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Dacomitinib

Class: Antineoplastic Agents
- Epidermal Growth Factor Receptor Inhibitors
- EGFR Inhibitors
- EGF Receptor Inhibitors
- Kinase Inhibitors
- Receptor Tyrosine Kinase Inhibitors
- Tyrosine Kinase Inhibitors
Chemical Name: (E)-N-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]-4-piperidin-1-ylbut-2-enamide;hydrate
Molecular Formula: C24H27ClFN5O3
CAS Number: 1042385-75-0
Brands: Vizimpro

Medically reviewed by Drugs.com on Jun 21, 2021. Written by ASHP.

Introduction

Antineoplastic agent; epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor.

Uses for Dacomitinib

Non-small Cell Lung Cancer (NSCLC)

First-line treatment of metastatic NSCLC in patients with tumors positive for EGFR exon 19 deletions (del19) or exon 21 (L858R) substitution mutations as detected by an FDA-approved diagnostic test (e.g., therascreen EGFR RGQ PCR Kit, cobas EGFR Mutation Test). Information on FDA-approved companion diagnostic tests for the detection of EGFR mutations in NSCLC is available at [Web].

Designated an orphan drug by FDA for use in this condition.

Dacomitinib Dosage and Administration

General

  • Confirm presence of EGFR del19 or L858R substitution mutations by an FDA-approved diagnostic test prior to initiating therapy for previously untreated metastatic NSCLC.

  • To minimize risk of treatment-related rash or exfoliative skin reactions, routinely moisturize skin and limit exposure to sunlight by wearing protective clothing and/or using a sunscreen during dacomitinib therapy. (See Dermatologic Effects under Cautions.)

Administration

Oral Administration

Administer orally once daily without regard to meals at approximately the same time each day.

If a dose of dacomitinib is missed or vomited, do not take the missed dose and take the next dose at the regularly scheduled time. Do not take extra tablets to make up for missed dose.

Dosage

Adults

NSCLC
Oral

45 mg once daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Dosage Modification for Toxicity
Oral

Temporary interruption, dosage reduction, and/or discontinuance of therapy may be necessary based on severity of adverse reactions.

If dosage reduction from 45 mg once daily is necessary, reduce dosage to 30 mg once daily. If further dosage reduction necessary, reduce dosage to 15 mg once daily. The manufacturer provides no specific recommendations for further dosage reductions.

Pulmonary Effects
Oral

If interstitial lung disease occurs, permanently discontinue drug. (See Pulmonary Effects under Cautions.)

GI Toxicity
Oral

If grade 2 diarrhea occurs, interrupt dacomitinib therapy until toxicity improves to grade 1 or less, and then resume at same dosage. If grade 2 diarrhea recurs, interrupt dacomitinib therapy until toxicity improves to grade 1 or less, and then resume at a reduced dosage. (See Diarrhea under Cautions.)

If grade 3 or 4 diarrhea occurs, interrupt dacomitinib therapy until toxicity improves to grade 1 or less, and then resume at a reduced dosage.

Dermatologic Toxicity
Oral

If persistent grade 2 dermatologic reactions occur, interrupt dacomitinib therapy until toxicity improves to grade 1 or less, and then resume at same dosage. If persistent grade 2 dermatologic reactions recur, interrupt dacomitinib therapy until toxicity improves to grade 1 or less, and then resume at a reduced dosage. (See Dermatologic Effects under Cautions.)

If grade 3 or 4 dermatologic reactions occur, interrupt dacomitinib therapy until toxicity improves to grade 1 or less, and then resume at a reduced dosage.

Other Toxicity
Oral

If any other grade 3 or 4 adverse reaction occurs, interrupt dacomitinib therapy until toxicity improves to grade 2 or less, and then resume at a reduced dosage.

Special Populations

Hepatic Impairment

Mild hepatic impairment (total bilirubin concentration not exceeding the ULN with AST concentration exceeding the ULN or total bilirubin concentration exceeding the ULN, but ≤1.5 times the ULN, with any AST concentration): No initial dosage adjustment required.

Moderate hepatic impairment (total bilirubin concentration >1.5 times the ULN, but ≤3 times the ULN, with any AST concentration): No initial dosage adjustment required.

Severe hepatic impairment (total bilirubin concentration >3 times the ULN, but ≤10 times the ULN, with any AST concentration): No specific dosage recommendations at this time.

Renal Impairment

Mild or moderate renal impairment (Clcr 30–89 mL/minute): No initial dosage adjustment required.

Severe renal impairment (Clcr <30 mL/minute): No specific dosage recommendations at this time.

Geriatric Patients

No specific dosage recommendations at this time.

Cautions for Dacomitinib

Contraindications

  • Manufacturer states none known.

Warnings/Precautions

Pulmonary Effects

Interstitial lung disease or pneumonitis, sometimes fatal, reported.

Monitor for manifestations of interstitial lung disease or pneumonitis. In patients who develop progressive pulmonary symptoms (e.g., dyspnea, cough, fever), temporarily interrupt therapy and promptly evaluate patient for interstitial lung disease. If diagnosis of interstitial lung disease is confirmed, permanently discontinue dacomitinib.

Diarrhea

Diarrhea occurs frequently. Diarrhea resulting in death also reported. Increased incidence and greater severity of diarrhea observed with second-generation pan-human epidermal growth factor receptor (pan-HER) inhibitors (e.g., dacomitinib, afatinib) compared with single-target tyrosine kinase inhibitors selective for EGFR (e.g., erlotinib, gefitinib).

If diarrhea occurs, promptly initiate appropriate therapy (e.g., loperamide, diphenoxylate in fixed combination with atropine, fluid replacement) as necessary. Dosage modification may be necessary. (See Dosage Modification for Toxicity under Dosage and Administration.)

Dermatologic Effects

Dermatologic toxicity (e.g., rash, exfoliative skin reaction, paronychia) occurs frequently. Incidence and severity of rash and exfoliative skin reactions may increase with sun exposure.

Advise patients to routinely moisturize skin and limit exposure to sunlight during dacomitinib therapy. (See Advice to Patients.)

If grade 2 or greater rash occurs, dosage modification may be necessary and systemic anti-infective therapy should be initiated. (See Dosage Modification for Toxicity under Dosage and Administration.) If grade 1 rash occurs, initiate topical anti-infective and corticosteroid therapy.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm. Disruption or blockade of EGFR signaling has been associated with preimplantation loss, increased embryofetal loss, postnatal death, developmental anomalies, and visceral abnormalities in animals. Embryofetal toxicity (e.g., decreased fetal body weight, postimplantation loss) observed in animals.

Confirm pregnancy status prior to initiating dacomitinib therapy. Avoid pregnancy during therapy. Women of childbearing potential should use effective contraceptive methods while receiving dacomitinib and for ≥17 days after the last dose. Apprise patients of potential fetal hazard.

Specific Populations

Pregnancy

May cause fetal harm. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether dacomitinib or its metabolites distribute into human milk or affect milk production or the nursing infant. Women should not breast-feed during therapy and for ≥17 days after the last dose.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Grade 3 or 4 adverse reactions, dosage interruptions, or discontinuance of dacomitinib due to adverse reactions may occur more frequently in geriatric patients ≥65 years of age.

Hepatic Impairment

Pharmacokinetics not affected by mild or moderate hepatic impairment. (See Hepatic Impairment under Dosage and Administration and also see Elimination: Special Populations, under Pharmacokinetics.)

Pharmacokinetics not established in patients with severe hepatic impairment (total bilirubin concentration >3 times the ULN, but ≤10 times the ULN, with any AST concentration).

Renal Impairment

In population pharmacokinetic analyses, pharmacokinetics not altered by mild or moderate renal impairment (Clcr 30 to <90 mL/minute); initial dosage adjustment not necessary in such patients. (See Renal Impairment under Dosage and Administration and also see Absorption: Special Populations, under Pharmacokinetics.)

Pharmacokinetics not established in patients with severe renal impairment (Clcr <30 mL/minute) and in those receiving dialysis.

Common Adverse Effects

Diarrhea, rash, paronychia, stomatitis, decreased appetite, dry skin, decreased weight, alopecia, cough, pruritus, anemia, hypobilirubinemia, lymphopenia, elevated ALT or AST concentrations, hyperglycemia, hypocalcemia, hypokalemia, hyponatremia, elevated Scr concentrations, elevated alkaline phosphatase concentrations, hypomagnesemia.

Interactions for Dacomitinib

Metabolized principally by oxidation and glutathione conjugation. Metabolized by CYP2D6 to active O-desmethyldacomitinib metabolite and by CYP3A4 to other minor oxidative metabolites.

In vitro, dacomitinib is potent inhibitor and substrate of CYP2D6, but does not induce CYP isoenzymes 1A2, 2B6, or 3A4. In vitro, dacomitinib and O-desmethyldacomitinib do not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, or 3A4/5.

In vitro, dacomitinib inhibits UGT1A1, but does not inhibit UGT1A4, 1A6, 1A9, 2B7, or 2B15.

Dacomitinib is substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). In vitro, dacomitinib inhibits P-gp, BCRP, and organic cation transporter (OCT) 1, but does not inhibit organic anion transporter (OAT) 1, OAT3, OCT2, organic anion transport protein (OATP) 1B1, or OATP1B3.

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP2D6 inhibitors: Pharmacokinetic interaction not observed to date. (See Specific Drugs under Interactions.)

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP2D6: Possible pharmacokinetic interaction (increased systemic exposure of CYP2D6 substrate) and increased incidence of drug toxicity. Avoid concomitant use with sensitive CYP2D6 substrates or CYP2D6 substrates with a narrow therapeutic index. (See Specific Drugs under Interactions.)

Drugs Affecting Gastric Acidity

Possible pharmacokinetic interaction (decreased plasma dacomitinib concentrations) and possible reduction in dacomitinib efficacy with drugs that cause gastric pH elevation. (See Specific Drugs under Interactions.)

Specific Drugs

Drug

Interaction

Comments

Antacids (e.g., magnesium oxide)

Magnesium oxide: No substantial effect on pharmacokinetics of dacomitinib

No dosage modification necessary

Dextromethorphan

Increased AUC and peak concentrations of dextromethorphan by 9.6- and 9.7-fold, respectively

Avoid concomitant use

Histamine H2-receptor antagonists (e.g., cimetidine, famotidine, nizatidine, ranitidine)

Not studied

Administer ≥6 hours after or 10 hours before dacomitinib

Paroxetine

No substantial effect on pharmacokinetics of total active forms of dacomitinib (i.e., parent drug plus O-desmethyldacomitinib)

No initial dosage adjustment necessary

Proton-pump inhibitors

Rabeprazole: Decreased AUC and peak concentrations of dacomitinib by 39 and 51%, respectively

Avoid concomitant use

Consider substituting histamine H2-receptor antagonist (administered ≥6 hours after or 10 hours before dacomitinib) or antacid for proton-pump inhibitor

Dacomitinib Pharmacokinetics

Absorption

Bioavailability

Mean absolute bioavailability of dacomitinib is 80%.

Following oral administration, peak plasma concentrations are attained at a median of approximately 6 hours.

Steady-state concentrations are achieved within 14 days of repeated dosing with 5.7-fold accumulation.

Pharmacokinetics are dose proportional over a dosage range of 2–60 mg once daily.

Based on dose-exposure safety relationships, higher dacomitinib exposures at the recommended dosage are associated with an increased incidence of grade 3 or greater adverse effects, particularly dermatologic toxicities (e.g., rash, dermatitis acneiform) and diarrhea.

Food

Food does not substantially affect bioavailability.

Plasma Concentrations

O-desmethyldacomitinib accounts for 7.4–19% of the total steady-state trough concentrations.

Special Populations

Mild or moderate hepatic impairment (Child-Pugh class A or B) has no clinically important effect on AUC or peak plasma concentration. Not studied in patients with severe hepatic impairment (total bilirubin concentration >3 times the ULN, but ≤10 times the ULN, with any AST concentration).

Population pharmacokinetic analyses suggest that mild or moderate renal impairment (Clcr 30 to <90 mL/minute) has no clinically important effect on pharmacokinetics. Not studied in patients with severe renal impairment (Clcr <30 mL/minute) or in those receiving dialysis.

CYP2D6 poor or extensive metabolizer phenotype has no clinically important effect on pharmacokinetics.

Distribution

Extent

Not known whether dacomitinib or its metabolites are distributed into milk.

Plasma Protein Binding

Approximately 98%.

Elimination

Metabolism

Metabolized principally by oxidation and glutathione conjugation. Principally metabolized by CYP2D6 to form O-desmethyldacomitinib and by CYP3A4 to form minor oxidative metabolites.

Elimination Route

Excreted in feces (79%; approximately 20% as unchanged drug) and urine (3%; <1% as unchanged drug).

Half-life

Dacomitinib: 70.3 hours.

O-desmethyldacomitinib: 72.8 hours.

Special Populations

Population pharmacokinetic analyses suggest that mild (total bilirubin concentration not exceeding the ULN with AST concentration exceeding the ULN or total bilirubin concentration exceeding the ULN, but ≤1.5 times the ULN, with any AST concentration) or moderate (total bilirubin concentration >1.5 times the ULN, but ≤3 times the ULN, with any AST concentration) hepatic impairment has no clinically important effect on clearance.

Age (20–92 years), body weight, gender, race (Asian versus non-Asian), EGFR mutation status, and baseline albumin concentrations do not substantially affect clearance.

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).

Actions

  • Selective and irreversible inhibitor of EGFR (HER1/ErbB1), HER2/ErbB2, HER4/ErbB4, and mutated EGFR (e.g., exon 19 deletion [del19], exon 21 substitution [L858R]) tyrosine kinases.

  • EGFR is expressed on the cell surface of both normal and cancer cells and plays a role in cell growth and proliferation. Some EGFR-activating mutations (del19 or L858R substitution mutations) within NSCLC cells can promote tumor cell growth, block apoptosis, increase production of angiogenic factors, and facilitate metastasis.

  • Inhibits phosphorylation of wild-type EGFR and HER2 and tumor growth in xenograft models of NSCLC or ovarian cancer in mice with tumors harboring HER2 or EGFR del19 or L858R mutations, including some with secondary T790M mutation (which confers resistance to the first-generation tyrosine kinase inhibitors ).

  • Antitumor activity in xenograft models of human glioblastoma cells driven by EGFR gene amplifications, including EGFR variant III (EGFRvIII, EGFR exon 2–7 deletion [del2–7] ), in mice.

  • Inhibits DDR1, DDR2, EPHA6, LCK, MNK1 at clinically relevant concentrations in vitro.

Advice to Patients

  • Importance of instructing patients to read the manufacturer's patient information.

  • If a dose is missed or vomited, importance of administering the next dose at the regularly scheduled time; an additional dose should not be administered to make up for a missed dose.

  • Risk of interstitial lung disease. Importance of immediately informing clinician if new or worsening respiratory symptoms occur (e.g., dyspnea, cough, fever).

  • Risk of diarrhea. Importance of informing clinician at the first sign of loose stools.

  • Risk of dermatologic reactions. Importance of routinely moisturizing skin and limiting exposure to sunlight by wearing protective clothing and using sunscreen during dacomitinib therapy. Importance of immediately informing clinician if new or worsening rash or erythematous or exfoliative reactions occur.

  • Risk of fetal harm. Necessity of advising women of childbearing potential that they should use effective methods of contraception while receiving dacomitinib and for ≥17 days after the last dose of the drug. Importance of women informing their clinicians if they are or plan to become pregnant. If pregnancy occurs, advise pregnant women of potential risk to the fetus.

  • Importance of advising women to avoid breast-feeding while receiving dacomitinib and for ≥17 days after the last dose of the drug.

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs (e.g., antacids, histamine H2-receptor antagonists, proton-pump inhibitors) and herbal supplements, as well as any concomitant illnesses.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Dacomitinib

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

15 mg

Vizimpro

Pfizer

30 mg

Vizimpro

Pfizer

45 mg

Vizimpro

Pfizer

AHFS DI Essentials™. © Copyright 2021, Selected Revisions July 1, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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