ALOFISEL 5x10^6 CELULE/ml 5 x 10{6} celule / ml dispersion for injection medication leaflet

Alofisel 5 × 106 cells/mL suspension for injection

2.1 General description

Alofisel (darvadstrocel) is expanded human allogeneic mesenchymal adult stem cells extracted fromadipose tissue (expanded adipose stem cells - eASC).

2.2 Qualitative and quantitative composition

Each vial contains 30 × 106 cells (eASC) in 6 mL of suspension, corresponding to a concentration of5 × 106 cells/mL.

For the full list of excipients, see section 6.1.

Suspension for injection (injection)

The suspension of cells may have settled in the bottom of the vial forming a sediment. After gentlere-suspension, the product is a white to yellowish homogeneous suspension.

Alofisel is indicated for the treatment of complex perianal fistulas in adult patients withnon-active/mildly active luminal Crohn’s disease, when fistulas have shown an inadequate response toat least one conventional or biologic therapy. Alofisel should be used only after conditioning of thefistulas (see section 4.2).

Alofisel should only be administered by specialist physicians experienced in the diagnosis andtreatment of conditions for which Alofisel is indicated.

A single dose of darvadstrocel consists of 120 × 106 cells supplied in 4 vials. Each vial contains30 × 106 cells in 6 mL of suspension. The full content of the 4 vials must be administered for thetreatment of up to two internal openings and up to three external openings. This means that with adose of 120 × 106 cells it is possible to treat up to three fistula tracts that open to the perianal area.

The efficacy or safety of repeat administration of Alofisel has not been established.

Data on the use of darvadstrocel in the elderly population are limited, however, given the cell-basednature of darvadstrocel and its local administration route it is not expected that the benefit-risk profileof darvadstrocel in elderly patients will differ from that observed in non-elderly patients. Therefore, nodose adjustment is required in elderly patients.

Data on the use of darvadstrocel in patients with hepatic impairment are not available. However, giventhe cell-based nature of darvadstrocel and its local administration route it is not expected that thebenefit-risk profile of darvadstrocel in hepatically impaired patients will differ from that observed innon-hepatically impaired patients. Therefore, no dose adjustment is required in hepatically impairedpatients.

Data on the use of darvadstrocel in patients with renal impairment are not available. However, giventhe cell-based nature of darvadstrocel and its local administration route it is not expected that thebenefit-risk profile of darvadstrocel in renally impaired patients will differ from that observed innon-renally impaired patients. Therefore, no dose adjustment is required in renally impaired patients.

The safety and efficacy of darvadstrocel in children and adolescents aged 0 to 17 years have not yetbeen established. No data are available.

For injection in the fistula tract tissue in a surgical environment under anaesthesia (general or regional(see section 4.4)) as described below.

In line with standards for the management of complex perianal fistulas, characterisation of thepatient’s fistulas is needed prior to treatment. It is recommended that at least 2 to 3 weeks before theadministration day, preparatory surgery is performed comprising exploration (under anaesthesia) offistula anatomy (number of existing fistulas and openings), topography (extent and relationship withthe sphincters and other pelvic muscles), potential associated complications (such as abscesses) andwhether local mucosal disease is mild or inactive. Vigorous curettage of all fistula tracts isrecommended, with special emphasis in the internal openings area, using a metallic curette. In case ofan abscess, incision and drainage are needed, and setons should be placed, if appropriate, inaccordance with routine surgical procedures. Before scheduling Alofisel administration, the surgeonmust ensure that no abscesses are present.

Immediately prior to the administration of Alofisel, the fistula tracts should be conditioned as follows:a) If setons are in place, they must be removed.b) Identify the location of the internal openings. For this, injection of a sodium chloride9 mg/mL (0.9%) solution through the external openings until it gets out through theinternal openings is recommended. The injection of any other substance through the fistulatracts, such as hydrogen peroxide, methylene blue, iodine solutions or hypertonic glucosesolutions is not allowed, as these agents compromise the viability of the cells to be injected(see section 4.4 and section 4.5).

c) Perform a vigorous curettage of all fistula tracts, with special emphasis in the internalopenings areas, using a metallic curette.

d) Suture closed the internal openings.

After conditioning of the fistula tracts, Alofisel should be administered according to the following twosteps:

1. Preparationa) The expiry time: date of Alofisel should be re-confirmed; vials should then beremoved from the outer packaging.b) Re-suspend the cells by gently tapping the bottom of the vials until a homogeneoussuspension is obtained, avoiding bubble formation. Each vial should be usedimmediately after re-suspension to prevent the cells from re-sedimenting.

c) Remove the cap from the vial, gently turn the vial upside down, and gently aspiratethe whole content using a syringe with a conventional needle no thinner than 22G(see section 4.4).

d) Replace the needle with a longer needle, also no thinner than 22G, in order to reachthe intended sites of injection. For example, a needle for spinal anaesthesiameasuring around 90 mm in length is required.

e) Repeat steps (b), (c) and (d) for each of the vials in turn after the cells from onevial have been injected.

2. Injection

Two of the vials should be used for the internal openings and the remaining two forinjection along the walls of the fistula tracts (via external openings). After inserting theneedle tip into each intended injection site, perform a slight aspiration to avoidintravascular administration.

a) Injection around the internal openings of the fistula tracts: insert the needle throughthe anus and proceed as follows:

- If there is a single internal opening, inject the content of each of the two vials (oneafter the other) in small deposits into the tissue surrounding the single internalopening.

- If there are two internal openings, inject the content of the first of two vials insmall deposits into the tissue around one internal opening. Then inject the contentof the second vial in small deposits into the tissue around the second internalopening.

b) Injection along the walls of the fistula tracts: insert the needle through the externalopenings and, from within the fistula lumen:

- If there is a single external opening, inject separately the content of each of theremaining two vials superficially into the tissue walls along the length of the fistulatracts, making small deposits of the cell suspension.

- If there are two or three external openings, inject the content of the remaining twovials equally between the associated tracts.

The procedure for injection along the walls of the fistula tracts should beperformed based on prior knowledge of the anatomy and topology of the fistulatracts, as determined during the fistula characterisation. Ensure cells are notinjected into the lumen of the fistula tracts to avoid leakage of cells.

Softly massage the area around the external openings for 20-30 seconds and cover the externalopenings with a sterile bandage.

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

The traceability requirements of cell-based therapy medicinal products must apply. To ensuretraceability the name of the product, the batch number and the name of the treated patient must be keptfor a period of 30 years after the expiry date of the product.

Alofisel may contain trace amounts of either gentamicin or benzylpenicillin and streptomycin. Thisshould be considered in patients with known hypersensitivity to these classes of antibiotics.

Local anaesthesia is not recommended due to the unknown effect of local anaesthetics on the injectedcells (see section 4.2).

The injection of any substance other than sodium chloride 9 mg/mL (0.9%) solution (e.g. hydrogenperoxide, methylene blue, iodine solutions or hypertonic glucose solutions) (see section 4.2 andsection 4.5) through the fistula tracts is not allowed before, during, or after the injection of Alofisel asthese may compromise the viability of the cells and, therefore, may affect the effectiveness of thetreatment.

Alofisel must not be administered using a needle thinner than 22G. Thinner gauge needles can causecell disruption during injection and may compromise cell viability and, therefore, may affect efficacyof treatment.

Transmission of an infectious agent

As Alofisel is a living stem cell therapy it cannot be sterilised, a risk of transmission of infectiousagents exists, although the risk is considered to be low and controlled in the manufacturing process.

Healthcare professionals administering darvadstrocel must, therefore, monitor patients for signs andsymptoms of infections after treatment and treat appropriately, if needed.

Conditioning reactions

Conditioning of fistulas has been associated with proctalgia and procedural pain (see section 4.8).

Blood, organ, tissue and cell donation

Patients treated with Alofisel must not donate blood, organs, tissues and cells for transplantation.

No in vivo interaction studies have been performed.

In vitro interaction studies have shown that the cell viability and immunomodulatory function of

Alofisel is not affected by the presence of clinically-relevant concentrations of conventional therapiesfor Crohn’s disease (infliximab, methotrexate and azathioprine).

The injection of any substance other than sodium chloride 9 mg/mL (0.9%) solution (e.g. hydrogenperoxide, methylene blue, iodine solutions or hypertonic glucose solutions) (see section 4.2 andsection 4.4) through the fistula tracts and use of local anaesthesia is not recommended due to theunknown effect on the injected cells (see section 4.4).

There are no data from the use of darvadstrocel in pregnant women.

Animal studies are not available with respect to reproductive toxicity (see section 5.3).

Darvadstrocel is not recommended during pregnancy and in women of childbearing potential not usingcontraception.

It is unknown whether darvadstrocel is excreted in human milk. A risk to the breast-fed infant cannotbe excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstainfrom Alofisel therapy taking into account the benefit of breast-feeding for the child and the benefit oftherapy for the woman.

No data are available.

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

The most common treatment-emergent adverse events were anal abscess (Alofisel: 19.4% patients;control group: 13.7% patients), proctalgia (Alofisel: 14.6% patients; control group: 11.8% patients)and anal fistula (Alofisel: 10.7% patients; control group: 7.8% patients).

The following listing of adverse reactions is based on the clinical trial and post-marketing experienceis displayed by system organ class. The frequency of adverse reactions is defined using the followingconvention: 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 fromavailable data).

Table 1. Adverse reactions

System Organ Class Frequency Adverse Reactions

Infections and infestations Common Anal abscess

Gastrointestinal disorders Common Proctalgia*

Common Anal fistula

Injuring, poisoning and procedural Common Procedural pain*complications

*Conditioning reactions occurring up to seven days after the fistula preparation for treatment administration.

Anal abscess

Up to week 52, 20 (19.4%) and 14 (13.7%) patients developed 21 and 19 anal abscesses in the Alofiseland control groups, respectively, of which 4 and 5 anal abscesses in respective groups (3.9% patientsin both groups) were of severe intensity. Up to week 104, 15 (14.6%) and 8 (7.8%) patients developed15 and 9 serious anal abscesses in the Alofisel and control groups, respectively.

Proctalgia

Up to week 52, 15 (14.6%) and 12 (11.8%) patients developed 20 and 17 proctalgia in the Alofisel andcontrol groups, respectively, none of these proctalgia being serious in any group up to week 104.

There were no patients in Alofisel group with proctalgia of severe intensity and 3.9% patients with 4proctalgia in the control group.

Anal fistula

Up to week 52, 11 (10.7%) and 8 (7.8%) patients developed 12 and 8 anal fistulas in the Alofisel andcontrol groups, respectively, none of these being of severe intensity. Up to week 104, 5 (4.9%) andone (< 1.0%) patients developed 5 and 1 serious anal fistulas in the Alofisel and control groups,respectively.

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.

No data regarding overdose of Alofisel is available.

Pharmacotherapeutic group: Immunosuppressants, other immunosuppressants, ATC code: L04AX08.

Darvadstrocel contains expanded adipose stem cells (eASC), which exhibit immunomodulatory andanti-inflammatory effects at inflammation sites.

Anal fistulas typically present as fissures penetrating the intestinal lumen and perianal skin surface,and are characterised by local inflammation that is exacerbated by bacterial infections and faecalcontamination. In the inflamed area, there is infiltration of activated lymphocytes and local release ofinflammatory cytokines.

Inflammatory cytokines, in particular IFN-γ released by activated immune cells (i.e., lymphocytes),activate eASC. Once activated, eASC impair proliferation of activated lymphocytes and reduce therelease of pro-inflammatory cytokines. This immunoregulatory activity reduces inflammation, whichmay allow the tissues around the fistula tract to heal.

Pharmacodynamic effect

In the ADMIRE-CD study, 63/103 of the eASC-treated patient population were analysed for thepresence of donor-specific antibodies (DSA) at baseline and week 12. At week 12, 23/63 (36%)showed anti-donor antibody production. Of patients with DSA at week 12, 7/23 (30%) had cleared

DSA by week 52. Lack of de novo DSA generation was observed between week 12 and week 52. Noassociation between DSA results and safety or efficacy up to week 52 was seen in the subset tested.

The efficacy of Alofisel was assessed in the ADMIRE-CD study. This was a randomised, doubleblind, parallel group, placebo-controlled, multicentre clinical trial to assess efficacy and safety of

Alofisel for the treatment of complex perianal fistulas in Crohn’s disease patients.

A total of 212 patients were randomised, and 205 patients received a local injection of eitherdarvadstrocel 120 × 106 cells or placebo in a 1:1 design. Patients had draining complex perianalfistulas with an inadequate response to at least one of the following treatments: antibiotics,immunosuppressants or anti-TNFs. Concomitant use of stable doses of immunosuppressants (18% ofpatients) or anti-TNFs (33%) or both (28%) was allowed during the study.

The primary endpoint was the combined remission at week 24 after study treatment, defined as clinicalclosure of all treated fistulas (absence of draining despite gentle finger compression) and absence ofcollection (> 2 cm) confirmed by blinded central MRI. The key secondary endpoints were defined asclinical remission (clinical closure of all treated fistula) and response (clinical closure of at least 50%of all treated fistulas) at week 24. In addition, a long-term follow-up was conducted up to week 52.

Alofisel group Control group P value(Alofisel+standard of (Placebo+standard ofcare*) care*)

N=103 N=102

Combined remission at52 35 0.019week 24 (% patients)

Combined remission at56 38 0.009week 52 (% patients)

* Including abscess drainage, seton placement/removal, curettage, suture of internal openings and medical treatments

Results of the key secondary endpoints show that the proportion of patients with clinical remission atweek 24 was 55% in the Alofisel group and 42% in the control group (p = 0.052) and thecorresponding figures for response were 69% and 55% (p = 0.039).

The proportion of patients with clinical remission at week 52 was 59% in the Alofisel group and 41%in the control group (p = 0.012) and corresponding figures for response were 66% and55% (p = 0.114). In a limited number of patients followed up to week 104, clinical remission atweek 104 was 56% in the Alofisel group and 40% in the control group.

In Alofisel group, the number of patients who had combined remission at week 24 and subsequentlydeveloped anal abscess/anal fistula by week 52 was 2.9% (3/103), whereas the number of patientswithout combined remission at week 24 who subsequently developed anal abscess/anal fistula byweek 52 was 9.7% (10/103).

In control group, the number of patients who had combined remission at week 24 who developed analabscess/anal fistula by week 52 was 4.9% (5/102), whereas the number of patients without combinedremission at week 24 who developed anal abscess/anal fistula by week 52 was 2.9% (3/102).

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

Alofisel in one or more subsets of the paediatric population in the treatment of anal fistula (seesection 4.2 for information on paediatric use).

The nature and intended clinical use of darvadstrocel are such that conventional studies ofpharmacokinetics (absorption, distribution, metabolism and elimination) are not applicable.

Biodistribution studies in preclinical models were conducted with the objective of evaluating thepersistence of eASC at the site of injection and their potential migration into other tissues or organsystems. After perianal and intrarectal injection of human eASC in athymic rats, cells were present inthe rectum and jejunum at the site of injection for at least 14 days and were undetectable after3 months. eASC were not present in any of the tissues analysed after 3 months or 6 months.

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

Reproductive and developmental toxicity studies have not been performed for darvadstrocel becausepreclinical biodistribution studies indicated no migration and integration of eASC into reproductiveorgans following administration of eASC via different routes.

The effect of ex vivo expansion on the genetic stability of cells has been assessed in vitro without anyindication of carcinogenic potential.

Dulbecco’s Modified Eagle´s Medium (DMEM) (containing amino acids, vitamins, salts andcarbohydrates).

Human albumin.

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

72 hours.

Store between 15ºC and 25ºC.

Keep the medicinal product within the outer carton to protect from light and moisture, and inside theshipping container at all times until its administration, to maintain the required temperature.

Preserve the container away from heat and direct light sources.

Do not refrigerate or freeze.

Do not irradiate or otherwise sterilise.

implantation

Type I glass vial. Each vial contains 6 mL of eASC suspension and is closed with a rubber stopper anda flip-off seal. The vials are placed inside a cardboard box.

Pack size: 4 vials.1 dose consists of 4 vials of 6 mL (in total 24 mL).

Preparation prior to administration

Alofisel must not be filtered or administered using a needle thinner than 22G (see section 4.4).

Immediately before use, Alofisel must be re-suspended by gently tapping the bottom of the vial until ahomogeneous suspension is obtained, avoiding bubble formation. For further information on the use of

Alofisel see section 4.2.

Precautions to be taken for the disposal of the medicinal product

Unused medicinal product and all material that has been in contact with Alofisel (solid and liquidwaste) must be handled and disposed of as potentially infectious waste in accordance with localguidelines on handling of human-derived material.

Takeda Pharma A/S

Delta Park 452665 Vallensbaek Strand

Denmark

EU/1/17/1261/001

Date of first authorisation: 23 March 2018

Date of latest renewal: 10 January 2023

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

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