[Web]

Introduction

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

Uses for Dacomitinib (Systemic)

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 v2). Information on FDA-approved companion diagnostic tests for the detection of EGFR mutations in NSCLC is available at [Web]. Dacomitinib is one of several generally recommended therapies for adults with previously-untreated NSCLC with EGFR-activating mutations for whom osimertinib is not an option.

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

Dacomitinib (Systemic) Dosage and Administration

General

Pretreatment Screening

• Confirm the presence of epidermal growth factor receptor (EGFR) exon 19 deletions (del19) or exon 21 (L858R) substitution mutations in the tumor specimens of patients with metastatic non-small cell lung cancer (NSCLC) by an FDA-approved diagnostic test prior to initiating therapy.

• Verify pregnancy status for females of reproductive potential prior to treatment.

Patient Monitoring

• Monitor for pulmonary symptoms indicative of interstitial lung disease or pneumonitis.

Other General Considerations

• To minimize the incidence and severity of treatment-related rash or exfoliative skin reactions, patients should routinely moisturize their skin and limit sun exposure by wearing protective clothing and/or using a sunscreen upon initiation of and during dacomitinib therapy.

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, take the prescribed dose at the next scheduled time. Do not take an additional dose to make up for the missed dose.

Dosage

Adults

Non-small Cell Lung Cancer (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 the type and 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.

Interstitial Lung Disease

If interstitial lung disease (any grade) occurs, permanently discontinue drug.

Diarrhea

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.

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 Reactions

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.

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

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.

Dosage Modification for Acid-reducing Agents

Avoid concomitant use of dacomitinib and proton-pump inhibitors. If therapy with an acid suppressive agent is necessary in a patient receiving dacomitinib, use a histamine H₂-receptor antagonist or locally-acting antacid instead of a proton-pump inhibitor. Administer dacomitinib ≥6 hours before or 10 hours after administration of a histamine H₂-receptor antagonist.

Special Populations

Hepatic Impairment

Mild, moderate or severe hepatic impairment (Child-Pugh class A, B, or C): No dosage adjustment required.

Renal Impairment

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

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

Geriatric Use

No specific dosage recommendations at this time.

Contraindications

• None.

Warnings/Precautions

Interstitial Lung Disease

Interstitial lung disease or pneumonitis, sometimes fatal, reported.

Monitor for respiratory manifestations of interstitial lung disease or pneumonitis. In patients who present with worsening of respiratory 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 with atropine sulfate) as necessary. Dosage modification may be necessary depending on the severity of the diarrhea.

Dermatologic Reactions

Dermatologic toxicity (e.g., rash, exfoliative skin reaction, paronychia) frequently reported. 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 upon initiation of dacomitinib and during treatment.

If persistent grade 2 or greater rash occurs, dosage modification may be necessary and oral anti-infective therapy should be initiated. If grade 1 rash occurs, initiate topical anti-infective and steroid therapy.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on mechanism of action and findings from animal studies. Embryo-fetal toxicity (e.g., decreased fetal body weight, postimplantation loss) and maternal toxicity observed in animals.

Confirm pregnancy status prior to initiating dacomitinib therapy. Females of reproductive potential should use effective contraceptive methods while receiving dacomitinib and for ≥17 days after the last dose. Apprise pregnant women and females of reproductive potential of potential fetal risk.

Specific Populations

Pregnancy

May cause fetal harm based on mechanism of action and findings from animal studies. In animals, disruption or blockade of EGFR signaling has been associated with preimplantation loss, increased embryofetal loss during various stages of gestation, postnatal death, developmental anomalies, and visceral abnormalities.

Lactation

Not known whether dacomitinib or its metabolites distribute into human milk; effects on breast-fed infants and milk production also unknown. Advise women not to breast-feed during therapy and for ≥17 days after the last dose.

Females and Males of Reproductive Potential

Pregnancy testing recommended in females of reproductive potential before starting dacomitinib. Females of reproductive potential should use an effective method of contraception while taking dacomitinib 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

No clinically significant differences in the pharmacokinetics of dacomitinib observed in subjects with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B or C).

Renal Impairment

In population pharmacokinetic analyses, pharmacokinetics of dacomitinib not altered by mild or moderate renal impairment (Cl_cr 30 to <90 mL/minute); dosage adjustment not necessary in such patients.

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

Common Adverse Effects

Adverse effects reported in ≥20% of patients: diarrhea, rash, paronychia, stomatitis, decreased appetite, dry skin, decreased weight, alopecia, cough, pruritus.

General

Pretreatment Screening

• Confirm the presence of epidermal growth factor receptor (EGFR) exon 19 deletions (del19) or exon 21 (L858R) substitution mutations in the tumor specimens of patients with metastatic non-small cell lung cancer (NSCLC) by an FDA-approved diagnostic test prior to initiating therapy.

• Verify pregnancy status for females of reproductive potential prior to treatment.

Patient Monitoring

• Monitor for pulmonary symptoms indicative of interstitial lung disease or pneumonitis.

Other General Considerations

• To minimize the incidence and severity of treatment-related rash or exfoliative skin reactions, patients should routinely moisturize their skin and limit sun exposure by wearing protective clothing and/or using a sunscreen upon initiation of and during dacomitinib therapy.

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, take the prescribed dose at the next scheduled time. Do not take an additional dose to make up for the missed dose.

Dosage

Adults

Non-small Cell Lung Cancer (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 the type and 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.

Interstitial Lung Disease

If interstitial lung disease (any grade) occurs, permanently discontinue drug.

Diarrhea

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.

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 Reactions

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.

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

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.

Dosage Modification for Acid-reducing Agents

Avoid concomitant use of dacomitinib and proton-pump inhibitors. If therapy with an acid suppressive agent is necessary in a patient receiving dacomitinib, use a histamine H₂-receptor antagonist or locally-acting antacid instead of a proton-pump inhibitor. Administer dacomitinib ≥6 hours before or 10 hours after administration of a histamine H₂-receptor antagonist.

Special Populations

Hepatic Impairment

Mild, moderate or severe hepatic impairment (Child-Pugh class A, B, or C): No dosage adjustment required.

Renal Impairment

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

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

Geriatric Use

No specific dosage recommendations at this time.

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 a 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.

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 CYP2D6 substrates where minimal increases in the substrate concentration may lead to serious or life-threatening toxicities.

Drugs Affecting Gastric Acidity

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

Specific Drugs