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

Alofisel should only be administered by specialist physicians experienced in the diagnosis and treatment of conditions for which Alofisel is indicated. Posology A single dose of darvadstrocel consists of 120 x 106 cells supplied in 4 vials. Each vial contains 30 x 106 cells in 6 mL of dispersion. The full content of the 4 vials must be administered for the treatment of up to two internal openings and up to three external openings. This means that with a dose of 120 x 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. Special populations Elderly Data on the use of darvadstrocel in the elderly population are limited, however, given the cell-based nature of darvadstrocel and its local administration route it is not expected that the benefit-risk profile of darvadstrocel in elderly patients will differ from that observed in non-elderly patients. Therefore, no dose adjustment is required in elderly patients. Hepatic impairment Data on the use of darvadstrocel in patients with hepatic impairment are not available. However, given the cell-based nature of darvadstrocel and its local administration route it is not expected that the benefit-risk profile of darvadstrocel in hepatically impaired patients will differ from that observed in non-hepatically impaired patients. Therefore, no dose adjustment is required in hepatically impaired patients. Renal impairment Data on the use of darvadstrocel in patients with renal impairment are not available. However, given the cell-based nature of darvadstrocel and its local administration route it is not expected that the benefit-risk profile of darvadstrocel in renally impaired patients will differ from that observed in non-renally impaired patients. Therefore, no dose adjustment is required in renally impaired patients. Paediatric population The safety and efficacy of darvadstrocel in children and adolescents aged 0 to 17 years have not yet been established. No data are available. Method of administration Perilesional use. 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 the patient’s fistulas is needed prior to treatment. It is recommended that at least 2 to 3 weeks before the administration day, preparatory surgery is performed comprising exploration (under anaesthesia) of fistula anatomy (number of existing fistulas and openings), topography (extent and relationship with the sphincters and other pelvic muscles), potential associated complications (such as abscesses) and whether local mucosal disease is mild or inactive. Vigorous curettage of all fistula tracts is recommended, with special emphasis in the internal openings area, using a metallic curette. In case of an abscess, incision and drainage are needed, and setons should be placed, if appropriate, in accordance with routine surgical procedures. Before scheduling Alofisel administration, the surgeon must 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 chloride 9 mg/mL (0.9%) solution through the external openings until it gets out through the internal openings is recommended. The injection of any other substance through the fistula tracts, such as hydrogen peroxide, methylene blue, iodine solutions or hypertonic glucose solutions 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 internal openings 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 two steps: 1. Preparation a) The expiry time: date of Alofisel should be re-confirmed; vials should then be removed from the outer packaging. b) Re-suspend the cells by gently tapping the bottom of the vials until a homogeneous dispersion is obtained, avoiding bubble formation. Each vial should be used immediately 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 aspirate the 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 reach the intended sites of injection. For example, a needle for spinal anaesthesia measuring 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 one vial have been injected. 2. Injection Two of the vials should be used for the internal openings and the remaining two for injection along the walls of the fistula tracts (via external openings). After inserting the needle tip into each intended injection site, perform a slight aspiration to avoid intravascular administration. a) Injection around the internal openings of the fistula tracts: insert the needle through the anus and proceed as follows: - If there is a single internal opening, inject the content of each of the two vials (one after the other) in small deposits into the tissue surrounding the single internal opening. - If there are two internal openings, inject the content of the first of two vials in small deposits into the tissue around one internal opening. Then inject the content of the second vial in small deposits into the tissue around the second internal opening. b) Injection along the walls of the fistula tracts: insert the needle through the external openings and, from within the fistula lumen: - If there is a single external opening, inject separately the content of each of the remaining two vials superficially into the tissue walls along the length of the fistula tracts, making small deposits of the cell dispersion. - If there are two or three external openings, inject the content of the remaining two vials equally between the associated tracts. The procedure for injection along the walls of the fistula tracts should be performed based on prior knowledge of the anatomy and topology of the fistula tracts, as determined during the fistula characterisation. Ensure cells are not injected 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 external openings with a sterile bandage.

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

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. Alofisel may contain trace amounts of benzylpenicillin and streptomycin. This should 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 injected cells (see section 4.2). The injection of any substance other than sodium chloride 9 mg/mL (0.9%) (e.g. hydrogen peroxide, methylene blue, iodine solutions or hypertonic glucose solutions) (see section 4.2 and section 4.5) through the fistula tracts is not allowed before, during, or after the injection of Alofisel as these may compromise the viability of the cells and, therefore, may affect the effectiveness of the treatment. Alofisel is indicated only for injection in the fistula tract tissue as described in section 4.2. Alofisel must not be administered using a needle thinner than 22G. Thinner gauge needles can cause cell disruption during injection and may compromise cell viability and, therefore, may affect efficacy of treatment. As Alofisel is a living stem cell therapy it cannot be sterilised, and therefore could contain potentially infected biological material although the risk is considered to be low and controlled in the manufacturing. Patients should be followed up for potential signs of infection after administration. Conditioning reactions Conditioning of fistulas has been associated with proctalgia and procedural pain (see section 4.8).

No in vivo

Pregnancy 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 using contraception. Breast-feeding As a precautionary measure, darvadstrocel is not recommended for administration during breast-feeding. Fertility No data are available.

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

Summary of the safety profile Based on clinical trial and post-marketing data, the most commonly reported adverse drug reactions were anal abscess, proctalgia and anal fistula with the most commonly reported serious adverse drug reactions of anal abscess and anal fistula. Tabulated list of adverse reactions The following listing of adverse reactions is based on the clinical trial and post-marketing experience and is displayed by system organ class. The frequency of adverse reactions is defined from clinical trial experience 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). Table 1. Adverse reactions System Organ Class Frequency Adverse Reactions Infections and infestations Common Anal abscess* Common Proctalgia*,† Gastrointestinal disorders Common Anal fistula* Injuring, poisoning and procedural complications Common Procedural pain*,† *Also seen in post-marketing experience †Conditioning reactions occurring up to seven days after the fistula preparation for treatment administration. Description of selected adverse reactions The following adverse reactions were identified in the multicentre, pivotal clinical trial ADMIRE-CD. Anal abscess Up to week 52, 20 (19.4%) and 14 (13.7%) patients developed 21 and 19 anal abscesses in the Alofisel and control groups, respectively, of which 4 and 5 anal abscesses in respective groups (3.9% patients in both groups) were of severe intensity. Treatment-related anal abscess were reported in 8 (7.8%) and 9 (8.8%) patients in the Alofisel and control groups, respectively. Up to week 104, 15 (14.6%) and 8 (7.8%) patients developed 15 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 and control groups, respectively, none of these proctalgia being serious in any group up to week 104. Treatment-related proctalgia were reported in 5 (4.9%) and 8 (7.8%) patients in the Alofisel and control groups, respectively. There were no patients in Alofisel group with proctalgia of severe intensity and 3.9% patients with 4 proctalgia 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 and control groups, respectively, none of these being of severe intensity. Treatment-related anal fistula were reported in 3 (2.9%) and 3 (2.9%) patients in the Alofisel and control groups, respectively. Up to week 104, 5 (4.9%) and one (< 1.0%) patients developed 5 and 1 serious anal fistulas in the Alofisel and control groups, respectively. 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 Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

No case of has been reported.

Pharmacotherapeutic group: {not yet assigned}, ATC code: {not yet assigned}. Mechanism of action Darvadstrocel contains expanded adipose stem cells (eASC), which exhibit immunomodulatory and anti-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 faecal contamination. In the inflamed area, there is infiltration of activated lymphocytes and local release of inflammatory cytokines. Inflammatory cytokines, in particular IFN-? released by activated immune cells (i.e., lymphocytes), activate eASC. Once activated, eASC impair proliferation of activated lymphocytes and reduce the release of pro-inflammatory cytokines. This immunoregulatory activity reduces inflammation, which may 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 the presence 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. No association between DSA results and safety or efficacy up to Week 52 was seen in the subset tested. Clinical efficacy The efficacy of Alofisel was assessed in the ADMIRE-CD study. This was a randomised, double blind, 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 either Alofisel 120 million cells or placebo in a 1:1 design. Patients had draining complex perianal fistulas 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% of patients) 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 clinical closure of all treated fistulas (absence of draining despite gentle finger compression) and absence of collection (> 2 cm) confirmed by blinded central MRI. The key secondary endpoints were defined as clinical 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 (Alofisel+standard of care*) N=103 Control group (Placebo+standard of care*) N=102 P value Combined remission at Week 24 (% patients) 52 35 0.019 Combined remission at Week 52 (% patients) 56 38 0.009 * 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 at Week 24 was 55% in the Alofisel group and 42% in the control group (p = 0.052) and the corresponding 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% and 55% (p = 0.114). In a limited number of patients followed up to Week 104, clinical remission at Week 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 subsequently developed anal abscess/anal fistula by Week 52 was 2.9% (3/103), whereas the number of patients without combined remission at Week 24 who subsequently developed anal abscess/anal fistula by Week 52 was 9.7% (10/103). In control group, the number of patients who had combined remission at Week 24 who developed anal abscess/anal fistula by Week 52 was 4.9% (5/102), whereas the number of patients without combined remission at Week 24 who developed anal abscess/anal fistula by Week 52 was 2.9% (3/102). Paediatric population 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 (see section 4.2 for information on paediatric use).

The product is intended for local injection. The nature and intended clinical use of darvadstrocel are such that conventional studies of pharmacokinetics (absorption, distribution, metabolism and elimination) are not applicable. Biodistribution studies in preclinical models were conducted with the objective of evaluating the persistence of eASC at the site of injection and their potential migration into other tissues or organ systems. After perianal and intrarectal injection of human eASC in athymic rats, cells were present in the rectum and jejunum at the site of injection for at least 14 days and were undetectable after 3 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 safety pharmacology and repeated dose toxicity. Reproductive and developmental toxicity studies have not been performed for darvadstrocel because preclinical biodistribution studies indicated no migration and integration of eASC into reproductive organs 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 any indication of carcinogenic potential.

Dulbecco’s Modified Eagle´s Medium (DMEM) (containing amino acids, vitamins, salts and carbohydrates). Human albumin.

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

72 hours.

Store between 15 ºC and 25 ºC. Keep the medicinal product within the outer carton to protect from light and moisture, and inside the shipping 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.

and special equipment for use, administration or implantation Type I glass vial. Each vial contains 6 mL of eASC dispersion and is closed with a rubber stopper and a 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).

and other handling 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 a homogeneous dispersion 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 liquid waste) must be handled and disposed of as potentially infectious waste in accordance with local guidelines on handling of human-derived material.

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