TRODELVY Powder for solution for infusion Ref.[28090] Active ingredients: Sacituzumab govitecan

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Neutropenia

Sacituzumab govitecan can cause severe or life-threatening neutropenia (see section 4.8). Fatal infections in the setting of neutropenia have been observed in clinical studies with sacituzumab govitecan, primarily in the first two cycles of treatment.

Primary prophylaxis with G-CSF should be considered starting in the first cycle of treatment in patients at increased risk of febrile neutropenia, e.g., older patients (in particular aged 65 years and older), patients with previous neutropenia, poor performance status, organ dysfunction (including renal, liver or cardiovascular dysfunction), or multiple comorbid conditions. Monitor ANC during treatment.

Sacituzumab govitecan should not be administered if the ANC is below 1500/mm³ on Day 1 of any cycle or if the neutrophil count is below 1000/mm³ on Day 8 of any cycle. Sacituzumab govitecan should not be administered in case of neutropenic fever. Dose modifications may be required due to neutropenia or febrile neutropenia. Treat neutropenia with G-CSF and consider prophylaxis in subsequent cycles as clinically indicated (see sections 4.2 and 4.8).

Diarrhoea

Sacituzumab govitecan can cause severe diarrhoea (see section 4.8). Diarrhoea in some cases was observed to have led to dehydration and subsequent acute kidney injury. Sacituzumab govitecan should not be administered in case of Grade 3-4 diarrhoea at the time of scheduled treatment and treatment should only be continued when resolved to ≤ Grade 1 (see section 4.2 and 4.8). At the onset of diarrhoea, and if no infectious cause can be identified, treatment with loperamide should be initiated. Additional supportive measures (e.g. fluid and electrolyte substitution) may also be employed as clinically indicated.

Patients who exhibit an excessive cholinergic response to treatment with sacituzumab govitecan (e.g. abdominal cramping, diarrhoea, salivation, etc.) can receive appropriate treatment (e.g. atropine) for subsequent treatments with sacituzumab govitecan.

Hypersensitivity

Sacituzumab govitecan can cause severe and life-threatening hypersensitivity (see section 4.8). Anaphylactic reactions have been observed in clinical studies with sacituzumab govitecan and the use of sacituzumab govitecan is contraindicated in patients with a known hypersensitivity to sacituzumab govitecan (see section 4.3).

Pre-infusion treatment, including antipyretics, H1 and H2 blockers, or corticosteroids (e.g. 50 mg hydrocortisone or equivalent, orally or intravenously), for patients receiving sacituzumab govitecan is recommended. Patients should be closely observed for infusion-related reactions during each sacituzumab govitecan infusion and for at least 30 minutes after completion of each infusion. The infusion rate of sacituzumab govitecan should be slowed down or infusion interrupted if the patient develops an infusion-related reaction. Sacituzumab govitecan should be permanently discontinued if life-threatening infusion-related reactions occur (see section 4.2).

Nausea and vomiting

Sacituzumab govitecan is emetogenic (see section 4.8). Antiemetic preventive treatment with two or three medicinal products (e.g. dexamethasone with either a 5-hydroxytryptamine 3 [5-HT3] receptor antagonist or a Neurokinin-1 [NK-1] receptor antagonist as well as other medicinal products as indicated) is recommended for prevention of chemotherapy-induced nausea and vomiting (CINV).

Sacituzumab govitecan should not be administered in case of Grade 3 nausea or Grade 3-4 vomiting at the time of scheduled treatment administration and treatment should only be continued with additional supportive measures when resolved to ≤ Grade 1 (see section 4.2). Additional antiemetics and other supportive measures may also be employed as clinically indicated. All patients should be given takehome medicinal products with clear instructions for prevention and treatment of nausea and vomiting.

Use in patients with reduced UGT1A1 activity

SN-38 (the small molecule moiety of sacituzumab govitecan) is metabolised via uridine diphosphate-glucuronosyl transferase (UGT1A1). Genetic variants of the UGT1A1 gene such as the UGT1A1*28 allele lead to reduced UGT1A1 enzyme activity. Individuals who are homozygous for UGT1A1*28 allele are at increased risk for neutropenia, febrile neutropenia, and anaemia and are at increased risk for other adverse reactions following initiation of sacituzumab govitecan treatment (see section 4.8). A higher incidence of Grade 3-4 neutropenia, febrile neutropenia, and anaemia was observed in patients homozygous for the UGT1A1*28 allele and patients heterozygous for the UGT1A1*6 allele compared to patients homozygous for the wild-type allele. Approximately 20% of the Black population, 10% of the White population, and 2% of the East Asian population are homozygous for the UGT1A1*28 allele. Approximately 0.2% of the Black population, 0.3% of the White population, and 27% of the East Asian population are heterozygous for the UGT1A1*6 allele. Decreased function alleles other than UGT1A1*28 and *6 may be present in certain populations. Patients with known reduced UGT1A1 activity should be closely monitored for adverse reactions. When unknown, no testing of UGT1A1 status is required as the management of adverse reactions including the recommended dose modifications will be the same for all patients.

Embryo-foetal toxicity

Based on its mechanism of action, sacituzumab govitecan can cause teratogenicity and/or embryo-foetal lethality when administered to a pregnant woman. Sacituzumab govitecan contains a genotoxic component, SN-38, and targets rapidly dividing cells. Pregnant women and women of childbearing potential should be informed of the potential risk to the foetus. The pregnancy status of females of reproductive potential should be verified prior to the initiation of sacituzumab govitecan (see section 4.6).

Sodium

This medicinal product will be further prepared for administration with sodium-containing solution (see section 6.6) and this should be considered in relation to the total sodium intake to the patient from all sources per day.

No interaction studies have been performed.

UGT1A1 inhibitors

Concomitant administration of sacituzumab govitecan with inhibitors of UGT1A1 may increase the incidence of adverse reactions due to potential increase in systemic exposure to SN-38. Sacituzumab govitecan should be used with caution in patients receiving UGT1A1 inhibitors (e.g. propofol, ketoconazole, EGFR tyrosine kinase inhibitors).

UGT1A1 inducers

Exposure to SN-38 may be reduced in patients concomitantly receiving UGT1A1 enzyme inducers. Sacituzumab govitecan should be used with caution in patients receiving UGT1A1 inducers (e.g. carbamazepine, phenytoin, rifampicin, ritonavir, tipranavir).

Based on the limited data available from patients who received UGT1A1 inhibitors (n=15) or inducers (n=7) while being treated with sacituzumab govitecan, free SN-38 exposures in these patients were comparable to those in patients who did not receive UGT1A1 inhibitor or inducer.

Women of childbearing potential/Contraception in males and females

Women of childbearing potential have to use effective contraception during treatment and for 6 months after the last dose. Male patients with female partners of childbearing potential have to use effective contraception during treatment with sacituzumab govitecan and for 3 months after the last dose.

Pregnancy

There are no available data on the use of sacituzumab govitecan in pregnant women. However, based on its mechanism of action, sacituzumab govitecan can cause teratogenicity and/or embryo-foetal lethality when administered during pregnancy. Sacituzumab govitecan contains a genotoxic component, SN-38, and targets rapidly dividing cells.

Sacituzumab govitecan should not be used during pregnancy unless the clinical condition of the woman requires treatment with sacituzumab govitecan.

The pregnancy status of women of childbearing potential should be verified prior to the initiation of sacituzumab govitecan.

Women who become pregnant must immediately contact their doctor.

Breast-feeding

It is unknown whether sacituzumab govitecan or its metabolites are excreted in human milk. A risk to breastfed newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with sacituzumab govitecan and for 1 month after the last dose.

Fertility

Based on findings in animals, sacituzumab govitecan may impair fertility in females of reproductive potential (see section 5.3). No human data on the effect of sacituzumab govitecan on fertility are available.

Sacituzumab govitecan has minor influence on the ability to drive and use machines, e.g. dizziness, fatigue (see section 4.8).

Summary of the safety profile

The most common adverse reactions reported in patients treated with sacituzumab govitecan were: neutropenia (67.3%), nausea (62.1%), diarrhoea (59.9%), fatigue (57.4%), alopecia (48.3%), anaemia (40.1%), constipation (36.7%), vomiting (31.3%), and decreased appetite (23.3%).

The most common grade 3 or higher adverse reactions were neutropenia (48.6%), diarrhoea (10.0%), leukopenia (9.6%), anaemia (7.7%), fatigue (5.8%), febrile neutropenia (5.6%), and lymphopenia (3.1%).

The most frequently reported serious adverse reactions in patients treated with sacituzumab govitecan were febrile neutropenia (4.5%), diarrhoea (3.7%), neutropenia (2.9%) and pneumonia (2.1%).

Tabulated list of adverse reactions

The frequencies of adverse reactions are based on pooled data from four clinical studies involving 963 patients who received sacituzumab govitecan 10 mg/kg body weight for the treatment of metastatic TNBC and HR+/HER2- breast cancer. The median exposure to sacituzumab govitecan in this data set was 5.29 months.

The adverse reaction frequencies are based on all-cause adverse event frequencies, where a proportion of the events for an adverse reaction may have other causes than sacituzumab govitecan, such as the disease, other medicinal products or unrelated causes. The severity of adverse drug reactions was assessed based on the Common Terminology Criteria for Adverse Events (CTCAE), defining grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life threatening, and 5 = death.

Adverse reactions are listed by System Organ Class and frequency category. Frequency categories are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000); and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 3. List of adverse reactions:

¹ Includes the following preferred terms: neutropenia; neutrophil count decreased.
² Includes the following preferred terms: anaemia; haemoglobin decreased; red blood cell count decreased.
³ Includes the following preferred terms: leukopenia; white blood cell count decreased.
⁴ Includes the following preferred terms: lymphopenia; lymphocyte count decreased.
⁵ Includes the following preferred terms: thrombocytopenia; platelet count decreased.
⁶ Hypersensitivity events reported up to the end of the day after treatment was administered. Includes events coded to the following preferred terms: rash, infusion related reaction, hypersensitivity, periorbital oedema, catheter site dermatitis, contrast media reaction, dermatitis allergic, dermatitis contact, eczema, rash erythematous, urticaria, anaphylactic reaction, bronchospasm, conjunctivitis allergic, dermatitis, dermatitis acneiform, dermatitis exfoliative generalised, drug hypersensitivity, infusion related hypersensitivity reaction, rash macular, rash maculo-papular, rash papular, rash pustular, rhinitis allergic, swelling face, swelling of eyelid, swollen tongue, Type IV hypersensitivity reaction, cough with pruritus, cough with rash, dyspnoea with pruritus, dyspnoea with rash, dyspnoea with wheezing and rash, hypotension with dyspnoea.
⁷ Includes the following preferred terms: dyspnoea; dyspnoea exertional.
⁸ Includes the preferred term of neutropenic colitis and events reported as typhlitis.
⁹ Includes the following preferred terms: fatigue, asthenia.

Description of selected adverse reactions

Neutropenia

The median time to onset of neutropenia (including febrile neutropenia) following the start of the first treatment cycle was 20 days. The median duration of neutropenia was 10 days.

Neutropenia occurred in 67.3% of patients treated with sacituzumab govitecan, including Grade 3-4 neutropenia in 48.6% of patients. Neutropenia was the reason for dose reduction in 14.2% of patients. Neutropenic colitis was observed in 1.3% of patients. Fatal infections secondary to neutropenia (including neutropenic colitis) occurred in 0.6% of patients.

Febrile neutropenia occurred in 5.6% of patients treated with sacituzumab govitecan. Febrile neutropenia was the reason for dose reduction in 2.7% of patients.

Use in patients with reduced UGT1A1 activity

The incidence of Grade 3-4 neutropenia was 59.6% in patients homozygous for the UGT1A1*28 allele, 50.7% in patients heterozygous for the UGT1A1*28 allele, and 44.9% in patients homozygous for the wild-type allele. The incidence of Grade 3-4 febrile neutropenia was 10.6% in patients homozygous for the UGT1A1*28 allele, 5.9% in patients heterozygous for the UGT1A1*28 allele, and 4.3% in patients homozygous for the wild-type allele. The incidence of Grade 3-4 anaemia was 10.6% in patients homozygous for the UGT1A1*28 allele, 6.4% in patients heterozygous for the UGT1A1*28 allele, and 6.3% in patients homozygous for the wild-type allele. For patients heterozygous for the UGT1A1*6 allele, the incidences of Grade 3-4 neutropenia, febrile neutropenia, and anaemia were 53.8%, 7.7%, and 7.7%, respectively.

Compared to patients homozygous for the wild-type allele, earlier median onset of neutropenia and anaemia was observed in patients homozygous for the UGT1A1*28 allele and in patients heterozygous for the UGT1A1*28 allele.

Diarrhoea

The median time to onset of diarrhoea following the start of the first treatment cycle was 13 days. The median duration of diarrhoea was 7 days.

Diarrhoea occurred in 59.9% of patients treated with sacituzumab govitecan. Grade 3 events occurred in 10.0% of patients. Four of 963 patients (<1%) discontinued treatment because of diarrhoea.

Hypersensitivity

Hypersensitivity reactions reported up to the end of the day following dosing occurred in 12.8% of patients treated with sacituzumab govitecan. Grade 3 and above hypersensitivity occurred in 0.5% of patients treated with sacituzumab govitecan. The incidence of hypersensitivity reactions leading to permanent discontinuation of sacituzumab govitecan was 0.2%.

Immunogenicity

Across clinical studies in patients treated with sacituzumab govitecan, 13 (1.2%) of 1058 patients developed antibodies to sacituzumab govitecan following administration; 10 of these patients (0.9% of all patients treated with sacituzumab govitecan) had neutralizing antibodies against sacituzumab govitecan.

Special Populations

There was a higher discontinuation rate due to adverse reactions in patients aged 65 years or older (8%) compared with younger patients (4%) with metastatic breast cancer. Higher incidence rates of febrile neutropenia and severe diarrhoea were observed in patients aged 65 years or older. A higher incidence rate of fatal infections was observed in patients aged 65 years or older. There was a higher incidence rate of serious adverse events in patients aged 75 years or older (52%) compared to patients aged 65 years or older (35%) and patients younger than 65 years (25%) with metastatic breast cancer.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.