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Safety Data

ENHERTU has serious Warnings and Precautions. Click here for information related to monitoring for and management of ILD/pneumonitis. Please click here for full Prescribing Information, including Boxed WARNINGS, and click here for Medication Guide.

In previously treated HER2+ (IHC 3+) metastatic solid tumors Adverse reactions observed with ENHERTU

Common adverse reactions (10% all Grades or 2% Grade 3 or 4)1

Adverse reaction ENHERTU
(N=347)a
All Grades (%) Grade 3 or 4 (%)
Gastrointestinal
disorders
Nausea 69 7
Vomiting 35 3.5
Diarrhea 31 4.3
Constipation 28 0.6
Stomatitisb 20 0.9
Abdominal painc 18 2
Dyspepsia 12 0.3
General disorders and administration site conditions Fatigued 59 10
Pyrexia 11 0
Edemae 11 0.6
Metabolism and nutrition disorders Decreased appetite 34 2.6
Skin and subcutaneous tissue disorders Alopecia 34 0.3
Rashf 13 0.6
Infections and infestations Upper respiratory tract infectiongg 20 0
Pneumonia 6 2.3
Musculoskeletal and connective tissue disorders Musculoskeletal painh 19 0.3
Respiratory, thoracic, and mediastinal disorders Coughi 18 0
Interstitial lung diseasej 16 0.6
Dyspneak 12 1.7
Nervous system disorders Headachel 15 0
Investigations Decreased weight 10 0.3
Adverse reaction ENHERTU
(N=347)a
All
Grades
(%)
Grade
3 or 4
(%)
Gastrointestinal disorders
Nausea 69 7
Vomiting 35 3.5
Diarrhea 31 4.3
Constipation 28 0.6
Stomatitisb 20 0.9
Abdominal painc 18 2
Dyspepsia 12 0.3
General disorders and administration site conditions
Fatigued 59 10
Pyrexia 11 0
Edemae 11 0.6
Metabolism and nutrition disorders
Decreased appetite 34 2.6
Skin and subcutaneous tissue disorders
Alopecia 34 0.3
Rashf 13 0.6
Infections and infestations
Upper respiratory tract infectiong 20 0
Pneumonia 6 2.3
Musculoskeletal and connective tissue disorders
Musculoskeletal painh 19 0.3
Respiratory, thoracic, and mediastinal disorders
Coughi 18 0
Interstitial lung diseasej 16 0.6
Dyspneak 12 1.7
Nervous system disorders
Headachel 15 0
Investigations
Decreased weight 10 0.3

aSafety was evaluated in 347 adult patients with unresectable or metastatic HER2+ (IHC 3+) solid tumors who received ENHERTU 5.4 mg/kg in DB-01, DP-02, DL-01, and DC-02. Median duration of treatment was 8.3 months (range: 0.7 to 30.2).1

bIncluding stomatitis, mucosal inflammation, aphthous ulcer, mouth ulceration, oral mucosa erosion, oral mucosal blistering, oral mucosal eruption, tongue ulceration, cheilitis.1

cIncluding abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, gastrointestinal pain.1

dIncluding fatigue, asthenia, malaise, lethargy.1

eIncluding edema peripheral, edema, localized edema, face edema, skin edema, periorbital edema, eyelid edema.1

fIncluding rash, pustular rash, maculo-papular rash, papular rash, macular rash, pruritic rash, dermatitis acneiform, dermatitis, eczema, palmar plantar erythrodysesthesia syndrome.1

gIncluding influenza, influenza-like illness, upper respiratory tract infection, nasopharyngitis, pharyngitis, sinusitis, rhinitis, laryngitis.1

hIncluding back pain, myalgia, pain in extremity, musculoskeletal pain, muscle spasms, bone pain, neck pain, musculoskeletal chest pain, limb discomfort.1

iIncluding cough, productive cough, upper-airway cough syndrome.1

jInterstitial lung disease includes events that were adjudicated as drug-induced ILD: pneumonitis, ILD, organizing pneumonia, respiratory failure, acute respiratory failure, alveolitis, lung opacity, lymphangitis, pneumonia, bacterial pneumonia, pulmonary fibrosis, and radiation pneumonitis. Grade 5 adjudicated drug-induced ILD events were pneumonitis, respiratory failure, acute respiratory failure, lymphangitis, pulmonary fibrosis.1

kIncluding dyspnea, exertional dyspnea.1

lIncluding migraine, headache, sinus headache.1

Other clinically relevant adverse reactions reported in <10% of patients were1:

  • Respiratory, thoracic, and mediastinal disorders: epistaxis (9%)
  • Nervous system disorders: dizziness (9%)m and dysgeusia (6%)
  • Skin and subcutaneous disorders: pruritus (5%) and skin hyperpigmentation (4.3%)n
  • Eye disorders: blurred vision (4%)o
  • Metabolism and nutrition disorders: dehydration (3.2%)
  • Gastrointestinal disorders: abdominal distension (2.6%), flatulence (1.7%), and gastritis (0.9%)
  • Blood and lymphatic system disorders: febrile neutropenia (1.7%)
  • Injury, poisoning, and procedural complications: infusion-related reactions (1.4%)p

Safety was evaluated in 347 adult patients with unresectable or metastatic HER2+ (IHC 3+) solid tumors treated with ENHERTU 5.4 mg/kg in DB-01, DP-02, DL-01, and DC-02.1

mIncluding dizziness, postural dizziness, and vertigo.1

nIncluding skin hyperpigmentation, skin discoloration, pigmentation disorder.1

oIncluding blurred vision and visual impairment.1

pIncluding administration-related reaction, anaphylactic reaction, hypersensitivity, infusion-related reaction and infusion-related hypersensitivity reaction.1

Serious adverse reactions occurred in 34% of patients1

  • Serious adverse reactions in >1% of patients who received ENHERTU were sepsis, pneumonia, vomiting, urinary tract infection, abdominal pain, nausea, pneumonitis, pleural effusion, hemorrhage, COVID-19, fatigue, acute kidney injury, anemia, cellulitis, and dyspnea

Fatalities due to adverse reactions occurred in 6.3% of patients1

  • Fatalities included ILD/pneumonitis (2.3%), cardiac arrest (0.6%), COVID-19 (0.6%), and sepsis (0.6%), and the following events occurred in one patient each (0.3%): acute kidney injury, cerebrovascular accident, general physical health deterioration, pneumonia, and hemorrhagic shock

Adverse reactions requiring dose discontinuation, interruption, or reduction1

15%
permanent discontinuations
due to adverse reactions

ILD/pneumonitis accounted for 10%

48%
dose interruptions
due to adverse reactions

The most frequent adverse reactions (>2%) associated with dose interruption were decreased neutrophil count, anemia, COVID-19, fatigue, decreased white blood cell count, and ILD/pneumonitis

27%
dose reductions
due to adverse reactions

The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, decreased neutrophil count, ILD/pneumonitis, and diarrhea

In previously treated HER2+ (IHC 3+) metastatic solid tumors Laboratory abnormalities observed with ENHERTU

Selected laboratory abnormalities1

Laboratory parameter ENHERTU (N=347)q
All Gradesr (%) Grades 3 or 4r (%)
Hematology Decreased white blood cell count 75 11
Decreased hemoglobin 67 10
Decreased neutrophil count 66 21
Decreased lymphocyte count 58 21
Decreased platelet count 51 7
Chemistry Increased aspartate aminotransferase 45 1.5
Increased alanine aminotransferase 44 1.5
Increased blood alkaline phosphatase 36 1.2
Decreased blood potassium 29 6
Decreased
sodium
22 2.9
Increased blood bilirubin 15 0.6
Increased blood creatinine 14 0.6
Laboratory parameter ENHERTU
(N=347)q
All Gradesr (%) Grades 3 or 4r (%)
Hematology
Decreased white blood cell count 75 11
Decreased hemoglobin 67 10
Decreased neutrophil count 66 21
Decreased lymphocyte count 58 21
Decreased platelet count 51 7
Chemistry
Increased aspartate aminotransferase 45 1.5
Increased alanine aminotransferase 44 1.5
Increased blood alkaline phosphatase 36 1.2
Decreased blood potassium 29 6
Decreased sodium 22 2.9
Increased blood bilirubin 15 0.6
Increased blood creatinine 14 0.6

qSafety was evaluated in 347 adult patients with unresectable or metastatic HER2+ (IHC 3+) solid tumors who received ENHERTU 5.4 mg/kg in DB-01, DP-02, DL-01, and DC-02.1

rPercentages were calculated using the number of patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator.1

Drug interaction studies1

  • Effect of CYP3A and OATP inhibitors on DXd (clinical studies): There were no clinically meaningful drug-drug interactions between ENHERTU and itraconazole (CYP3A inhibitor) as well as ritonavir (OATP1B/CYP3A inhibitor)
  • Effect of DXd on CYP enzymes (in vitro studies): DXd did not inhibit common CYP enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A), nor induce CYP1A2, CYP2B6, or CYP3A
  • Effect of DXd on transporters (in vitro studies): At clinically relevant concentrations, DXd has a low potential to inhibit the transporters OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, P-gp, BCRP, or BSEP
  • Effect of other drugs on DXd (in vitro studies): DXd is a substrate of OATP1B1, OATP1B3, MATE2-K, P-gp, MRP1, and BCRP

BCRP, breast cancer resistance protein; BSEP, bile salt export pump; COVID-19, Coronavirus Disease 2019; CYP, cytochrome P450; DXd, deruxtecan; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; ILD, interstitial lung disease; MATE, multidrug and toxin compound extrusion; MRP, multidrug resistance protein; OAT, organic anion transporter; OATP, organic anion transporting polypeptide; OCT, organic cation transporter; P-gp, P-glycoprotein.

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

ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC3+) 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. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Contraindications

None.

Warnings and Precautions

Interstitial Lung Disease / Pneumonitis

Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ENHERTU. 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 ILD/pneumonitis (Grade 1), interrupt ENHERTU until resolved to Grade 0, then if resolved in ≤28 days from date of onset, maintain dose. If resolved in >28 days from date of onset, reduce dose one level. Consider corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥0.5 mg/kg/day prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), permanently discontinue ENHERTU. Promptly initiate systemic corticosteroid treatment as soon as ILD/pneumonitis is suspected (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.

Solid Tumors (IHC3+) and Other Solid Tumors (5.4 mg/kg)

In patients with 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 1.0% of patients treated with ENHERTU.

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. For Grade 3 neutropenia (Absolute Neutrophil Count [ANC] <1.0 to 0.5 x 109/L), interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose. For Grade 4 neutropenia (ANC <0.5 x 109/L), interrupt ENHERTU until resolved to Grade 2 or less, then reduce dose by one level. For febrile neutropenia (ANC <1.0 x 109/L and temperature >38.3º C or a sustained temperature of ≥38º C for more than 1 hour), interrupt ENHERTU until resolved, then reduce dose by one level.

Solid Tumors (IHC3+) and Other Solid Tumors (5.4 mg/kg)

In patients with solid tumors treated with ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in 63% of patients. Seventeen 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% of patients.

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. When LVEF is >45% and absolute decrease from baseline is 10-20%, continue treatment with ENHERTU. When LVEF is 40-45% and absolute decrease from baseline is <10%, continue treatment with ENHERTU and repeat LVEF assessment within 3 weeks. When LVEF is 40-45% and absolute decrease from baseline is 10-20%, interrupt ENHERTU and 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. When LVEF is <40% or absolute decrease from baseline is >20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF of <40% or absolute decrease from baseline of >20% is confirmed, permanently discontinue ENHERTU. Permanently discontinue ENHERTU in patients with symptomatic congestive heart failure. Treatment with ENHERTU has not been studied in patients with a history of clinically significant cardiac disease or LVEF <50% prior to initiation of treatment.

Solid Tumors (IHC3+) and Other Solid Tumors (5.4 mg/kg)

In patients with solid tumors treated with ENHERTU 5.4 mg/kg, LVEF decrease was reported in 3.8% of patients, of which 0.6% were Grade 3.

Embryo-Fetal Toxicity

ENHERTU can cause fetal harm when administered to a pregnant woman. 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.

Additional Dose Modifications

Thrombocytopenia

For Grade 3 thrombocytopenia (platelets <50 to 25 x 109/L) interrupt ENHERTU until resolved to Grade 1 or less, then maintain dose. For Grade 4 thrombocytopenia (platelets <25 x 109/L) interrupt ENHERTU until resolved to Grade 1 or less, then reduce dose by one level.

Adverse Reactions

Solid Tumors (IHC3+) and Other Solid Tumors (5.4 mg/kg)

The pooled safety population reflects exposure to ENHERTU 5.4 mg/kg intravenously every 3 weeks in 1799 patients in Study DS8201-A-J101 (NCT02564900), DESTINY-Breast01, DESTINY-Breast02, DESTINY-Breast03, DESTINY-Breast04, DESTINY-Lung01, DESTINY-Lung02, DESTINY-CRC02, and DESTINY-PanTumor02. Among these patients, 65% were exposed for >6 months and 38% were exposed for >1 year. In this pooled safety population, the most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (73%), decreased white blood cell count (70%), decreased hemoglobin (66%), decreased neutrophil count (63%), decreased lymphocyte count (58%), fatigue (56%), decreased platelet count (48%), increased aspartate aminotransferase (47%), increased alanine aminotransferase (43%), vomiting (40%), increased blood alkaline phosphatase (38%), alopecia (34%), constipation (33%), decreased appetite (32%), decreased blood potassium (31%), diarrhea (29%), musculoskeletal pain (24%), and abdominal pain (20%).

HER2-Positive (IHC3+) Unresectable or Metastatic Solid Tumors

The safety of ENHERTU was evaluated in 347 adult patients with unresectable or metastatic HER2-positive (IHC3+) solid tumors who received ENHERTU 5.4 mg/kg intravenously once every 3 weeks in DESTINY-Breast01, DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02. The median duration of treatment was 8.3 months (range 0.7 to 30.2).

Serious adverse reactions occurred in 34% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were sepsis, pneumonia, vomiting, urinary tract infection, abdominal pain, nausea, pneumonitis, pleural effusion, hemorrhage, COVID-19, fatigue, acute kidney injury, anemia, cellulitis, and dyspnea. Fatalities due to adverse reactions occurred in 6.3% of patients including ILD/pneumonitis (2.3%), cardiac arrest (0.6%), COVID-19 (0.6%), and sepsis (0.6%). The following events occurred in one patient each (0.3%): acute kidney injury, cerebrovascular accident, general physical health deterioration, pneumonia, and hemorrhagic shock.

ENHERTU was permanently discontinued in 15% of patients, of which ILD/pneumonitis accounted for 10%. Dose interruptions due to adverse reactions occurred in 48% of patients. The most frequent adverse reactions (>2%) associated with dose interruption were decreased neutrophil count, anemia, COVID-19, fatigue, decreased white blood cell count, and ILD/pneumonitis. Dose reductions occurred in 27% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, decreased neutrophil count, ILD/pneumonitis, and diarrhea.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased white blood cell count (75%), nausea (69%), decreased hemoglobin (67%), decreased neutrophil count (66%), fatigue (59%), decreased lymphocyte count (58%), decreased platelet count (51%), increased aspartate aminotransferase (45%), increased alanine aminotransferase (44%), increased blood alkaline phosphatase (36%), vomiting (35%), decreased appetite (34%), alopecia (34%), diarrhea (31%), decreased blood potassium (29%), constipation (28%), decreased sodium (22%), stomatitis (20%), and upper respiratory tract infection (20%).

Use in Specific Populations

  • Pregnancy: ENHERTU can cause fetal harm when administered to a pregnant woman. 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.
  • Lactation: There are no data regarding the presence of ENHERTU 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: Pregnancy testing: Verify pregnancy status of females of reproductive potential prior to initiation of ENHERTU. Contraception: Females: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for 7 months after the last dose. Males: 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. Infertility: ENHERTU may impair male reproductive function and fertility.
  • Pediatric Use: Safety and effectiveness of ENHERTU have not been established in pediatric patients.
  • Geriatric Use: Of the 192 patients with HER2-positive (IHC 3+) unresectable or metastatic solid tumors treated with ENHERTU 5.4 mg/kg in DESTINY-PanTumor02, DESTINY-Lung01, or DESTINY-CRC02, 39% were 65 years or older and 9% were 75 years or older. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients.
  • Renal Impairment: A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment. Monitor patients with moderate renal impairment more frequently. The recommended dosage of ENHERTU has not been established for patients with severe renal impairment (CLcr <30 mL/min).
  • Hepatic Impairment: In patients with moderate hepatic impairment, due to potentially increased exposure, closely monitor for increased toxicities related to the topoisomerase inhibitor, DXd. The recommended dosage of ENHERTU has not been established for patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST).

To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or fda.gov/medwatch.

To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or fda.gov/medwatch.

Please click here for full Prescribing Information, including Boxed WARNINGS, and click here for Medication Guide.

INDICATION

ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC3+) 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. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Reference
  • ENHERTU. Prescribing information. Daiichi Sankyo, Inc.; 2024.
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