1.

NAME OF THE MEDICINAL PRODUCT

Alofisel®
5 ×106 cells/mL suspension for injection
2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

2.1 General description
Alofisel (darvadstrocel) is expanded human allogeneic mesenchymal adult stem cells extracted from
adipose 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 of
5×106 cells/mL.
For the full list of excipients, see section 6.1.
3.

PHARMACEUTICAL FORM

Suspension for injection (injection)
White to yellowish homogenous suspension containing a sediment, which is readily dispersed onshaking.
Patient information brochure
The marketing of Alofisel is subject to a risk management plan (RMP) including a 'Patient
information brochure'. The 'Patient information brochure', emphasizes importantsafety information that the patient should be aware of before and during treatment.
Please explain to the patient the need to review the brochure before starting treatment.
Prescriber guideThis product is marketed with prescriber guide providing important safety information. Please
ensure you are familiar with this material as it contains important safety information.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

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

Posology and method of administration

Alofisel should only be administered by specialist physicians experienced in the diagnosis andtreatment of conditions for which Alofisel is indicated.
Posology
A single dose of darvadstrocel consists of 120 ×106cells supplied in 4 vials. Each vial contains
30 ×106cells in 6 mL of suspension. The full content of the 4 vials must be administered for the1

treatment of up to two internal openings and up to three external openings. This means that with adose of 120 ×106cells 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, nodose 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 thebenefit-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 thebenefit-risk profile of darvadstrocel in renally impaired patients will differ from that observed in nonrenally 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
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 is
recommended, 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, 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 theinternal 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.

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After conditioning of the fistula tracts, Alofisel should be administered according to the following two
steps:
1.
Preparationa) 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
suspension 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 reachthe 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 onevial 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 theneedle tip into each intended injection site, perform a slight aspiration to avoid
intravascular administration.
a) Injection around the internal openings of the fistulas 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 (oneafter 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 insmall 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 fistulas 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 fistula
tracts, 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 be
performed based on prior knowledge of the anatomy and topology of the fistula
tracts, as determined during the fistulas 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 external
openings with a sterile bandage.
4.3

Contraindications

Hypersensitivity to the active substance, bovine serum or any of the excipients listed in section 6.1
4.4

Special warnings and precautions for use

Traceability
The traceability requirements of cell-based therapy medicinal products must apply. To ensure
traceability the name of the Product, the batch number and the name of the treated patient must be
clearly kept for a period of 30 years after the expiry date of the product.

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GeneralAlofisel 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 injected
cells (see section 4.2).
The injection of any substance other than sodium chloride 9 mg/mL (0.9%) solution (e.g. hydrogen
peroxide, 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 cause
cell 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 infectious
agents 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.
4.5

Interaction with other medicinal products and other forms of interaction

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 therapies
for Crohn’s disease (infliximab, methotrexate and azathioprine).
The injection of any substance other than sodium chloride 9 mg/mL (0.9%) solution (e.g. hydrogen
peroxide, 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).
4.6

Fertility, pregnancy and lactation

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
It is unknown whether darvadstrocel is excreted in human milk. A risk to the breast-fed infant cannot
be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain

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from Alofisel therapy taking into account the benefit of breast-feeding for the child and the benefit oftherapy for the woman.
Fertility
No data are available.
4.7

Effects on ability to drive and use machines

Darvadstrocel has no or negligible influence on the ability to drive and use machines.
4.8

Undesirable effects

Summary of the safety profile
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).
Tabulated list of adverse reactions
The following listing of adverse reactions is based on the clinical trial and post-marketing experience
is displayed by system organ class. The frequency of adverse reactions is defined 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
Infections and infestations
Gastrointestinal disorders

Frequency
Adverse Reactions
CommonAnal abscessCommonProctalgia*
CommonAnal fistula
Injuring, poisoning and procedural Common
Procedural pain*
complications*Conditioning reactions occurring up to seven days after the fistula preparation for treatment
administration.
Description of selected adverse reactions
Anal abscess
Up to week 52, 20 (19.4%) and 14 (13.7%) patients developed 21 and 19 anal abscess in the Alofiseland control groups, respectively, of which 4 and 5 anal abscess in respective groups (3.9% patients inboth groups) were of severe intensity. 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 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 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 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.

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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.
Any suspected adverse events should be reported to the Ministry of Health according to the National
Regulation by using an online form https://sideeffects.health.gov.il
4.9

Overdose

No data regarding overdose of Alofisel is available.
5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Immunosuppressants, Other immunosuppressants, ATC code: L04AX08.
Mechanism of action
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 faecal
contamination. In the inflamed area, there is infiltration of activated lymphocytes and local release of
inflammatory 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, 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 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. 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
darvadstrocel 120 × 106 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 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(Alofisel+standard ofcare*)
N= 103
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Control group(Placebo+standard ofcare*)
N= 102

P valueCombined remission at week
52
35
0.019
24 (% patients)
Combined remission at week
56
38
0.009
52 (% patients)* Including abscess drainage, seton placement/removal, curettage, suture of internal openings andmedical 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 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% 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 byweek 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).
5.2

Pharmacokinetic properties

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 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.
5.3

Preclinical safety dataNon-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.
6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Dulbecco’s Modified Eagle´s Medium (DMEM).
Human serum albumin 20%.
`
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
products.

76.3

Shelf life

The expiry date of the product is indicated on the packaging materials.
6.4

Special precautions for storage

Store between 15ºC and 25ºC.
Keep the medicinal product within the secondary packaging (cardboard box) 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.
6.5

Nature and contents of container and special equipment for use, administration or
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).
6.6

Special precautions for disposal 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 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 productUnused 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 human-derived material.
7.

MARKETING AUTHORISATION HOLDER

Takeda Israel Ltd.
25 Efal st.,P.O.B 4140
Petach Tikva 4951125
8.

MANUFACTURER

TiGenix, S.A.U
C/ Marconi 1, parque tecnologico de madrid,
28760 Tres Cantos
Madrid, Spain
9.

MARKETING AUTHORISATION NUMBER

161-67-35458-00
Revised in Jan 2023 according to MOHs guidelines.
Based on EU SmPC approved in January 2023
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