Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
If a systemic hypersensitivity reaction (immediate or delayed) occurs, administration of tralokinumab should be discontinued and appropriate therapy initiated.
Patients treated with tralokinumab who develop conjunctivitis that does not resolve following standard treatment should undergo ophthalmological examination (see section 4.8).
Patients with known helminth infections were excluded from participation in clinical studies. It is unknown if tralokinumab will influence the immune response against helminth infections by inhibiting IL-13 signalling.
Patients with pre-existing helminth infections should be treated before initiating treatment with tralokinumab. If patients become infected while receiving tralokinumab and do not respond to antihelminth treatment, treatment with tralokinumab should be discontinued until infection resolves.
Live and live attenuated vaccines should not be given concurrently with tralokinumab as clinical safety and efficacy have not been established. Immune responses to the non-live tetanus and meningococcal vaccines were assessed (see section 4.5). It is recommended that patients should be brought up to date with live and live attenuated immunisations in agreement with current immunisation guidelines prior to treatment with tralokinumab.
This medicine contains less than 1 mmol sodium (23 mg) per 150 mg dose, that is to say essentially “sodium-free”.
The safety and efficacy of concurrent use of tralokinumab with live and live attenuated vaccines has not been studied.
Immune responses to non-live vaccines were assessed in a study in which adult patients with atopic dermatitis were treated with an initial dose of 600 mg (four 150 mg injections) followed by 300 mg every second (other) week administered as subcutaneous injection. After 12 weeks of tralokinumab administration, patients were vaccinated with a combined tetanus, diphtheria, and acellular pertussis vaccine, and a meningococcal vaccine and immune responses were assessed 4 weeks later. Antibody responses to both tetanus vaccine and meningococcal vaccine were similar in tralokinumab-treated and placebo-treated patients. No adverse interactions between either of the non-live vaccines or tralokinumab were noted in the study. Therefore, patients receiving tralokinumab may receive concurrent inactivated or non-live vaccinations.
For information on live and live attenuated vaccines, see section 4.4.
Tralokinumab is not expected to undergo metabolism by hepatic enzymes or renal elimination. Clinically relevant interactions between tralokinumab and inhibitors, inducers, or substrates of metabolising enzymes are not expected, and no dose adjustment is needed.
The effects of tralokinumab on the pharmacokinetics (PK) of CYP substrates, caffeine (CYP1A2), warfarin (CYP2C9), metoprolol (CYP2D6), omeprazole (CYP2C19) and midazolam (CYP3A), were evaluated in atopic dermatitis patients after repeated administration. No effects were observed for caffeine and warfarin. Small numerical changes, which were not clinically significant, were observed for Cmax of omeprazole, AUC of metoprolol and AUC and Cmax of midazolam (the largest difference being for midazolam Cmax with a decrease of 22%). Therefore, clinically relevant impact of tralokinumab on the pharmacokinetics of concomitant medicinal products metabolised by the CYP enzymes is not expected.
There is limited amount of data from the use of tralokinumab in pregnant women.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).
As a precautionary measure, it is preferable to avoid the use of tralokinumab during pregnancy.
It is unknown whether tralokinumab is excreted in human milk or absorbed systemically after ingestion. A decision must be made whether to discontinue breast-feeding or to discontinue tralokinumab therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Animal studies did not show any effects on male and female reproductive organs and on sperm count, motility and morphology (see section 5.3).
Tralokinumab has no or negligible influence on the ability to drive and use machines.
The most common adverse reactions are upper respiratory tract infections (23.4%; mainly reported as common cold), injection site reactions (7.2%), conjunctivitis (5.4%) and conjunctivitis allergic (2.0%).
Adverse reactions observed from clinical trials are presented in Table 1 by system organ class and frequency, using the following categories: 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). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The frequencies are based on the initial treatment period of up to 16 weeks in the pool of 5 studies in the atopic dermatitis population.
Table 1. List of adverse reactions:
| MedDRA System Organ Class | Frequency | Adverse reaction |
|---|---|---|
| Infections and infestations | Very common Common | Upper respiratory tract infections Conjunctivitis |
| Blood and lymphatic system disorders | Common | Eosinophilia |
| Eye disorders | Common Uncommon | Conjunctivitis allergic Keratitis |
| General disorders and administration site conditions | Common | Injection site reactions |
The long-term safety of tralokinumab was assessed in 2 monotherapy studies up to 52 weeks, and in a combination study with topical corticosteroids up to 32 weeks. The long-term safety of tralokinumab is further assessed in an open-label extension study (ECZTEND) for up to 5 years of treatment in adults and adolescents with moderate-to-severe AD (atopic dermatitis) receiving 300 mg of tralokinumab every two weeks (Q2W). Interim safety data up to 39 months were generally consistent with the safety profile observed up to week 16 in the pool of 5 adult studies.
Conjunctivitis occurred more frequently in atopic dermatitis patients who received tralokinumab (5.4%) compared to placebo (1.9%) in the initial treatment period of up to 16 weeks in the pool of 5 studies. Conjunctivitis was reported at a higher frequency in patients with severe atopic dermatitis compared to subjects with moderate atopic dermatitis in both the tralokinumab group (6.0 vs 3.3%; initial treatment period) and placebo group (2.2 vs 0.8%; initial treatment period). Most patients recovered or were recovering during the treatment period.
The rate of conjunctivitis in the interim safety data from the long-term open-label extension study (ECZTEND) was 3.37 events/100 patient years of exposure, compared with 22.0 events/100 patient years of exposure in the initial 16 weeks treatment period.
Keratitis was reported in 0.5% of subjects treated with tralokinumab during the initial treatment period. Of these, half were classified as keratoconjunctivitis, all were non-serious and mild or moderate in severity, and none led to treatment discontinuation.
The rate of keratitis in the interim safety data from the long-term open-label extension study (ECZTEND) was 0.15 events/100 patient years of exposure, compared with 1.7 events/100 patient years of exposure in the initial 16 weeks treatment period.
Adverse reactions of eosinophilia were reported in 1.3% of patients treated with tralokinumab and 0.3% of patients treated with placebo during the initial treatment period of up to 16 weeks in the pool of 5 studies. Tralokinumab-treated patients had a greater mean initial increase from baseline in eosinophil count compared to patients treated with placebo. Eosinophilia (≥ 5 000 cells/mcL) was measured in 1.2% of tralokinumab-treated patients and 0.3% of placebo-treated patients in the initial treatment period. However, the increase in the tralokinumab-treated patients was transient, and mean eosinophil counts returned to baseline during continued treatment. The safety profile for subjects with eosinophilia was comparable to the safety profile for all subjects.
Eczema herpeticum was reported in 0.3% of the subjects treated with tralokinumab and in 1.5% of subjects in the placebo group in the initial treatment period of up to 16 weeks in the pool of 5 studies in atopic dermatitis. The rate of eczema herpeticum in the initial 16 weeks treatment period was 1.2 events/100 years of exposure. The rate of eczema herpeticum in the interim safety data from the long-term open-label extension study (ECZTEND) was 0.60 events/100 years of exposure.
As with all therapeutic proteins, there is a potential for immunogenicity with tralokinumab.
Anti-drug-antibody (ADA) responses were not associated with any impact on tralokinumab exposure, safety, or efficacy.
In ECZTRA 1, ECZTRA 2, ECZTRA 3, and the vaccine-response study, the incidence of ADA up to 16 weeks was 1.4% for patients treated with tralokinumab and 1.3% for patients treated with placebo; neutralising antibodies were seen in 0.1% of patients treated with tralokinumab and 0.2% of patients treated with placebo.
The ADA incidence for subjects who received tralokinumab up to 52 weeks was 4.6%; 0.9% had persistent ADA and 1.0% had neutralising antibodies.
Injection site reactions (including pain and redness) occurred more frequently in patients who received tralokinumab (7.2%) compared to placebo (3.0%) in the initial treatment period of up to 16 weeks in the pool of 5 studies. Across all treatment periods in the 5 studies in atopic dermatitis, the vast majority (99%) of injection site reactions were mild or moderate in severity, and few patients (<1%) discontinued tralokinumab treatment. Most injections site reactions reported had a short duration with approximately 76% of the events resolving within 1 to 5 days.
The rate of injection site reactions in the interim safety data from the long-term open-label extension study (ECZTEND) was 5.8 events/100 patient years of exposure, compared with 51.5 events/100 patient years of exposure in the initial 16 weeks treatment period.
The safety of tralokinumab was assessed in patients 12 to 17 years of age (adolescents) with moderate-to-severe atopic dermatitis in a monotherapy study of 289 adolescents (ECZTRA 6) and in a long-term open-label extension study (ECZTEND) including 127 adolescents transferred from ECZTRA 6. The safety profile of tralokinumab in these patients followed through the initial treatment period of 16 weeks and the long-term treatment period of 52 weeks (ECZTRA 6), as well as in the interim safety data from the long-term open-label extension study up to 21 months (ECZTEND) were similar to the safety profile from studies in adults. However, a lower frequency of subjects with conjunctivitis was observed with tralokinumab in adolescents (1.0%) than in adults (5.4%), and, unlike in adults, the frequency of conjunctivitis allergic was similar for tralokinumab and placebo in adolescent patients.
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.
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