Overview
11 DESCRIPTION Dacomitinib is an oral kinase inhibitor with a molecular formula of C 24 H 25 ClFN 5 O 2 ∙ H 2 O and a molecular weight of 487.95 Daltons. The chemical name is: (2 E )- N -{4-[(3-Chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}-4-(piperidin-1-yl)but-2-enamide monohydrate and its structural formula is: Dacomitinib is a white to pale yellow powder.
Mechanism of Action
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Dacomitinib is an irreversible inhibitor of the kinase activity of the human EGFR family (EGFR/HER1, HER2, and HER4) and certain EGFR activating mutations (exon 19 deletion or the exon 21 L858R substitution mutation). In vitro dacomitinib also inhibited the activity of DDR1, EPHA6, LCK, DDR2, and MNK1 at clinically relevant concentrations. Dacomitinib demonstrated dose-dependent inhibition of EGFR and HER2 autophosphorylation and tumor growth in mice bearing subcutaneously implanted human tumor xenografts driven by HER family targets including mutated EGFR. Dacomitinib also exhibited antitumor activity in orally-dosed mice bearing intracranial human tumor xenografts driven by EGFR amplifications. 12.
Indications
- 1 INDICATIONS AND USAGE VIZIMPRO is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA-approved test [see Dosage and Administration (2.1) ] . VIZIMPRO is a kinase inhibitor indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA-approved test. ( 1 )
Common Doses
- 45 mg
- 30 mg
- 15 mg
Dosage
2 DOSAGE AND ADMINISTRATION Recommended Dosage: 45 mg orally once daily with or without food. ( 2.2 ) 2.1 Patient Selection Select patients for the first-line treatment of metastatic NSCLC with VIZIMPRO based on the presence of an EGFR exon 19 deletion or exon 21 L858R substitution mutation in tumor specimens. Information on FDA-approved tests for the detection of EGFR mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics. 2.2 Recommended Dosage The recommended dosage of VIZIMPRO is 45 mg taken orally once daily, until disease progression or unacceptable toxicity occurs.
Contraindications
- 4 CONTRAINDICATIONS None. None. ( 4 )
Side Effects
- 6 ADVERSE REACTIONS The following adverse drug reactions are described elsewhere in the labeling: • Interstitial Lung Disease [see Warnings and Precautions (5.1) ] • Diarrhea [see Warnings and Precautions (5.2) ] • Dermatologic Adverse Reactions [see Warnings and Precautions (5.3) ] Most common adverse reactions (incidence >20%) are diarrhea, rash, paronychia, stomatitis, decreased appetite, dry skin, decreased weight, alopecia, cough, and pruritus. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.
Interactions
- 7 DRUG INTERACTIONS • Proton Pump Inhibitors (PPIs): Avoid use with VIZIMPRO; use locally-acting antacids or H2-receptor antagonist; administer VIZIMPRO at least 6 hours before or 10 hours after H2-receptor antagonist. ( 2.4 , 7.1 ) • CYP2D6 Substrates: Avoid concomitant use with VIZIMPRO where minimal increases in concentration of the CYP2D6 substrate may lead to serious or life-threatening toxicities. ( 7.2 ) 7.1 Effect of Other Drugs on VIZIMPRO Concomitant use with a PPI decreases dacomitinib concentrations, which may reduce VIZIMPRO efficacy.