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VIZIMPRO (dacomitinib)

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Health Professional Information

INDICATIONS

VIZIMPRO (dacomitinib) is indicated for:

the first-line treatment of adult patients with unresectable locally advanced or metastatic non‑small cell lung cancer (NSCLC) with confirmed epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations.

A validated test is required to identify EGFR mutation status (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).

Pediatrics

Pediatrics (<18 years) : The safety and efficacy of VIZIMPRO in children (<18 years of age) have not been established. No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

Geriatrics

Geriatrics (≥65 years) : In the Phase III study (ARCHER 1050), 94/227 (41.4%) treated with VIZIMPRO were ≥ 65 years of age. No clinically meaningful difference in effectiveness was identified between < 65 year and ≥ 65 year age groups. Patients ≥ 65 years had more serious adverse events (SAEs) (33.0% vs 23.3%), more Grade 3 adverse events (AEs) (55.3% vs 48.1%) and more permanent treatment discontinuations due to AEs (26.6% vs 11.3%) than patients < 65 years. Elderly patients should be closely monitored for drug-related toxicities. Although conclusions cannot be drawn due to the small sample size (28/227; 12.3%), exploratory subgroup analyses did not show a benefit in efficacy endpoints for patients aged above 75 years treated with VIZIMPRO when compared to patients aged above 75 years treated with gefitinib.

Contraindications

VIZIMPRO (dacomitinib) is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see Section 6 - DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

Serious Warnings And Precautions Box

Serious Warnings and Precautions

VIZIMPRO (dacomitinib) should be initiated and supervised by a qualified physician who is experienced in the use of anticancer medicinal products.

  • EGFR mutation-positive status must be confirmed prior to starting VIZIMPRO (see DOSAGE AND ADMINISTRATION - Dosing Considerations; WARNINGS AND PRECAUTIONS – Monitoring and Laboratory Tests; CLINICAL TRIALS)

The following are clinically significant and/or life-threatening adverse events:

  • Diarrhea, including fatalities (see WARNINGS AND PRECAUTIONS, Gastrointestinal)
  • Severe skin toxicity, including exfoliative skin reactions (see WARNINGS AND PRECAUTIONS, Skin)
  • Interstitial lung disease (IDL)/pneumonitis, including fatalities (see WARNINGS AND PRECAUTIONS, Respiratory)

Dosage And Administration

Dosing Considerations

Confirm the presence of EGFR exon 19 deletion or exon 21 L858R substitution mutations prior to initiation of VIZIMPRO (dacomitinib) therapy using a validated test (see WARNINGS AND PRECAUTIONS – Monitoring and Laboratory Tests).

Recommended Dose and Dosage Adjustment

The recommended dose of VIZIMPRO is 45 mg taken once daily until disease progression or unacceptable toxicity occurs.

Dose modifications may be required based on individual safety and tolerability. If dose reduction is necessary, then the dose of VIZIMPRO should be reduced as described in Table 1.  Dose modification and management guidelines for specific Adverse Drug Reactions (ADRs) are provided in Table 2.

Table 1. Recommended Dose Modifications for VIZIMPRO Adverse Drug Reactions

Dose Level

Dose (once daily)

Recommended starting dose

45 mg

First dose reduction

30 mg

Second dose reduction

15 mg

Table 2. VIZIMPRO Dose Modification and Management Recommendations for Adverse Drug Reactions

Adverse Drug Reactions

Dose Modification

Interstitial lung disease (ILD/Pneumonitis)

  • Withhold VIZIMPRO during ILD/Pneumonitis diagnostic evaluation.
  • Permanently discontinue VIZIMPRO if any Grade ILD/Pneumonitis is confirmed.

Diarrhea

  • For Grade 1 diarrhea, no dose modification is required. Initiate treatment with anti-diarrheal medications (e.g., loperamide) at first onset of diarrhea. Encourage adequate oral fluid intake during diarrhea.
  • For Grade 2 diarrhea, if not improved to Grade ≤1 within 24 hours while using anti-diarrheal medications (e.g., loperamide) and adequate oral fluid intake, withhold VIZIMPRO until recovery to Grade ≤1. Resume VIZIMPRO at the same dose level or consider a reduction of one dose level if Grade 2 diarrhea reoccurs.
  • For Grade >3 diarrhea, withhold VIZIMPRO. Treat with anti‑diarrheal medications (e.g., loperamide), and adequate oral fluid intake or intravenous fluids or electrolytes as appropriate, until recoveryto Grade ≤1, resume VIZIMPRO with a reduction of 1 dose level.

Skin-related adverse reactions

  • For Grade 1 rash or erythematous skin conditions, no dose modification is required. Initiate treatment (e.g., antibiotics, topical steroids, and emollients).
  • For Grade 1 exfoliative skin conditions, no dose modification is required. Initiate treatment(e.g., oral antibiotics and topical steroids).
  • For Grade 2 rash, erythematous or exfoliative skin conditions, no dose modification is required. Initiate treatment and provide additional treatment (e.g., oral antibiotics and topical steroids).
  • For persistent Grade 2 rash, erythematous or exfoliative skin conditions, withhold VIZIMPRO. Upon recovery to Grade ≤1, resume VIZIMPRO at the same dose level or consider a reduction of 1 dose level.
  • For Grade ≥3 rash, erythematous or exfoliative skin conditions, withhold VIZIMPRO. Initiate or continue treatment and/or provide additional treatment (e.g., broad spectrum oral or intravenous antibiotics and topical steroids). Upon recovery to Grade ≤1, resume VIZIMPRO with a reduction of 1 dose level.

Other

  • For intolerable Grade 2 toxicity, withhold VIZIMPRO until symptoms resolve to Grade ≤1. Upon recovery, resume VIZIMPRO with a reduction of 1 dose level
  • For Grade ≥3 toxicity, withhold VIZIMPRO until symptoms resolve to Grade ≤2. Upon recovery, resume VIZIMPRO with a reduction of 1 dose level.

Special Populations and Conditions

Hepatic impairment:  No starting dose adjustments are required when administering VIZIMPRO to patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. The recommended dose of VIZIMPRO has not been established in subjects with severe (Child-Pugh class C) hepatic impairment (see Section 10.3 - ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

Renal impairment:  No starting dose adjustments are required when administering VIZIMPRO to patients with mild or moderate renal impairment (CrCl ≥30 mL/min).  The recommended dose of VIZIMPRO has not been established in patients with severe renal impairment (CrCl <30 mL/min) or requiring hemodialysis (see Section 10.3 - Pharmacokinetics).

Elderly population: No starting dose adjustment of VIZIMPRO in elderly (≥65 years of age) patients is required (see Section 10.3 - Pharmacokinetics).

Pediatric population:  The safety and efficacy of VIZIMPRO in children (<18 years of age) have not been established.  Health Canada has not authorized an indication for pediatric use.

Administration

VIZIMPRO should be taken once daily, with or without food, until disease progression or unacceptable toxicity occurs.

Advise patients to take their dose at the same time each day. However, it is recommended that dosing take place under consistent conditions (i.e. always fasted or always after the same type of meal) to avoid any unexpected increases in dacomitinib plasma concentrations.

Missed Dose

If the patient vomits or misses a dose, an additional dose should not be taken and the next prescribed dose should be taken at the usual time the next day.

Overdosage

The highest dose of dacomitinib studied in a limited number of patients was 105 mg (6 doses every 12 hours every 14 days).  The adverse drug reactions observed at doses greater than 45 mg once a day were primarily gastrointestinal, dermatological, and constitutional (e.g., fatigue, malaise, and weight loss).

There is no known antidote for dacomitinib. In case of suspected overdose, withhold VIZIMPRO (dacomitinib) and initiate symptomatic treatment and general supportive measures.

For management of a suspected drug overdose, contact your regional poison control centre.

Dosage Forms, Strengths, Composition And Packaging

Table 3 – Dosage Forms, Strengths, Composition and Packaging

Route of Administration

Dosage Form / Strength/Composition

Non-medicinal Ingredients

Oral

Tablet 15 mg, 30 mg, 45 mg

Lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate

Film coating contains: Opadry II® Blue 85F30716 containing: FD&C Blue #2/Indigo Carmine Aluminum Lake; Macrogol/PEG 3350; polyvinyl alcohol – part hydrolyzed; talc; titanium dioxide

45 mg tablets: blue film-coated, immediate release, round biconvex tablet, debossed with “Pfizer” on one side and “DCB45” on the other.

30 mg tablets: blue film-coated, immediate release, round biconvex tablet, debossed with “Pfizer” on one side and “DCB30” on the other.

15 mg tablets: blue film-coated, immediate release, round biconvex tablet, debossed with “Pfizer” on one side and “DCB15” on the other.

HDPE bottles with desiccant and child-resistant caps containing 30 film-coated tablets.

Aluminum/aluminum blister containing 10 film-coated tablets. Each pack contains 30 film-coated tablets.

Warnings And Precautions

The warnings and precautions listed below are based on pooled data from 394 patients who received VIZIMPRO 45 mg once daily for the treatment of NSCLC with EGFR-activating mutations across clinical studies.

General

Drugs metabolized by CYP2D6
VIZIMPRO increases exposure (or decrease exposure of active metabolites) of other drugs metabolized by CYP2D6, which may cause toxicity.  Avoid concomitant use of VIZIMPRO with CYP2D6 substrates where minimal increases in concentration of the CYP2D6 substrate may lead to serious or life threatening toxicities (see Section 9 – DRUG INTERACTIONS).

Carcinogenesis and Mutagenesis

Carcinogenicity studies have not been performed with dacomitinib.

Driving and Operating Machinery

No studies on the effects of VIZIMPRO on the ability to drive or operate machinery have been conducted.  However, patients experiencing fatigue while taking VIZIMPRO should exercise caution when driving or operating machinery.

Gastrointestinal

Diarrhea
Diarrhea has been reported in 86.3% of VIZIMPRO-treated patients.  Grade 3 diarrhea was reported in 10.7% of patients. Serious cases of diarrhea were reported in 1.8% of patients. Cases with a fatal outcome were reported in 0.3% of patients. The median time to the first episode of any grade diarrhea was 1 week and the median time to the worst episode of diarrhea was 2 weeks in patients receiving VIZIMPRO. The median duration of any grade and Grade ≥ 3 diarrhea was 20 weeks and 1 week, respectively. Diarrhea has led to temporary discontinuation, dose reduction and permanent discontinuation in 10.4%, 7.7% and 0.5% of patients. Diarrhea in VIZIMPRO-treated patients has been associated with acute renal insufficiency and severe electrolyte imbalance. 

Start proactive management of diarrhea at the first sign of diarrhea especially within the first 2 weeks of starting VIZIMPRO, including adequate hydration combined with anti-diarrheal medications and continued until loose bowel movements cease for 12 hours. Use anti-diarrheal medications (e.g., loperamide) and, if necessary, escalate to the highest recommended approved dose. Monitor for dehydration. Patients may require interruption and/or dose reduction of therapy with VIZIMPRO. Patients should maintain adequate oral hydration and patients who become dehydrated may require administration of intravenous fluids and electrolytes (see Section 4 – DOSAGE AND ADMINISTRATION – Table 2).

Hepatotoxicity and transaminases increased

Transaminases increased (alanine aminotransferase increased, aspartate aminotransferase increased, transaminases increased) have been reported during treatment with VIZIMPRO. Transaminases increased were reported in 15.2% of patients receiving VIZIMPRO and were Grades 1 to 3, with the majority Grade 1 12.4%. Dose reductions, dosing interruptions and permanent treatment discontinuation were required for 0%, 1.0% and 0.3% of patients, respectively. The median time to the first episode of any grade transaminases increased was 12 weeks and the median time to the worst episode of transaminases increased was 12 weeks in patients receiving VIZIMPRO. The median duration of any grade and Grade ≥ 3 transaminases increased was 12 weeks and 1 week, respectively. Among NSCLC patients treated with dacomitinib 45 mg QD, there have been isolated reports of hepatotoxicity in 5 (1.3%) patients. Across the dacomitinib program, hepatic failure led to a fatal outcome in 1 patient, therefore periodic liver laboratory testing is recommended. In patients who develop severe elevations in transaminases while taking dacomitinib, treatment should be interrupted.

Monitoring and Laboratory Tests

EGFR mutation status
EGFR mutation status (EGFR exon 19 deletions or exon 21 L858R substitution mutations) must be confirmed prior to initiating treatment with VIZIMPRO. Only patients with activating EGFR mutations should be treated with VIZIMPRO. A well validated and robust test should be used to avoid the possibility of false negative or false positive determinations.

Clinical characteristics of never smoker, adenocarcinoma histology, and female gender have been shown to be independent predictors of positive EGFR mutation status for both non-Asian and Asian patients. Asian patients also have a higher incidence of EGFR mutation positive tumors than non-Asian patients. These clinical characteristics should not be used to guide treatment choice; however they may be helpful in guiding mutation testing. A patient must be defined as EGFR mutation positive before starting VIZIMPRO therapy.

Clinical Chemistry
Renal function and serum electrolytes (potassium, calcium and magnesium) should be monitored regularly during treatment, particularly in patients at risk of dehydration (see WARNINGS AND PRECAUTIONS Gastrointestinal and Cardiovascular). Promptly correct any abnormalities.

Ophthalmologic

Keratitis
Keratitis occurred in 1.8% of VIZIMPRO-treated patients with 0.3% of those cases being serious. Dose reductions, dose interruptions and permanent discontinuation were required for 0.3%, 0.3% and 0.3% of patients, respectively. The median time to the first episode of any grade keratitis was 40 weeks and the median time to the worst episode of keratitis was 40 weeks in patients receiving VIZIMPRO. The median duration of any grade and Grade ≥ 3 keratitis was 17 weeks and 10 weeks, respectively.

Advise patients to seek medical advice promptly in the event of developing eye symptoms. Patients presenting with symptoms indicative of keratitis should be referred promptly to an ophthalmologist. Withhold VIZIMPRO for Grade 2, 3 or 4 keratitis and resume at reduced dose level once ≤ Grade 1.

Respiratory

lnterstitial Lung Disease (ILD)/Pneumonitis
ILD/pneumonitis, including a fatal event, has been reported in 2.0% of patients receiving VIZIMPRO; 0.8% of the cases were serious (see Section 8.2 – ADVERSE REACTIONS, Clinical Adverse Reactions – ILD). Dose reductions, dose interruptions and permanent discontinuation were required for 0 %, 0.5% and 1.3% of patients, respectively. The median time to the first episode of any grade ILD/pneumonitis was 16 weeks and the median time to the worst episode of ILD/pneumonitis was 16 weeks in patients receiving VIZIMPRO. The median duration of any grade and Grade ≥ 3 ILD/pneumonitis was 21 weeks and 3 weeks, respectively.

Careful assessment of all patients with an acute onset and/or unexplained worsening of pulmonary symptoms (e.g., dyspnea, cough, fever) should be performed to exclude ILD/pneumonitis. Treatment with VIZIMPRO should be withheld pending investigation of these symptoms. If ILD/pneumonitis is confirmed, permanently discontinue VIZIMPRO and institute appropriate treatment as necessary (see Section 4 - DOSAGE AND ADMINISTRATION – Table 2).

Sexual Health

Reproduction
Based on findings from animal studies, VIZIMPRO can cause fetal harm when administered to a pregnant woman [see Section 14 - Nonclinical Toxicology]. There are no adequate and well-controlled studies in pregnant women using VIZIMPRO. In animal reproduction studies, administration of dacomitinib to pregnant rats during organogenesis resulted in embryo-fetal toxicity at maternal exposures that were approximately 2.4 times the unbound AUC at the recommended human dose.

Advise women of childbearing potential to avoid becoming pregnant while receiving VIZIMPRO. Advise women of childbearing potential and male partners of women of child bearing potential to use effective contraception during treatment with VIZIMPRO and for at least 2 months following permanent treatment discontinuation.

Fertility
Fertility studies have not been performed with VIZIMPRO. Nonclinical safety studies showed reversible epithelial atrophy in the cervix and vagina of rats and no effects on reproductive organs of male rats or dogs [see Section 14 - NONCLINICAL TOXICOLOGY]. 

Skin

Rash
Rash has been reported in 77.9% of VIZIMPRO-treated patients and 20.8% were Grade 3 in severity. Dose reductions, dose interruptions and permanent discontinuation were required for 27.3%, 18.8% and 1.8% of patients, respectively.

Exfoliative skin conditions
Severe skin reactions, including exfoliative rash, skin exfoliation, erythema multiforme and bullous dermatitis, occurred in 7.4% of patients. Grade 3 exfoliative skin reactions have been reported in 1.8% of VIZIMPRO-treated patients. Exfoliative skin reactions led to dose reduction in 1.0% of patients; to dose interruptions in 1.5% of patients and to permanent discontinuation in 0.3% of patients. Although causality could not be assessed due to concomitant medications, one case of Grade 4 Stevens-Johnson syndrome has been reported in a patient treated with VIZIMPRO.

The median time to the first episode of any grade rash and erythematous skin conditions was approximately 2 weeks and the median time to the worst episode of rash and erythematous skin conditions was 7 weeks in patients receiving VIZIMPRO. The median duration of any grade and Grade ≥ 3 rash and erythematous skin conditions was 44 weeks and 3 weeks, respectively. The median time to the first episode of any grade exfoliative skin conditions was 8 weeks and the median time to the worst episode of exfoliative skin conditions was 9 weeks. The median duration of any grade and Grade ≥ 3 exfoliative skin conditions was 7 weeks and 2 weeks, respectively.

Rash, erythematous and exfoliative skin conditions may occur or worsen in areas exposed to the sun. For patients who are exposed to the sun, protective clothing and use of sunscreen is advisable. Early intervention is advisable. Patients may require interruption and/or dose reduction of therapy with VIZIMPRO and additional treatment as warranted (eg., antibiotics, topical steroids, and emollients (see Section 4 – DOSAGE AND ADMINISTRATION – Table 2).

Paronychia
Paronychia has been reported in 60.7% of patients treated with VIZIMPRO; Grade 3 paronychia occurred in 7.9% of patients. Dose reductions, dose interruptions and permanent treatment discontinuations were required for 13.8%, 9.9 % and 0% of patients, respectively. The median time to the first episode of any grade Paronychia was 7 weeks and the median time to the worst episode of Paronychia was 10 weeks in patients receiving VIZIMPRO. The median duration of any grade and Grade ≥ 3 paronychia was 45 weeks and 3 weeks, respectively.

Patients should be advised to avoid trauma to the nails or finger tips and avoid chemicals that can be harmful, such as soaps, detergents and nail products. Patients should be advised to keep the hands clean and dry. If mild paronychia develops, topical antibiotics/antiseptics and/or steroids may be beneficial. For moderate to severe cases, topical or systemic antibiotics and/or steroids as well as periodic silver nitrate application may be beneficial.

Palmar-plantar erythrodysesthesia syndrome
In pivotal studies of NSCLC patients with EGFR-activating mutations, palmar-plantar erythrodysesthesia (PPE) occurred in 15.2% of patients treated with VIZIMPRO. Grade 3 PPE were reported for 1.5% of patients. Dose reductions, dose interruptions and permanent treatment discontinuations were required for 2.6%, 1.3% and 0% of patients, respectively. The median time to the first episode of any grade PPE syndrome was 4 weeks and the median time to the worst episode of PPE syndrome was 6 weeks in patients receiving VIZIMPRO. The median duration of any grade and Grade ≥ 3 PPE was 15 weeks and 2 weeks, respectively.

Palmar-plantar erythrodysesthesia syndrome may occur or worsen in areas exposed to the sun. For patients who are exposed to the sun, protective clothing and use of sunscreen is advisable. Early intervention is advisable. Patients may require interruption and/or dose reduction of therapy with VIZIMPRO and additional treatment as warranted (eg., antibiotics, topical steroids, and emollients (see Section 4 – DOSAGE AND ADMINISTRATION – Table 2).

Special Populations

Pregnant Women

Pregnancy
VIZIMPRO can cause fetal harm when administered to a pregnant woman based on its mechanism of action. In pregnant rats, effects were limited to lower maternal body weight gain and food consumption, and lower fetal body weights [see Section 14 - NONCLINICAL TOXICOLOGY].

There are no adequate and well-controlled studies in pregnant women using VIZIMPRO.

Advise female patients taking VIZIMPRO during pregnancy or who become pregnant while taking VIZIMPRO of the potential hazard to the fetus.

Breast-feeding

It is not known whether VIZIMPRO and its metabolites are excreted in human milk.  Because of the potential for serious adverse drug reactions (ADRs) in breastfed infants from exposure to dacomitinib, mothers should be advised against breastfeeding while receiving VIZIMPRO and for 2 months following permanent treatment discontinuation.

Pediatrics

Pediatrics (<18 years): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.  The safety and efficacy of VIZIMPRO in children (<18 years of age) have not been established.

Geriatrics

Geriatrics (≥65 years): In ARCHER 1050, 94/227 (41%) treated with VIZIMPRO were ≥ 65 years of age.  Patients ≥ 65 years of age had a higher incidence of the following AEs compared to patients younger than 65 years of age: decreased appetite (40.4% vs 24.1%), rash (26.6% vs 11.3%), mucosal inflammation (16.0% vs 4.5%) and asthenia (19.1% vs 8.3%).

Cardiac Impairment

VIZIMPRO has not been studied in patients with cardiac impairment. Therefore the safety of VIZIMPRO in this patient population is unknown.

Patients with Brain Metastases

VIZIMPRO has not been studied in patients with a history or presence of brain or meningeal metastases. Therefore the safety of VIZIMPRO in this patient population is unknown.

Race

In ARCHER 1050, 170/227 (74.9%) of patients treated with VIZIMPRO were Asian and 57/227 (25.1%) were non-Asian. Non-Asian treated with VIZIMPRO experienced more SAEs (43.9% vs 21.8%), more Grade 3 or 4 AEs (63.1% vs 50.0%), more Grade 5 AEs (15.8% vs 7.6%).

The following AEs occurred more frequently in Asian patients compared to non-Asian: diarrhea (90.6% vs 77.2%), dermatitis acneiform (56.5% vs 26.3%), decreased appetite (33.5% vs 22.8%), stomatitis (51.2% vs 21.1%), paronychia (64.7% vs 52.6%), weight decreased (34.1% vs 0%), upper respiratory tract infection (16.5% vs 0%), aspartate aminotransferase increased (23.5% vs 3.5%), alanine aminotransferase increased (24.1% vs 5.3%) and mouth ulceration (16.5% vs 0%).

Non-Asian patients experienced the following adverse events at a greater frequency compared to Asian patients: rash (50.9% vs 6.5%), dry skin (36.8% vs 24.7%), dyspnea (22.8% vs 10.0%), mucosal inflammation (35.1% vs 0.6%), asthenia (35.1% vs 5.3%) and skin fissures (21.1% vs 5.3%).

Gender

In ARCHER 1050, female patients (146/227: 64.3%) had a greater incidence of Grade 3 AEs (57.5% vs 39.5%), of dose reductions (75.3% vs 49.4%), dose interruptions (60.3% vs 51.9%) and treatment discontinuation (13.6% vs 19.9%) than male patients (81/227: 35.7%) treated with VIZIMPRO.

Female patients experienced the following adverse events at a greater frequency than male patients: weight decreased (28.8% vs 19.8%), conjunctivitis (22.6% vs 12.3%), alopecia (29.5% vs 12.3%).

Adverse Reactions

Adverse Reaction Overview

The adverse reactions described in this section are based on 227 patients with unresectable locally advanced or metastatic NSCLC with EGFR-activating mutations who participated in a multicenter, multinational, randomized (1:1), open label Phase 3 study (ARCHER 1050 – see Section 13 CLINICAL TRIALS) of dacomitinib versus gefitinib as firstline treatmentP. The median duration of treatment was 66.6 weeks for VIZIMPRO and 52.1 weeks for gefitinib.

The most commonly reported (>20%) all-causality adverse reactions in patients receiving VIZIMPRO were diarrhea (87.2%), rash (77.1%), stomatitis (69.6%), paronychia (65.6%), decreased appetite (30.8%), dry skin (29.5%), weight decreased (25.6%), conjunctivitis (24.2%), transaminases increased (23.8%), alopecia (23.3%), and cough (21.1%).

Serious all-causality adverse reactions were reported in 27.3% of patients treated with VIZIMPRO. The most frequently (≥ 0.5%) reported serious adverse reactions in patients receiving VIZIMPRO were diarrhea (2.2%), interstitial lung disease (1.3%), rash (0.9%), and decreased appetite (0.9%).

Adverse reactions leading to dose reduction were reported in 66.1% of patients treated with VIZIMPRO. The most frequently reported (> 5%) reasons for dose reductions due to any adverse reactions in patients receiving VIZIMPRO were rash (33.0%), paronychia (17.6%), and diarrhea (8.4%).

Adverse events requiring dose interruptions occurred in 57.3% of patients treated with VIZIMPRO. The most frequent adverse reactions (> 5%) leading to dose interruptions were rash (25.1%), paronychia (13.2%) and diarrhea (9.7%).

Adverse reactions leading to permanent treatment discontinuations were reported in 17.6% of patients treated with VIZIMPRO. The most commonly reported (> 0.5%) reasons for permanent discontinuations associated with adverse reactions in patients receiving VIZIMPRO were: rash (2.6%), interstitial lung disease (1.8%), stomatitis (0.9%) and diarrhea (0.9%).

Clinical Trial Adverse Reactions

Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Tables 4 and 5 summarize common adverse reactions and laboratory abnormalities in patients who received VIZIMPRO in ARCHER 1050.

Table 4. Treatment-emergent Adverse Reactions With ≥10% Incidence in Patients in ARCHER 1050
 
Preferred terms (PTs) were retrieved by applying the Medical Dictionary for Regulatory Activities (MedDRA) version 19.1.
Severity grade of adverse reactions according to the NCI CTCAE version 4.03
Abbreviations: NSCLC=non-small cell lung cancer; NCI CTCAE= National Cancer Institute Common Toxicity Criteria for Adverse Events, ARs = Adverse reactions
a
Grade 1 through 5 are included in All Grades.
b
Grade 5 event in the VIZIMPRO arm
c
Conjunctivitis includes the following PTs: Conjunctivitis, Dry eye, Blepharitis, Keratitis, Noninfective conjunctivitis.
d
Stomatitis includes the following PTs: Aphthous ulcer, Cheilitis, Dry mouth, Mucosal inflammation, Mouth ulceration, Oral pain, Oropharyngeal pain, Stomatitis.
e
Rash (also referred to as Rash and erythematous skin conditions) includes the following PTs: Acne, Dermatitis acneiform, Erythema, Rash, Rash erythematous, Rash generalized, Rash macular, Rash maculo-papular, Rash popular.
f
Nail disorder includes the following PTs: Ingrowing nail, Nail discoloration, Nail disorder, Nail infection, Nail toxicity, Onychoclasis, Onychomadesis, Onycholysis, Paronychia.
g
Dry skin includes the following PTs: Dry skin, Xerosis.
h
Pruritus includes the following PTs: Pruritus, Rash pruritic
i
Transaminases increased includes the following preferred terms: Alanine aminotransferase increased, Aspartate aminotransferase increased, Transaminases increased.

System Organ Class

Adverse Reactions

Dacomitinib

(N=227)

Gefitinib

(N=224)

All Gradesa

%

Grade 3

%

Grade 4

%

All Grades

%

Grade 3

%

Grade 4

%

Eye disorders

Conjunctivitisc

24

0.4

0

9

0

0

Gastrointestinal disorders

Diarrheab

Stomatitisd

Nausea

Constipation

87

70

19

13

8

4

1.3

0

0

0.4

0

0

56

34

22

14

0.9

0.4

0.4

0

0

0

0

0

General disorders and administration site conditions

Asthenia

13

2

0

13

1.3

0

Investigation

Transaminases increasedi

23.8

0.9

0.0

40.2

9.8

0.0

Metabolism and nutrition disorders

Decreased appetite

Decreased weight

31

26

3

4

0

0.9

25

6

0.4

1.8

0

0

Musculoskeletal and connective tissue disorders

Pain in extremity

Musculoskeletal pain

14

12

0

0.9

0

0

12

13

0

0

0

0

Psychiatric disorders

Insomnia

11

0.4

0

15

0

0

Respiratory

Cough

Dyspnea

Upper respiratory tract infection

21

13

12

0

1.8

1.3

0

0.4

0

19

13

13

0.4

1.8

0

0

0

0

Skin and subcutaneous tissue disorders

Rashe

Nail disorderf

Dry sking

Alopecia

Pruritush

Palmar-plantar erythrodysesthesia syndrome

Dermatitis

77

66

30

23

20

15

11

24

8

1.8

0.4

0.9

0.9

1.8

0

0

0

0

0

0

0

58

21

19

13

14

3

4

0.9

1.3

0.4

0

1.3

0

0.4

0

0

0

0

0

0

0

Clinical Trial Adverse Reactions that were reported in <10% of patients

Additional adverse reactions (all grades) that were reported in <10% of patients who received VIZIMPRO 45 mg in ARCHER 1050 include:

General disorders and administration site conditions: fatigue (9.3%)
Skin and subcutaneous tissue disorders: hypertrichosis (1.3%), skin exfoliation (3.1%), exfoliative rash (0.4%), skin fissures (9.3%)
Gastrointestinal disorders: vomiting (8.8%)
Nervous system disorder: dysgeusia (7.0%)
Respiratory, thoracic and mediastinal disorders: interstitial lung disease (1.3%)a, pneumonitis (1.3%)
Metabolism and nutrition: dehydration (1.3%)

a1 Grade 5 event in the VIZIMPRO arm

For First-Line Pool, additional adverse reactions (all grades) that were reported in <10% of patients but not reported in ARCHER 1050 include:

Skin and subcutaneous tissue disorders: erythema multiforme 1.2%, nail bed bleeding 0.4%, nail bed inflammation 0.4%.

ECG Findings:

In ARCHER 1050, ECG assessments were performed at baseline and after 15 days of treatment with VIZIMPRO 45 mg QD in 211 patients. The mean change from baseline in the PR interval on day 15 was 6.9 ms (90% CI 4.8, 8.9) (See ACTION AND CLINICAL PHARMACOLOGY, Cardiac Electrophysiology).

Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Table 5. Common Laboratory Abnormalities (>20% for all NCI CTCAE Grades) in ARCHER 1050

ALT=alanine aminotransferase; AST= aspartate aminotransferase

a
Based on the number of patients with available baseline and follow-up laboratory data

Laboratory Test Abnormalitya

VIZIMPRO

Gefitinib

Change from Baseline

All Grades (%)

Change from Baseline to Grade 3 or Grade 4 (%)

Change from Baseline

All Grades (%)

Change from Baseline to Grade 3 or Grade 4 (%)

Hematology

Anemia

44

0.9

26

2.7

White blood cells decreased

14

0.5

21

0.5

Lymphopenia

47

7.3

40

3.5

Chemistry

Alkaline phosphatase elevation

22

0.5

22

2.0

AST elevation

35

0.5

57

7.7

ALT elevation

40

1.4

63

13

Total bilirubin elevation

16

0.5

22

0.5

Hypocalcemia

33

1.4

28

2.0

Hypomagnesemia

23

0.5

9

0

Hypokalemia

29

7.2

18

2.0

Hyperglycemia

36

1.0

38

2.5

Hyponatremia

26

2.9

20

1.5

Creatinine

95

0

88

0.5

Hypoalbuminemia

44

0

34

0

Clinical Trial Adverse Reactions (Pediatrics)

The safety and efficacy of VIZIMPRO in children (<18 years of age) have not been established.

Drug Interactions

Overview

Dacomitinib is metabolized by CYP2D6. Coadministration of dacomitinib with strong inhibitors of CYP2D6 did not result in clinically relevant changes in exposure of dacomitinib. Dacomitinib is a strong inhibitor of CYP2D6; dose reduction may be needed for coadministered drugs that are predominantly metabolized by CYP2D6.

The aqueous solubility of dacomitinib is pH dependent, with low (acidic) pH resulting in higher solubility. Proton pump inhibitors (PPIs) should be avoided while receiving treatment with VIZIMPRO. Local antacids may be used if needed.

The related findings and precautions are discussed further below.

Drug-Drug Interactions

The drugs listed in this table are based on either drug interaction studies, or potential interactions due to the expected magnitude and seriousness of the interaction.

Table 6 - Established or Potential Drug-Drug Interactions
 
Legend: CT = Clinical Trial; T = Theoretical

<Proper/Common name>

Source of Evidence

Effect

Clinical comment

Proton Pump Inhibitors:

dexlansoprazole, esomeprazole,

omeprazole,

lansoprazole,

pantoprazole, and rabeprazole

CT/T

Coadministration of a single 45 mg dacomitinib dose with multiple doses of the rabeprazole decreased dacomitinib Cmax and AUC0-96h by approximately 51% and 39%, respectively.

Avoid while receiving treatment with VIZIMPRO.

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

procainamide,

pimozide, and

thioridazine

CT/T

Coadministration of single 45 mg oral dose of dacomitinib increased the mean exposure (AUClast and Cmax) of dextromethorphan, a probe CYP2D6 substrate, by 855% and 874%, respectively, compared with administration of dextromethorphan alone.

Avoid while receiving treatment with VIZIMPRO.

CYP2D6 inhibitors

CT

Coadministration of a single 45 mg oral dose of dacomitinib in the presence of paroxetine (30 mg), a potent CYP2D6 inhibitor, resulted in a 37% increase in dacomitinib exposure (AUC).

The change in dacomitinib disposition due to paroxetine coadministration is unlikely to be clinically relevant. Dose adjustment of dacomitinib is not required upon concomitant administration with a CYP2D6 inhibitor.

Coadministration of Dacomitinib and CYP2D6 Inhibitors

Coadministration of a single 45 mg oral dose of dacomitinib in the presence of paroxetine (30 mg), a potent CYP2D6 inhibitor, resulted in a 37% increase in dacomitinib exposures (AUC). The change in dacomitinib disposition due to paroxetine coadministration is unlikely to be clinically relevant and dose adjustment of dacomitinib is not required upon concomitant administration with a CYP2D6 inhibitor.

Coadministration of Dacomitinib and CYP2D6 Substrates

Coadministration of single 45 mg oral dose of dacomitinib increased the mean exposure (AUC and Cmax) of dextromethorphan, a probe CYP2D6 substrate, 9.55-fold and 9.74-fold, respectively, compared with administration of dextromethorphan alone. Avoid concomitant use of VIZIMPRO with CYP2D6 substrates where minimal increases in concentration of the CYP2D6 substrate may lead to serious or life threatening toxicities. For concomitant use of other CYP2D6 substrate drugs, follow their respective labels for dose recommendation regarding co-administration with strong CYP2D6 inhibitors. Drugs with active metabolites formed via CYP2D6 should be replaced by an alternative within the therapeutic class as their exposure with the coadministration of dacomitinib may be subtherapeutic.

Coadministration of Dacomitinib with Agents That Increase Gastric pH

The aqueous solubility of dacomitinib is pH dependent, with low (acidic) pH resulting in higher solubility. Data from a study in healthy subjects indicated that coadministration of a single 45 mg dacomitinib dose with multiple doses of the PPI rabeprazole decreased dacomitinib Cmax and AUC0-96h (area under the concentration-time curve from time 0 to 96 hours post dose) by approximately 51% and 39%, respectively when compared to a single 45 mg dose of VIZIMPRO administered alone. Proton pump inhibitors (PPIs) should be avoided while receiving treatment with VIZIMPRO.

Based on data from observations in 8 patients, there were no clinically significant effects of local antacid (Maalox® Maximum Strength) administration on Cmax and AUCinf of dacomitinib. Local antacids may be used if needed. The impact of histamine-2 receptor (H2) antagonists on dacomitinib pharmacokinetics has not been studied.

Effect of Dacomitinib and O-desmethyl Dacomitinib on CYP Enzymes

In vitro, dacomitinib and its metabolite O-desmethyl dacomitinib have a low potential to inhibit the activities of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4/5 at clinically relevant concentrations, but they may inhibit the activity of CYP2D6.

In vitro, dacomitinib has a low potential to induce CYP1A2, CYP2B6, or CYP3A4 at clinically relevant concentrations.

Effect of Dacomitinib on Drug Transporters

In vitro,dacomitinib has a low potential to inhibit the activities of drug transporters P-gp (systemically), organic anion transporters (OAT)1 and OAT3, organic cation transporter (OCT)2, organic anion transporting polypeptide (OATP)1B1, and OATP1B3, but may inhibit the activity of P-gp (in the GI tract), BCRP (systemically and GI tract), and OCT1, at clinically relevant concentrations.

Effect of Dacomitinib on UGT Enzymes

In vitro, dacomitinib has a low potential to inhibit uridine-diphosphate glucuronosyltransferase (UGT) 1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15, but may inhibit UGT1A1 at clinically relevant concentrations.

Drug-Food Interactions

VIZIMPRO can be taken with or without food.

Drug-Herb Interactions

No data are available.

Drug-Laboratory Test Interactions

No data are available.

Drug-Lifestyle Interactions

No data are available.

Action And Clinical Pharmacology

Mechanism of Action

Dacomitinib is a pan-human epidermal growth factor receptor (HER) (EGFR/HER1, HER2, and HER4) inhibitor, with clinical activity against mutated EGFR with deletions in exon 19 or the L858R substitution in exon 21. Unlike first generation EGFR TKIs (gefinitib and erlotinib), which are reversible inhibitors that selectively target EGFR, dacomitinib is a second generation TKI that binds selectively and irreversibly to all three HER family targets thereby providing prolonged inhibition. Dacomitinib demonstrates dose-dependent target inhibition and antitumor efficacy in mice bearing human tumor xenografts driven by HER family targets including mutated EGFR.

Dacomitinib distributes to the brain in mice, with approximately equal brain and plasma average concentrations following oral dosing. Dacomitinib exhibits target inhibition and antitumor regression efficacy in orally-dosed dacomitinib- versus control-treated mice bearing intracranial human tumor xenografts driven by EGFR.

Pharmacodynamics

Cardiac Electrophysiology: The effect of dacomitinib on electrocardiogram (ECG) parameters was evaluated using time-matched ECG evaluating the change from baseline and corresponding pharmacokinetic data in 32 patients with advanced NSCLC. VIZIMPRO was administered for 4 days at a supratherapeutic dose of 45 mg q12h, which resulted in a mean dacomitinib Cmax value of 96.8 ng/mL, which is similar to the mean steady-state Cmax reported for the therapeutic 45 mg once daily dose administered continuously to steady-state (mean Cmax ranged from 79.5 to 108 ng/mL).

Dacomitinib 45 mg q12h resulted in prolongation of the PR interval at all time points assessed on Day 4 of treatment, with a change ranging from 2.7 ms (90% CI: 0.5, 4.9) to 6.6 ms (90% CI: 4.5, 8.8). No clinically meaningful effect on the QTc or the QRS complex were observed on the Day 4 assessment.

Pharmacokinetics

Table 7 - Summary of Dacomitinib Pharmacokinetic Parameters in Patients with Cancers
 

Cmax

Tmax

t½ (h)

AUCR0-∞

CL/F

Vd/F

Single dose mean

17.6-23.2 ng/mL

5 to 6 hours

54 to 80 hours

1348-1810 ng.hr/mL

24.9-33.4 L/hr

2424-2537 L

Dacomitinib steady state was achieved within 14 days following repeated dosing and the estimated geometric mean (CV%) accumulation ratio was 5.7 (28%) based on AUC.

Absorption: Following the administration of a single 45 mg dose of dacomitinib tablets, the mean oral bioavailability of dacomitinib is 80% compared to intravenous administration, with maximal plasma concentration (Cmax) occurring 5 to 6 hours (range: 2 to 24 hours) after oral dosing. Following dacomitinib 45 mg daily dosing, steady state was reached within 14 days.

Co-administration of dacomitinib with a high fat meal increased dacomitinib exposure, with the adjusted geometric mean ratios of 114.18% (90% CI: 109.41, 124.47) for AUCinf and 123.65% (90% CI: 105.27, 145.24) for Cmax, respectively, compared to overnight fasting. Food does not alter bioavailability to a clinically meaningful extent. Dacomitinib can be administered with or without food. However, it is recommended that dosing take place under consistent conditions (i.e. always fasted or always after the same type of meal) to avoid any unexpected increases in dacomitinib plasma concentrations.

Dacomitinib is a substrate for the membrane transport proteins P-glycoprotein (P-gp) and Breast Cancer Resistant Protein (BCRP). However, based on the oral bioavailability of 80% these membrane transport proteins are unlikely to have any impact on dacomitinib absorption.

Distribution: Dacomitinib is extensively distributed throughout the body with a mean steady state volume of distribution of 1889 L following intravenous administration. In vitro binding of dacomitinib to human plasma proteins is approximately 98% and is independent of drug concentrations.

Metabolism: In humans, dacomitinib undergoes oxidation and glutathione conjugation as the major metabolic pathways. Following oral administration of a single 45 mg dose of [14C]dacomitinib, the most abundant circulating metabolite was O-desmethyl dacomitinib. This metabolite exhibited in vitro pharmacologic activity that was similar to that of dacomitinib in the in vitro biochemical assays. In feces, dacomitinib, O-desmethyl dacomitinib, a cysteine conjugate of dacomitinib, and a mono-oxygenated metabolite of dacomitinib were the major drug-related components. In vitro studies indicated that CYP2D6 was the major CYP isozyme involved in the formation of O-desmethyl dacomitinib, while CYP3A4 contributed to the formation of other minor oxidative metabolites.

Elimination: The plasma half-life of dacomitinib ranges from 54 to 80 hours. In six healthy male subjects given a single-oral dose of [14C] radiolabeled dacomitinib, a median of 82% of the total administered radioactivity was recovered in 552 hours; feces (79% of dose) was the major route of excretion, with 3% of the dose recovered in urine.

Special Populations and Conditions

Pediatrics: The safety and efficacy of dacomitinib in children (<18 years of age) have not been established.

Pregnancy and Breast-feeding: There are no adequate and well-controlled studies in pregnant women using dacomitinib.

Age, gender, race, and body weight: Based on population pharmacokinetic analyses, patient age, race (Asian versus non-Asian), gender, and body weight do not have a clinically relevant effect on predicted steady-state clearance of dacomitinib.

Hepatic Impairment: In a dedicated hepatic impairment trial, following a single oral dose of 30 mg VIZIMPRO, dacomitinib exposure (AUC and Cmax) was unchanged in mild hepatic impairment (Child Pugh A; N=8) and decreased by 15% and 20%, respectively in moderate hepatic impairment (Child Pugh B; N=9) when compared to subjects with normal hepatic function (N=8). Dacomitinib pharmacokinetics has not been studied in subjects with severe hepatic impairment (Child-Pugh class C). In addition, based on a population pharmacokinetic analysis using data from 1381 patients, that included 158 patients with mild hepatic impairment (total bilirubin ≤ Upper Limit of Normal (ULN) and AST >ULN, or total bilirubin >1.0 to 1.5 × ULN and any AST; , mild hepatic impairment had no effect on the pharmacokinetics of dacomitinib. From the small number of patients in the moderate group (total bilirubin >1.5 to 3 × ULN and any AST; N=5), there is no evidence for a change in dacomitinib pharmacokinetics.

Renal Impairment: Approximately 3% of a single [14-C] 45 mg dose was excreted in the urine. No clinical studies have been conducted in patients with impaired renal function. Based on population pharmacokinetic analyses, mild (60 mL/min≤CrCl <90 mL/min; N=590) and moderate (30 mL/min≤CrCl<60 mL/min; N=218) renal impairment, did not alter dacomitinib pharmacokinetics, relative to subjects with normal (CrCl ≥90mL/min; N=567) renal function. Limited pharmacokinetic data are available in patients with severe renal impairment (CrCl < 30 mL/min) (N=4). The pharmacokinetics of dacomitinib have not been studied in patients requiring hemodialysis.

Storage, Stability And Disposal

Store between 15°C and 30°C in the original package to protect from moisture.

 

Control #: 214572
February 22, 2019

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