INDICATIONS AND IMPORTANT SAFETY INFORMATION

Indications

Enhertu as monotherapy is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received one or more prior anti-HER2-based regimens.

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in SmPC

Warnings and Precautions

Interstitial lung disease/pneumonitis

Cases of interstitial lung disease (ILD), and/or pneumonitis, have been reported with Enhertu. Fatal outcomes have been observed. Patients should be advised to immediately report cough, dyspnoea, fever, and/or any new or worsening respiratory symptoms. Patients should be monitored for signs and symptoms of ILD/pneumonitis. Evidence of ILD/ pneumonitis should be promptly investigated. Patients with suspected ILD/pneumonitis should be evaluated by radiographic imaging, preferably a computed tomography (CT) scan. Consultation with a pulmonologist should be considered. For asymptomatic (Grade 1) ILD/pneumonitis, consider corticosteroid treatment (e.g., ≥ 0.5mg/kg/day prednisolone or equivalent). Enhertu should be withheld until recovery to Grade 0 and may be resumed according to instructions in SmPC. For symptomatic ILD/pneumonitis (Grade 2 or greater), promptly initiate 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. Enhertu should be permanently discontinued in patients who are diagnosed with symptomatic (Grade 2 or greater) ILD/pneumonitis. Patients with a history of ILD/pneumonitis or patients with moderate or severe renal impairment may be at increased risk of developing ILD/pneumonitis and should be monitored carefully.

Neutropenia

Cases of neutropenia, including febrile neutropenia, were reported in clinical studies of Enhertu. Complete blood counts should be monitored 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.

Left ventricular ejection fraction decrease

Left ventricular ejection fraction (LVEF) decrease has been observed with anti-HER2 therapies.

Standard cardiac function testing (echocardiogram or MUGA scanning) should be performed to assess LVEF prior to initiation of Enhertu and at regular intervals during treatment as clinically indicated. LVEF decrease should be managed through treatment interruption. Enhertu should be permanently discontinued if LVEF of less than 40% or absolute decrease from baseline of greater than 20% is confirmed. Enhertu should be permanently discontinued in patients with symptomatic congestive heart failure (CHF).

Embryo-foetal toxicity

Enhertu can cause foetal harm when administered to a pregnant woman. In post-marketing reports, use of trastuzumab, a HER2 receptor antagonist, during pregnancy resulted in cases of oligohydramnios manifesting as fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Based on findings in animals and its mechanism of action, the topoisomerase I inhibitor component of Enhertu, DXd, can also cause embryo-foetal harm when administered to a pregnant woman.

The pregnancy status of females of reproductive potential should be verified prior to the initiation of Enhertu. The patient should be informed of the potential risks to the foetus. Females of reproductive potential should be advised to use effective contraception during treatment and for at least 7 months following the last dose of Enhertu. Male patients with female partners of reproductive potential should be advised to use effective contraception during treatment with Enhertu and for at least 4 months after the last dose of Enhertu.

Patients with moderate or severe hepatic impairment

There are limited data in patients with moderate hepatic impairment and no data in patients with severe hepatic impairment. As metabolism and biliary excretion are the primary routes of elimination of the topoisomerase I inhibitor, DXd, Enhertu should be administered with caution in patients with moderate and severe hepatic impairment.

Adverse Reactions

The pooled safety population has been evaluated for patients who received at least one dose of Enhertu 5.4 mg/kg (n =573) across multiple tumour types in clinical studies. The median duration of treatment in this pool was 11.3 months (range: 0.7 to 37.9 months).

The most common adverse reactions were nausea (77.0%), fatigue (57.2%), vomiting (46.8%), alopecia (38.0%), neutropenia (34.6%), constipation (33.9%), decreased appetite (33.7%), anaemia (32.3%), diarrhoea (30.7%), musculoskeletal pain (27.4%), transaminases increased (24.4%), leukopenia (24.1%), thrombocytopenia (23.0%), and upper respiratory tract infection (22.7%)..

The most common National Cancer Institute – Common Terminology Criteria for Adverse Events (NCI-CTCAE v.5.0) Grade 3 or 4 adverse reactions were neutropenia (17.5%), anaemia (8.4%), fatigue (6.3%), nausea (6.3%), leukopenia (5.9%), thrombocytopenia (5.8%), lymphopenia (4.4%), hypokalaemia (4.0%), transaminases increased (2.8%), vomiting (2.6%), diarrhoea (2.1%), pneumonia (1.4%), febrile neutropenia (1.4%), and decreased appetite (1.2%). Grade 5adverse reactions occurred in 1.6% of patients, including ILD (1.4%).

Dose interruptions due to adverse reactions occurred in 33.9% of patients treated with Enhertu. The most frequent adverse reactions associated with dose interruption were neutropenia (14.0%), fatigue (3.8%), leukopenia (3.7%), thrombocytopenia (3.3%), anaemia (3.3%), upper respiratory tract infection (3.0%), nausea (2.6%), ILD (2.4%), and pneumonia (2.3%). Dose reductions occurred in 18.8% of patients treated with Enhertu. The most frequent adverse reactions associated with dose reduction were nausea (4.9%), fatigue (3.7%), and neutropenia (3.0%). Discontinuation of therapy due to an adverse reaction occurred in 11.9% of patients treated with Enhertu. The most frequent adverse reaction associated with permanent discontinuation was ILD (8.6%).