Vizimpro

VIZIMPRO is indicated for the first-line treatment of patients with metastatic non-small cell 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

Recommended Dosage: 45 mg orally once daily with or without food. (

Tablets:

• •45 mg: blue film-coated, immediate release, round biconvex tablet, debossed with "Pfizer" on one side and "DCB45" on the other side.
• •30 mg: blue film-coated, immediate release, round biconvex tablet, debossed with "Pfizer" on one side and "DCB30" on the other side.
• •15 mg: blue film-coated, immediate release, round biconvex tablet, debossed with "Pfizer" on one side and "DCB15" on the other side.

• •Lactation: Advise not to breastfeed. (
  8.2 Lactation

  Risk Summary

  There is no information regarding the presence of dacomitinib or its metabolites in human milk or their effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants from VIZIMPRO, advise women not to breastfeed during treatment with VIZIMPRO and for at least 17 days after the last dose.
  )

• •Interstitial Lung Disease (ILD): Permanently discontinue VIZIMPRO if ILD is confirmed. (
  5.1 Interstitial Lung Disease (ILD)

  Severe and fatal ILD/pneumonitis occurred in patients treated with VIZIMPRO and occurred in 0.5% of the 394 VIZIMPRO-treated patients; 0.3% of cases were fatal.

  Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Withhold VIZIMPRO and promptly investigate for ILD in patients who present with worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough, and fever). Permanently discontinue VIZIMPRO if ILD is confirmed

  [see Adverse Reactions (6.1)]

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• •Diarrhea: Withhold and reduce the dose of VIZIMPRO based on the severity. (
  2.3 Dosage Modifications for Adverse Reactions

  Reduce the dose of VIZIMPRO for adverse reactions as described in Table 1. Dosage modifications for specific adverse reactions are provided in Table 2.

  Table 1. VIZIMPRO Recommended Dose Reductions for Adverse Reactions

  Dose Level	Dose (Once Daily)
  First dose reduction	30 mg
  Second dose reduction	15 mg

  Permanently discontinue VIZIMPRO.Withhold VIZIMPRO until recovery to less than or equal to Grade 1; then resume VIZIMPRO at the same dose level.

  For recurrent Grade 2 diarrhea, withhold until recovery to less than or equal to Grade 1; then resume VIZIMPRO at a reduced dose.Withhold VIZIMPRO until recovery to less than or equal to Grade 1; then resume VIZIMPRO at a reduced dose.Withhold VIZIMPRO for persistent dermatologic adverse reactions; upon recovery to less than or equal to Grade 1, resume VIZIMPRO at the same dose level.

  For recurrent persistent Grade 2 dermatologic adverse reactions, withhold until recovery to less than or equal to Grade 1; then resume VIZIMPRO at a reduced dose.Withhold VIZIMPRO until recovery to less than or equal to Grade 1; then resume VIZIMPRO at a reduced dose.Withhold VIZIMPRO until recovery to less than or equal to Grade 2; then resume VIZIMPRO at a reduced dose.

  Table 2. VIZIMPRO Dosage Modifications for Adverse Reactions

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  Adverse Reaction	Severity National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03.	Dosage Modification
  Interstitial lung disease (ILD) [see Warnings and Precautions (5.1)]	Any Grade
  Diarrhea [see Warnings and Precautions (5.2)]	Grade 2
  	Grade 3 or 4
  Dermatologic Adverse Reactions [see Warnings and Precautions (5.3)]	Grade 2
  	Grade 3 or 4
  Other	Grade 3 or 4
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  5.2 Diarrhea

  Severe and fatal diarrhea occurred in patients treated with VIZIMPRO. Diarrhea occurred in 86% of the 394 VIZIMPRO-treated patients; Grade 3 or 4 diarrhea was reported in 11% of patients and 0.3% of cases were fatal.

  Withhold VIZIMPRO for Grade 2 or greater diarrhea until recovery to less than or equal to Grade 1 severity, then resume VIZIMPRO at the same or a reduced dose depending on the severity of diarrhea

  [see Dosage and Administration (2.3)and Adverse Reactions (6.1)].

  Promptly initiate anti-diarrheal treatment (loperamide or diphenoxylate hydrochloride with atropine sulfate) for diarrhea.
  )
• •Dermatologic Adverse Reactions: Withhold and reduce the dose of VIZIMPRO based on the severity. (
  2.3 Dosage Modifications for Adverse Reactions

  Reduce the dose of VIZIMPRO for adverse reactions as described in Table 1. Dosage modifications for specific adverse reactions are provided in Table 2.

  Table 1. VIZIMPRO Recommended Dose Reductions for Adverse Reactions

  Dose Level	Dose (Once Daily)
  First dose reduction	30 mg
  Second dose reduction	15 mg

  Permanently discontinue VIZIMPRO.Withhold VIZIMPRO until recovery to less than or equal to Grade 1; then resume VIZIMPRO at the same dose level.

  For recurrent Grade 2 diarrhea, withhold until recovery to less than or equal to Grade 1; then resume VIZIMPRO at a reduced dose.Withhold VIZIMPRO until recovery to less than or equal to Grade 1; then resume VIZIMPRO at a reduced dose.Withhold VIZIMPRO for persistent dermatologic adverse reactions; upon recovery to less than or equal to Grade 1, resume VIZIMPRO at the same dose level.

  For recurrent persistent Grade 2 dermatologic adverse reactions, withhold until recovery to less than or equal to Grade 1; then resume VIZIMPRO at a reduced dose.Withhold VIZIMPRO until recovery to less than or equal to Grade 1; then resume VIZIMPRO at a reduced dose.Withhold VIZIMPRO until recovery to less than or equal to Grade 2; then resume VIZIMPRO at a reduced dose.

  Table 2. VIZIMPRO Dosage Modifications for Adverse Reactions

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  •

  •

  •

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  Adverse Reaction	Severity National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03.	Dosage Modification
  Interstitial lung disease (ILD) [see Warnings and Precautions (5.1)]	Any Grade
  Diarrhea [see Warnings and Precautions (5.2)]	Grade 2
  	Grade 3 or 4
  Dermatologic Adverse Reactions [see Warnings and Precautions (5.3)]	Grade 2
  	Grade 3 or 4
  Other	Grade 3 or 4
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  5.3 Dermatologic Adverse Reactions

  Rash and exfoliative skin reactions occurred in patients treated with VIZIMPRO. Rash occurred in 78% of the 394 VIZIMPRO-treated patients; Grade 3 or 4 rash was reported in 21% of patients. Exfoliative skin reactions of any severity were reported in 7% of patients. Grade 3 or 4 exfoliative skin reactions were reported in 1.8% of patients.

  Withhold VIZIMPRO for persistent Grade 2 or any Grade 3 or 4 dermatologic adverse reaction until recovery to less than or equal to Grade 1 severity, then resume VIZIMPRO at the same or a reduced dose depending on the severity of the dermatologic adverse reaction

  [see Dosage and Administration (2.3)and Adverse Reactions (6.1)].

  The incidence and severity of rash and exfoliative skin reactions may increase with sun exposure. At the time of initiation of VIZIMPRO, 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 or more severe dermatologic adverse reactions.
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• •Embryo-Fetal Toxicity: VIZIMPRO can cause fetal harm. Advise females of reproductive potential to use effective contraception. (
  5.4 Embryo-Fetal Toxicity

  Based on findings from animal studies and its mechanism of action, VIZIMPRO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of dacomitinib to pregnant rats during the period of organogenesis resulted in an increased incidence of post-implantation loss and reduced fetal body weight at doses resulting in exposures near the exposure at the 45 mg human dose. The absence of EGFR signaling has been shown to result in embryolethality as well as post-natal death in animals. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with VIZIMPRO and for at least 17 days after the final dose

  [see Use in Specific Populations (8.1and 8.3)]

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  8.1 Pregnancy

  Risk Summary

  Based on findings from animal studies and its mechanism of action, VIZIMPRO can cause fetal harm when administered to a pregnant woman

  [see Clinical Pharmacology (12.1)]

  . There are no available data on VIZIMPRO use in pregnant women. In animal reproduction studies, oral administration of dacomitinib to pregnant rats during the period of organogenesis resulted in an increased incidence of post-implantation loss and reduced fetal body weight at doses resulting in exposures near the exposure at the 45 mg human dose

  (see Data)

  . The absence of EGFR signaling has been shown to result in embryolethality as well as post-natal death in animals

  (see Data)

  . Advise pregnant women of the potential risk to a fetus

  [see Use in Special Populations (8.3)]

  .

  In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

  Data

  Animal Data

  Daily oral administration of dacomitinib to pregnant rats during the period of organogenesis resulted in an increased incidence of post-implantation loss, maternal toxicity, and reduced fetal body weight at 5 mg/kg/day (approximately 1.2 times the exposure based on area under the curve [AUC] at the 45 mg human dose).

  Disruption or depletion of EGFR in mouse models has shown EGFR is critically important in reproductive and developmental processes including blastocyst implantation, placental development, and embryo-fetal/post-natal survival and development. Reduction or elimination of embryo-fetal or maternal EGFR signaling in mice can prevent implantation, and can cause embryo-fetal loss during various stages of gestation (through effects on placental development), developmental anomalies, early death in surviving fetuses, and adverse developmental outcomes in multiple organs in embryos/neonates.
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  8.3 Females and Males of Reproductive Potential

  Pregnancy Testing

  Verify the pregnancy status of females of reproductive potential prior to initiating VIZIMPRO

  [

  see Use in Specific Populations (8.1)].

  Contraception

  VIZIMPRO can cause fetal harm when administered to a pregnant woman

  [see Use in Specific Populations (8.1)].

  Females

  Advise females of reproductive potential to use effective contraception during treatment with VIZIMPRO and for at least 17 days after the final dose.
  )