DATROWAY Powder for concentrate for solution for infusion Ref.[115207] Active ingredients: Datopotamab deruxtecan

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.

Interstitial lung disease/pneumonitis

Cases of interstitial lung disease (ILD), including pneumonitis, have been reported in patients treated with Datroway (see section 4.8). 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. Consultation with a pulmonologist should be considered. For asymptomatic (Grade 1) ILD/pneumonitis, consider corticosteroid treatment (e.g. ≥0.5 mg/kg/day prednisolone or equivalent). Datroway should be delayed until recovery to Grade 0 and may be resumed according to instructions in Table 2 (see section 4.2). For symptomatic ILD/pneumonitis (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. Datroway should be permanently discontinued in patients who are diagnosed with symptomatic (Grade 2 or greater) ILD/pneumonitis (see section 4.2). Patients with a history of ILD/pneumonitis may be at increased risk of developing ILD/pneumonitis and should be monitored carefully.

Keratitis

Datroway can cause ocular surface undesirable effects including keratitis. Signs and symptoms of keratitis may include dry eye, increased lacrimation, photophobia, and detrimental changes to vision (see section 4.8).

Patients should be advised to use preservative-free lubricant eye drops several times daily for prophylaxis. Patients should be advised to avoid use of contact lenses unless directed by an eye care professional. Patients should be promptly referred for appropriate ophthalmologic assessments for any new or worsening ocular signs and symptoms that could suggest keratitis. Keratitis should be monitored and if diagnosis is confirmed, Datroway should be dose delayed, dose reduced, or permanently discontinued (see section 4.2).

Patients with clinically significant corneal disease were excluded from the study (see section 5.1). Patients with pre-existing keratitis should be carefully monitored.

Stomatitis

Stomatitis, including mouth ulcers and oral mucositis, have been reported in patients being treated with Datroway (see section 4.8).

In addition to practicing good oral hygiene, when starting Datroway and throughout treatment, daily use of a steroid-containing mouthwash (e.g. dexamethasone oral solution 0.1 mg/mL 4 times daily or a similar steroid-containing mouthwash regimen) is recommended for prophylaxis and treatment. Where clinically indicated, antifungal agents may be considered in accordance with local guidelines. In the absence of a prophylactic steroid-containing mouthwash, use of bland mouth rinses (e.g. a non-alcoholic and/or bicarbonate-containing mouthwash) per local guidelines is recommended. Ice chips or ice water held in the mouth throughout the infusion may also be considered. If stomatitis does occur, frequency of mouthwashes may be increased and/or other topical treatments may be used. Based on the severity of the adverse reaction, dose delay, dose reduce, or permanently discontinue Datroway (see section 4.2).

Embryo-foetal toxicity

Based on findings in animals and its mechanism of action, the topoisomerase I inhibitor component of Datroway can cause embryo-foetal harm when administered to a pregnant woman.

The pregnancy status of females of childbearing potential should be verified prior to the initiation of Datroway. 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 Datroway. Male patients with female partners of reproductive potential should be advised to use effective contraception during treatment with Datroway and for at least 4 months after the last dose of Datroway (see section 4.6).

Patients with moderate or severe hepatic impairment

There are limited data in patients with moderate hepatic impairment and severe hepatic impairment. As metabolism and biliary excretion are the primary routes of elimination of the topoisomerase I inhibitor, DXd, Datroway should be administered with caution in patients with moderate and severe hepatic impairment (see sections 4.2 and 5.2).

Excipient with known effect

This medicine contains 1.5 mg of polysorbate 80 in each vial. Polysorbates may cause allergic reactions.

No clinical drug interaction studies with datopotamab deruxtecan have been conducted. However, clinical drug-drug interaction studies were conducted with trastuzumab deruxtecan (T-DXd), which contains the same DXd payload as Datroway. The C_max of DXd was not affected by ritonavir (inhibitor of CYP3A4 and OATP1B1 and 1B3) or itraconazole (inhibitor of CYP3A4). The AUC was increased 1.2-fold by both inhibitors which was not considered clinically relevant. Therefore, inhibitors of CYP3A4, OATP1B1 and OATP1B3 will most likely not have a clinically relevant effect on the PK of deruxtecan released from datopotamab deruxtecan.

Women of childbearing potential/Contraception in females and males

The pregnancy status of women of childbearing potential should be verified prior to initiation of Datroway.

Women of childbearing potential should use effective contraception during treatment with Datroway and for at least 7 months following the last dose.

Men with female partners of childbearing potential should use effective contraception during treatment with Datroway and for at least 4 months following the last dose.

Pregnancy

There are no available data on the use of Datroway in pregnant women. However, based on findings in animals and its mechanism of action, the topoisomerase I inhibitor component, DXd, can be expected to cause embryo-foetal harm when administered to pregnant women (see section 5.3).

Datroway is not recommended during pregnancy and in women of childbearing potential not using contraception. Patients should be informed of the potential risks to the foetus before they become pregnant and to contact their doctor immediately if they become pregnant.

Breast-feeding

It is not known if datopotamab deruxtecan is excreted in human milk. Human IgG is excreted in human milk. Because of the potential for serious adverse reactions in breast-fed children, women should discontinue breast-feeding prior to initiating treatment with Datroway. Women may begin breast-feeding 1 month after concluding treatment.

Fertility

No human data on the effect of datopotamab deruxtecan on fertility are available. Based on results from animal toxicity studies, Datroway may impair male and female reproductive function and fertility (see section 5.3).

Both men and women should seek advice on fertility preservation before treatment. It is not known whether datopotamab deruxtecan or its metabolites are found in seminal fluid. Male patients must not freeze or donate sperm throughout the treatment period, and for at least 4 months after the final dose of Datroway. Females must not donate, or retrieve for their own use, ova throughout the treatment period and for at least 7 months after the final dose of Datroway.

Datroway may influence the ability to drive and use machines. Patients should be advised to use caution when driving or operating machines in case they experience fatigue or vision changes during treatment with Datroway (see section 4.8).

Summary of safety profile

The pooled safety profile has been assessed from two clinical studies involving 443 patients who received Datroway 6 mg/kg body weight for the treatment of breast cancer. The median exposure to Datroway in this data set was 6.2 months (range 0.7 to 28.5 months).

The most common adverse reactions were stomatitis (64.8%), nausea (57.6%), fatigue (42.7%), alopecia (37.2%), constipation (33.0%), vomiting (26.0%), dry eye (25.5%), COVID-19 (17.8%), keratitis (17.8%), anaemia (17.2%), decreased appetite (16.3%), AST increased (16.0%), rash (15.3%), diarrhoea (12.9%), neutropenia (12.0%) and alanine aminotransferase (ALT) increased (10.4%).

The most common Grade ¾ adverse reactions were stomatitis (7.9%), fatigue (4.3%), anaemia (3.2%), AST increased (2.7%), vomiting (1.6%), ALT increased (1.6%), nausea (1.4%), urinary tract infection (1.4%), COVID-19 (1.1%), decreased appetite (1.1%), neutropenia (1.1%) and pneumonia (1.1%). Grade 5 adverse reactions occurred in 0.7% of patients and were due to ILD/pneumonitis, dyspnoea and sepsis.

The most common serious adverse reactions were COVID-19 (1.4%), urinary tract infection (1.1%), ILD/pneumonitis (1.1%) and sepsis (1.1%).

The frequency of treatment discontinuation due to adverse reactions was 3.6%. The most common adverse reaction leading to treatment discontinuation was ILD/pneumonitis (2.0%). The frequency of dose reductions due to adverse reactions was 21.0%. The most common adverse reactions leading to dose reduction were stomatitis (12.9%), fatigue (3.2%), nausea (1.8%) and keratitis (1.4%). The frequency of dose interruptions due to adverse reactions was 19.6%. The most common adverse reactions leading to dose interruption were stomatitis (5.2%), COVID-19 (4.1%), fatigue (2.3%), ILD/pneumonitis (1.6%), pneumonia (1.6%), keratitis (1.4%) and infusion-related reaction (1.1%).

Tabulated list of adverse reactions

Table 3 presents adverse reactions reported with Datroway. Adverse reactions are listed by System Organ Class and frequency category. 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 datopotamab deruxtecan, 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 Grade 5 = death.

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. Adverse reactions in patients treated with datopotamab deruxtecan 6 mg/kg:

^a Including COVID-19, COVID-19 pneumonia, SARS-CoV-2 test positive.
^b Including pneumonia, lower respiratory tract infection and lower respiratory tract infection fungal.
^c Including neutropenia and neutrophil count decreased.
^d Including keratitis, punctate keratitis and ulcerative keratitis.
^e Including conjunctivitis, conjunctival disorder, conjunctival hyperaemia and conjunctival irritation.
^f Including interstitial lung disease and pneumonitis.
^g Including stomatitis, aphthous ulcer, glossitis, mouth ulceration, odynophagia, oral pain, oropharyngeal pain
and pharyngeal inflammation.
^h Including rash, erythematous rash, maculo-papular rash and pruritic rash.
ⁱ Including skin hyperpigmentation and skin discolouration.
^j Including fatigue and asthenia.
^k Infusion-related reaction includes as any reaction (infusion-related reaction, pruritus and rash) occurring within the same day as Datroway infusion.

Description of selected adverse reactions

Interstitial lung disease/pneumonitis

ILD/pneumonitis occurred in 4.7% of the pool of patients with breast cancer treated with Datroway 6 mg/kg, of which 3.6% were adjudicated as drug-related ILD/pneumonitis by independent review. Most ILD/pneumonitis cases were Grade 1 (2.9%). Grade 2 events occurred in 0.9% of patients. Grade 3 events occurred in 0.9% of patients. Adjudicated drug-related Grade 5 events occurred in 0.2% of patients. Median time to first onset was 5.8 months (range: 1.1 to 10.8).

Ocular surface undesirable effects

Ocular surface undesirable effects occurred in 49.0% of the pool of patients treated with Datroway, of which 35.0% were Grade 1, 12.2% were Grade 2 and 1.8% were Grade 3. Keratitis occurred in 17.8% of the pool of patients treated with Datroway, of which 13.3% were Grade 1, 3.6% were Grade 2 and 0.9% were Grade 3. The median time to onset was 4.1 months (range: 0 to 23.2). Discontinuation due to keratitis occurred in 0.5% of patients.

Stomatitis

Stomatitis occurred in 64.8% of the pool of patients treated with Datroway, of which 29.3% were Grade 1, 27.5% were Grade 2 and 7.9% were Grade 3. Median time to first onset was 0.6 months (range: 0.03 to 12.2). Discontinuation due to stomatitis occurred in 0.5% of patients.

Haematological events

In study TROPION-Breast01 neutropenia occurred in 11.7% of patients treated with Datroway (1.1% were Grade ≥3). Leukopenia occurred in 3.6% of patients treated with Datroway (none were Grade ≥3). Colony stimulating factor was used by 2.7% of patients treated with Datroway.

Elderly

Of the 443 patients with breast cancer treated with Datroway 6 mg/kg, 23.3% were 65 years or older and 4.7% were 75 years or older. Data are limited to establish the safety in patients 85 years or older.

There was a numerically lower proportion of Grade ¾ adverse reactions (24.3% vs 25.0%) and a numerically higher proportion of serious adverse reactions (9.7% vs 6.8%) and adverse reactions leading to discontinuation (3.9% vs 3.5%) observed in patients aged 65 years or older compared to patients younger than 65 years old.

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.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Sodium chloride solution for infusion must not be used for reconstitution or dilution since it may cause particulate formation.