U.S. FDA APPROVED  DRUGS DURING 2019

Sr.No-  47/19

 These highlights do not include all the information needed to use                                   ENHERTU safely and effectively.

See full prescribing information for ENHERTU. ENHERTU® (fam-trastuzumab deruxtecan-nxki) for injection, for intravenous use

Initial U.S. Approval: 2019

WARNING: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITY-           

See full prescribing information for complete boxed warning.

• Interstitial lung disease (ILD) and pneumonitis, including fatal cases, have been reported with ENHERTU. Monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Permanently discontinue ENHERTU in all patients with Grade 2 or higher ILD/pneumonitis. Advise patients of the risk and to immediately report symptoms.

 • Exposure to ENHERTU during pregnancy can cause embryo-fetal harm. Advise patients of these risks and the need for effective contraception. 

INDICATIONS AND USAGE-

 ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting.

 This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

ADVERSE REACTIONS

 The most common adverse reactions (=20%) were nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anemia, neutropenia, diarrhea, leukopenia, cough, and thrombocytopenia.

CONTRAINDICATIONS-

 None. 

WARNINGS AND PRECAUTIONS

 • Neutropenia: Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. Manage through treatment interruption or dose reduction.

 • Left Ventricular Dysfunction: Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. Manage through treatment interruption or discontinuation.

Permanently discontinue ENHERTU in patients with symptomatic congestive heart failure (CHF). 

DOSAGE AND ADMINISTRATION

 • Do not substitute ENHERTU for or with trastuzumab or ado trastuzumab emtansine.

 • For intravenous infusion only. Do not administer as an intravenous push or bolus. Do not use Sodium Chloride Injection, USP. 

 • The recommended dosage of ENHERTU is 5.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity. 

• Management of adverse reactions (ILD, neutropenia, or left ventricular dysfunction) may require temporary interruption, dose reduction, or discontinuation of ENHERTU.

DOSAGE FORMS AND STRENGTHS-

 For injection: 100 mg lyophilized powder in a single-dose vial

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Interstitial Lung Disease-                                                                                           

• Inform patients of the risks of severe or fatal ILD. Advise patients to contact their healthcare provider immediately for any of the following: cough, shortness of breath, fever, or other new or worsening respiratory symptoms ].

Neutropenia                                                                                                                        • Advise patients of the possibility of developing neutropenia and to immediately contact their healthcare provider should they develop a fever, particularly in association with any signs of infection

 Left Ventricular Dysfunction

• Advise patients to contact their healthcare provider immediately for any of the following: new onset or worsening shortness of breath, cough, fatigue, swelling of ankles/legs, palpitations, sudden weight gain, dizziness, loss of consciousness 

 Embryo-Fetal Toxicity

• Inform female patients of the potential risk to a fetus. Advise female patients to contact their healthcare provider of a known or suspected pregnancy

• Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 7 months after the last dose .

• Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 4 months after the last dose 

Lactation

• Advise women not to breastfeed during treatment and for 7 months after the last dose of ENHERTU

Infertility

• Advise males of reproductive potential that ENHERTU may impair fertility 

Manufactured by: Daiichi Sankyo, Inc., Basking Ridge, NJ 07920 U.S. License No. 2128 Marketed by: Daiichi Sankyo, Inc., Basking Ridge, NJ 07920 and AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850

CLINICAL PHARMACOLOGY

1. Mechanism of Action-

Fam-trastuzumab deruxtecan-nxki is a HER2-directed antibody-drug conjugate. The antibody is a humanized anti-HER2 IgG1.

2. Pharmacodynamics -

Cardiac Electrophysiology-                                                                                                The administration of multiple doses of ENHERTU (6.4 mg/kg every 3 weeks, which is 1.2 times the recommended dosage) did not show large mean effect (i.e. >20 ms) on the QTc interval in an open label, single-arm study in 51 patients with HER2-expressing metastatic breast cancer.

3, Pharmacokinetics-                                                                                                    The pharmacokinetics of fam-trastuzumab deruxtecan-nxki was evaluated in patients with cancer. Following a single dose, exposures (Cmax and AUC) of fam-trastuzumab deruxtecan-nxki and released topoisomerase inhibitor (DXd) increased proportionally over a dose range of 3.2 mg/kg to 8 mg/kg (approximately 0.6 to 1.5 times the recommended dose).

At the recommended dosage of ENHERTU, the geometric mean (coefficient of variation [CV]%) Cmax of fam trastuzumab deruxtecan-nxki and DXd were 122 µg/mL (20%) and 4.4 ng/mL (40%), respectively, and the AUC of fam trastuzumab deruxtecan-nxki and DXd were 735 µg·day/mL (31%) and 28 ng·day/mL (38%), respectively, based on population pharmacokinetic analysis.

Distribution-                                                                                                              Based on population pharmacokinetic analysis, the estimated volume of distribution of the central compartment (Vc) of fam-trastuzumab deruxtecan-nxki was 2.77 L. For humans, DXd plasma protein binding is approximately 97% and the blood to plasma ratio is approximately 0.6, in vitro.

Elimination-                                                                                                                   The median elimination half-life (t1/2) of fam-trastuzumab deruxtecan-nxki was approximately 5.7 days. Based on population pharmacokinetic analysis, the estimated systemic clearance of fam-trastuzumab deruxtecan-nxki was 0.42 L/day.

The median apparent elimination half-life (t1/2) of DXd was approximately 5.8 days. Based on population pharmacokinetic analysis, the estimated apparent systemic clearance of DXd was 19.2 L/h.

Metabolism-                                                                                                                   The humanized HER2 IgG1 monoclonal antibody is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. In vitro, DXd is primarily metabolized by CYP3A4.

Specific Populations-                                                                                                     No clinically significant differences in the pharmacokinetics of fam-trastuzumab deruxtecan-nxki or DXd were observed for age (23-96 years), race (Asian [n=291] and non-Asian [n=221]), sex, body weight (34.6-125.4 kg), mild (total bilirubin =ULN and any AST >ULN or total bilirubin >1 to 1.5 times ULN and any AST, n=215) hepatic impairment, mild (creatinine 11 Reference ID: 4537820 clearance [CLcr] =60 and <90 mL/min, n=206) or moderate (CLcr =30 and <60 mL/min; n=58) renal impairment based on population pharmacokinetic analysis.

Drug Interaction Studies-                                                                                         Clinical Studies Effect of CYP3A Inhibitors on DXd: Coadministration of itraconazole, a strong CYP3A inhibitor, with multiple doses of ENHERTU increased steady state AUC0-17 days of fam-trastuzumab deruxtecan-nxki by 11% and DXd by 18%. The impact of these changes is not clinically meaningful.

Effect of OATP Inhibitors on DXd: Coadministration of ritonavir, a dual inhibitor of OATP1B/CYP3A, with multiple doses of ENHERTU increased steady state AUC0-17 days of fam-trastuzumab deruxtecan-nxki by 19% and DXd by 22%. The impact of these changes is not clinically meaningful.

USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-

Based on its mechanism of action, ENHERTU can cause fetal harm when administered to a pregnant woman.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

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

 Lactation Risk Summary-

There is no data regarding the presence of fam-trastuzumab deruxtecan-nxki in human milk, the effects on the breastfed child, or the effects on milk production.

Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with ENHERTU and for 7 months after the last dose.

2. Females and Males of Reproductive Potential -

Pregnancy Testing Verify pregnancy status of females of reproductive potential prior to initiation of ENHERTU.

Contraception Females-                                                                                              ENHERTU can cause fetal harm when administered to a pregnant woman 

Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 7 months following the last dose.

Males-                                                                                                                        Because of the potential for genotoxicity, advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 4 months following the last dose