Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Vizimpro: 15 mg, 30 mg, 45 mg [contains fd&c blue #2 aluminum lake]
Pharmacology
Mechanism of Action
Dacomitinib is an irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor which has activity against EGFR/HER1, HER2, and HER4, as well as some EGFR-activating mutations (exon 19 deletion or exon 21 L858R substitution mutation). Dacomitinib also has activity against DDR1, EPHA6, LCK, DDR2, and MNK1 (in vitro).
Pharmacokinetics/Pharmacodynamics
Distribution
Vss: 1,889 L
Metabolism
Hepatic, primarily via oxidation and glutathione conjugation; CYP2D6 is involved in the formation of O-desmethyl dacomitinib (active), and CYP3A4 contributes to the formation of minor oxidative metabolites
Excretion
Feces: 79% (20% as parent drug); Urine: 3% (<1% as parent drug)
Time to Peak
~6 hours (range: 2 to 24 hours)
Half-Life Elimination
70 hours
Protein Binding
~98%
Use in Specific Populations
Special Populations: Hepatic Function Impairment
In a single-dose 30 mg study, dacomitinib AUCinf and Cmax were decreased by 15% and 20%, respectively, in patients with moderate hepatic impairment as compared to subjects with normal hepatic function.
Use: Labeled Indications
Non-small cell lung cancer, metastatic: First-line treatment of metastatic non-small cell lung cancer (NSCLC) in patients with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations as detected by an approved test.
Contraindications
There are no contraindications listed in the US manufacturer's labeling.
Canadian labeling: Hypersensitivity to dacomitinib or any component of the formulation.
Dosage and Administration
Dosing: Adult
Note: Prior to treatment, confirm tumor epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations.
Non-small cell lung cancer, metastatic, first-line (EGFR exon 19 deletion- or exon 21 L858R substitution mutation-positive): Oral: 45 mg once daily until disease progression or unacceptable toxicity (Wu 2017)
Missed doses: If a dose is missed or vomited, do not make up the missed/vomited dose; administer the next dose as scheduled.
Dosing: Geriatric
Refer to adult dosing.
Dosing: Adjustment for Toxicity
Note: Recommended dose reductions for adverse reactions:
Initial/usual dose: 45 mg once daily
First dose reduction: 30 mg once daily
Second dose reduction: 15 mg once daily
Dermatologic toxicity:
Grade 2: Temporarily interrupt dacomitinib therapy for persistent grade 2 reactions; upon recovery to ≤ grade 1, resume dacomitinib at the same dose. If grade 2 dermatologic toxicity recurs, withhold until recovery to ≤ grade 1, then resume therapy at a reduced dose.
Grade 3 or 4: Temporarily interrupt dacomitinib therapy until recovery to ≤ grade 1, then resume therapy at a reduced dose.
Gastrointestinal toxicity:
Diarrhea, grade 2: Temporarily interrupt dacomitinib therapy until recovery to ≤ grade 1, then resume dacomitinib at the same dose. If grade 2 diarrhea recurs, withhold until recovery to ≤ grade 1, then resume therapy at a reduced dose.
Diarrhea, grade 3 or 4: Temporarily interrupt dacomitinib therapy until recovery to ≤ grade 1, then resume therapy at a reduced dose.
Pulmonary toxicity: Interstitial lung disease (any grade): Permanently discontinue.
Other toxicities: Grade 3 or 4 adverse reaction: Temporarily interrupt dacomitinib therapy until recovery to ≤ grade 2, then resume therapy at a reduced dose.
Administration
Oral: Administer at the same time each day with or without food. Avoid the concomitant use of proton pump inhibitors with dacomitinib. If using an H2 blocker or antacid, administer dacomitinib at least 6 hours before or 10 hours after the H2 blocker or antacid.
Storage
Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).
Drug Interactions
Amphetamines: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Amphetamines. Monitor therapy
ARIPiprazole: CYP2D6 Inhibitors (Strong) may increase the serum concentration of ARIPiprazole. Management: See full interaction monograph for details. Consider therapy modification
ARIPiprazole Lauroxil: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of ARIPiprazole Lauroxil. Management: Please refer to the full interaction monograph for details concerning the recommended dose adjustments. Consider therapy modification
AtoMOXetine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of AtoMOXetine. Management: Initiate atomoxetine at a reduced dose (adult doses -- patients up to 70kg: 0.5mg/kg/day; patients 70kg or more: 40mg/day) in patients receiving a strong CYP2D6 inhibitor. Consider therapy modification
Benzhydrocodone: CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Benzhydrocodone. Monitor therapy
Brexpiprazole: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Brexpiprazole. Management: Reduce brexpiprazole dose to 50% of usual with a strong CYP2D6 inhibitor, reduce to 25% of usual if used with both a strong CYP2D6 inhibitor and a CYP3A4 inhibitor; these recommendations do not apply if treating major depressive disorder. Consider therapy modification
CloZAPine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of CloZAPine. Monitor therapy
Codeine: CYP2D6 Inhibitors (Strong) may diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Consider therapy modification
CYP2D6 Substrates (High risk with Inhibitors): Dacomitinib may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Management: Avoid concurrent use of dacomitinib with CYP2D6 subtrates that have a narrow therapeutic index. Consider therapy modification
Deutetrabenazine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Deutetrabenazine. Management: The total daily dose of deutetrabenazine should not exceed 36 mg, and the maximum single dose of deutetrabenazine should not exceed 18 mg with concurrent use of a strong CYP2D6 inhibitor. Consider therapy modification
DOXOrubicin (Conventional): CYP2D6 Inhibitors (Strong) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to strong CYP2D6 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification
DULoxetine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of DULoxetine. Monitor therapy
Eliglustat: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Eliglustat. Management: Reduce the eliglustat dose to 84 mg daily. Avoid use of eliglustat in combination with a strong CYP2D6 inhibitor and a strong or moderate CYP3A4 inhibitor. Consider therapy modification
Fesoterodine: CYP2D6 Inhibitors may increase serum concentrations of the active metabolite(s) of Fesoterodine. Monitor therapy
FluvoxaMINE: CYP2D6 Inhibitors (Strong) may increase the serum concentration of FluvoxaMINE. Monitor therapy
Galantamine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Galantamine. Monitor therapy
Histamine H2 Receptor Antagonists: May decrease the serum concentration of Dacomitinib. Management: Administer dacomitinib at least 6 hours before or 10 hours after an histamine H2-receptor antagonist (H2RA). Consider therapy modification
HYDROcodone: CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of HYDROcodone. Specifically, concentrations of hydromorphone may be decreased. Monitor therapy
Iloperidone: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Iloperidone. Specifically, concentrations of the metabolite P88 may be increased. CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Iloperidone. Specifically, concentrations of the metabolite P95 may be decreased. CYP2D6 Inhibitors (Strong) may increase the serum concentration of Iloperidone. Management: Reduce iloperidone dose by half when administered with a strong CYP2D6 inhibitor. Consider therapy modification
Lofexidine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Lofexidine. Monitor therapy
Mequitazine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Mequitazine. Avoid combination
Metoclopramide: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Metoclopramide. Management: Reduce metoclopramide dose to 5 mg 4 times daily (30 minutes before each meal and at bedtime) and limit the maximum daily dose to 20 mg if combined with strong CYP2D6 inhibitors. Consider therapy modification
Nebivolol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Nebivolol. Monitor therapy
Nicergoline: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Nicergoline. Specifically, concentrations of the MMDL metabolite may be increased. CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Nicergoline. Specifically, concentrations of the MDL metabolite may be decreased. Monitor therapy
Perhexiline: CYP2D6 Inhibitors may increase the serum concentration of Perhexiline. Management: Consider alternatives to this combination if possible. If combined, monitor for increased perhexiline serum concentrations and toxicities (eg, hypoglycemia, neuropathy, liver dysfunction). Perhexiline dose reductions will likely be required. Consider therapy modification
Pimozide: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Pimozide. Avoid combination
Pitolisant: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Pitolisant. Management: Reduce the pitolisant dose by 50% if a strong CYP2D6 inhibitor is initiated. For patients receiving strong CYP2D6 inhibitors, initiate pitolisant at 8.9 mg once daily and increase after 7 days to a maximum of 17.8 mg once daily. Consider therapy modification
Primaquine: CYP2D6 Inhibitors (Strong) may diminish the therapeutic effect of Primaquine. Management: Monitor for signs and symptoms of possible treatment failure with primaquine in patients who are taking strong CYP2D6 inhibitors. If efficacy of primaquine is compromised, may consider adjusting therapies. Consider therapy modification
Proton Pump Inhibitors: May decrease the serum concentration of Dacomitinib. Management: Avoid concurrent use of dacomitinib with proton pump inhibitors. Antacids may be used. Histamine H2-receptor antagonists (HR2A) may be used if dacomitinib is given at least 6 hours before or 10 hours after the H2RA. Avoid combination
Tamoxifen: CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Tamoxifen. Specifically, strong CYP2D6 inhibitors may decrease the metabolic formation of highly potent active metabolites. Avoid combination
Tamsulosin: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Tamsulosin. Monitor therapy
Tetrabenazine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Tetrabenazine. Specifically, concentrations of the active alpha- and beta-dihydrotetrabenazine metabolites may be increased. Management: Tetrabenazine adult dose should be reduced by 50% when starting a strong CYP2D6 inhibitor. Maximum tetrabenazine adult dose is 50 mg/day when used with a strong CYP2D6 inhibitor. Consider therapy modification
Thioridazine: CYP2D6 Inhibitors may increase the serum concentration of Thioridazine. Avoid combination
TraMADol: CYP2D6 Inhibitors (Strong) may diminish the therapeutic effect of TraMADol. CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of TraMADol. CYP2D6 Inhibitors (Strong) may increase the serum concentration of TraMADol. Monitor therapy
Valbenazine: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Valbenazine. Monitor therapy
Vortioxetine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Vortioxetine. Management: The vortioxetine dose should be reduced by 50% when used together with a strong CYP2D6 inhibitor. Following cessation of the strong CYP2D6 inhibitor, the vortioxetine dose should be returned to the normal level. Consider therapy modification
Adverse Reactions
>10%:
Cardiovascular: Chest pain (10%)
Central nervous system: Insomnia (11%)
Dermatologic: Skin rash (69% to 78%), paronychia (64%), xeroderma (30%), alopecia (23%), pruritus (21%), palmar-plantar erythrodysesthesia (15%), dermatitis (11%)
Endocrine & metabolic: Hypoalbuminemia (44%), hyperglycemia (36%), hypocalcemia (33%), hypokalemia (29%), hyponatremia (26%), weight loss (26%), hypomagnesemia (22%)
Gastrointestinal: Diarrhea (87%), stomatitis (45%; grades 3/4: 4%), decreased appetite (31%), nausea (19%), constipation (13%), oral mucosa ulcer (12%)
Hematologic & oncologic: Anemia (44%; grades 3/4: <1%), lymphocytopenia (42%; grades 3/4: 6%)
Hepatic: Increased serum alanine aminotransferase (40%), increased serum aspartate aminotransferase (35%), increased serum alkaline phosphatase (22%), hyperbilirubinemia (16%)
Neuromuscular & skeletal: Limb pain (14%), asthenia (13%), musculoskeletal pain (12%)
Ophthalmic: Conjunctivitis (19%)
Renal: Increased creatinine clearance (24%)
Respiratory: Cough (21%), nasal signs and symptoms (19%), dyspnea (13%), upper respiratory tract infection (12%)
1% to 10%:
Central nervous system: Fatigue (9%)
Dermatologic: Skin fissure (9%), exfoliation of skin (4% to 7%), hypertrichosis (1%)
Endocrine & metabolic: Dehydration (1%)
Gastrointestinal: Vomiting (9%), dysgeusia (7%)
Ophthalmic: Keratitis (2%)
Respiratory: Interstitial pulmonary disease (3%)
<1%, postmarketing, and/or case reports: Pneumonitis
Warnings/Precautions
Concerns related to adverse effects:
- Dermatologic toxicity: Rash and exfoliative skin reactions have occurred with dacomitinib, including grade 3 or 4 events. Rash has been observed in over three-quarters of patients treated with dacomitinib. Sun exposure may increase the incidence and severity of dermatologic toxicity; limit sun exposure and utilize sunscreen when beginning dacomitinib treatment. Initiate moisturizers at the time of dacomitinib treatment initiation. Temporarily interrupt dacomitinib for persistent grade 2 or any grade 3 or 4 dermatologic toxicity until recovery to ≤ grade 1; may resume therapy at the same or reduced dose (depending on the severity of the reaction). Initiate topical antibiotics and topical steroids for grade 1 rash; administer oral antibiotics for grade 2 or higher dermatologic toxicity. Dry skin and nail disorders have been commonly reported with dacomitinib.
- Gastrointestinal toxicity: Severe and fatal diarrhea has occurred in patients treated with dacomitinib. Diarrhea was reported in the majority of patients; grade 3 or 4 events have been reported. Temporarily interrupt dacomitinib for grade 2 or higher diarrhea, then resume at the same or reduced dose (depending on severity) once diarrhea has resolved to grade 1 or less. Promptly initiate antidiarrheal treatment (eg, loperamide or diphenoxylate and atropine). Mucositis/stomatitis has been observed with dacomitinib.
- Pulmonary toxicity: Interstitial lung disease (ILD), including severe and fatal ILD/pneumonitis, has been reported with dacomitinib. Monitor for pulmonary symptoms suggestive of ILD/pneumonitis. Temporarily interrupt dacomitinib and promptly evaluate for ILD in patients with worsening respiratory symptoms (such as dyspnea, cough, and fever). Permanently discontinue dacomitinib if ILD is confirmed.
Concurrent drug therapy issues:
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
- Drugs that affect gastric pH: Avoid the concomitant use of proton pump inhibitors with dacomitinib. If using an H2 blocker or antacids, administer dacomitinib at least 6 hours before or 10 hours after the H2 blocker or antacid.
Special populations:
- Elderly: Patients ≥65 years of age may experience a higher incidence of grade 3 and 4 adverse events, more frequent dose interruptions, and more frequent treatment discontinuations.
Other warnings/precautions:
- Appropriate use: Confirm the presence of epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations in tumor specimen prior to therapy initiation. Information on diagnostic tests approved for detection of EGFR mutations may be found at www.fda.gov/companiondiagnostics.
Monitoring Parameters
Prior to treatment, confirm epidermal growth factor receptor exon 19 deletion or exon 21 L858R substitution mutation status; pregnancy test (in females of reproductive potential) prior to therapy initiation. Monitor for signs/symptoms of interstitial lung disease/pneumonitis (eg, dyspnea, cough, fever), diarrhea, and dermatologic toxicity. Monitor adherence.
Pregnancy
Pregnancy Considerations
Based on data from animal reproduction studies and the mechanism of action, dacomitinib use during pregnancy may cause fetal harm. Verify pregnancy status in females of reproductive potential prior to initiating dacomitinib. Females of reproductive potential should use effective contraception during therapy and for at least 17 days after the last dacomitinib dose.
Patient Education
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience hair loss, nail changes, mouth irritation, mouth sores, lack of appetite, weight loss, dry skin, nausea, vomiting, constipation, common cold symptoms, eye irritations, painful extremities, muscle pain, trouble sleeping, or change in taste. Have patient report immediately to prescriber signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit), signs of electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting), severe diarrhea, persistent diarrhea, skin reaction, redness or irritation of palms or soles of feet, chest pain, severe loss of strength and energy, or signs of a severe pulmonary disorder (lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse) (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
