents the incidence of patients who had a QTcF prolongation >500msec.
Serious adverse reactions were reported in 4% of patients treated with TAGRISSO; the most common serious adverse reactions (≥1%) were pneumonia (2.9%), ILD/pneumonitis (2.1%), and pulmonary embolism (1.8%). Dose reductions occurred in 2.9% of patients treated with TAGRISSO. The most frequent adverse reactions leading to dose reductions or interruptions were prolongation of the QT interval as assessed by ECG (4.3%), diarrhea (2.5%), and lymphopenia (1.1%). Adverse reactions leading to permanent discontinuation occurred in 13% of patients treated with TAGRISSO. The most frequent adverse reaction leading to discontinuation of TAGRISSO was ILD/pneumonitis (3.9%).
Clinically relevant adverse reactions in FLAURA in <10% of patients receiving TAGRISSO were alopecia (7%), epistaxis (6%), interstitial lung disease (3.9%), palmar-plantar erythrodysesthesia syndrome (1.4%), QTc interval prolongation (1.1%), and keratitis (0.4%). QTc interval prolongation represents the incidence of patients who had a QTcF prolongation >500msec.
Dose reductions occurred in 2.9% of patients treated with TAGRISSO. The most frequent adverse reactions leading to dose reductions or interruptions were prolongation of the QT interval as assessed by ECG (1.8%), neutropenia (1.1%), and diarrhea (1.1%). Adverse reactions resulting in permanent discontinuation of TAGRISSO occurred in 7% of patients treated with TAGRISSO. The most frequent adverse reaction leading to discontinuation of TAGRISSO was ILD/pneumonitis (3%).
Clinically relevant adverse reactions in AURA3 in <10% of patients receiving TAGRISSO were epistaxis (5%), interstitial lung disease (3.9%), alopecia (3.6%), palmar-plantar erythrodysesthesia syndrome (1.8%), QTc interval prolongation (1.4%), keratitis (1.1%), and erythema multiform (0.7%). QTc interval prolongation represents the incidence of patients who had a QTcF prolongation >500msec.
CLINICAL PHARMACOLOGY
Pharmacodynamics
Cardiac Electrophysiology
The QTc interval prolongation potential of osimertinib was assessed in 210 patients who received TAGRISSO 80 mg daily in AURA2. A central tendency analysis of the QTcF data at steady-state demonstrated that the maximum mean change from baseline was 16.2 msec (upper bound of two-sided 90% confidence interval (CI) 17.6 msec). A pharmacokinetic/pharmacodynamic analysis in AURA2 suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of TAGRISSO 80 mg.
PATIENT COUNSELING INFORMATION
QTc Interval Prolongation
Inform patients of symptoms that may be indicative of significant QTc prolongation including dizziness, lightheadedness, and syncope. Advise patients to report these symptoms and to inform their physician about the use of any heart or blood pressure medications [see WARNINGS AND PRECAUTIONS (5.2)].

Postmarketing Surveillance

Contingency Table:

Current Drug

Other Drugs

QT Prolongation

24010

Other ADRs

17573

38364014

Odds Ratio = 7.456

Drug Property Information

ATC Code(s):

L01EB04 - osimertinib

L01EB -
L01E -
L01 - ANTINEOPLASTIC AGENTS
L - ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

Active Ingredient:OSIMERTINIB

Active Ingredient UNII:3C06JJ0Z2O

Drugbank ID:DB09330

PubChem Compound:71496458

CTD ID: C000596361

PharmGKB:PA166131626

CAS Number:1421373-65-0

Dosage Form(s):tablet, film coated

Route(s) Of Administrator:oral

Daily Dose:

Chemical Structure:

SMILE Code:
COC1=C(NC2=NC=CC(=N2)C2=CN(C)C3=C2C=CC=C3)C=C(NC(=O)C=C)C(=C1)N(C)CCN(C)C

Reference

1: Case Report: QT Prolongation and Abortive Sudden Death Observed in an 85-Year-Old Female Patient With Advanced Lung Cancer Treated With Tyrosine Kinase Inhibitor Osimertinib.

[Kondo Moë,Kisanuki Megumi,Kokawa Yosuke,Gohara Seiichiro,Kawano Osamu,Kagiyama Shuntaro,Maruyama Toru,Odashiro Keita,Maehara Yoshihiko]
Front Cardiovasc Med,2021 Mar 19;8:655808. PMID: 33816581

2: Osimertinib-induced cardiac failure with QT prolongation and torsade de pointes in a patient with advanced pulmonary adenocarcinoma.

[Ikebe Saori,Amiya Ryohei,Minami Seigo,Ihara Shoichi,Higuchi Yoshiharu,Komuta Kiyoshi]
Int Cancer Conf J,2020 Oct 15;10(1):68-71. PMID: 33489705

3: Osimertinib induced cardiomyopathy: A case report.

[Shinomiya Shun,Kaira Kyoichi,Yamaguchi Ou,Ishikawa Keitaro,Kagamu Hiroshi]
Medicine (Baltimore),2020 Sep 25;99(39):e22301. PMID: 32991436

4: A case of torsades de pointes induced by the third-generation EGFR-TKI, osimertinib combined with moxifloxacin.

[Bian Shuang,Tang Xiaomiao,Lei Wei]
BMC Pulm Med,2020 Jun 24;20(1):181. PMID: 32580784

5: Current perspective: Osimertinib-induced QT prolongation: new drugs with new side-effects need careful patient monitoring.

[Schiefer Mart,Hendriks Lizza E L,Dinh Trang,Lalji Ulrich,Dingemans Anne-Marie C]
Eur J Cancer,2018 Mar;91:92-98. PMID: 29413968

6: AC0010, an Irreversible EGFR Inhibitor Selectively Targeting Mutated EGFR and Overcoming T790M-Induced Resistance in Animal Models and Lung Cancer Patients.

[Xu Xiao,Mao Long,Xu Wanhong,Tang Wei,Zhang Xiaoying,Xi Biao,Xu Rongda,Fang Xin,Liu Jia,Fang Ce,Zhao Li,Wang Xiaobo,Jiang Ji,Hu Pei,Zhao Hongyun,Zhang Li]
Mol Cancer Ther,2016 Nov;15(11):2586-2597. PMID: 27573423

Search for drugs: