DRUG INTERACTIONS-

? Proton Pump Inhibitors (PPIs): Avoid use with VIZIMPRO; use locally-acting antacids or H2-receptor antagonist; administer VIZIMPRO at least 6 hours before or 10 hours after H2-receptor antagonist.

 ? CYP2D6 Substrates: Avoid concomitant use with VIZIMPRO where minimal increases in concentration of the CYP2D6 substrate may lead to serious or life-threatening toxicities

BRIEF SUMMARY

DACOMITINIB- (Sept 2018)

Indn-     To treat metastatic non-small-cell cancer  

Comp-     Tablets: 15 mg, 30 mg, and 45 mg.    Recommended Dosage: 45 mg orally once daily with or without food.

ADR-     Most common adverse reactions are (incidence >20%) diarrhea, rash, paronychia, stomatitis, decreased appetite, dry skin, decreased weight, alopecia, cough, and pruritus.

WARNINGS-        

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

 Diarrhea: Withhold and reduce the dose of based on the severity.  

Pat Inform-

Interstitial Lung Disease (ILD)-                                                                                        • Advise patients of the risks of severe or fatal ILD, including pneumonitis. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms .

Diarrhea-                                                                                                                               • Advise patients to contact their healthcare provider at the first signs of diarrhea. Advise patients that intravenous hydration and/or anti-diarrheal medication (e.g., loperamide) may be required to manage diarrhea.

=============================================================

U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  40

ADVERSE REACTIONS-

Most common adverse reactions are (incidence >20%) diarrhea, rash, paronychia, stomatitis, decreased appetite, dry skin, decreased weight, alopecia, cough, and pruritus.

CONTRAINDICATIONS-                                                                                                      None.

WARNINGS AND PRECAUTIONS-        

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

 Diarrhea: Withhold and reduce the dose of VIZIMPRO based on the severity.  

 Dermatologic Adverse Reactions: Withhold and reduce the dose of VIZIMPRO based on the severity.

  Embryo-Fetal Toxicity: VIZIMPRO can cause fetal harm. Advise females of reproductive potential to use effective contraception.

PATIENT COUNSELING INFORMATION-

 Advise the patient to read the FDA-approved patient labeling (Patient Information).

Interstitial Lung Disease (ILD)-                                                                                        • Advise patients of the risks of severe or fatal ILD, including pneumonitis. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms .

Diarrhea-                                                                                                                               • Advise patients to contact their healthcare provider at the first signs of diarrhea. Advise patients that intravenous hydration and/or anti-diarrheal medication (e.g., loperamide) may be required to manage diarrhea.

Dermatologic Adverse Reactions-                                                                                    • Advise patients to initiate use of moisturizers and to minimize sun exposure with protective clothing and use of sunscreen at the time of initiation of VIZIMPRO. Advise patients to contact their healthcare provider immediately to report new or worsening rash, erythematous and exfoliative reactions.

Drug Interactions-                                                                                                             • Advise patients to avoid use of PPIs while taking VIZIMPRO. Short-acting antacids or H2 receptor antagonists may be used if needed. Advise patients to take VIZIMPRO at least 6 hours before or 10 hours after taking an H2-receptor antagonist  

Embryo-Fetal Toxicity-                                                                                                       • Advise females of reproductive potential that VIZIMPRO can result in fetal harm and to use effective contraception during treatment with VIZIMPRO and for 17 days after the last dose of VIZIMPRO. Advise females of reproductive potential to contact their healthcare provider with a known or suspected pregnancy.

Lactation-                                                                                                                             • Advise women not to breastfeed during treatment with VIZIMPRO and for 17 days after the last dose of VIZIMPRO.

This product’s label may have been updated. For full prescribing information, please visit www.VIZIMPRO.com.

Distributed by Pfizer Lab USA

CLINICAL PHARMACOLOGY-

1.Mechanism of Action-                                                                                                     Dacomitinib is an irreversible inhibitor of the kinase activity 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). In vitro dacomitinib also inhibited the activity of DDR1, EPHA6, LCK, DDR2, and MNK1 at clinically relevant concentrations.

2. Pharmacodynamics-                                                                                                       Cardiac Electrophysiology-                                                                                               The effect of dacomitinib on the QT interval corrected for heart rate (QTc) was evaluated using time-matched electrocardiograms (ECGs) evaluating the change from baseline and corresponding pharmacokinetic data in 32 patients with advanced NSCLC.

Dacomitinib had no large effect on QTc (i.e., >20 ms) at maximum dacomitinib concentrations achieved with VIZIMPRO 45 mg orally once daily.

Exposure-Response Relationships- Higher exposures, across the range of exposures with the recommended dose of 45 mg daily, correlated with an increased probability of Grade =3 adverse events, specifically dermatologic toxicities and diarrhea. 

3. Pharmacokinetics-                                                                                                         The maximum dacomitinib plasma concentration (Cmax) and AUC at steady state increased proportionally over the dose range of VIZIMPRO 2 mg to 60 mg orally once daily (0.04 to 1.3 times the recommended dose) across dacomitinib studies in patients with cancer.

At a dose of 45 mg orally once daily, the geometric mean [coefficient of variation (CV%)] Cmax was 108 ng/mL (35%) and the AUC0-24h was 2213 ng•h/mL (35%) at steady state in a dose-finding clinical study conducted in patients with solid tumors.

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-                                                                                                                   The mean absolute bioavailability of dacomitinib is 80% after oral administration. The median dacomitinib time to reach maximum concentration (Tmax) occurred at approximately 6.0 hours (range 2.0 to 24 hours) after a single oral dose of VIZIMPRO 45 mg in patients with cancer.

Effect of Food-                                                                                             Administration of VIZIMPRO with a high-fat, high-calorie meal (approximately 800 to 1000 calories with 150, 250, and 500 to 600 calories from protein, carbohydrate and fat, respectively) had no clinically meaningful effect on dacomitinib pharmacokinetics.

Distribution-                                                                                                                  The geometric mean (CV%) volume of distribution of dacomitinib (Vss) was 1889 L (18%). In vitro binding of dacomitinib to human plasma proteins is approximately 98% and is independent of drug concentrations from 250 ng/mL to 1000 ng/mL.

Elimination-                                                                                                          Following a single 45 mg oral dose of VIZIMPRO in patients with cancer, the mean (CV%) plasma half-life of dacomitinib was 70 hours (21%), and the geometric mean (CV%) apparent plasma clearance of dacomitinib was 24.9 L/h (36%).

Metabolism-                                                                                                               Hepatic metabolism is the main route of clearance of dacomitinib, 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.

The steady-state plasma trough concentration of O-desmethyl dacomitinib ranges from 7.4% to 19% of the parent. In vitro studies indicated that cytochrome P450 (CYP) 2D6 was the major isozyme involved in the formation of O-desmethyl dacomitinib, while CYP3A4 contributed to the formation of other minor oxidative metabolites.

Excretion -                                                                                                                           Following a single oral 45 mg dose of [14C] radiolabeled dacomitinib, 79% of the radioactivity was recovered in feces (20% as dacomitinib) and 3% in urine (<1% as dacomitinib). 

 Specific Populations-                                                                                          Patients with Renal Impairment-                                                                              Based on population pharmacokinetic analyses, mild (60 mL/min = CLcr <90 mL/min; N=590) and moderate (30 mL/min = CLcr <60 mL/min; N=218) renal impairment did not alter dacomitinib pharmacokinetics, relative to the pharmacokinetics in patients with normal renal function (CLcr =90 mL/min; N=567).

The pharmacokinetics of dacomitinib has not been adequately characterized in patients with severe renal impairment (CLcr <30 mL/min) (N=4) or studied in patients requiring hemodialysis.

Patients with Hepatic Impairment-                                                                                 In a dedicated hepatic impairment trial, following a single oral dose of 30 mg VIZIMPRO, dacomitinib exposure (AUCinf and Cmax) was unchanged in subjects with mild hepatic impairment (Child-Pugh A; N=8) and decreased by 15% and 20%, respectively in subjects with moderate hepatic impairment (Child-Pugh B; N=9) when compared to subjects with normal hepatic function (N=8).

Drug Interaction Studies-                                                                                              Clinical Studies-                                                                                                               Effect of Acid-Reducing Agents on Dacomitinib -Coadministration of a single 45 mg dose of VIZIMPRO with multiple doses of rabeprazole (a proton pump inhibitor) decreased dacomitinib Cmax by 51% and AUC0-96h by 39% .

Coadministration of VIZIMPRO with a local antacid (Maalox® Maximum Strength, 400 mg/5 mL) did not cause clinically relevant changes dacomitinib concentrations/

The effect of H2 receptor antagonists on dacomitinib pharmacokinetics has not been studied.

Effect of Strong CYP2D6 Inhibitors on Dacomitinib-                                                       Coadministration of a single 45 mg dose of VIZIMPRO with multiple doses of paroxetine (a strong CYP2D6 inhibitor) in healthy subjects increased the total AUClast of dacomitinib plus its active metabolite (O-desmethyl dacomitinib) in plasma by approximately 6%, which is not considered clinically relevant.

Effect of Dacomitinib on CYP2D6 Substrates-                                                                 Coadministration of a single 45 mg oral dose of VIZIMPRO increased dextromethorphan (a CYP2D6

 USE IN SPECIFIC POPULATIONS-

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.

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.

Advise pregnant women of the potential risk to a fetus.

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.

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

3. Females and Males of Reproductive Potential Pregnancy Testing -

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

Contraception-                                                                                                                   VIZIMPRO can cause fetal harm when administered to a pregnant woman.

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

4.. Pediatric Use-                                                                                                                  The safety and effectiveness of VIZIMPRO in pediatrics have not been established.

5. Geriatric Use-                                                                                                                  Of the total number of patients (N=394) in five clinical studies with EGFR mutation-positive NSCLC who received VIZIMPRO at a dose of 45 mg orally once daily [ARCHER 1050 (N=227), Study A7471009 (N=38), Study A7471011 (N=83), Study A7471028 (N=16), and Study A7471017 (N=30)] 40% were 65 years of age and older.

Exploratory analyses across this population suggest a higher incidence of Grade 3 and 4 adverse reactions (67% versus 56%, respectively), more frequent dose interruptions (53% versus 45%, respectively), and more frequent discontinuations (24% versus 10%, respectively) for adverse reactions in patients 65 years or older as compared to those younger than 65 years.

6.Renal Impairment-                                                                                                           No dose adjustment is recommended for patients with mild or moderate renal impairment (creatinine clearance [CLcr] 30 to 89 mL/min estimated by Cockcroft-Gault). The recommended dose of VIZIMPRO has not been established for patients with severe renal impairment (CLcr <30 mL/min).

7. Hepatic Impairment-                                                                                                       No dose adjustment is recommended in patients with mild (total bilirubin = upper limit of normal [ULN] with AST > ULN or total bilirubin > 1 to 1.5 × ULN with any AST) or moderate (total bilirubin > 1.5 to 3 × ULN and any AST) hepatic impairment.

The recommended dose of VIZIMPRO has not been established for patients with severe hepatic impairment (total bilirubin > 3 to 10 × ULN and any AST).