dacomitinib (Rx)

Brand and Other Names:Vizimpro
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Dosing & Uses

AdultPediatric

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

  • Mild or moderate (total bilirubin ≤3x upper limit of normal [ULN] and any AST): No dosage adjustment necessary
  • Severe (total bilirubin 3-10x ULN and any AST): Recommended dose not established

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

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Interactions

Interaction Checker

and dacomitinib

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      Serious - Use Alternative

        Significant - Monitor Closely

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            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

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            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
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            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.

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            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)

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            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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            Formulary

            FormularyPatient Discounts

            Adding plans allows you to compare formulary status to other drugs in the same class.

            To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

            Adding plans allows you to:

            • View the formulary and any restrictions for each plan.
            • Manage and view all your plans together – even plans in different states.
            • Compare formulary status to other drugs in the same class.
            • Access your plan list on any device – mobile or desktop.

            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.