This is a summary of the European public assessment report (EPAR) for Alofisel. It explains how the Agency assessed the medicine to recommend its authorisation in the EU and its conditions of use. It is not intended to provide practical advice on how to use Alofisel.
For practical information about using Alofisel, patients should read the package leaflet or contact their doctor or pharmacist.
What is Alofisel and what is it used for?
Alofisel is a medicine that is used to treat complex anal fistulas in adults with Crohn’s disease (an inflammatory condition of the gut) when a conventional or biological medicine has not worked well enough.
Fistulas are abnormal passages between the lower parts of the gut and the skin near the anus. Complex fistulas are those with several abnormal passages and openings, or with passages that go deep inside the body, or where there are other complications such as collection of pus.
Alofisel contains the active substance darvadstrocel, which comprises stem cells removed from fat tissue of adult donors. It is a type of advanced therapy medicine called a ‘somatic cell therapy product’. This is a type of medicine that contains cells or tissues that have been modified so that they can be used to cure, diagnose or prevent a disease.
Because the number of patients with anal fistula is low, the disease is considered ‘rare’, and Alofisel was designated an ‘orphan medicine’ (a medicine used in rare diseases) on 8 October 2009.
How is Alofisel used?
Alofisel should be given only by specialist doctors experienced in the diagnosis and treatment of the condition for which it is used. The medicine can only be obtained with a prescription.
Alofisel is given just once. The patient is given an anaesthetic (either to put the patient to sleep or to numb the treatment area). After preparing the fistulas for treatment in an operating room, the contents of two vials (each containing 30 million cells) are injected around the internal openings and two further vials through the external openings into the walls of the fistula.
For further information, see the package leaflet.
How does Alofisel work?
Alofisel is made up of ‘mesenchymal stem cells’ from the fat tissue of a donor. To make this medicine, the cells are selected and cultivated in the laboratory to increase their number. When injected into the walls of the fistula, these cells can help to reduce inflammation and support the growth of new tissue. This encourages the fistula to heal and close.
What benefits of Alofisel have been shown in studies?
One main study, involving 212 patients with Crohn’s disease and complex anal fistulas, found Alofisel more effective than placebo (a dummy treatment) 24 weeks after treatment. Treatment with conventional or biological medicines had not worked in these patients. The main measure of effectiveness, called ‘combined remission’, was the closing of abnormal external openings together with lack of fluid collections of more than 2 cm associated with internal passages (since these are likely to re-open the fistula). Of the patients treated with Alofisel, combined remission occurred in almost 50% of patients (53 out of 107); this compared with 34% of patients (36 out of 105) receiving placebo.
What are the risks associated with Alofisel?
The most common side effects with Alofisel (which may affect up to 1 in 10 people) are anal abscess (a swollen area with a collection of pus), proctalgia (anal pain), anal fistula and pain during treatment.
Alofisel must not be used in patients with hypersensitivity (allergy) to bovine serum (the clear liquid in blood from cattle) or to any of the ingredients of Alofisel.
Why is Alofisel approved?
The European Medicines Agency decided that Alofisel’s benefits are greater than its risks and recommended that it be approved for use in the EU. Alofisel is of value in the treatment of complex anal fistulas that have not responded well to other treatments. Data on the safety of Alofisel are limited but they provide enough information on the pattern of side effects.
What measures are being taken to ensure the safe and effective use of Alofisel?
The company that markets Alofisel will provide educational material for healthcare professionals on how to give the medicine correctly and on the possibility of passing on an infection to the patient. The company will also complete a study to continue to collect information on the effectiveness and safety of Alofisel.
Recommendations and precautions to be followed by healthcare professionals and patients for the safe and effective use of Alofisel have also been included in the summary of product characteristics and the package leaflet.
Other information about Alofisel
The European Commission granted a marketing authorisation valid throughout the European Union for Alofisel on 23 March 2018.
For more information about treatment with Alofisel, read the package leaflet (also part of the EPAR) or contact your doctor or pharmacist.
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
See section 4.8 for how to report adverse reactions.
1. NAME OF THE MEDICINAL PRODUCT
Alofisel 5 million cells/mL suspension for injection
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
2.1 General description
Darvadstrocel is an 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 a suspension of 30 million cells (eASC) in 6 mL solution, corresponding to a
concentration of 5 million cells/mL.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Suspension for injection.
The suspension of cells may have settled in the bottom of the vial forming a sediment. After resuspension,
the product is a white to yellowish homogeneous suspension.
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 at
least one conventional or biologic therapy. Alofisel should be used after conditioning of fistula, see
section 4.2.
4.2 Posology and method of administration
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 Alofisel consists of 120 million cells distributed in 4 vials. Each vial contains
30 million cells in 6 mL of suspension. 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 million cells it is possible to treat up to three fistula tracts that open to the perianal area.
There is currently limited experience with the efficacy or safety of repeat administration of Alofisel.
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
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of darvadstrocel in elderly patients will differ from that observed in non-elderly patients. Therefore, no
dose adjustment is required in elderly patients.
Hepatic or renal impairment
Data on the use of darvadstrocel in patients with hepatic or 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 hepatically or renally impaired patients will
differ from that observed in non-hepatically or non-renally impaired patients. Therefore, no dose
adjustment is required in hepatically or renally impaired patients.
Paediatric population
The safety and efficacy of darvadstrocel in children aged 0 to 17 years have not yet been established.
No data are available.
Method of administration
For intralesional use in a surgical environment under anaesthesia (general or regional).
In line with standards for the management of complex perianal fistulas, characterisation of the
patient’s fistulas is needed prior to treatment. This comprises an in-depth knowledge of their anatomy
(number of existing fistulas and openings), topography (extent and relationship with the sphincters and
other pelvic muscles), and potential associated complications (such as abscesses). Before scheduling
Alofisel administration, the surgeon must ensure that no abscesses are present and that local mucosal
disease is mild or inactive. In case of an abscess, incision and drainage are needed, and setons should
be placed, if appropriate, in accordance with routine surgical procedures.
Prior to the administration of Alofisel, the fistula tracts should be conditioned as follows:
Firstly, if setons are in place, they must be removed. Conditioning of the fistula tracts comprises the
following steps:
a) Identify the location of the internal openings. For this, it is recommended to inject a
sodium chloride 9 mg/mL (0.9%) solution through the external openings until it gets out
through the internal openings. 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.
b) Perform a vigorous curettage of all fistula tracts, with special emphasis in the internal
openings areas, using a metallic curette.
c) Suture the internal openings to close them.
After conditioning of the fistula tracts, Alofisel should be administered according to the following two
steps:
1. Preparation
a) 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.
b) Remove the cap from the vial, turn the vial upside down, and gently aspirate the
whole content using a syringe with a conventional needle no thinner than 22G.
c) Replace the needle with a longer needle, also no thinner than 22G, in order to reach
the intended sites of injection. A needle for spinal anaesthesia measuring around
90 mm in length is required.
d) Repeat steps (a), (b) and (c) 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 the
external openings. As commonly done for intra-tissue injections, just after injecting the
needle 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:
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- 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 into the tissue around the second internal opening and make
small deposits of the cell suspension.
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 the
remaining 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 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 fistulas 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.
4.3 Contraindications
Hypersensitivity to any of the excipients listed in section 6.1 or to bovine serum.
4.4 Special warnings and precautions for use
Alofisel may contain trace amounts of benzylpenicillin and streptomycin. This should be considered in
patients with known acute hypersensitivity (history of anaphylactic reactions) to these classes of
compounds.
Local anaesthesia is not recommended due to the unknown effect of local anaesthetics on the injected
cells.
The use of hydrogen peroxide, methylene blue, iodine solutions or hypertonic glucose solutions
through the fistula tracts is not allowed before, during, or after the injection of Alofisel as this may
compromise cells viability and, therefore, may affect the effectiveness of the treatment.
Alofisel is indicated for intralesional injection only. 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).
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).
Dyes and local anaesthesia is not recommended due to the unknown effect of local anaesthetics on the
injected cells (see section 4.4).
4.6 Fertility, pregnancy and lactation
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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 breastfeeding.
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 experience and 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 Frequency Adverse Reactions
Infections and infestations Common Anal abscess
Gastrointestinal disorders Common Proctalgia*
Common Anal fistula
Injuring, poisoning and procedural
complications
Common Procedural pain*
*Conditioning reactions occurring up to seven days after the fistula cleaning 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 adverse events
in the Alofisel and control groups, respectively, of which 4 and 5 adverse events in respective groups
(3.9% patients in both groups) were of severe intensity. Up to Week 104, 15 (14.6%) and 8 (7.8%)
patients developed 15 and 9 serious adverse events of anal abscess 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 adverse events in
the Alofisel and control groups, respectively, none of these events being serious in any group up to
Week 104. There were no patients in Alofisel group with events of proctalgia of severe intensity and
3.9% patients with 4 events in the control group.
6
Anal fistula
Up to Week 52, 11 (10.7%) and 8 (7.8%) patients developed 12 and 8 anal fistula adverse events in the
Alofisel and control groups, respectively, none of these being of severe intensity. Up to Week 104, 5
(4.9%) and one (<1.0%) patients developed 5 and 1 anal fistula serious adverse events 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 national reporting system
listed in Appendix V.
4.9 Overdose
No case of overdose has been reported.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
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-γ 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, 36% of the eASC-treated patient population showed anti-donor antibody
production at Week 12. Of patients with donor-specific antibodies (DSA) at Week 12, 30% had
cleared DSA by Week 52. Lack of de novo DSA generation was observed between Week 12 and
Week 52. Limited data exist but there does not appear to be a detrimental effect of DSA on efficacy
and safety.
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 intralesional injection of
either Alofisel 120 million cells or placebo in a 1:1 design. Patients were to have 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
7
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
* It might include 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
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6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Dulbecco’s Modified Eagle´s Medium (DMEM) (containing amino acids, vitamins, salts and
carbohydrates).
Human albumin.
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
products.
6.3 Shelf life
48 hours.
6.4 Special precautions for storage
Store between 15ºC and 25ºC.
Keep the product within the outer carton 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 and do not refrigerate or freeze.
Do not irradiate.
6.5 Nature and contents of container and special equipment for use, administration or
implantation
Alofisel is supplied as one treatment dose contained in 4 Type I glass vials. Each vial contains 6 mL of
eASC suspension and is closed with a rubber stopper and a flip-off seal. The vials are placed inside a
cardboard box.
6.6 Special precautions for disposal and other handling
Any unused product or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
TiGenix S.A.U.
C/ Marconi 1
Parque Tecnológico de Madrid
28760 Tres Cantos, Madrid
Spain
Tel: +34 91 804 92 64
Fax: +34 91 804 92 63
info@tigenix.com
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/17/1261/001
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
9
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu
10
ANNEX II
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE
SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR
BATCH RELEASE
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY
AND USE
C. OTHER CONDITIONS AND REQUIREMENTS OF THE
MARKETING AUTHORISATION
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL
PRODUCT
11
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
Name and address of the manufacturer of the biological active substance
TIGENIX, S.A.U.
C/ Marconi, 1, Parque Tecnológico de Madrid, 28760 Tres Cantos, Madrid, Spain
Name and address of the manufacturer responsible for batch release
TIGENIX, S.A.U.
C/ Marconi, 1, Parque Tecnológico de Madrid, 28760 Tres Cantos, Madrid, Spain
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product
Characteristics, section 4.2).
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING
AUTHORISATION
• Periodic Safety Update Reports
The requirements for submission of periodic safety update reports for this medicinal product are
set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of
Directive 2001/83/EC and any subsequent updates published on the European medicines webportal.
The marketing authorisation holder shall submit the first periodic safety update report for this product
within 6 months following authorisation.
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
• Risk Management Plan (RMP)
The MAH shall perform the required pharmacovigilance activities and interventions detailed in
the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed
subsequent updates of the RMP.
An updated RMP should be submitted:
• At the request of the European Medicines Agency;
• Whenever the risk management system is modified, especially as the result of new information
being received that may lead to a significant change to the benefit/risk profile or as the result of
an important (pharmacovigilance or risk minimisation) milestone being reached.
• Additional risk minimisation measures
Prior to the launch of Alofisel in each Member State, the Marketing Authorisation Holder (MAH)
must agree about the content and format of the educational programme, including communication
media, distribution modalities and any other aspects of the programme, with the National Competent
Authority. The aim of the educational programme is to provide information on how to correctly
administer the product in order to minimise the risk of medication errors and to increase awareness
about the potential transmission of infectious agents.
12
The MAH shall ensure that in each Member State where Alofisel is marketed, all healthcare
professionals who are expected to handle and administer Alofisel have access to the educational
package for health professionals.
• The educational material for health professionals should contain:
• The Summary of Product Characteristics
• Guide for pharmacists with instructions on the appropriate reception and storage of
Alofisel.
• Guide in form of a video for surgeons and other health professionals involved in the
preparation and administration of Alofisel.
• Guide for surgeons and other health professionals describing the method of
administration
• Guide for health professionals providing information on potential for microbial
information and advice on steps to follow in case a positive culture is identified.
• These shall contain the following key elements:
• Relevant information on the risk of medication errors and the po
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ANNEX III
LABELLING AND PACKAGE LEAFLET
14
A. LABELLING
15
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1. NAME OF THE MEDICINAL PRODUCT
ALOFISEL 5 million cells/mL suspension for injection
Darvadstrocel
2. STATEMENT OF ACTIVE SUBSTANCE(S)
This medicine contains cells of human origin. Each vial contains 6 mL of a suspension of 30 million
of darvadstrocel.
3. LIST OF EXCIPIENTS
Also contains: Dulbecco’s Modified Eagle´s Medium (DMEM) and Human albumin.
4. PHARMACEUTICAL FORM AND CONTENTS
Suspension for injection
1 dose consists of 4 vials of 6 mL (in total 24 mL)
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Intralesional use
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE SIGHT AND REACH OF CHILDREN
Keep out of the sight and reach of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
8. EXPIRY DATE
EXP {XX-XXX-XXXX at XX:XX CET}
9. SPECIAL STORAGE CONDITIONS
Store between 15ºC and 25ºC.
Do not refrigerate or freeze.
Keep the product within the outer carton.
16
Do not irradiate.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
TiGenix S.A.U.
C/Marconi 1
Parque Tecnológico de Madrid
28760 Tres Cantos
Madrid - Spain
12. MARKETING AUTHORISATION NUMBER(S)
EU/1/17/1261/001
13. BATCH NUMBER, DONATION AND PRODUCT CODES
Lot {XXXXX-XXXXX-XXX}
14. GENERAL CLASSIFICATION FOR SUPPLY
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
17. UNIQUE IDENTIFIER – 2D BARCODE
Not applicable.
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA
Not applicable.
17
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
GLASS VIAL
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION
ALOFISEL 5 million cells/mL suspension for injection
Darvadstrocel
Intralesional use
2. METHOD OF ADMINISTRATION
3. EXPIRY DATE
EXP {XX-XXX-XXXX at XX:XX CET}
4. BATCH NUMBER<, DONATION AND PRODUCT CODES>
Lot {XXXXX-XXXXX-XXX}
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
6 mL
30 million cells
6. OTHER
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B. PACKAGE LEAFLET
19
Package leaflet: Information for the patient
Alofisel 5 million cells/mL suspension for injection
Darvadstrocel
This medicine is subject to additional monitoring. This will allow quick identification of new
safety information. You can help by reporting any side effects you may get. See the end of Section 4
for how to report side effects.
Read all of this leaflet carefully before you are given this medicine because it contains important
information for you.
− Keep this leaflet. You may need to read it again.
− If you have any further questions, ask your doctor or surgeon.
− If you get any side effects, talk to your surgeon or doctor. This includes any possible side effects
not listed in this leaflet. See section 4.
What is in this leaflet
1. What Alofisel is and what it is used for
2. What you need to know before you are given Alofisel
3. How Alofisel is given
4. Possible side effects
5. How to store Alofisel
6. Contents of the pack and other information
1. What Alofisel is and what it is used for
Alofisel is a medicine used for the treatment of complex perianal fistulas in adult patients with
Crohn´s disease (a disease causing inflammation of the gut) when the other symptoms of the disease
are controlled or have a mild intensity. Perianal fistulas are abnormal channels that connect parts of
the lower bowel (rectum and anus) and the skin near the anus, so that one or more openings appear
near the anus. Perianal fistulas are described as complex if they have multiple channels and openings,
if they penetrate deep inside your body or if they are associated with other complications such as
collections of pus (infected liquid also called abscesses). Perianal fistulas can cause pain, irritation and
discharge of pus through the openings to the skin.
Alofisel is used when the fistulas have not responded sufficiently well to previous treatment. When
injected close to the perianal fistulas, Alofisel reduces their inflammation, increasing the likelihood of
the fistulas healing.
Alofisel will be used after adequate preparation of the fistula, see section 3.
The active ingredient of Alofisel is darvadstrocel which consists of stem cells which are taken from
the fat tissue of a healthy adult donor (so-called allogenic stem cells) and then grown in a laboratory.
Adult stem cells are a special type of cells found in many adult tissues, whose primary role is the
repair of the tissue in which they are found.
2. What you need to know before you are given Alofisel
You must not be given Alofisel:
− If you are allergic to any of the ingredients of this medicine (listed in section 6) or to bovine
serum.
Warnings and precautions
Talk to your doctor or surgeon before you are given Alofisel.
20
Alofisel may contain traces of benzylpenicillin or streptomycin (antibiotics). This should be
considered if you are allergic to these antibiotics, as these antibiotics are used in the manufacturing
process of this medicine.
Alofisel is a living cell therapy and, therefore, the final product cannot be sterilised. The product is
checked at different stages during its manufacture to ensure that it is free of infection. Because the
final check takes place just before Alofisel is sent to the hospital, the results of this last check are not
known when it is given to you. In the unlikely event that the results detected an infection, your
treatment team will be informed who will tell you if you need any laboratory tests of treatment for the
infection. If after the procedure you feel ill or have fever, please inform your physician as soon as you
can.
Children and adolescents
Do not give this medicine to children (i.e. aged under 18 years) because the potential benefits and risks
are unknown.
Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask
your doctor/surgeon for advice before you are given this medicine. Treatment with Alofisel is not
recommended during pregnancy or while breast-feeding. Women of childbearing age should use
effective contraception during treatment with Alofisel.
Driving and using machines
Alofisel is not likely to affect your ability to drive or use tools or machines.
3. How Alofisel is given
Alofisel is given by a surgeon very near or into your fistulas.
The recommended dose is 120 million cells.
Before treatment with Alofisel, you will be given an anaesthetic.
Once you have been anaesthetised (general or regional anaesthesia), your surgeon will:
• clean the fistulas with salt water and remove any scar tissue.
• stitch up the inner openings of the fistulas.
• inject Alofisel. Half of the dose will be injected into the tissue around the inner openings of the
fistulas, and half of the dose in the tissue walls along the fistulas.
• massage softly for 20 to 30 seconds the area where the fistula opens on to the skin near your anus.
If you have any further questions on the use of this medicine, ask your doctor or surgeon.
4. Possible side effects
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Some side effects of Alofisel treatment are related to the process of cleaning your fistulas. In general,
these side effects are quite mild and disappear in the days following the fistula procedure.
Common side effects (may affect up to 1 to 10 patients):
• anal abscess
• anal fistula
• proctalgia (pain in the rectum or anus).
• procedural pain (pain after fistula cleaning)
Reporting of side effects
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If you get any side effects, talk to your doctor or surgeon. This includes any possible side effects not
listed in this leaflet. You can also report side effects directly via the national reporting system listed in
Appendix V. By reporting side effects you can help provide more information on the safety of this
medicine.
5. How to store Alofisel
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the label.
Do not store above 25°C or below 15°C.
Do not refrigerate or freeze.
Keep the medicine inside the cardboard box.
Alofisel must not be irradiated.
As this medicine will be used during surgery, the hospital staff is responsible for the correct storage of
the medicine before and during its use, as well as for its correct disposal.
6. Contents of the pack and other information
What Alofisel contains
− The active ingredient of Alofisel is darvadstrocel which consists of human stem cells obtained
from the fat tissue of a healthy adult donor that are subsequently grown (expanded) in the
laboratory and provided at a concentration of 5 million cells per millilitre in vials which each
contain 6 millilitres, i.e. 30 million cells per vial.
− There are two excipients used for storage of the cells: one is a liquid called Dulbecco’s
Modified Eagle´s Medium containing nutrients for the cells (amino acids, vitamins, salts and
carbohydrates), and the other is human albumin, which is a natural protein found in the human
body.
What Alofisel looks like and contents of the pack
Alofisel is a suspension for injection. During shipment, the cells may have settled in the bottom of the
vials forming a sediment and will need to be resuspended. After the cells have been resuspended (by
gentle manual tapping), Alofisel is a white to yellowish homogenous suspension.
Alofisel is supplied on an individual patient basis. An individual dose of Alofisel comprises 4 glass
vials each containing 6 millilitres of Alofisel contained within a cardboard box.
Marketing Authorisation Holder and manufacturer
TiGenix S.A.U.
C/Marconi 1
Parque Tecnológico de Madrid
28760 Tres Cantos, Madrid
Spain
Tel: +34 91 804 92 64
Fax: +34 91 804 92 63
info@tigenix.com
This leaflet was last revised inOther sources of information
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Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europe.eu.
