Dacomitinib

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.

• Metastatic non-small cell lung cancer (NSCLC) with EGFR exon 19 deletion or exon 21 L858R substitution mutations

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 irreversibly inhibits the kinase activity of the human EGFR family (EGFR/HER1, HER2, and HER4) and certain EGFR-activating mutations (exon 19 deletion or exon 21 L858R substitution), thereby preventing cancer cell growth and proliferation.

Adult: 45 mg orally once daily, continue until disease progression or unacceptable toxicity occurs.

First dose reduction: 30 mg (once daily)

Second dose reduction: 15 mg (once daily)

Administer with or without food at the same time each day. Swallow the tablet whole, do not chew, crush or break it.

If the patient vomits or misses a dose, do not take an additional dose or make up a missed dose but continue with the next scheduled dose.

Common Side Effects (Incidence >20%):

• Diarrhea (87%)
• Rash (69%)
• Paronychia (64%)
• Stomatitis (45%)
• Anemia (44%)
• Hypoalbuminemia (44%)
• Lymphopenia (42%)
• Increased ALT (40%)
• Hyperglycemia (36%)
• Increased AST (35%)
• Hypocalcemia (33%)
• Decreased appetite (31%)
• Dry skin (30%)
• Hypokalemia (29%)
• Decreased weight (26%)
• Hyponatremia (26%)
• Increased creatinine (24%)
• Alopecia (23%)
• Increased alkaline phosphatase (22%)
• Hypomagnesemia (22%)
• Pruritus (21%)
• Cough (21%)
• Nasal mucosal disorder (19%)
• Conjunctivitis (19%)
• Nausea (19%)
• Hyperbilirubinemia (16%)
• Palmar-plantar erythrodysesthesia syndrome (15%)
• Pain in extremity (14%)
• Dyspnea (13%)
• Constipation (13%)
• Asthenia (13%)
• Mouth ulceration (12%)
• Musculoskeletal pain (12%)
• Upper respiratory tract infection (12%)
• Dermatitis (11%)
• Insomnia (11%)

Serious Side Effects:

• Interstitial Lung Disease (ILD)/Pneumonitis
• Severe diarrhea

• Severe and fatal ILD/pneumonitis occurred; monitor for pulmonary symptoms indicative of ILD/pneumonitis. Permanently discontinue if ILD is confirmed.
• Severe and fatal diarrhea occurred; promptly initiate antidiarrheal treatment.
• Withhold and reduce dose based on severity of diarrhea and dermatologic reactions.
• Advise females of reproductive potential to use effective contraception.

• Severe hepatic impairment (total bilirubin 3-10x ULN): Recommended dose not established.
• Severe renal impairment (CrCl <30 mL/min): Recommended dose not established.

Proton Pump Inhibitors (PPIs): Avoid use with Dacomitinib; use locally-acting antacids or H2-receptor antagonists. Administer Dacomitinib at least 6 hours before or 10 hours after H2-receptor antagonist.

CYP2D6 Substrates: Avoid concomitant use where minimal increases in concentration may lead to serious or life-threatening toxicities.

Can be taken with or without food. Administer Dacomitinib at least 6 hours before or 10 hours after H2-receptor antagonist.

Pregnancy Category D. Based on animal studies and its mechanism of action, fetal harm may occur when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment and for at least 17 days after final dose.

There is no information regarding presence of dacomitinib or its metabolites in human milk. Because of potential for serious adverse reactions, advise women not to breastfeed during treatment and for at least 17 days after last dose.

Safety and effectiveness in pediatric populations have not been established.

No specific dosage adjustment is necessary for elderly patients.

Renal impairment: No dosage adjustment necessary for mild or moderate renal impairment (CrCl 30-89 mL/min). Recommended dose not established for severe renal impairment (CrCl <30 mL/min).

Hepatic impairment: No dosage adjustment necessary for mild or moderate hepatic impairment. Recommended dose not established for severe hepatic impairment (total bilirubin 3-10x ULN).

No adequate information on overdose is available. Overdose may lead to diarrhea, skin reactions, and other toxic effects. Seek medical attention.

Do not store above 30°C. Keep away from light and out of reach of children.

Dacomitinib