Enhertu

(Fam-Trastuzumab Deruxtecan-Nxki)

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Dosage & Administration

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

(

2.2 Recommended Dosage and Schedules

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

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

Permanently discontinue ENHERTU in case of severe infusion reactions.

Premedication

ENHERTU is highly emetogenic

[see Adverse Reactions (6.1)]

, which includes delayed nausea and/or vomiting. Administer prophylactic antiemetic medications per local institutional guidelines for prevention of chemotherapy-induced nausea and vomiting.

Recommended Dosage for HER2-Positive, HER2-Low, or HER2-Ultralow Metastatic Breast Cancer, HER2-Mutant Unresectable or Metastatic NSCLC, and HER2-Positive (IHC 3+) Unresectable or Metastatic Solid Tumors.

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 HER2-Positive 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.

2.4 Preparation and 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 hazardous 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

.
* If not used immediately, store the reconstituted ENHERTU vials in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF) for up to 24 hours from the time of reconstitution, protect the vial from light.

Do not freeze

.
* The product does not contain a preservative. Discard unused ENHERTU after 24 hours refrigerated.

Dilution

Withdraw the calculated amount from the vial(s) using a sterile syringe. 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.

* 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.
* Discard any unused portion left in the vials.

Administration

If not used immediately, store the diluted ENHERTU in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF) for up to 24 hours or at room temperature between 20ºC to 25ºC (68ºF to 77 ºF) for up to 4 hours including preparation and infusion time.

Protect from light.

Do not freeze

The maximum time from reconstitution of the vial through the end of administration should not exceed 24 hours.

* If the prepared infusion solution was stored refrigerated (2ºC to 8ºC [36ºF to 46ºF]), allow the solution to reach room temperature prior to administration. Cover the infusion bag to protect from light.
* Administer ENHERTU as an intravenous infusion only with an infusion set made of polyolefin or polybutadiene.
* Administer ENHERTU with a 0.20 or 0.22 micron in-line polyethersulfone (PES) or polysulfone (PS) filter.
* Do NOT administer as an intravenous push or bolus.
* Cover the infusion bag to protect from light during administration.
* Do not mix ENHERTU with other drugs or administer other drugs through the same intravenous line.
* First infusion: Administer infusion over 90 minutes.
* Subsequent infusions: Administer over 30 minutes if prior infusions were well tolerated.

)
*

For intravenous infusion only

. Do not administer as an intravenous push or bolus. DO NOT use Sodium Chloride Injection, USP. (

2.4 Preparation and Administration

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

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

Reconstitution

[see Dosage and Administration (2.2)]

Do not shake

.
* If not used immediately, store the reconstituted ENHERTU vials in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF) for up to 24 hours from the time of reconstitution, protect the vial 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 shake

.
* Cover the infusion bag to protect from light.
* Discard any unused portion left in the vials.

Administration

Protect from light.

Do not freeze

The maximum time from reconstitution of the vial through the end of administration should not exceed 24 hours.

)
* Premedicate for prevention of chemotherapy-induced nausea and vomiting. (

2.2 Recommended Dosage and Schedules

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

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

Permanently discontinue ENHERTU in case of severe infusion reactions.

Premedication

ENHERTU is highly emetogenic

[see Adverse Reactions (6.1)]

, which includes delayed nausea and/or vomiting. Administer prophylactic antiemetic medications per local institutional guidelines for prevention of chemotherapy-induced nausea and vomiting.

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 HER2-Positive 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.

)
* The recommended dosage of ENHERTU for HER2-positive, HER2-low, or HER2-ultralow breast cancer, HER2-mutant NSCLC, and HER2-positive (IHC 3+) solid tumors is 5.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity. (

2.2 Recommended Dosage and Schedules

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

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

Permanently discontinue ENHERTU in case of severe infusion reactions.

Premedication

ENHERTU is highly emetogenic

[see Adverse Reactions (6.1)]

, which includes delayed nausea and/or vomiting. Administer prophylactic antiemetic medications per local institutional guidelines for prevention of chemotherapy-induced nausea and vomiting.

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 HER2-Positive 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 Dosage 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: Dosage Reduction Schedule
Dose Reduction Schedule	Breast Cancer, NSCLC, and IHC 3+ Solid Tumors	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: Dosage 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 5.0 (NCI CTCAE v.5.0).
Interstitial Lung Disease (ILD)/ Pneumonitis [see Warnings and Precautions (5.1)]	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.
	Symptomatic ILD/pneumonitis (Grade 2 or greater)		* Permanently discontinue ENHERTU. * Promptly initiate corticosteroid treatment as soon as ILD/pneumonitis is suspected.
Neutropenia [see Warnings and Precautions (5.2)]	Grade 3 (less than 1.0 to 0.5 × 10⁹/L)		* Interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose.
Neutropenia [see Warnings and Precautions (5.2)]	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 [see Warnings and Precautions (5.2)]	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 [see Adverse Reactions (6.1)]	Grade 3 (platelets less than 50 to 25 × 10⁹/L)		* Interrupt ENHERTU until resolved to Grade 1 or less, then maintain dose.
Thrombocytopenia [see Adverse Reactions (6.1)]	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 [see Warnings and Precautions (5.3)]	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.
	LVEF 40% to 45%	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.

)
* The recommended dosage of ENHERTU for HER2-positive gastric cancer is 6.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity. (

2.2 Recommended Dosage and Schedules

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

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

Permanently discontinue ENHERTU in case of severe infusion reactions.

Premedication

ENHERTU is highly emetogenic

[see Adverse Reactions (6.1)]

, which includes delayed nausea and/or vomiting. Administer prophylactic antiemetic medications per local institutional guidelines for prevention of chemotherapy-induced nausea and vomiting.

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 HER2-Positive 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 Dosage 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

Table 1: Dosage Reduction Schedule
Dose Reduction Schedule	Breast Cancer, NSCLC, and IHC 3+ Solid Tumors	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: Dosage 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 5.0 (NCI CTCAE v.5.0).
Interstitial Lung Disease (ILD)/ Pneumonitis [see Warnings and Precautions (5.1)]	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.
	Symptomatic ILD/pneumonitis (Grade 2 or greater)		* Permanently discontinue ENHERTU. * Promptly initiate corticosteroid treatment as soon as ILD/pneumonitis is suspected.
Neutropenia [see Warnings and Precautions (5.2)]	Grade 3 (less than 1.0 to 0.5 × 10⁹/L)		* Interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose.
Neutropenia [see Warnings and Precautions (5.2)]	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 [see Warnings and Precautions (5.2)]	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 [see Adverse Reactions (6.1)]	Grade 3 (platelets less than 50 to 25 × 10⁹/L)		* Interrupt ENHERTU until resolved to Grade 1 or less, then maintain dose.
Thrombocytopenia [see Adverse Reactions (6.1)]	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 [see Warnings and Precautions (5.3)]	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.
	LVEF 40% to 45%	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.

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

2.3 Dosage 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

Table 1: Dosage Reduction Schedule
Dose Reduction Schedule	Breast Cancer, NSCLC, and IHC 3+ Solid Tumors	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: Dosage 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 5.0 (NCI CTCAE v.5.0).
Interstitial Lung Disease (ILD)/ Pneumonitis [see Warnings and Precautions (5.1)]	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.
	Symptomatic ILD/pneumonitis (Grade 2 or greater)		* Permanently discontinue ENHERTU. * Promptly initiate corticosteroid treatment as soon as ILD/pneumonitis is suspected.
Neutropenia [see Warnings and Precautions (5.2)]	Grade 3 (less than 1.0 to 0.5 × 10⁹/L)		* Interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose.
Neutropenia [see Warnings and Precautions (5.2)]	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 [see Warnings and Precautions (5.2)]	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 [see Adverse Reactions (6.1)]	Grade 3 (platelets less than 50 to 25 × 10⁹/L)		* Interrupt ENHERTU until resolved to Grade 1 or less, then maintain dose.
Thrombocytopenia [see Adverse Reactions (6.1)]	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 [see Warnings and Precautions (5.3)]	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.
	LVEF 40% to 45%	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.

)

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Enhertu Prescribing Information

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

2.3 Dosage 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

Table 1: Dosage Reduction Schedule
Dose Reduction Schedule	Breast Cancer, NSCLC, and IHC 3+ Solid Tumors	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: Dosage 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 5.0 (NCI CTCAE v.5.0).
Interstitial Lung Disease (ILD)/ Pneumonitis [see Warnings and Precautions (5.1)]	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.
	Symptomatic ILD/pneumonitis (Grade 2 or greater)		Permanently discontinue ENHERTU. Promptly initiate corticosteroid treatment as soon as ILD/pneumonitis is suspected.
Neutropenia [see Warnings and Precautions (5.2)]	Grade 3 (less than 1.0 to 0.5 × 10⁹/L)		Interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose.
Neutropenia [see Warnings and Precautions (5.2)]	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 [see Warnings and Precautions (5.2)]	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 [see Adverse Reactions (6.1)]	Grade 3 (platelets less than 50 to 25 × 10⁹/L)		Interrupt ENHERTU until resolved to Grade 1 or less, then maintain dose.
Thrombocytopenia [see Adverse Reactions (6.1)]	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 [see Warnings and Precautions (5.3)]	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.
	LVEF 40% to 45%	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.

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)]

. A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment.

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)]

HER2-Positive, HER2-Low, and HER2-Ultralow Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)

In patients with metastatic breast cancer, HER2-mutant NSCLC, and other solid tumors treated with ENHERTU 5.4 mg/kg, ILD occurred in 12% of patients. Median time to first onset was 5.5 months (range: 0.9 to 31.5). Fatal outcomes due to ILD and/or pneumonitis occurred in 0.9% of patients treated with ENHERTU.

HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)

In 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).

]

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
5.4 Embryo-Fetal Toxicity
Based on its mechanism of action, ENHERTU can cause fetal harm when administered to a pregnant woman. In postmarketing reports, use of a HER2-directed antibody during pregnancy resulted in cases of oligohydramnios manifesting as fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Based on its mechanism of action, the topoisomerase inhibitor component of ENHERTU, DXd, can also cause embryo-fetal harm when administered to a pregnant woman because it is genotoxic and targets actively dividing cells
[see Use in Specific Populations (8.1), Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)]
. Advise patients of the potential risks to a fetus.
Verify the pregnancy status of females of reproductive potential prior to the initiation of ENHERTU. Advise females of reproductive potential to use effective contraception during treatment and for 7 months after the last dose of ENHERTU. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for 4 months after the last dose of ENHERTU
[see Use in Specific Populations (8.1, 8.3)]
.
,
8.1 Pregnancy
Risk Summary
Based on its mechanism of action, ENHERTU can cause fetal harm when administered to a pregnant woman. There are no available data on the use of ENHERTU in pregnant women. In postmarketing reports, use of a HER2-directed antibody during pregnancy resulted in cases of oligohydramnios manifesting as fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death (
see Data
). Based on its mechanism of action, the topoisomerase inhibitor component of ENHERTU, DXd, can also cause embryo-fetal harm when administered to a pregnant woman because it is genotoxic and targets actively dividing cells
[see Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)]
. Advise patients of the potential risks to a fetus.
There are clinical considerations if ENHERTU is used in pregnant women, or if a patient becomes pregnant within 7 months after the last dose of ENHERTU (
see Clinical Considerations
).
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 to 4% and 15 to 20%, respectively.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
Monitor women who received ENHERTU during pregnancy or within 7 months prior to conception for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care.
Data
Human Data
There are no available data on the use of ENHERTU in pregnant women. In postmarketing reports in pregnant women receiving a HER2-directed antibody, cases of oligohydramnios manifesting as fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death have been reported. These case reports described oligohydramnios in pregnant women who received a HER2-directed antibody either alone or in combination with chemotherapy. In some case reports, amniotic fluid index increased after use of a HER2-directed antibody was stopped.
Animal Data
There were no animal reproductive or developmental toxicity studies conducted with fam-trastuzumab deruxtecan-nxki.
,
8.3 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
[see Use in Specific Populations (8.1)]
. Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for 7 months after 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 4 months after the last dose
[see Nonclinical Toxicology (13.1)]
.
Infertility
Based on findings in animal toxicity studies, ENHERTU may impair male reproductive function and fertility
[see Nonclinical Toxicology (13.1)]
.
]
.

Indications and Usage (

1.2 HER2-Low and HER2-Ultralow Metastatic Breast Cancer

ENHERTU is indicated for the treatment of adult patients with unresectable or metastatic

Hormone receptor (HR)-positive HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer, as determined by an FDA-approved test, that has progressed on one or more endocrine therapies in the metastatic setting
[see Dosage and Administration (2.1)]
.
HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined by an FDA-approved test, who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy
[see Dosage and Administration (2.1)]
.

)

01/2025

Indications and Usage (

1.1 HER2-Positive Metastatic Breast Cancer

ENHERTU is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+ or ISH positive) breast cancer who have received a prior anti-HER2-based regimen either:

in the metastatic setting, or
in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy.

1.4 HER2-Positive Locally Advanced or Metastatic Gastric Cancer

ENHERTU is indicated for the treatment of adult patients with locally advanced or metastatic HER2-positive (IHC 3+ or IHC 2+/ISH positive) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen.

1.5 HER2-Positive (IHC 3+) Unresectable or Metastatic Solid Tumors

ENHERTU is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options.

This indication is approved under accelerated approval based on objective response rate and duration of response

[see Clinical Studies (14.5)]

. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

)

04/2024

Dosage and Administration (

2.1 Patient Selection

HER2-Low or HER2-Ultralow Unresectable or Metastatic Breast Cancer

Select patients for treatment of unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer with ENHERTU based on HER2 expression

[see Clinical Studies (14.2)]

HER2-Mutant Unresectable or Metastatic NSCLC

Select patients for the treatment of unresectable or metastatic HER2-mutant NSCLC with ENHERTU based on the presence of activating HER2 (ERBB2) mutations in tumor or plasma specimens

[see Clinical Studies (14.3)]

. If no mutation is detected in a plasma specimen, test tumor tissue.

HER2-Positive Locally Advanced or Metastatic Gastric Cancer

Select patients with locally advanced or metastatic HER2-positive gastric cancer based on HER2 protein overexpression or HER2 gene amplification (IHC 3+ or IHC 2+/ISH positive). Reassess HER2 status if it is feasible to obtain a new tumor specimen after prior trastuzumab-based therapy and before treatment with ENHERTU.

HER2-Positive (IHC 3+) Unresectable or Metastatic Solid Tumors

Select patients for treatment of unresectable or metastatic solid tumors with ENHERTU based on HER2-positive (IHC 3+) specimens

[see Clinical Studies (14.5)]

. An FDA-approved test for the detection of HER2-positive (IHC 3+) solid tumors for treatment with ENHERTU is not currently available.

Additional Patient Selection Information

Information on FDA-approved tests for the detection of HER2 protein expression, HER2 gene amplification, and activating HER2 mutations 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.

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

Permanently discontinue ENHERTU in case of severe infusion reactions.

Premedication

ENHERTU is highly emetogenic

[see Adverse Reactions (6.1)]

, which includes delayed nausea and/or vomiting. Administer prophylactic antiemetic medications per local institutional guidelines for prevention of chemotherapy-induced nausea and vomiting.

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 HER2-Positive 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.

)

01/2025

Dosage and Administration (

2.1 Patient Selection

HER2-Low or HER2-Ultralow Unresectable or Metastatic Breast Cancer

Select patients for treatment of unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer with ENHERTU based on HER2 expression

[see Clinical Studies (14.2)]

HER2-Mutant Unresectable or Metastatic NSCLC

Select patients for the treatment of unresectable or metastatic HER2-mutant NSCLC with ENHERTU based on the presence of activating HER2 (ERBB2) mutations in tumor or plasma specimens

[see Clinical Studies (14.3)]

. If no mutation is detected in a plasma specimen, test tumor tissue.

HER2-Positive Locally Advanced or Metastatic Gastric Cancer

HER2-Positive (IHC 3+) Unresectable or Metastatic Solid Tumors

Select patients for treatment of unresectable or metastatic solid tumors with ENHERTU based on HER2-positive (IHC 3+) specimens

[see Clinical Studies (14.5)]

. An FDA-approved test for the detection of HER2-positive (IHC 3+) solid tumors for treatment with ENHERTU is not currently available.

Additional Patient Selection Information

Information on FDA-approved tests for the detection of HER2 protein expression, HER2 gene amplification, and activating HER2 mutations 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.

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

Permanently discontinue ENHERTU in case of severe infusion reactions.

Premedication

ENHERTU is highly emetogenic

[see Adverse Reactions (6.1)]

, which includes delayed nausea and/or vomiting. Administer prophylactic antiemetic medications per local institutional guidelines for prevention of chemotherapy-induced nausea and vomiting.

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 HER2-Positive 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 Dosage 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

Table 1: Dosage Reduction Schedule
Dose Reduction Schedule	Breast Cancer, NSCLC, and IHC 3+ Solid Tumors	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: Dosage 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 5.0 (NCI CTCAE v.5.0).
Interstitial Lung Disease (ILD)/ Pneumonitis [see Warnings and Precautions (5.1)]	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.
	Symptomatic ILD/pneumonitis (Grade 2 or greater)		Permanently discontinue ENHERTU. Promptly initiate corticosteroid treatment as soon as ILD/pneumonitis is suspected.
Neutropenia [see Warnings and Precautions (5.2)]	Grade 3 (less than 1.0 to 0.5 × 10⁹/L)		Interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose.
Neutropenia [see Warnings and Precautions (5.2)]	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 [see Warnings and Precautions (5.2)]	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 [see Adverse Reactions (6.1)]	Grade 3 (platelets less than 50 to 25 × 10⁹/L)		Interrupt ENHERTU until resolved to Grade 1 or less, then maintain dose.
Thrombocytopenia [see Adverse Reactions (6.1)]	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 [see Warnings and Precautions (5.3)]	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.
	LVEF 40% to 45%	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 and Administration

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

ENHERTU (fam-trastuzumab deruxtecan-nxki) is a hazardous 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
.
If not used immediately, store the reconstituted ENHERTU vials in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF) for up to 24 hours from the time of reconstitution, protect the vial from light.
Do not freeze
.
The product does not contain a preservative. Discard unused ENHERTU after 24 hours refrigerated.

Dilution

Withdraw the calculated amount from the vial(s) using a sterile syringe. 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.
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.
Discard any unused portion left in the vials.

Administration

If not used immediately, store the diluted ENHERTU in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF) for up to 24 hours or at room temperature between 20ºC to 25ºC (68ºF to 77 ºF) for up to 4 hours including preparation and infusion time.
Protect from light.
Do not freeze
.
The maximum time from reconstitution of the vial through the end of administration should not exceed 24 hours.
If the prepared infusion solution was stored refrigerated (2ºC to 8ºC [36ºF to 46ºF]), allow the solution to reach room temperature prior to administration. Cover the infusion bag to protect from light.
Administer ENHERTU as an intravenous infusion only with an infusion set made of polyolefin or polybutadiene.
Administer ENHERTU with a 0.20 or 0.22 micron in-line polyethersulfone (PES) or polysulfone (PS) filter.
Do NOT administer as an intravenous push or bolus.
Cover the infusion bag to protect from light during administration.
Do not mix ENHERTU with other drugs or administer other drugs through the same intravenous line.
First infusion: Administer infusion over 90 minutes.
Subsequent infusions: Administer over 30 minutes if prior infusions were well tolerated.

)

04/2024

Dosage and Administration (

2.2 Recommended Dosage and Schedules

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

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

Permanently discontinue ENHERTU in case of severe infusion reactions.

Premedication

ENHERTU is highly emetogenic

[see Adverse Reactions (6.1)]

, which includes delayed nausea and/or vomiting. Administer prophylactic antiemetic medications per local institutional guidelines for prevention of chemotherapy-induced nausea and vomiting.

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 HER2-Positive 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.

2.4 Preparation and Administration

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

ENHERTU (fam-trastuzumab deruxtecan-nxki) is a hazardous 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
.
If not used immediately, store the reconstituted ENHERTU vials in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF) for up to 24 hours from the time of reconstitution, protect the vial from light.
Do not freeze
.
The product does not contain a preservative. Discard unused ENHERTU after 24 hours refrigerated.

Dilution

Withdraw the calculated amount from the vial(s) using a sterile syringe. 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.
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.
Discard any unused portion left in the vials.

Administration

If not used immediately, store the diluted ENHERTU in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF) for up to 24 hours or at room temperature between 20ºC to 25ºC (68ºF to 77 ºF) for up to 4 hours including preparation and infusion time.
Protect from light.
Do not freeze
.
The maximum time from reconstitution of the vial through the end of administration should not exceed 24 hours.
If the prepared infusion solution was stored refrigerated (2ºC to 8ºC [36ºF to 46ºF]), allow the solution to reach room temperature prior to administration. Cover the infusion bag to protect from light.
Administer ENHERTU as an intravenous infusion only with an infusion set made of polyolefin or polybutadiene.
Administer ENHERTU with a 0.20 or 0.22 micron in-line polyethersulfone (PES) or polysulfone (PS) filter.
Do NOT administer as an intravenous push or bolus.
Cover the infusion bag to protect from light during administration.
Do not mix ENHERTU with other drugs or administer other drugs through the same intravenous line.
First infusion: Administer infusion over 90 minutes.
Subsequent infusions: Administer over 30 minutes if prior infusions were well tolerated.

)

02/2024

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)]

. A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment.

[see Dosage and Administration (2.3)]

HER2-Positive, HER2-Low, and HER2-Ultralow Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)

HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)

5.2 Neutropenia

Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU.

Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. Based on the severity of neutropenia, ENHERTU may require dose interruption or reduction

[see Dosage and Administration (2.3)]

HER2-Positive, HER2-Low, and HER2-Ultralow Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)

In patients with metastatic breast cancer, HER2-mutant NSCLC, and other solid tumors treated with ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in 65% of patients. Nineteen percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 22 days (range: 2 to 939). Febrile neutropenia was reported in 1.2% of patients.

HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)

In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, a decrease in neutrophil count was reported in 72% of patients. Fifty-one percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 16 days (range: 4 to 187). Febrile neutropenia was reported in 4.8% of patients.

5.3 Left Ventricular Dysfunction

Patients treated with ENHERTU may be at increased risk of developing left ventricular dysfunction. Left ventricular ejection fraction (LVEF) decrease has been observed with anti-HER2 therapies, including ENHERTU.

Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. Manage LVEF decrease through treatment interruption. Permanently discontinue ENHERTU if LVEF of less than 40% or absolute decrease from baseline of greater than 20% is confirmed. Permanently discontinue ENHERTU in patients with symptomatic congestive heart failure (CHF)

[see Dosage and Administration (2.3)]

Treatment with ENHERTU has not been studied in patients with a history of clinically significant cardiac disease or LVEF less than 50% prior to initiation of treatment.

HER2-Positive, HER2-Low, and HER2-Ultralow Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)

In patients with metastatic breast cancer, HER2-mutant NSCLC, and other solid tumors treated with ENHERTU 5.4 mg/kg, LVEF decrease was reported in 4.6% of patients, of which 0.6% were Grade 3 or 4.

HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)

In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, no clinical adverse events of heart failure were reported; however, on echocardiography, 8% were found to have asymptomatic Grade 2 decrease in LVEF.

)

01/2025

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)]

. A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment.

[see Dosage and Administration (2.3)]

HER2-Positive, HER2-Low, and HER2-Ultralow Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)

HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)

5.2 Neutropenia

Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU.

[see Dosage and Administration (2.3)]

HER2-Positive, HER2-Low, and HER2-Ultralow Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)

HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)

5.3 Left Ventricular Dysfunction

[see Dosage and Administration (2.3)]

Treatment with ENHERTU has not been studied in patients with a history of clinically significant cardiac disease or LVEF less than 50% prior to initiation of treatment.

HER2-Positive, HER2-Low, and HER2-Ultralow Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)

In patients with metastatic breast cancer, HER2-mutant NSCLC, and other solid tumors treated with ENHERTU 5.4 mg/kg, LVEF decrease was reported in 4.6% of patients, of which 0.6% were Grade 3 or 4.

HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)

)

04/2024

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)]

. A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment.

[see Dosage and Administration (2.3)]

HER2-Positive, HER2-Low, and HER2-Ultralow Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)

HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)

5.2 Neutropenia

Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU.

[see Dosage and Administration (2.3)]

HER2-Positive, HER2-Low, and HER2-Ultralow Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)

HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)

5.3 Left Ventricular Dysfunction

[see Dosage and Administration (2.3)]

Treatment with ENHERTU has not been studied in patients with a history of clinically significant cardiac disease or LVEF less than 50% prior to initiation of treatment.

HER2-Positive, HER2-Low, and HER2-Ultralow Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)

In patients with metastatic breast cancer, HER2-mutant NSCLC, and other solid tumors treated with ENHERTU 5.4 mg/kg, LVEF decrease was reported in 4.6% of patients, of which 0.6% were Grade 3 or 4.

HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)

)

02/2024

ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of:

adult patients with unresectable or metastatic HER2-positive (IHC 3+ or ISH positive) breast cancer who have received a prior anti-HER2-based regimen either:
- in the metastatic setting, or
- in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy. (
  1.1 HER2-Positive Metastatic Breast Cancer
  ENHERTU is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+ or ISH positive) breast cancer who have received a prior anti-HER2-based regimen either:
  in the metastatic setting, or
  in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy.
  )
adult patients with unresectable or metastatic
- Hormone receptor (HR)-positive, HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer, as determined by an FDA-approved test, that has progressed on one or more endocrine therapies in the metastatic setting. (1.2)
- HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined by an FDA-approved test, who have received a prior chemotherapy in the metastatic setting; or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. (
  1.2 HER2-Low and HER2-Ultralow Metastatic Breast Cancer
  ENHERTU is indicated for the treatment of adult patients with unresectable or metastatic
  Hormone receptor (HR)-positive HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer, as determined by an FDA-approved test, that has progressed on one or more endocrine therapies in the metastatic setting
  [see Dosage and Administration (2.1)]
  .
  HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined by an FDA-approved test, who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy
  [see Dosage and Administration (2.1)]
  .
  )
adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy.* (
1.3 HER2-Mutant Unresectable or Metastatic Non-Small Cell Lung Cancer
ENHERTU is indicated for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy.
This indication is approved under accelerated approval based on objective response rate and duration of response
[see Clinical Studies (14.3)]
. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
)
adult patients with locally advanced or metastatic HER2-positive (IHC 3+ or IHC 2+/ISH positive) gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen. (
1.4 HER2-Positive Locally Advanced or Metastatic Gastric Cancer
ENHERTU is indicated for the treatment of adult patients with locally advanced or metastatic HER2-positive (IHC 3+ or IHC 2+/ISH positive) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen.
)
adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options.* (
1.5 HER2-Positive (IHC 3+) Unresectable or Metastatic Solid Tumors
ENHERTU is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options.
This indication is approved under accelerated approval based on objective response rate and duration of response
[see Clinical Studies (14.5)]
. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
)

These indications are approved under accelerated approval based on objective 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. (

14.3 HER2-Mutant Unresectable or Metastatic Non-Small Cell Lung Cancer

ENHERTU was evaluated in DESTINY-Lung01 (NCT03505710) and at two dose levels in DESTINY-Lung02 (NCT04644237). Patients were prospectively selected for treatment with ENHERTU based on the presence of activating HER2 (ERBB2) mutations by local testing using tissue. Samples from DESTINY-Lung01 were retrospectively tested using Oncomine^™Dx Target Test (Life Technologies Corporation, Tissue-test) and Guardant360^®CDx test (Guardant Health Inc., Plasma test). Demographic and baseline disease characteristics were similar for patients in DESTINY-Lung01 and DESTINY-Lung02, except for race (34% Asian vs 79% Asian, respectively). Response rates were consistent across dose levels. Increased rates of ILD/pneumonitis were observed at the higher dose. The approved recommended dose of 5.4 mg/kg intravenously every 3 weeks in the DESTINY-Lung02 study is described below

[see Adverse Reactions (6.1)].

The efficacy of ENHERTU was evaluated in DESTINY-Lung02, a multicenter, multicohort, randomized, blinded, dose-optimization trial. Eligible patients were required to have unresectable or metastatic HER2-mutant non-squamous NSCLC with disease progression after one prior systemic therapy. Patients with a history of steroid dependent ILD/pneumonitis, clinically significant cardiac disease, clinically active brain metastases, and ECOG performance status >1 were excluded. Patients received ENHERTU 5.4 mg/kg by intravenous infusion every 3 weeks until disease progression or unacceptable toxicity. Tumor imaging was obtained every 6 weeks and CT/MRI of the brain was mandatory for patients with stable brain metastases at baseline.

Results from an interim efficacy analysis in a pre-specified patient cohort are described below. The major efficacy outcomes were confirmed ORR as assessed by BICR using RECIST v1.1 and DOR.

The median age was 58 years (range 30 to 78); 69% were female; 79% were Asian, 12% were White, and 10% were other races; 29% had an ECOG performance status of 0 and 71% had 1; 33% had stable brain metastases; 94% had a mutation in the ERBB2 kinase domain and 6% had a mutation in the extracellular domain. The median number of prior regimens was 2 (range: 1 to 12); 100% of patients received prior platinum therapy, 71% received prior immunotherapy, and 44% received both in combination. Fifty percent of patients were never-smokers and 50% were former smokers; 96% of patients had adenocarcinoma histology.

Efficacy results are provided in Table 24.

Table 24: Efficacy Results for DESTINY-Lung02Data cut-off: 22 June 2022
Efficacy Parameter	DESTINY-Lung02 N=52
ORR 95% CI calculated using Clopper-Pearson method NE=not estimable
Confirmed Objective Response Rate (95% CI)	57.7% (43.2, 71.3)
Complete Response	1.9%
Partial Response	55.8%
Duration of Response Median, months (95% CI)Median DOR based on Kaplan-Meier estimate; 95% CI calculated using Brookmeyer-Crowley method	8.7 (7.1, NE)

14.5 HER2-Positive (IHC 3+) Unresectable or Metastatic Solid Tumors

The efficacy of ENHERTU was evaluated in 192 adult patients with previously treated unresectable or metastatic HER2-positive (IHC 3+) solid tumors who were enrolled in one of three multicenter trials: DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02. All three studies excluded patients with a history of ILD/pneumonitis requiring treatment with steroids or ILD/pneumonitis at screening and clinically significant cardiac disease. Patients were also excluded for active brain metastases or ECOG performance status >1. Patients received ENHERTU 5.4 mg/kg by intravenous infusion every three weeks. Treatment was administered until disease progression, death, withdrawal of consent, or unacceptable toxicity. The major efficacy outcome measure in all three of the studies was confirmed objective response rate (ORR) and an additional efficacy outcome measure was duration of response (DOR). All outcomes were assessed by independent central review (ICR) based on RECIST v1.1.

DESTINY-PanTumor02

DESTINY-PanTumor02 (NCT04482309) was a multicenter, multicohort, open-label trial that included 111 adult patients with locally advanced, unresectable, or metastatic HER2-positive (IHC 3+ by either local or central assessment) solid tumors that progressed following at least one prior systemic regimen in the advanced/metastatic setting or that had no satisfactory alternative treatment option.

The median age was 64 years (range 23 to 85); 59% were female; 58% were White, 34% were Asian, and 4% were Black or African American; 3% of patients were of Hispanic/Latino ethnicity. Patients had an ECOG performance status of either 0 (49%) or 1 (51%) at baseline. The median number of prior regimens in any treatment setting was 2.

DESTINY-Lung01

DESTINY-Lung01 (NCT03505710) was a multicenter, open-label, 2-cohort trial that included 17 patients with previously treated, unresectable, or metastatic, centrally confirmed HER2-positive (IHC 3+) NSCLC. Patients must have relapsed from or be refractory to standard treatment or have no available standard treatment.

The median age was 59 years (range 31 to 74); 59% were male; 65% were White, 18% were Asian, and 12% were Black or African American. Patients had an ECOG performance status of either 0 (12%) or 1 (88%) at baseline. The median number of prior regimens in any treatment setting was 3.

DESTINY-CRC02

DESTINY-CRC02 (NCT04744831) was a multicenter, randomized, 2-arm trial that included 64 patients with previously treated, unresectable or metastatic centrally confirmed HER2-positive (IHC 3+) colorectal cancer (CRC). Unless contraindicated, patients must have received fluoropyrimidine, oxaliplatin and irinotecan. If clinically indicated, patients must have received anti-EGFR treatment, anti-VEGF treatment and anti-PDL1 therapy.

The median age was 58 years (range 25 to 78); 53% were male; 55% were Asian and 41% were White; 1.6% of patients were of Hispanic/Latino ethnicity. Patients had an ECOG performance status of either 0 (58%) or 1 (42%) at baseline. The median number of prior regimens in any treatment setting was 4.

Efficacy results are summarized in Table 26 and Table 27.

Table 26: Efficacy Results in HER2-Positive (IHC 3+) Patients in DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02
Efficacy Parameter	DESTINY-PanTumor02 N=111	DESTINY-Lung01 N=17	DESTINY-CRC02 N=64
CI=Confidence interval + Denotes ongoing response
Confirmed ORR (95% CI)Assessed by independent central reviewCI is derived based on the Clopper-Pearson method	51.4% (41.7, 61.0)	52.9% (27.8, 77.0)	46.9% (34.3, 59.8)
Complete Response Rate	2.7%	5.9%	0%
Partial Response Rate	48.6%	47.1%	46.9%
Duration of Response
MedianCalculated using the Kaplan-Meier technique, months (range)	19.4 (1.3, 27.9+)	6.9 (4.0, 11.7+)	5.5 (1.3+, 9.7+)

Table 27: Efficacy Results in HER2-positive (IHC 3+) Patients by Tumor Type in DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02
Tumor Type	Patients	Confirmed ORRAssessed by independent central review	DOR Range
	N	% (95% CI)CI is derived based on the Clopper-Pearson method	(months)
CI=Confidence interval, NA=Not applicable, PD=Progressive disease, PR=Partial response, SD=Stable disease + Denotes ongoing response
Colorectal Cancer	64	46.9 (34.3, 59.8)	(1.3+, 9.7+)
Bladder Cancer	27	37.0 (19.4, 57.6)	(2.8, 19.7+)
Biliary Tract Cancer	22	45.5 (24.4, 67.8)	(2.1, 22.0+)
NSCLC	17	52.9 (27.8, 77.0)	(4.0, 11.7+)
Endometrial Cancer	16	56.3 (29.9, 80.2)	(5.8, 23.7+)
Ovarian Cancer	15	66.7 (38.4, 88.2)	(1.3, 27.9+)
Cervical Cancer	10	70.0 (34.8, 93.3)	(7.2+, 25.0+)
Salivary Gland Cancer	9	66.7 (29.9,92.5)	(5.6, 20.1)
Pancreatic Cancer	5	0 (0, 52.2)	NA
Oropharyngeal Neoplasm	1	PR	15.3
Vulvar Cancer	1	PR	2.6
Extramammary Paget's Disease	1	PR	19.4
Lacrimal Gland Cancer	1	PR	19.8+
Lip and/or Oral Cavity Cancer	1	SD	NA
Esophageal Adenocarcinoma	1	PR	2.8
Esophageal Squamous Cell Carcinoma	1	PD	NA

)

Do not substitute ENHERTU for or with trastuzumab or ado-trastuzumab emtansine.
(
2.2 Recommended Dosage and Schedules
Do not substitute ENHERTU for or with trastuzumab or ado-trastuzumab emtansine.
Slow or interrupt the infusion rate if the patient develops infusion-related symptoms.
Permanently discontinue ENHERTU in case of severe infusion reactions.
Premedication
ENHERTU is highly emetogenic
[see Adverse Reactions (6.1)]
, which includes delayed nausea and/or vomiting. Administer prophylactic antiemetic medications per local institutional guidelines for prevention of chemotherapy-induced nausea and vomiting.
Recommended Dosage for HER2-Positive, HER2-Low, or HER2-Ultralow Metastatic Breast Cancer, HER2-Mutant Unresectable or Metastatic NSCLC, and HER2-Positive (IHC 3+) Unresectable or Metastatic Solid Tumors.
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 HER2-Positive 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.
,
2.4 Preparation and 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 hazardous 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
.
If not used immediately, store the reconstituted ENHERTU vials in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF) for up to 24 hours from the time of reconstitution, protect the vial from light.
Do not freeze
.
The product does not contain a preservative. Discard unused ENHERTU after 24 hours refrigerated.
Dilution
Withdraw the calculated amount from the vial(s) using a sterile syringe. 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.
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.
Discard any unused portion left in the vials.
Administration
If not used immediately, store the diluted ENHERTU in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF) for up to 24 hours or at room temperature between 20ºC to 25ºC (68ºF to 77 ºF) for up to 4 hours including preparation and infusion time.
Protect from light.
Do not freeze
.
The maximum time from reconstitution of the vial through the end of administration should not exceed 24 hours.
If the prepared infusion solution was stored refrigerated (2ºC to 8ºC [36ºF to 46ºF]), allow the solution to reach room temperature prior to administration. Cover the infusion bag to protect from light.
Administer ENHERTU as an intravenous infusion only with an infusion set made of polyolefin or polybutadiene.
Administer ENHERTU with a 0.20 or 0.22 micron in-line polyethersulfone (PES) or polysulfone (PS) filter.
Do NOT administer as an intravenous push or bolus.
Cover the infusion bag to protect from light during administration.
Do not mix ENHERTU with other drugs or administer other drugs through the same intravenous line.
First infusion: Administer infusion over 90 minutes.
Subsequent infusions: Administer over 30 minutes if prior infusions were well tolerated.
)
For intravenous infusion only
. Do not administer as an intravenous push or bolus. DO NOT use Sodium Chloride Injection, USP. (
2.4 Preparation and 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 hazardous 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
.
If not used immediately, store the reconstituted ENHERTU vials in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF) for up to 24 hours from the time of reconstitution, protect the vial from light.
Do not freeze
.
The product does not contain a preservative. Discard unused ENHERTU after 24 hours refrigerated.
Dilution
Withdraw the calculated amount from the vial(s) using a sterile syringe. 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.
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.
Discard any unused portion left in the vials.
Administration
If not used immediately, store the diluted ENHERTU in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF) for up to 24 hours or at room temperature between 20ºC to 25ºC (68ºF to 77 ºF) for up to 4 hours including preparation and infusion time.
Protect from light.
Do not freeze
.
The maximum time from reconstitution of the vial through the end of administration should not exceed 24 hours.
If the prepared infusion solution was stored refrigerated (2ºC to 8ºC [36ºF to 46ºF]), allow the solution to reach room temperature prior to administration. Cover the infusion bag to protect from light.
Administer ENHERTU as an intravenous infusion only with an infusion set made of polyolefin or polybutadiene.
Administer ENHERTU with a 0.20 or 0.22 micron in-line polyethersulfone (PES) or polysulfone (PS) filter.
Do NOT administer as an intravenous push or bolus.
Cover the infusion bag to protect from light during administration.
Do not mix ENHERTU with other drugs or administer other drugs through the same intravenous line.
First infusion: Administer infusion over 90 minutes.
Subsequent infusions: Administer over 30 minutes if prior infusions were well tolerated.
)
Premedicate for prevention of chemotherapy-induced nausea and vomiting. (
2.2 Recommended Dosage and Schedules
Do not substitute ENHERTU for or with trastuzumab or ado-trastuzumab emtansine.
Slow or interrupt the infusion rate if the patient develops infusion-related symptoms.
Permanently discontinue ENHERTU in case of severe infusion reactions.
Premedication
ENHERTU is highly emetogenic
[see Adverse Reactions (6.1)]
, which includes delayed nausea and/or vomiting. Administer prophylactic antiemetic medications per local institutional guidelines for prevention of chemotherapy-induced nausea and vomiting.
Recommended Dosage for HER2-Positive, HER2-Low, or HER2-Ultralow Metastatic Breast Cancer, HER2-Mutant Unresectable or Metastatic NSCLC, and HER2-Positive (IHC 3+) Unresectable or Metastatic Solid Tumors.
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 HER2-Positive 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.
)

The recommended dosage of ENHERTU for HER2-positive, HER2-low, or HER2-ultralow breast cancer, HER2-mutant NSCLC, and HER2-positive (IHC 3+) solid tumors is 5.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity. (

2.2 Recommended Dosage and Schedules

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

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

Permanently discontinue ENHERTU in case of severe infusion reactions.

Premedication

ENHERTU is highly emetogenic

[see Adverse Reactions (6.1)]

, which includes delayed nausea and/or vomiting. Administer prophylactic antiemetic medications per local institutional guidelines for prevention of chemotherapy-induced nausea and vomiting.

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 HER2-Positive 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 Dosage 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

Table 1: Dosage Reduction Schedule
Dose Reduction Schedule	Breast Cancer, NSCLC, and IHC 3+ Solid Tumors	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: Dosage 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 5.0 (NCI CTCAE v.5.0).
Interstitial Lung Disease (ILD)/ Pneumonitis [see Warnings and Precautions (5.1)]	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.
	Symptomatic ILD/pneumonitis (Grade 2 or greater)		Permanently discontinue ENHERTU. Promptly initiate corticosteroid treatment as soon as ILD/pneumonitis is suspected.
Neutropenia [see Warnings and Precautions (5.2)]	Grade 3 (less than 1.0 to 0.5 × 10⁹/L)		Interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose.
Neutropenia [see Warnings and Precautions (5.2)]	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 [see Warnings and Precautions (5.2)]	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 [see Adverse Reactions (6.1)]	Grade 3 (platelets less than 50 to 25 × 10⁹/L)		Interrupt ENHERTU until resolved to Grade 1 or less, then maintain dose.
Thrombocytopenia [see Adverse Reactions (6.1)]	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 [see Warnings and Precautions (5.3)]	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.
	LVEF 40% to 45%	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.

)

The recommended dosage of ENHERTU for HER2-positive gastric cancer is 6.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity. (

2.2 Recommended Dosage and Schedules

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

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

Permanently discontinue ENHERTU in case of severe infusion reactions.

Premedication

ENHERTU is highly emetogenic

[see Adverse Reactions (6.1)]

, which includes delayed nausea and/or vomiting. Administer prophylactic antiemetic medications per local institutional guidelines for prevention of chemotherapy-induced nausea and vomiting.

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 HER2-Positive 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 Dosage 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

Table 1: Dosage Reduction Schedule
Dose Reduction Schedule	Breast Cancer, NSCLC, and IHC 3+ Solid Tumors	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: Dosage 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 5.0 (NCI CTCAE v.5.0).
Interstitial Lung Disease (ILD)/ Pneumonitis [see Warnings and Precautions (5.1)]	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.
	Symptomatic ILD/pneumonitis (Grade 2 or greater)		Permanently discontinue ENHERTU. Promptly initiate corticosteroid treatment as soon as ILD/pneumonitis is suspected.
Neutropenia [see Warnings and Precautions (5.2)]	Grade 3 (less than 1.0 to 0.5 × 10⁹/L)		Interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose.
Neutropenia [see Warnings and Precautions (5.2)]	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 [see Warnings and Precautions (5.2)]	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 [see Adverse Reactions (6.1)]	Grade 3 (platelets less than 50 to 25 × 10⁹/L)		Interrupt ENHERTU until resolved to Grade 1 or less, then maintain dose.
Thrombocytopenia [see Adverse Reactions (6.1)]	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 [see Warnings and Precautions (5.3)]	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.
	LVEF 40% to 45%	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.

)

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

2.3 Dosage 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

Table 1: Dosage Reduction Schedule
Dose Reduction Schedule	Breast Cancer, NSCLC, and IHC 3+ Solid Tumors	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: Dosage 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 5.0 (NCI CTCAE v.5.0).
Interstitial Lung Disease (ILD)/ Pneumonitis [see Warnings and Precautions (5.1)]	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.
	Symptomatic ILD/pneumonitis (Grade 2 or greater)		Permanently discontinue ENHERTU. Promptly initiate corticosteroid treatment as soon as ILD/pneumonitis is suspected.
Neutropenia [see Warnings and Precautions (5.2)]	Grade 3 (less than 1.0 to 0.5 × 10⁹/L)		Interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose.
Neutropenia [see Warnings and Precautions (5.2)]	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 [see Warnings and Precautions (5.2)]	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 [see Adverse Reactions (6.1)]	Grade 3 (platelets less than 50 to 25 × 10⁹/L)		Interrupt ENHERTU until resolved to Grade 1 or less, then maintain dose.
Thrombocytopenia [see Adverse Reactions (6.1)]	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 [see Warnings and Precautions (5.3)]	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.
	LVEF 40% to 45%	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.

)

Lactation: Advise not to breastfeed. (
8.2 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.
)
Females and Males of Reproductive Potential: Verify pregnancy status of females prior to initiation of ENHERTU. (
8.3 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
[see Use in Specific Populations (8.1)]
. Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for 7 months after 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 4 months after the last dose
[see Nonclinical Toxicology (13.1)]
.
Infertility
Based on findings in animal toxicity studies, ENHERTU may impair male reproductive function and fertility
[see Nonclinical Toxicology (13.1)]
.
)

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