Dosing & Uses
Dosage Forms & Strengths
tablet
- 15mg
- 30mg
- 45mg
Non-small Cell Lung Cancer
Indicated for first-line treatment of patients with metastatic non-small 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
45 mg PO qDay
Continue until disease progression or unacceptable toxicity occurs
Also see Administration
Dosage Modifications
First dose reduction: 30 mg qDay
Second dose reduction: 15 mg qDay
Interstitial lung disease (ILD)
- Any grade: Permanently discontinue treatment
Diarrhea
- Grade 2: Withhold treatment until recovery to Grade ≤1; then resume treatment at the same dose level
- For recurrent Grade 2 OR Grade ≥3: Withhold until recovery to Grade ≤1; then resume treatment at a reduced dose
Dermatologic adverse reactions
- Grade 2: Withhold treatment for persistent dermatologic adverse reactions; upon recovery to Grade ≤1, resume treatment at same dose level
- For recurrent persistent Grade 2 OR Grade ≥3 dermatologic adverse reactions, withhold until recovery to Grade ≤1; then resume treatment at a reduced dose
Other adverse reactions
- Grade 3 or 4: Withhold treatment until recovery to Grade ≤2; then resume treatment at a reduced dose
Renal impairment
- Mild or moderate (CrCl 30-89 mL/min estimated by Cockcroft-Gault equation): No dosage adjustment necessary
- Severe (CrCl <30 mL/min): Recommended dose not established
Hepatic impairment
- No dosage modification recommended in patients with mild, moderate or severe hepatic impairment (Child-Pugh A, B or C)
Dosing Considerations
Patient selection
- Select patients for treatment based on presence of an EGFR exon 19 deletion or exon 21 L858R substitution mutation in tumor specimens
- Information on FDA-approved tests for detection of EGFR mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics
Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
>10% (All Grades)
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%)
1-10% (All Grades)
Chest pain (10%)
Fatigue (9%)
Vomiting (9%)
Skin fissures (9%)
Dysgeusia (7%)
Skin exfoliation/exfoliative skin reactions (3.5%)
Interstitial lung disease (2.6%)
Keratitis (1.8%)
Hypertrichosis (1.3%)
Dehydration (1.3%)
1-10% (Grade 3 or 4)
Hypokalemia (7%)
Lymphopenia (6%)
Decreased appetite (3.1%)
Hyponatremia (2.9%)
Decreased weight (2.2%)
Dyspnea (2.2%)
Asthenia (2.2%)
Upper respiratory tract infection (1.3%)
Dry skin (1.8%)
Dermatitis (1.8%)
Increased ALT (1.4%)
Hypocalcemia (1.4%)
Hyperglycemia (1%)
<1% (Grade 3 or 4)
Alopecia
Pruritus
Palmar-plantar erythrodysesthesia syndrome
Musculoskeletal pain
Insomnia
Anemia
Increased alkaline phosphatase
Hypomagnesemia
Hyperbilirubinemia
Increased AST
Warnings
Contraindications
None
Cautions
Severe and fatal ILD/pneumonitis occurred; monitor for pulmonary symptoms indicative of ILD/pneumonitis; withhold treatment and promptly investigate for ILD in patients who present with worsening of respiratory symptoms, which may be indicative of ILD (eg, dyspnea, cough, fever); permanently discontinue treatment if ILD is confirmed
Severe and fatal diarrhea occurred; promptly initiate antidiarrheal treatment (loperamide or diphenoxylate hydrochloride with atropine sulfate) for diarrhea
Based on findings from animal studies and its mechanism of action, fetal harm may occur when administered to a pregnant woman (see Pregnancy)
Dermatologic adverse reactions
- Rash and exfoliative skin reactions occurred; incidence and severity of rash and exfoliative skin reactions may increase with sun exposure
- At time of initiation of treatment, initiate use of moisturizers and appropriate measures to limit sun exposure
- Upon development of Grade 1 rash, initiate treatment with topical antibiotics and topical steroids
- Initiate oral antibiotics for Grade ≥2 severe dermatologic adverse reactions
Drug interactions overview
- Dacomitinib inhibits UGT1A1, P-gp, BCRP, and organic cation transporter (OCT)1
- Dacomitinib is a P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) substrate
Concomitant use of acid-reducing agents
- Avoid use with proton pump inhibitors (PPIs)
- As an alternative to PPIs, use locally acting antacids, or, if using a histamine 2 (H2)-receptor antagonist, administer dacomitinib at least 6 hr before or 10 hr after taking an H2-receptor antagonist
- Concomitant use with a PPI decreases dacomitinib concentrations, which may reduce dacomitinib efficacy
Effect of dacomitinib on CYP2D6 substrates
- Concomitant use of dacomitinib increases concentration of CYP2D6 substrates, which may increase the risk of toxicities of these drugs
- Avoid use with CYP2D6 substrates where minimal increases in concentration of the CYP2D6 substrate may lead to serious or life-threatening toxicities
Pregnancy
Pregnancy
Based on findings from animal studies and its mechanism of action, fetal harm may occur when administered to a pregnant woman
There are no available data on use in pregnant women
Verify pregnancy status of females of reproductive potential prior to initiating treatment
Advise females of reproductive potential to use effective contraception during treatment and for at least 17 days after final dose
Animal data
- In animal reproduction studies, oral administration of dacomitinib to pregnant rats during organogenesis period resulted in an increased incidence of postimplantation loss and reduced fetal body weight at doses resulting in similar exposures seen at the 45-mg human dose
- Absence of EGFR signaling resulted in embryo lethality as well as postnatal death in animals
- Advise pregnant women of the potential risk to a fetus
Lactation
There is no information regarding presence of dacomitinib or its metabolites in human milk or their effects on breastfed infants or on milk production
Because of potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment and for at least 17 days after last dose
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Irreversible kinase inhibitor 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)
Also inhibited the activity of DDR1, EPHA6, LCK, DDR2, and MNK1 in vitro at clinically relevant concentrations
Demonstrates dose-dependent inhibition of EGFR and HER2 autophosphorylation and tumor growth in mice bearing SC implanted human tumor xenografts driven by HER family targets including mutated EGFR; also, exhibits antitumor activity in orally dosed mice bearing intracranial human tumor xenografts driven by EGFR amplifications
Absorption
Peak plasma concentration: 108 ng/mL
Peak plasma time (single 45-mg dose): 6 hr
AUC: 2213 ng·hr/mL
Time to steady-state: 14 days
Bioavailability: 80%
Effect of food
- Administration with a high-fat, high-calorie meal (~800-1000 calories with 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively) had no clinically meaningful effect on dacomitinib pharmacokinetics
Distribution
Vd (steady-state): 1889 L
Protein binding: 98%
Metabolism
Hepatic metabolism is main route of clearance, with oxidation and glutathione conjugation as the major pathways
Following oral administration of a single 45-mg dose of [14C] dacomitinib, the most abundant circulating metabolite was O-desmethyl dacomitinib, which had similar in vitro pharmacologic activity as dacomitinib
Elimination
Half-life (single 45-mg dose): 70 hr
Clearance (single 45-mg dose): 24.9 L/hr
Excretion: Feces 79% (20% unchanged); urine 3% (<1% unchanged)
Administration
Oral Administration
Administer with or without food at the same time each day
If patient vomits or misses a dose, do not take an additional dose or make up a missed dose but continue with next scheduled dose
Storage
Store at 20-25°C (68-77°F); excursions permitted between 15-30°C (59-86°F)
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