Enhertu: Package Insert and Label Information

ENHERTU- trastuzumab deruxtecan injection, powder, lyophilized, for solution
Daiichi Sankyo Inc.

WARNING: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITY

  • 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 the need to immediately report symptoms [see Dosage and Administration (2.3), Warnings and Precautions (5.1)].
  • Embryo-Fetal Toxicity: Exposure to ENHERTU during pregnancy can cause embryo-fetal harm. Advise patients of these risks and the need for effective contraception [see Warnings and Precautions (5.4), Use in Specific Populations (8.1, 8.3)].

1 INDICATIONS AND USAGE

1.1 Metastatic Breast Cancer

ENHERTU is 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 [see Clinical Studies (14.1)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

1.2 Locally Advanced or Metastatic Gastric Cancer

ENHERTU is indicated for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen.

2 DOSAGE AND ADMINISTRATION

2.1 Patient Selection for Locally Advanced or Metastatic Gastric Cancer

Select patients with locally advanced or metastatic gastric cancer based on HER2 protein overexpression or HER2 gene amplification. Reassess HER2 status if it is feasible to obtain a new tumor specimen after prior trastuzumab-based therapy and before treatment with ENHERTU.

Information on FDA-approved tests for the detection of HER2 protein overexpression and HER2 gene amplification in gastric cancer is available at: http://www.fda.gov/CompanionDiagnostics.

2.2 Recommended Dosage and Schedules

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

First infusion: Administer infusion over 90 minutes.

Subsequent infusions: Administer over 30 minutes if prior infusions were well tolerated.

Slow or interrupt the infusion rate if the patient develops infusion-related symptoms.

Permanently discontinue ENHERTU in case of severe infusion reactions.

Recommended Dosage for Metastatic Breast Cancer

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.

Recommended Dosage for Locally Advanced or Metastatic Gastric Cancer

The recommended dosage of ENHERTU is 6.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.

2.3 Dose Modifications

Management of adverse reactions may require temporary interruption, dose reduction, or treatment discontinuation of ENHERTU as described in Tables 1 and 2.

Do not re-escalate the ENHERTU dose after a dose reduction is made.

If a planned dose is delayed or missed, administer as soon as possible; do not wait until the next planned cycle. Adjust the schedule of administration to maintain a 3-week interval between doses. Administer the infusion at the dose and rate the patient tolerated in the most recent infusion.

Table 1: Dose Reduction Schedule
Dose Reduction Schedule Breast Cancer Gastric Cancer
Recommended starting dose 5.4 mg/kg 6.4 mg/kg
First dose reduction 4.4 mg/kg 5.4 mg/kg
Second dose reduction 3.2 mg/kg 4.4 mg/kg
Requirement for further dose reduction Discontinue treatment. Discontinue treatment.
Table 2: Dose Modifications for Adverse Reactions
Adverse Reaction Severity Treatment Modification
Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTCAE v.4.03).
Interstitial Lung Disease (ILD)/Pneumonitis Asymptomatic ILD/pneumonitis (Grade 1) Interrupt ENHERTU until resolved to Grade 0, then:
  • if resolved in 28 days or less from date of onset, maintain dose.
  • if resolved in greater than 28 days from date of onset, reduce dose one level (see Table 1).
  • consider corticosteroid treatment as soon as ILD/pneumonitis is suspected [see Warnings and Precautions (5.1)].
Symptomatic ILD/pneumonitis (Grade 2 or greater)
  • Permanently discontinue ENHERTU.
  • Promptly initiate corticosteroid treatment as soon as ILD/pneumonitis is suspected [see Warnings and Precautions (5.1)].
Neutropenia Grade 3 (less than 1.0 to 0.5 × 109 /L)
  • Interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose.
Grade 4 (less than 0.5 × 109 /L)
  • Interrupt ENHERTU until resolved to Grade 2 or less.
  • Reduce dose by one level (see Table 1).
Febrile Neutropenia Absolute neutrophil count of less than 1.0 × 109 /L and temperature greater than 38.3°C or a sustained temperature of 38°C or greater for more than one hour
  • Interrupt ENHERTU until resolved.
  • Reduce dose by one level (see Table 1).
Thrombocytopenia Grade 3 (platelets less than 50 to 25 × 109 /L)
  • Interrupt ENHERTU until resolved to Grade 1 or less, then maintain dose.
Grade 4 (platelets less than 25 × 109 /L)
  • Interrupt ENHERTU until resolved to Grade 1 or less.
  • Reduce dose by one level (see Table 1).
Left Ventricular Dysfunction LVEF greater than 45% and absolute decrease from baseline is 10% to 20%
  • Continue treatment with ENHERTU.
LVEF 40% to 45% And absolute decrease from baseline is less than 10%
  • Continue treatment with ENHERTU.
  • Repeat LVEF assessment within 3 weeks.
And absolute decrease from baseline is 10% to 20%
  • Interrupt ENHERTU.
  • Repeat LVEF assessment within 3 weeks.
  • If LVEF has not recovered to within 10% from baseline, permanently discontinue ENHERTU.
  • If LVEF recovers to within 10% from baseline, resume treatment with ENHERTU at the same dose.
LVEF less than 40% or absolute decrease from baseline is greater than 20%
  • Interrupt ENHERTU.
  • Repeat LVEF assessment within 3 weeks.
  • If LVEF of less than 40% or absolute decrease from baseline of greater than 20% is confirmed, permanently discontinue ENHERTU.
Symptomatic congestive heart failure (CHF)
  • Permanently discontinue ENHERTU.

2.4 Preparation for Administration

In order to prevent medication errors, check the vial labels to ensure that the drug being prepared and administered is ENHERTU (fam-trastuzumab deruxtecan-nxki) and not trastuzumab or ado-trastuzumab emtansine.

Reconstitute and further dilute ENHERTU prior to intravenous infusion. Use appropriate aseptic technique.

ENHERTU (fam-trastuzumab deruxtecan-nxki) is a cytotoxic drug. Follow applicable special handling and disposal procedures.1

Reconstitution

  • Reconstitute immediately before dilution.
  • More than one vial may be needed for a full dose. Calculate the dose (mg), the total volume of reconstituted ENHERTU solution required, and the number of vial(s) of ENHERTU needed [see Dosage and Administration (2.2)].
  • Reconstitute each 100 mg vial by using a sterile syringe to slowly inject 5 mL of Sterile Water for Injection, USP into each vial to obtain a final concentration of 20 mg/mL.
  • Swirl the vial gently until completely dissolved. Do not shake.
  • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The solution should be clear and colorless to light yellow. Do not use if visible particles are observed or if the solution is cloudy or discolored.
  • If not used immediately, store the reconstituted ENHERTU vials in a refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours from the time of reconstitution, protected from light. Do not freeze.
  • The product does not contain a preservative. Discard unused ENHERTU after 24 hours refrigerated.

Dilution

  • Dilute the calculated volume of reconstituted ENHERTU in an intravenous infusion bag containing 100 mL of 5% Dextrose Injection, USP. Do not use Sodium Chloride Injection, USP. ENHERTU is compatible with an infusion bag made of polyvinylchloride or polyolefin (copolymer of ethylene and polypropylene).
  • Gently invert the infusion bag to thoroughly mix the solution. Do not shake.
  • Cover the infusion bag to protect from light.
  • If not used immediately, store at room temperature for up to 4 hours including preparation and infusion, or in a refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours, protected from light. Do not freeze.
  • Discard any unused portion left in the vial.

Administration

  • If the prepared infusion solution was stored refrigerated (2°C to 8°C [36°F to 46°F]), allow the solution to reach room temperature prior to administration.
  • Administer ENHERTU as an intravenous infusion only with an infusion set made of polyolefin or polybutadiene and a 0.20 or 0.22 micron in-line polyethersulfone (PES) or polysulfone (PS) filter. Do not administer as an intravenous push or bolus.
  • Do not mix ENHERTU with other drugs or administer other drugs through the same intravenous line.

3 DOSAGE FORMS AND STRENGTHS

For injection: 100 mg of fam-trastuzumab deruxtecan-nxki as a white to yellowish white lyophilized powder in a single-dose vial for reconstitution and further dilution

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Interstitial Lung Disease/Pneumonitis

Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ENHERTU [see Adverse Reactions (6.1)]. Advise patients to immediately report cough, dyspnea, fever, and/or any new or worsening respiratory symptoms. Monitor patients for signs and symptoms of ILD. Promptly investigate evidence of ILD. Evaluate patients with suspected ILD by radiographic imaging. Consider consultation with a pulmonologist. For asymptomatic (Grade 1) ILD, consider corticosteroid treatment (e.g., ≥0.5 mg/kg/day prednisolone or equivalent). Withhold ENHERTU until recovery [see Dosage and Administration (2.3)]. In cases of symptomatic ILD (Grade 2 or greater), promptly initiate systemic corticosteroid treatment (e.g., ≥1 mg/kg/day prednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least 4 weeks. Permanently discontinue ENHERTU in patients who are diagnosed with symptomatic (Grade 2 or greater) ILD [see Dosage and Administration (2.3)].

Metastatic Breast Cancer

In clinical studies, of the 234 patients with unresectable or metastatic HER2-positive breast cancer treated with ENHERTU 5.4 mg/kg, ILD occurred in 9% of patients. Fatal outcomes due to ILD and/or pneumonitis occurred in 2.6% of patients treated with ENHERTU. Median time to first onset was 4.1 months (range: 1.2 to 8.3).

Locally Advanced or Metastatic Gastric Cancer

In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range: 1.2 to 21.0).

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