ILUMETRI 100mg / ml injection solution in pre-filled syringe medication leaflet

Ilumetri 100 mg solution for injection in pre-filled syringe

Ilumetri 200 mg solution for injection in pre-filled syringe

Ilumetri 100 mg solution for injection in pre-filled pen

Ilumetri 200 mg solution for injection in pre-filled pen

Ilumetri 100 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 100 mg of tildrakizumab in 1 mL.

Ilumetri 200 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 200 mg of tildrakizumab in 2 mL.

Ilumetri 100 mg solution for injection in pre-filled pen

Each pre-filled pen contains 100 mg of tildrakizumab in 1 mL.

Ilumetri 200 mg solution for injection in pre-filled pen

Each pre-filled pen contains 200 mg of tildrakizumab in 2 mL.

Tildrakizumab is a humanised IgG1/k monoclonal antibody produced in Chinese Hamster Ovary(CHO) cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

Each Ilumetri 100 mg solution for injection in pre-filled syringe contains 0.5 mg of polysorbate 80(E 433).

Each Ilumetri 200 mg solution for injection in pre-filled syringe contains 1 mg of polysorbate 80(E 433).

Each Ilumetri 100 mg solution for injection in pre-filled pen contains 0.5 mg of polysorbate 80(E 433).

Each Ilumetri 200 mg solution for injection in pre-filled pen contains 1 mg of polysorbate 80 (E 433).

Solution for injection (injection)

The solution is clear to slightly opalescent and colourless to slightly yellow. The solution pH is in therange of 5.7 - 6.3 and the osmolality is between 258 and 311 mOsm/kg.

Ilumetri is indicated for the treatment of adults with moderate to severe plaque psoriasis who arecandidates for systemic therapy.

This medicinal product is intended for use under the guidance and supervision of a physicianexperienced in the diagnosis and treatment of plaque psoriasis.

The recommended dose is 100 mg by subcutaneous injection at weeks 0, and 4 and every 12 weeksthereafter.

At the physician’s discretion, in patients with high disease burden or in patients above 90 kg of bodyweight a dose of 200 mg may provide greater efficacy.

Consideration should be given to discontinuing treatment in patients who have shown no response after28 weeks of treatment. Some patients with initial partial response may subsequently improve withcontinued treatment beyond 28 weeks.

If a dose is missed, the dose should be administered as soon as possible. Thereafter, dosing should beresumed at the regular scheduled time.

No dose adjustment is required (see section 5.2).

Ilumetri has not been studied in these patient populations. No dose recommendations can be made. Forfurther information on elimination of tildrakizumab, see section 5.2.

The safety and efficacy of Ilumetri in children and adolescents below the age of 18 years have not yetbeen established. No data are available.

This medicinal product is administered by subcutaneous injection. Injection sites should be alternated.

Ilumetri should not be injected into areas where the skin is affected by plaque psoriasis or is tender,bruised, red, hard, thick, or scaly. The syringe or the pen must not be shaken. Each syringe or pen is forsingle use only.

After proper training in subcutaneous injection technique, patients may self-inject Ilumetri if aphysician determines that it is appropriate. However, the physician should ensure appropriate follow-up of patients. Patients should be instructed to inject the full amount of tildrakizumab according to theinstructions provided in the package leaflet. Comprehensive instructions for administration are given inthe package leaflet.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Clinically important active infection, e.g. active tuberculosis (see section 4.4).

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

Tildrakizumab has the potential to increase the risk of infection (see section 4.8).

Caution should be exercised when considering the use of tildrakizumab in patients with a chronicinfection or a history of recurrent or recent serious infection.

Patients should be instructed to seek medical advice if signs or symptoms suggestive of a clinicallyrelevant chronic or acute infection occur. If a patient develops a serious infection, the patient should beclosely monitored and tildrakizumab should not be administered until the infection resolves (seesection 4.3).

Pre-treatment evaluation for tuberculosis

Prior to initiating treatment, patients should be evaluated for tuberculosis (TB) infection. Patientsreceiving tildrakizumab should be closely monitored for signs and symptoms of active TB during andafter treatment. Anti-TB therapy should be considered prior to initiating treatment in patients with apast history of latent or active TB in whom an adequate course of treatment cannot be confirmed.

If a serious hypersensivity reaction occurs, administration of tildrakizumab should be discontinuedimmediately and appropriate therapy initiated (see section 4.3).

Prior to initiating treatment with tildrakizumab, consider completion of all appropriate immunisationsaccording to current immunisation guidelines. If a patient has received live viral or bacterialvaccination it is recommended to wait at least 4 weeks prior to starting treatment with tildrakizumab.

Patients treated with tildrakizumab should not receive live vaccines during treatment and for at least17 weeks after treatment (see section 4.5).

This medicine contains 0.5 mg of polysorbate 80 (E 433) in each pre-filled syringe or pre-filled pen of100 mg and 1 mg of polysorbate 80 (E 433) in each pre-filled syringe or pre-filled pen of 200 mg,which is equivalent to 0.5 mg/mL. Polysorbates may cause allergic reactions.

Vaccines

No data are available on the response to live or inactivated vaccines. Live vaccines should not be givenconcurrently with tildrakizumab (see section 4.4).

Interactions with cytochrome P450

Concomitant medicinal products affecting tildrakizumab pharmacokinetics are not expected since it iscleared from the body by general protein catabolism processes with no contribution of cytochrome

P450 (CYP450) enzymes, and it is not eliminated by renal or hepatic pathways. Furthermore,tildrakizumab does not impact the pharmacokinetics of concomitant medicinal products metabolised by

CYP450 enzymes either through direct or indirect mechanisms (see section 5.2).

Interactions with other immunosuppressive agents or phototherapy

The safety and efficacy of tildrakizumab in combination with other immunosupressive agents,including biologics, or phototherapy has not been evaluated.

Women of childbearing potential should use an effective method of contraception during treatment andfor at least 17 weeks after treatment.

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use oftildrakizumab in pregnant women. Animal studies do not indicate direct or indirect harmful effect withrespect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoidthe use of Ilumetri during pregnancy.

It is unknown whether tildrakizumab is excreted in human milk. Available toxicological data incynomolgus monkey have shown negligible levels of Ilumetri in milk on postnatal day 28 (seesection 5.3). In humans, during the first few days after birth antibodies may be transferred to thenewborns through milk. In this short period, a risk to the newborns/infants cannot be excluded. Adecision must be made whether to discontinue breast-feeding or to discontinue/abstain from Ilumetritherapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for thewoman.

The effect of Ilumetri on human fertility has not been evaluated. Animal studies do not indicate director indirect harmful effects with respect to fertility (see section 5.3).

Ilumetri has no or negligible influence on the ability to drive and use machines.

The most common adverse reactions are upper respiratory tract infections (12.6%), headache (4.0%),diarrhoea (1.6%), gastroenteritis (1.5%), back pain (1.5%), nausea (1.3%) and injection site pain(1.3%).

Adverse reactions from clinical studies (Table 1) are listed by MedDRA system organ class (SOC) andfrequency, using the following convention: 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 available data). Within each frequency grouping, adverse reactions arepresented in the order of decreasing seriousness.

Table 1. List of adverse reactions

MedDRA System organ Preferred term Frequency categoryclass

Infections and infestations Upper respiratory tract infectionsa Very common

Nervous system disorders Headache Common

Gastrointestinal disorders Gastroenteritis Common

Diarrhoea Common

Nausea Common

General disorders and Back pain Commonadministration siteconditions Injection site pain CommonaIncluding nasopharyngitis.

Long-term Safety

The safety profile of tildrakizumab observed during the long-term extensions periods of reSURFACE 1and reSURFACE 2 was consistent with that of the double-blind periods.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Doses up to 10 mg/kg intravenously have been safely administered in clinical trials.

In the event of overdose, it is recommended that the patient be monitored for any signs or symptoms ofadverse reactions and that appropriate symptomatic treatment be instituted immediately.

Pharmacotherapeutic group: Immunosuppressants, interleukin inhibitors, ATC code: L04AC17

Tildrakizumab is a humanised IgG1/k monoclonal antibody that specifically binds to the p19 proteinsubunit of the interleukin-23 (IL-23) cytokine without binding to IL-12 and inhibits its interaction withthe IL-23 receptor.

IL-23 is a naturally occurring cytokine that is involved in inflammatory and immune responses.

Tildrakizumab inhibits the release of proinflammatory cytokines and chemokines.

The multicentre, randomised, double-blind, placebo-controlled trials reSURFACE 1 and reSURFACE2 studies enrolled a total of 1,862 patients 18 years of age and older with plaque psoriasis who had aminimum body surface area involvement of 10%, a Physician Global Assessment (PGA) score of ≥ 3in the overall assessment (plaque thickness, erythema, and scaling) of psoriasis on a severity scale of 0to 5, a Psoriasis Area and Severity Index (PASI) score ≥ 12, and who were candidates for phototherapyor systemic therapy.

In these studies, patients were randomised to either placebo or tildrakizumab (including 200 mg and100 mg at 0, 4 and every twelve weeks thereafter [Q12W]), up to 52 or 64 weeks. In the activecomparator study (reSURFACE 2), patients were also randomised to receive etanercept 50 mg twiceweekly for 12 weeks, and weekly thereafter up to 28 weeks. Patients who did not respond to etanercepttreatment (<75% reduction in PASI from baseline) were switched to tildrakizumab 200 mg Q12W upto 52 weeks, while patients who responded to etanercept were discontinued from the study.

Eligible patients who completed the double-blind periods of reSURFACE 1 and reSURFACE 2with ≥ 50% improvement in PASI from baseline could participate in open-label extension phases ofthese studies in order to evaluate the long-term safety and maintenance of efficacy of continuoustildrakizumab treatment. Patients entering the extension periods of reSURFACE 1 and reSURFACE 2continued treatment at the same dose of tildrakizumab, 100 mg or 200 mg, that they were receiving atweek 64 or 52, respectively. Up to 6 years of follow-up data are available.

Overall demographic and baseline characteristics in reSURFACE 1 and reSURFACE 2 studies wereconsistent across individual trials. Patients were 18 to 82 years old, with a mean age of 45.9 years old.

The median baseline PASI score ranged from 17.7 to 18.4 across treatment groups. Baseline PGAscore was marked or severe in 33.4% of patients. Of all patients, 35.8% had received priorphototherapy, 41.1% had received prior conventional systemic therapy, 16.7% had received priorbiologic therapy for the treatment of plaque psoriasis. A total of 15.4% of study patients had a historyof psoriatic arthritis. Mean baseline Dermatology Life Quality Index (DLQI) ranged from 13.0 to 14.8.

Studies reSURFACE 1 and reSURFACE 2 assessed the changes from baseline at Week 12 in the twoco-primary endpoints: 1) PASI 75 and 2) PGA of “0” (cleared) or “1” (minimal), with at least a 2-pointimprovement from baseline. Other evaluated outcomes included the proportion of patients whoachieved PASI 90, PASI 100, the proportion of patients with DLQI 0 or 1, and maintenance of efficacyup to 52/64 weeks.

Results obtained at weeks 12, 28 and beyond (up to week 64 in reSURFACE 1 and up to week 52 inreSURFACE 2) are presented in Table 2 and Table 3.

Table 2. Summary of response rates in studies reSURFACE 1 and reSURFACE 2

Week 12 (2 doses)* Week 28 (3 doses)*200 mg 100 mg Placebo Etanercept 200 mg 100 mg EtanerceptreSURFACE1

Number of patients 308 309 154 - 298 299 -

PASI 75a (%) 62.3†b 63.8†b 5.8b - 81.9c 80.4c -

PGA of “clear” or“minimal” with ≥2 †b †b b c c -grade improvement 59.1 57.9 7.1 - 69.1 66.0from Baselinea (%)

PASI 90 (%) 35.4†b 34.6†b 2.6b - 59.0c 51.6c -

PASI 100 (%) 14.0†b 13.9†b 1.3b - 31.5c 23.5c -

DLQI Score 0 or 1 (%) 44.2† 41.5 † 5.3 - 56.7c 52.4c -reSURFACE2

Number of patients 314 307 156 313 299 294 289

PASI 75a (%) 65.6†‡b 61.2†‡b 5.8b 48.2b 72.6‡b 73.5‡b 53.6b

PGA of “clear” or“minimal” with ≥2 †¥b †b bgrade improvement 59.2 54.7 4.5 47.6b 69.2‡b 64.6‡b 45.3bfrom Baselinea (%)

PASI 90 (%) 36.6†‡b 38.8†‡b 1.3b 21.4b 57.7‡c 55.5‡c 29.4 c

PASI 100 (%) 11.8†‡b 12.4†‡b 0 4.8b 27.0‡c 22.8‡c 10.7c

DLQI Score 0 or 1 (%) 47.4†¥ 40.2† 8.0 35.5 65.0‡c 54.1‡c 39.4ca Co-primary efficacy endpoint at week 12.b Non-responder imputation for missing data.c No imputation for missing data.

*The number of doses administered refers only to tildrakizumab groups.n = number of patients in the full analysis set for which data was available, after imputation when applicable.p-values calculated using the Cochran-Mantel-Haenszel (CMH) test stratified by body weight (≤90 kg, >90 kg) and priorexposure to biologic therapy for psoriasis (yes/no).† p≤0.001 versus placebo; ‡ p≤0.001 versus etanercept; ¥ p≤0.05 versus etanercept.

The maintenance of response in studies reSURFACE 1 and reSURFACE 2 are presented in Table 3.

Maintenance and durability of PASI 90 response over time is presented in Figure 1.

Table 3. Maintenance of response in studies reSURFACE 1 and reSURFACE 2

Long term responsea,b200 mg 100 mgreSURFACE 1 Week 28 Week 64 Week 28 Week 64

Number of patients 116 114 115 112

PGA of “clear” or “minimal” with ≥2grade improvement from Baseline (%) 80.2 76.3 80.9 61.6

PASI 90 (%) 70.7 74.6 65.2 58.0

PASI 100 (%) 38.8 40.4 25.2 32.1

Long term responsea,b200 mg 100 mgreSURFACE 2 Week 28 Week 52 Week 28 Week 52

Number of patients 108 105 213 204

PGA of “clear” or “minimal” with ≥2 79.4grade improvement from Baseline (%) 88.0 84.8 84.0

PASI 90 (%) 75.0 81.9 74.2 78.4

PASI 100 (%) 34.3 46.7 30.2 35.3a Long-term response in patients who were responders (had achieved at least PASI 75) to tildrakizumab at week 28.b No imputation for missing data.

Figure 1. Maintenance and durability of PASI 90 response. Proportion of patients with PASI 90response over time up to week 64 (full analysis set part 3*)80 74.631.721.6

W4 W8 W12 W16 W22 W28 W32 W36 W40 W44 W48 W52 W56 W60 W64tildrakizumab 100 mg --> Placebo**tildrakizumab 100 mgtildrakizumab 200 mg --> Placebo**tildrakizumab 200 mg

Patients randomised to tildrakizumab 100 mg or tildrakizumab 200 mg in Part 1 who were PASI 75 responders at week 28(reSURFACE 1).

*No imputation of missing data.

**These patients were switched to placebo at week 28.

Responders (%)

Of the patients who completed the double-blind period, 506 (79%) in reSURFACE 1 and 730 (97%) inreSURFACE 2 entered the extension period. Across studies, at least 76% of patients who had a

PASI 90 response at the end of double-blind period, maintained a PASI 90 response during theextension period, when tildrakizumab 100 mg or 200 mg treatment was continued during a period of192 weeks (Figure 2 and Figure 3).

Figure 2. Percentage of patients who maintained a PASI 90 response by visit in the open-label extension of reSURFACE 1 (Full Analysis Set, Extension Period*)

*Among PASI 90 responders at the end of the double-blind study period. No imputation of missing data.

Note: Visit week is nominal, as study participants had a window of up to approximately 12 weeks from week 64 tobegin the extension.

Figure 3. Percentage of patients who maintained a PASI 90 response by visit in the open-label extension of reSURFACE 2 (Full Analysis Set, Extension Period*)

*Among PASI 90 responders at the end of the double-blind study period. No imputation of missing data.

Quality of life/patient-reported outcomes

At week 12 and across studies, tildrakizumab was associated with statistically significant improvementin health-related quality of life as assessed by the DLQI (Table 2). Improvements were maintainedover time with at week 52, 63.7% (100 mg) and 73.3% (200 mg) in reSURFACE 1, and 68.8%(100 mg) and 72.4% (200 mg) in reSURFACE 2 of patients who were PASI 75 responders at week 28having a DLQI of 0 or 1.

In pooled Phase 2b and Phase 3 analyses, 7.3% of tildrakizumab-treated patients developed antibodiesto tildrakizumab up to week 64. Of the subjects who developed antibodies to tildrakizumab, 38%(22/57 patients) had neutralizing antibodies. This represents 2.8% of all subjects receivingtildrakizumab.

In pooled phase 3 analyses, 8.3% of tildrakizumab-treated patients developed antibodies totildrakizumab up to 420 weeks of treatment. Of the tildrakizumab-treated patients who developedantibodies to tildrakizumab, 35% (36/102 patients) had antibodies that were classified as neutralizing,which represents 2.9% of all tildrakizumab-treated patients.

The development of neutralizing antibodies to tildrakizumab was associated with lower serumtildrakizumab concentrations.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Ilumetri in one or more subsets of the paediatric population in the treatment of plaque psoriasis (seesection 4.2 for information on paediatric use).

The subcutaneous formulation of tildrakizumab showed an absolute bioavailability ranging from 73%(90% CI: 46% - 115%, 200 mg subcutaneous vs. 3 mg/kg intravenous) to 80% (90% CI: 62% - 103%,50 mg subcutaneous vs. 0.5 mg/kg intravenous) in healthy subjects, as a result of cross study singledose comparison. Maximum concentration was reached at 6.2 days after injection. Populationpharmacokinetic analysis indicated a 31% higher bioavailability in healthy subjects compared topatients.

At steady state, following administration of 100 mg of tildrakizumab in subjects with moderate tosevere plaque psoriasis geometric means (% coefficient of variation [%CV]) of AUC0-τ and Cmax valueswere respectively 305 μg·day/mL (41%) and 8.1 μg/mL (34%), whereas they were 612 μg·day/mL(40%) and 16.3 μg/mL (33%) following administration of 200 mg.

Tildrakizumab has limited extravascular distribution with volume of distribution (Vd) values rangingfrom 76.9 to 106 mL/kg.

Tildrakizumab is catabolised into component amino acids by general protein degradation processes.

Small-molecule metabolic pathways (e.g., CYP450 enzymes, glucuronosyltransferases) do notcontribute to its clearance.

Clearance values range from 2.04 to 2.52 mL/day/kg and the half-life was 23.4 days (23% CV) insubjects with plaque psoriasis.

Tildrakizumab exhibited dose-proportional pharmacokinetics in subjects with plaque psoriasis over adose range from 50 mg to 400 mg following subcutaneous administration, with clearance beingindependent of dose.

Steady-state is achieved by 16 weeks with the clinical regimen of 0, 4, and every 12 weeks thereafter,with 1.1-fold accumulation in exposure between week-1 and week-12 independent of dose.

Population pharmacokinetic analysis indicated that age did not have a clinically significant influenceon the clearance of tildrakizumab in adult subjects with plaque psoriasis. Following administration of100 mg or 200 mg of tildrakizumab, subjects who are 65 years or older (n=81 and n=82, respectively)had a similar tildrakizumab clearance as compared to subjects less than 65 years old (n=884).

No formal trial of the effect of hepatic or renal impairment on the pharmacokinetics of tildrakizumabwas conducted. Tildrakizumab is catabolised into component amino acids by general proteindegradation processes and is not eliminated by renal or hepatic pathways.

Population pharmacokinetic modelling indicated that exposure decreased as body weight increased.

The geometric mean exposure (AUC0-τ at steady state) in adult patients weighing > 90 kg following a100 mg or 200 mg subcutaneous dose was predicted to be about 30% lower than in an adult patientweighing ≤90 kg (see section 4.2).

Results from a drug-drug interaction study conducted in plaque psoriasis subjects suggest thattildrakizumab had no clinically relevant effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6 and

CYP3A4. Therefore, tildrakizumab does not impact the pharmacokinetics of concomitant medicinalproducts metabolised by CYP enzyme (see section 4.5).

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, and repeated dose toxicity.

Animal mutagenicity and carcinogenicity studies have not been conducted with tildrakizumab. Studiesin mouse tumor models showed that selective inhibition of IL-23p19 does not increase carcinogenicrisk.

In cynomolgus monkeys, there was negligible secretion of the product into breast milk. One monthafter birth, the milk/serum ratio was ≤ 0.002. Tildrakizumab was shown to distribute across theplacental barrier. After repeated dosing to pregnant cynomolgus monkeys, serum concentrations werequantifiable in the fetus, but the reproduction toxicity studies did not reveal any untoward effects.

No effects on fertility parameters such as reproductive organs, menstrual cycle length, and/orhormones were observed in male and female cynomolgus monkeys that were administeredtildrakizumab at doses resulting in > 100 times the human exposure at the recommended clinical dosebased on AUC.

In a pre- and postnatal development toxicity study in monkeys, no related increase in pregnancy losswas observed at exposures up to 85 times the human exposure at the recommended dose. No harmfuleffects were noted in neonates at maternal exposures up to 9 times the human exposure at therecommended dose. Two neonatal deaths from monkeys administered tildrakizumab at maternalexposure of 85 times the human exposure at the recommended dose were attributed to possible viralinfection and considered of uncertain relationship to the treatment. The clinical significance of thesefindings is unknown.

L-Histidine

L-Histidine hydrochloride monohydrate

Polysorbate 80 (E 433)

Sucrose

Water for injections

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

3 years

Store in a refrigerator (2 °C - 8 °C).

Do not freeze.

Unopened syringe or pen of Ilumetri may be removed from the refrigeration and stored up to 25 °C fora single period of up to 30 days. Once removed from the refrigerator and stored under these conditions,discard after 30 days or by the expiry date printed on the container, whichever occurs first. A field forthe date is provided on the carton to record the removal from refrigerator date.

Store in the outer carton in order to protect from light.

Do not shake.

Ilumetri 100 mg solution for injection in pre-filled syringe1 mL solution in a type I glass pre-filled syringe with stainless steel 29G x ½” needle, covered with aneedle shield and rigid needle shield of polypropylene with a fluropolymer lamination, plunger stopperassembled in a passive safety device.

Pack size of 1 pre-filled syringe or 2 pre-filled syringes.

Not all pack sizes may be marketed.

Ilumetri 200 mg solution for injection in pre-filled syringe2 mL solution in a type I glass pre-filled syringe with stainless steel 27G x ½” needle, covered with aneedle shield and rigid needle shield of polypropylene with a fluropolymer lamination, plunger stopperassembled in a passive safety device.

Pack size of 1 pre-filled syringe.

Ilumetri 100 mg solution for injection in pre-filled pen1 ml, pre-filled syringe, comprising a syringe barrel of Type I glass with a staked/bonded needle and arigid needle shield and a sterile ready to use plunger stopper.

Pack size of 1 pre-filled pen.

Ilumetri 200 mg solution for injection in pre-filled pen2 mL, pre-filled syringe, comprising a syringe barrel of Type I glass with a staked/bonded needle and arigid needle shield and a sterile ready to use plunger stopper.

Pack size of 1 pre-filled pen.

Ilumetri is a sterile solution for injection in pre-filled syringe or pre-filled pen. The syringes and pensare for single use only.

Do not shake or freeze. The 100 mg and 200 mg syringe and the 100 mg pen should be taken out of therefrigerator 30 minutes before injecting to allow it to reach room temperature (up to 25 ºC). The200 mg pen should be taken out of the refrigerator 45 minutes before injecting to allow it to reachroom temperature (up to 25 ºC).

Prior to use, a visual inspection of the syringe or pen is recommended. A small air bubble may beapparent: this is normal. Do not use if the liquid contains easily visible particles, is cloudy or isdistinctly brown.

The instructions for use included with the package leaflet must be followed carefully.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Almirall, S.A.

Ronda General Mitre, 15108022 Barcelona

Spain

EU/1/18/1323/001

EU/1/18/1323/002

EU/1/18/1323/003

EU/1/18/1323/004

EU/1/18/1323/005

Date of first authorisation: 17 September 2018

Date of latest renewal: 24 July 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.