Holoclar

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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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 
 
Holoclar 79,000 - 316,000 cells/cm2 living tissue equivalent 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
2.1 General description 
 
Ex vivo expanded autologous human corneal epithelial cells containing stem cells. 
 
2.2 Qualitative and quantitative composition 
 
Holoclar consists of a transparent circular sheet of 300,000 to 1,200,000 viable autologous human 
corneal epithelial cells (79,000 - 316,000 cells/ cm2), including on average 3.5 % (0.4 to 16 %) limbal 
stem cells, and stem cell-derived transient amplifying and terminally differentiated cells, attached on a 
supportive 2.2 cm diameter fibrin layer and maintained in the transport medium.  
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Living tissue equivalent. 
Transparent, circular sheet. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of adult patients with moderate to severe limbal stem cell deficiency (defined by the 
presence of superficial corneal neovascularisation in at least two corneal quadrants, with central 
corneal involvement, and severely impaired visual acuity), unilateral or bilateral, due to physical or 
chemical ocular burns. A minimum of 1 - 2 mm2 of undamaged limbus is required for biopsy. 
 
4.2 Posology and method of administration 
 
Holoclar must be administered by an appropriately trained and qualified surgeon and is restricted to 
hospital use only.  
 
Posology 
 
This medicinal product is intended for autologous use only. 
 
The amount of cells to be administered is dependent on the size (surface in cm²) of the corneal surface. 
Each preparation of Holoclar contains an individual treatment dose with sufficient number of cells to 
cover the entire corneal surface. The recommended dose of Holoclar is 79,000 - 316,000 cells/ cm², 
corresponding to 1 cm² of product/cm² of defect. Each preparation of Holoclar is intended as a single 
treatment. The treatment may be repeated if considered indicated by the treating physician.  
 



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The administration should be followed by an appropriate antibiotic and anti-inflammatory treatment 
schedule, as recommended by the physician (see section 4.4).  
 
Special populations 
 
Elderly 
Data on the use of Holoclar in elderly populations are limited. No recommendation on posology can 
be made (see sections 4.8 and 5.1). 
 
Hepatic and renal impairment  
Data on the use of Holoclar in patients with hepatic and renal impairment are not available. 
 
Paediatric population 
The safety and efficacy of Holoclar in children and adolescents aged 0 to 18 years has not yet been 
established. Currently available data are described in section 4.8 and 5.1, but no recommendation on 
posology can be made.  
 
Method of administration  
For implantation. 
 
Full technical details on the procedures associated with the use of Holoclar are provided in the 
educational manual. 
 
Biopsy 
For the manufacture of Holoclar, a biopsy of 1 – 2 mm2 of undamaged limbus is required. The biopsy 
is performed using topical anaesthesia. The eye is subjected to ocular surface lavage with sterile 
balanced salt solution for eye irrigation followed by detachment of the conjunctiva from the limbus to 
expose the sample collection site of the cornea. An incision of 2 x 2 mm is made to remove the biopsy.  
The biopsy is placed in the sterile test tube supplied containing transport medium. The biopsy must be 
received by the manufacturer within 24 hours from the procurement. 
 
Post-biopsy treatment 
Following the biopsy, an appropriate regimen of prophylaxis with an antibiotic treatment must be 
given. 
 
In some cases, it may be possible that the source limbal stem cells of the patient are not expandable or 
that the release criteria are not met, due to poor biopsy quality, patient characteristics, or 
manufacturing failure. Therefore, it can occur that Holoclar cannot be delivered. The surgeon will be 
informed as early in the process as possible and should hence select an alternative treatment for the 
patient. 
 
Implantation 
Holoclar is intended solely for use in autologous limbal stem cell regeneration in line with the 
approved therapeutic indication and should be administered under aseptic conditions in conjunction 
with limbal peritomy, undermining of the conjunctiva and excision of the corneal fibrovascular tissue 
in preparation of the defect bed. Next, the insert is fitted under the undermined conjunctiva. The 
excess of insert is trimmed, and the edge covered with the conjunctiva applying 2 or 3 stitches 
(sutures) of vicryl or silk 8/0 in order to form a physical seal of the lesion and to secure the implant. 
The eyelids are kept closed over the insert with a steri-strip band. 
Holoclar is generally implanted under topical retrobulbar or parabulbar anaesthesia. Other 
anaesthesiology procedures may be followed at the discretion of the surgeon. 
 
Post-operative treatment 
Following implantation, an appropriate regimen of topical and systemic anti-inflammatory and 
prophylactic antibiotic treatment must be given. 
 



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The following regimen is suggested: doxycycline 100 mg tablets twice daily (or amoxicillin 500 mg 
twice daily) and prednisone orally at a daily dose of 0.5 mg / kg (to a maximum dose of 25 mg) per 
day should be administered from the day of surgery for 2 weeks. After 2 weeks the systemic antibiotic 
administration should be stopped and the daily dose of prednisone should be tapered to 0.25 mg / kg 
(maximum 12.5 mg) per day for 1 week, to 0.125 mg / kg (maximum 5.0 mg) per day for the 
following week and then stopped. 
 
Two weeks after surgery, a topical corticosteroid treatment should be started with preservative-free 
dexamethasone 0.1 % eye-drops, 1 drop three times per day for 2 weeks, then reduced to 1 drop twice 
daily for 1 week and 1 drop once daily for a further week. The topical corticosteroid can be maintained 
in case of persistent ocular inflammation. 
 
The implantation must be followed by an appropriate monitoring schedule. 
 
For information on the preparation and handling of Holoclar, please refer to section 6.6. 
 
4.3 Contraindications 
 
Hypersensitivity to any of the excipients listed in section 6.1 or to bovine serum and murine 3T3-J2 
cells. 
 
4.4 Special warnings and precautions for use 
 
Traceability  
The traceability requirements of cell-based advanced therapy medicinal products must apply. To 
ensure traceability the name of the product, the batch number and the name of the treated patient 
should be kept for a period of 30 years. 
 
General 
Holoclar is an autologous product and should under no circumstances be administered to anyone other 
than the donor patient. 
 
Holoclar contains lethally-irradiated murine 3T3 fibroblast cells and may contain traces of foetal 
bovine serum. Patients with a known hypersensitivity to mice or foetal bovine serum must not be 
treated (see section 4.3). 
 
Holoclar could contain potentially infected biological material. Although the risk is considered to be 
low and controlled in the manufacturing. 
 
Precautions for use 
Concomitant eyelids malposition, conjunctival scarring with fornix shortening, corneal anaesthesia 
and/or conjunctival anaesthesia or severe hypoaesthesia, pterygium and severe dry eye are potential 
complicating factors. When possible, concomitant eye problems should be corrected prior to Holoclar 
implantation. 
 
Patients with acute ocular inflammation or infections should be deferred until recovery has been 
documented since inflammation may compromise treatment success. 
 
Concomitant use of Holoclar with eye-drops containing benzalkonium chloride, and/or other 
preservatives is not recommended (see section 4.5). 
 
The procedure of Holoclar administration includes the use of antibiotics and corticosteroids (see 
section 4.2). For relevant safety information, physicians should consult the SmPC of these medicinal 
products.  
 
4.5 Interaction with other medicinal products and other forms of interaction 



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No interaction studies have been performed. 
 
Eye-drops containing benzalkonium chloride, and/or other preservatives, must be avoided. 
Benzalkonium chloride (as well as other quaternary ammonium compounds) is cytotoxic and eye-
drops containing this preservative may damage the newly-regenerated corneal epithelium. Other 
cytotoxic agents must be avoided. 
 
No interactions between Holoclar and the post-biopsy/post-operative treatment suggested in section 
4.2 have been reported.  
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
There are no data for the use of Holoclar in pregnant women. 
 
Animal studies are not available with respect to reproductive toxicity (see section 5.3). 
 
As a precautionary measure, and in light of the requirement of the post-operative pharmacological 
treatment, it is preferable to avoid the use of Holoclar during pregnancy.  
 
Breast-feeding 
As a precautionary measure, Holoclar is not recommended for implant during breast-feeding. 
 
Fertility 
No clinical data on the effects of Holoclar on fertility are available. 
 
4.7 Effects on ability to drive and use machines 
 
Holoclar has a major influence on the ability to drive and use machines due to the surgical nature of 
the underlying procedure for the implantation. Therefore, following treatment with Holoclar, driving 
and using machines must be limited and patients should follow the advice of their treating physician. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
The most serious adverse reactions are corneal perforation and ulcerative keratitis, which may occur 
within the 3 months from Holoclar implantation and are related to the corneal epithelial instability, and 
syncope vasovagal occurring in the first day after surgery due to eye pain. The most common adverse 
reactions are eye disorders. The most frequently occurring reaction related to the surgical procedure 
was conjunctival haemorrhage (5 %) which appears mostly during the first day after surgery and tends 
to be mild in intensity and disappears within a few days without treatment.  
 
Tabulated list of adverse reactions 
Adverse reactions reported in patients implanted with Holoclar are provided in the table. 
The following categories are used to rank the adverse reactions by frequency of occurrence: 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 the available data). Within 
each frequency grouping the adverse reactions are presented in the order of decreasing seriousness. 
 

MedDRA System organ class Adverse reaction Frequency 
Infections and infestations Corneal infection Uncommon 
Nervous system disorders Syncope vasovagal Uncommon 
Eye disorders Blepharitis Very common 



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Conjunctival haemorrhage, eye 
haemorrhage, corneal 
epithelium defect, eye pain, 
glaucoma/intraocular pressure 
increased, ulcerative keratitis 

Common 

Conjunctival adhesion, 
conjunctival hyperaemia, 
corneal oedema, corneal 
perforation, eye irritation, 
photophobia 

Uncommon 

Skin and subcutaneous tissue 
disorders Haemorrhage subcutaneous Uncommon 

General disorders and 
administration site conditions Metaplasia of the implant Uncommon 

Injury, poisoning and 
procedural complications Suture rupture Uncommon 

 
Description of selected adverse reactions 
Blepharitis (10.5 %), and corneal epithelium defect (3.5 %) were the most common individual adverse 
reactions not related to the surgical procedure. Glaucoma (3.5 %) was the most frequent adverse 
reaction considered related to the corticosteroid treatment (see sections 4.2 and 4.4). Reports of 
glaucoma included adverse reactions of intraocular pressure. 
 
Paediatric population 
There is no information on the safety of Holoclar in children up to 7 years of age and only limited 
information in patients 8 - 17 years of age. In the paediatric patients included in the studies HLSTM01 
(age 13, 14 and 16 years) and HLSTM02 (age 8 and 14 years) the profile of adverse reactions was not 
different from the adult population. 
 
Elderly 
There is only limited information in elderly (n=12, > 65 years old) and very elderly (n= 2, 75-84 years 
old) patients. 
 
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: Ophthalmologicals, other ophthalmologicals, ATC code: S01XA19 
 
Mechanism of action and pharmacodynamic effects 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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The mechanism of action of Holoclar is the replacement of corneal epithelium and lost limbal stem 
cells in patients in which the limbus has been destroyed by ocular burns. During the corneal repair 
process, the administered stem cells are intended to partially multiply, differentiate and migrate to 
regenerate corneal epithelium, as well as maintaining a reservoir of stem cells that can continually 
regenerate the corneal epithelium. 
 
Conventional pharmacodynamic studies for Holoclar have not been performed 
 
Clinical efficacy and safety 
The efficacy of the medicinal product was evaluated in a multi-centre, case-series, non-controlled, 
retrospective cohort study in 106 patients (HLSTM01 study) of both genders, treated for the presence 
of a moderate to severe limbal stem cell deficiency (LSCD). Moderate to severe LSCD was defined 
according to an invasion of at least two quadrants of the corneal surface by superficial neo vessels. A 
total of 104 patients, aged between 13 and 79 years (mean 46.8 years) were included in the primary 
efficacy analysis. At the time of product administration, the mean duration of the condition since the 
injury was 18 years (median 10 years), 99 % of patients had corneal opacity and 90 % of them had a 
severe impairment in visus (1/10th or less at Snellen chart). Success of the procedure was evaluated 
based on the presence of a stable corneal epithelium (i.e. absence of epithelial defects) without 
significant recurrence of neovascularisation (no more than one quadrant without central corneal 
involvement) at 12 months post-intervention. A total of 75 (72.1 %) treatments were reported with a 
successful outcome. These results were confirmed in a sensitivity analysis where superficial 
neovascularisation was evaluated by an independent assessor from blinded photos of patients’ eyes 
taken before and after Holoclar implantation.  
 
Additional clinically-relevant parameters were evaluated as secondary efficacy assessments.  
 
The proportion of patients with symptoms (pain, burning or photophobia) significantly decreased from 
pre-surgery (40 patients with at least one symptom; 38.5 %) to one year after the procedure (12 
patients; 11.5 %).  
 
Fifty-one patients (49.0 %) had an improvement in visual acuity of at least one full line on a Snellen 
chart (or one category for the severely impaired cases). The proportion of patients with improvement 
in visual acuity was higher among those without a scar of the corneal stroma (15/18 patients, 83.3 %) 
than in those with scarring (36/81 patients, 44.4 %). When categorical values for visual acuity were 
converted into the Logarithm of the Minimum Angle of Resolution (LogMAR), 47 % of cases (40 
over 85 with non-missing values) experienced an improvement equal or greater than 3 Snellen line 
equivalents. 
 
Fifty-seven patients underwent a keratoplasty after the use of the product with a success rate of 42.1 % 
(N=24) one year after the corneal transplantation (i.e. with a stable corneal epithelium without 
significant recurrence of neovascularisation). 
 
Elderly 
The HLSTM01 study enrolled a total of seven patients (6.7 % of the study population) with an age at 
baseline of 65 years or above, and seven additional patients (24.1 %) were included in HLSTM02. 
Although limited with regard to the number of subjects, data from both studies showed a success rate 
around 70 % of treated cases in the elderly population. This level of efficacy is similar to that observed 
in the treated patients overall. 
 
Paediatric population 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
Holoclar in one or more subsets of the paediatric population in the treatment of limbal stem cell 
deficiency due to ocular burns (see section 4.2 for information on paediatric use). 
 
This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This 
means that further evidence on this medicinal product is awaited. 



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The European Medicines Agency will review new information on this medicinal product at least every 
year and this SmPC will be updated as necessary. 
 
5.2 Pharmacokinetic properties 
 
The product is implanted locally. 
The nature and intended clinical use of Holoclar are such that conventional pharmacokinetic studies on 
absorption, biotransformation and elimination are not applicable. Immunohistochemical analysis of 
cornea taken from patients receiving keratoplasty after Holoclar treatment demonstrated that the 
transplanted stem cells establish a normal layer of stratified corneal epithelium, which do not migrate 
or invade basal ocular structures. 
 
5.3 Preclinical safety data 
 
Non-clinical safety data were limited to in vitro testing of tumorigenicity of the human autologous cell 
cultures. These tests included cell karyotype, cell growth in soft agar and growth factor-dependent 
proliferation. In vitro studies have revealed no evidence of anchorage-independent growth indicative 
of tumorigenic potential. 
 
The safety of Holoclar is demonstrated in the results obtained from the two retrospective clinical 
studies. 
 
Conventional non-clinical reproductive and developmental toxicity studies are not considered relevant, 
given the nature and the intended clinical use of the autologous product. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Transport medium (Dulbecco’s Modified Eagles Medium supplemented with L-glutamine)  
Fibrin support. 
 
6.2 Incompatibilities 
 
There have been no formal compatibility studies with Holoclar therefore this medicinal product should 
not be used with other medicinal products during the post-surgical period until the corneal epithelium 
integrity is fully restored. Exceptions include non-topical antibiotics for prophylaxis and 
corticosteroids during the immediate post-operative period. 
 
6.3 Shelf life 
 
36 hours. 
Holoclar must be applied no later than 15 minutes after opening the primary container.  
 
6.4 Special precautions for storage 
 
Store between 15° C–25° C 
Do not refrigerate or freeze 
Do not irradiate (e.g. X-rays) 
Do not sterilise 
Keep the steel primary container tightly closed to protect from bacterial, fungal and viral 
contamination. 
 
6.5 Nature and contents of container and special equipment for use, administration or 
implantation 



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Holoclar is supplied as one individual treatment dose contained in a screw-cap container. Each 
container contains 3.8 cm2 of autologous human corneal epithelium attached on a fibrin support and 
covered with transport medium. 
 
The container is put in a secondary plastic container which is then put in a sealed sterile plastic bag. 
The sealed bag is put in a non-sterile, thermally insulated box for organ transportation with a 
temperature monitor. Finally, the thermally insulated box is put in a zipped sealable bag for 
transportation. 
 
6.6 Special precautions for disposal and other handling 
 
Precautions to be taken before handling or administering the medicinal product 
This medicinal product contains biological material. Healthcare professionals handling Holoclar 
should take appropriate precautions (wearing gloves, protective clothing and eye protection) to avoid 
potential transmission of infectious diseases. 
 
Holoclar is intended solely for autologous use. Prior to implantation the patient’s identity should be 
carefully checked with the patient/donor identification on the shipment documentation and product 
container.  
 
Any shaking, inverting or other mechanical stress of the Holoclar container should be avoided. 
 
Holoclar must not be sterilised. The container and closure should be carefully visually inspected for 
any damage. If the Holoclar primary container is damaged, the visual appearance of the product is 
affected, and/or visual particulates are identified, the product must not be used and must be returned to 
the manufacturer. If the temperature monitored in the insulated box deviates from the storage 
conditions, contact the manufacturer. 
 
See the educational material for further information. 
 
Precautions to be taken for the disposal of the medicinal product 
The medicinal product contains potentially infected biological material. Local guidelines on handling 
human-derived material should be followed for unused medicinal products or waste material. All 
material that has been in contact with Holoclar (solid and liquid waste) should be handled and 
disposed of as potentially infectious waste in accordance with local guidelines on handling human-
derived material.  
 
Accidental exposure 
Accidental exposure to Holoclar must be avoided. Local guidelines on handling of human derived 
materials should be followed in case of accidental exposure, which may include washing of the 
contaminated skin and removal of contaminated clothes. Work surfaces and materials which have 
potentially been in contact with Holoclar must be decontaminated with appropriate disinfectant. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Holostem Terapie Avanzate s.r.l. 
Via Glauco Gottardi 100 
41125 Modena 
Italy 
Telephone: +39 059 2058070 
Telefax: +39 059 2058115 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  



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EU/1/14/987/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 17/02/2015 
Date of latest renewal: 
 
 
10. DATE OF REVISION OF THE TEXT 
 
<{MM/YYYY}> 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
  



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ANNEX II 
 

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE 
SUBSTANCE(S) AND MANUFACTURER(S) 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 

 
E. SPECIFIC OBLIGATION TO COMPLETE POST-

AUTHORISATION MEASURES FOR THE CONDITIONAL 
MARKETING AUTHORISATION 



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A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 

Name and address of the manufacturer of the biological active substance  

Holostem Terapie Avanzate s.r.l. 
Via Glauco Gottardi,100, Modena, 41125, Italy 
 
Name and address of the manufacturer responsible for batch release 

Holostem Terapie Avanzate s.r.l. 
Via Glauco Gottardi,100, Modena, 41125, Italy 
 
 
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 (PSURs) 
 
The requirements for submission of PSURs 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 web-portal. 

 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 

• Risk management plan (RMP) 
 
The marketing authorisation holder (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   
 
The following additional risk minimisation measures are necessary for the safe and effective use of 
the product:  
Educational material for healthcare professionals to provide training on the appropriate use of the 
product and to minimise risks, addressing the key elements of: 

- Patient selection 
- Traceability of patients and use of identifiers 
- Biopsy, implant and follow up care 



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- Contraindicated use of eye drops containing benzalkonium chloride  
- Risk of glaucoma and blepharitis 
- Encouraging enrolment in the registry 
- Reporting suspected side effects 

The education material should also include both an Educational Manual and a training programme 
which will incorporate verification of physicians’ comprehension of the training provided.  
Educational material for patients and/or carers to address the following key elements: 
- Contraindicated use of eye drops containing benzalkonium chloride 
- Side effects of post-transplant treatment with antibiotics and corticosteroids 
- Inform patients of the registry 
- Reporting suspected side effects 

 
 

E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES 
FOR THE CONDITIONAL MARKETING AUTHORISATION  

 
This being a conditional marketing authorisation and pursuant to Article 14a(4) of Regulation (EC) 
No 726/2004, the MAH shall complete, within the stated timeframe, the following measures: 
 

Description Due date 

Multinational, multicentre, prospective, open-label, uncontrolled 
interventional study (HOLOCORE) to assess the efficacy and safety of 
autologous cultivated limbal stem cells grafting for restoration of corneal 
epithelium in patients with limbal stem cell deficiency due to ocular burns 

Final CSR 
March 2023 
 

 

  



14 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



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A. LABELLING 
  



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
ZIPPED SEALABLE BAG 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Holoclar 79,000 - 316,000 cells/cm2 living tissue equivalent 
Ex vivo expanded autologous human corneal epithelial cells containing stem cells. 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
This product contains cells of human origin. 
Holoclar consists of a transparent circular sheet of 300,000 to 1,200,000 viable autologous human 
corneal epithelial cells (79,000 - 316,000 cells/cm2), including on average 3.5 % (0.4 to 16 %) limbal 
stem cells, and stem cell-derived transient amplifying and terminally differentiated cells, attached on a 
supportive 2.2 cm diameter fibrin layer and maintained in the transport medium.  
 
 
3. LIST OF EXCIPIENTS 
 
Transport medium (Dulbecco’s Modified Eagles Medium supplemented with L-glutamine).  
Fibrin support. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Living tissue equivalent.  
Each container contains 3.8 cm2 of autologous human corneal epithelium attached to a fibrin support 
and immersed in transport medium. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For single use only. 
Read the package leaflet before use. 
For implantation. 
 
 
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 
 
Potentially infected biological material. 
Handle with care, avoid, any shaking, inverting or other mechanical stress. 
For autologous use only. 
 



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8. EXPIRY DATE 
 
EXP: Day / Month / Year 
At time: Hour / Minute (CET) 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store between 15° C–25° C 
Keep the steel primary container tightly closed in order to protect from bacterial, fungal and viral 
contamination 
Do not freeze 
Do not sterilise 
Do not irradiate (e.g. X-rays) 
Each batch is shipped in a temperature-controlled thermally insulated box for organ transplant. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
This medicine contains potentially infected biological material. Unused medicine or waste material 
must be disposed of in compliance with the local guidelines on handling of waste of human-derived 
material. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Holostem Terapie Avanzate s.r.l., Via Glauco Gottardi 100, 41125 Modena, Italy 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/14/987/001 
 
 
13. BATCH NUMBER, DONATION AND PRODUCT CODES 

 
Batch: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 



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17. UNIQUE IDENTIFIER – 2D BARCODE 
 
<Not applicable.> 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
<Not applicable.> 
 
 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
PLASTIC BAG (TERTIARY) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Holoclar 79,000 - 316,000 cells/ cm2 living tissue equivalent. 
Ex vivo expanded autologous human corneal epithelial cells containing stem cells. 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
This product contains cells of human origin. 
Holoclar consists of a transparent circular sheet of 300,000 to 1,200,000 viable autologous human 
corneal epithelial cells (79,000 - 316,000 cells/ cm2), including on average 3.5 % (0.4 to 16 %) limbal 
stem cells, and stem cell-derived transient amplifying and terminally differentiated cells, attached on a 
supportive 2.2 cm diameter fibrin layer and maintained in the transport medium.  
 
 
3. LIST OF EXCIPIENTS 
 
Transport medium (Dulbecco’s Modified Eagles Medium supplemented with L-glutamine)  
Fibrin support. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Living tissue equivalent.  
Each container contains 3.8 cm2 of autologous human corneal epithelium attached to a fibrin support 
and immersed in transport medium. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For single use only. 
Read the package leaflet before use. 
For implantation. 
 
 
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 
 
Potentially infected biological material. 
Handle with care, avoid any shaking, inverting or other mechanical stress. 
For autologous use only. 
 
 



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8. EXPIRY DATE 
 
EXP: Day / Month / Year 
At time: Hour / Minute (CET) 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store between 15° C-25° C 
Keep the steel primary container tightly closed in order to protect from bacterial, fungal and viral 
contamination 
Do not freeze 
Do not sterilise 
Do not irradiate (e.g. X-rays) 
Each batch is shipped in a temperature-controlled thermally insulated box for organ transplant. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
This medicine contains potentially infected biological material. Unused medicine or waste material 
must be disposed of in compliance with the local guidelines on handling of waste of human-derived 
material. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Holostem Terapie Avanzate s.r.l., Via Glauco Gottardi 100, 41125 Modena, Italy 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/14/987/001  
 
 
13. BATCH NUMBER, DONATION AND PRODUCT CODES 

 
Batch 
Patient’s Forename and Surname: 
Patient’s Date of Birth: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 



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Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
<Not applicable.> 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
<Not applicable.> 
 
  



22 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
SCREW-CAP CONTAINER  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Holoclar 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
DATE: 
HOUR: (Time zone) 
 
 
4. BATCH NUMBER<, DONATION AND PRODUCT CODES> 
 
Batch 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 
M.A.H: Holostem Terapie Avanzate s.r.l. 
 
  



23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



24 

Package leaflet: Information for the patient 
 

Holoclar 79,000 – 316,000 cells/cm2 living tissue equivalent 
Ex vivo expanded autologous human corneal epithelial cells containing stem cells. 

 
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 surgeon. 
- If you get any side effects, talk to your surgeon. This includes any possible side effects not 

listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Holoclar is and what it is used for 
2. What you need to know before you are given Holoclar 
3. How Holoclar is given 
4. Possible side effects 
5. How Holoclar is stored 
6. Contents of the pack and other information 
 
 
1. What Holoclar is and what it is used for 
 
Holoclar is a medicine used for replacing damaged cells of the cornea (the clear layer that covers the 
coloured iris at the front of the eye) including limbal cells which normally help to maintain the health 
of your eye. 
 
Holoclar consists of a layer of your own cells which have been grown (ex vivo expanded) from a 
sample of limbal cells taken from your eye during a small surgical procedure called a biopsy. Each 
preparation of Holoclar is made individually and is for a single treatment only, although treatments can 
be repeated. The cells used to make Holoclar are known as autologous limbal cells: 
 

• Autologous means that they are your own cells. 
• The limbus is part of the eye. It is the rim surrounding the coloured centre (iris) of your 

eye. The picture shows where the limbus is in your eye. 
• The limbus contains limbal cells which normally help to maintain the health of your 

eye and some of these are stem cells which can make new cells. These new cells can 
replace the damaged cells in your eye. 

 

 



25 

 
Holoclar is implanted to repair the damaged surface of the eye in adults. When the eye is badly 
damaged by physical or chemical burns, lots of scarring can occur and the limbus can be damaged. 
Damage to the limbus stops normal healing, which means that the damage to your eye is never 
properly repaired. 
 
By taking some healthy limbal cells, a new layer of healthy tissue is grown in the laboratory on a 
supporting layer of fibrin, a protein scaffold. This layer of tissue is then implanted by a surgeon into the 
damaged cornea helping your eye to heal normally. 
 
 
2. What you need to know before you are given Holoclar 
 

You must not be given Holoclar: 
- if you are allergic to any of the ingredients of this medicine (listed in section 6) or to bovine 
serum and mouse cells 

 
Warnings and precautions 
Talk to your surgeon before you are given Holoclar. 
 
Holoclar is prepared individually from your own cells to match you, and must not be used for anyone other 
than yourself. 
 
If you have an acute eye infection or swollen, red (inflamed) eyes, your treatment should be delayed 
until you have recovered. 
 
When Holoclar is made, two ingredients from animals are used. One is foetal bovine serum which is 
from cows and is used to help grow your cells. The other ingredient is a special kind of inactivated 
mouse cell which is used to grow your limbal cells. If you are allergic to either of these ingredients, 
you will not be able to be given this medicine (see above under ‘You must not be given Holoclar’).  
 
If you have any of the following problems with your eyes, they should be treated before this medicine 
is used: 

• Uneven eyelids 
• Scarring of the conjunctiva (the protective layer over the white of your eye) with damage 

where it joins to the inside of the eyelids (fornix shortening) 
• Inability for your eye to sense pain (anaesthesia of the cornea or conjunctiva or hypoaesthia) 
• Growth of the conjunctiva over the cornea (pterygium) 
• Severe dry eye. 

 
Other cases in which Holoclar cannot be used 
Even if the surgeon has already taken a small sample of limbal cells (a biopsy) needed to produce the 
medicine, it is possible that you will not be able to have treatment with Holoclar. This is the case if the 
biopsy is not good enough to make Holoclar, the cells cannot be grown in the laboratory or the grown 
cells do not meet all the quality requirements. Your surgeon will inform you about this. 
 
Children and adolescents 
Only a very small number of children have been treated so far, so it is not known whether the 
medicine is safe for use in children or how effective it may be. 
 
Kidney and liver problems 
Please talk with your surgeon before the start of treatment if you have liver or kidney disease. 
 
Other medicines and Holoclar 



26 

Some eye-drops contain a preservative called ‘benzalkonium chloride’. This ingredient can damage 
the cells of which Holoclar is made. Do not use eye-drops containing benzalkonium chloride and/or 
other preservatives. Ask your doctor or pharmacist for advice. 
 
Pregnancy and breast-feeding 
If you are pregnant, think you might be pregnant or you are breast-feeding, treatment with this 
medicine should be delayed.  
 
Driving and using machines 
Holoclar is given by surgery on your eye and this will impact on your ability to drive and use 
machines. Therefore, do not drive or use machines after having Holoclar put in your eye until your 
surgeon tells you that it is safe to do so. Follow their advice carefully. 
 
 
3. How Holoclar is given 
 
Holoclar can only be prescribed and given by an eye surgeon in a hospital.  
Treatment with Holoclar is a two-step procedure. 
 
Visit 1: Biopsy taken 
On the first visit, the surgeon will carry out a biopsy, which means removing a very small amount of 
tissue containing limbal cells (from your eye). Before the biopsy, the surgeon will give you eye-
drops to anaesthetise your eye and surgically take the biopsy. This biopsy will then be used to make 
Holoclar. After biopsy has been taken, your surgeon will prescribe a course of antibiotics for you to 
reduce the chance of an infection.  
It will take several weeks to produce Holoclar. 
 
Visit 2: Holoclar implantation 
On the second visit the surgeon will: 
• Anaesthetise your eye  
• Remove the scarred surface of the cornea 
• Replace it with Holoclar 
On the day of surgery, the surgeon will anesthetise your eye and then will attach the edge of your new 
cornea with stitches to make sure that Holoclar stays in place. Your eyelid will be taped closed for 
three days and your eye will be bandaged for 10 to 15 days after the implantation. 
 
After surgery, you will be prescribed a course of medicines to ensure full healing: antibiotics to reduce 
the chance of an infection and steroids to reduce swelling and irritation. It is very important that you 
take all the medicines prescribed by your surgeon, otherwise Holoclar may not work. 
Please read the package leaflets for the individual medicines you are given for further information on 
these medicines. 
 
Ask your surgeon if you have any further questions about the treatment with Holoclar. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Most side effects affect the eye, some of which are caused by the surgery. Most side effects are 
mild and disappear in the weeks after surgery. 
 
The most serious side effects are problem with cornea (erosion) and perforation of the cornea, 
which may occur within the 3 months from Holoclar implantation. In such a case, please contact 
your surgeon. 
 



27 

Very common: may affect more than 1 in 10 people 
• Inflammation of the eyelids (blepharitis)  

 
Common: may affect up to 1 in 10 people 

• Bleeding around the site of the operation where Holoclar was inserted 
• Problems with cornea (erosion) 
• Increased pressure in the eye (glaucoma) 
• Eye pain 
• Inflammation of the cornea  

 
Uncommon: may affect up to 1 in 100 people 

• Eye disorders - stickiness of the eyelid, bloodshot eyes, swelling of the eye, perforation of 
the cornea and eye irritation 

• Sensitivity to light 
• Overgrowth around the implant (metaplasia) 
• Infection of the cornea 
• The stitches break 
• Fainting 
• Bleeding from the eye lid skin 

 
Reporting of side effects 
If you get any side effects, talk to your 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 Holoclar is stored 
 
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 Holoclar within the steel container in the plastic bag until surgery. This is to protect it from 
contamination by bacteria. 
Holoclar must not be irradiated or sterilised. 
 
Since this medicine will be used during your surgery, the hospital staff are responsible for the correct 
storage of the medicine before and during its use, as well as for the correct disposal. 
 
 
6. Contents of the pack and other information 
 

What Holoclar contains 
- The active substance consists of 300,000 - 1,200,000 of your living eye cells, on average 

3.5 % of which are stem cells. Each square centimetre of Holoclar contains 79,000 - 316,000 
cells. 

- There are two excipients: one is fibrin - a clear supportive layer used to keep Holoclar intact, the 
other one is a liquid containing amino acids, vitamins, salts and carbohydrates to store the cells in 
the vial called Dulbecco’s Modified Eagles Medium supplemented with L-glutamine. 

 
What Holoclar looks like and contents of the pack 
Holoclar is a layer of cells for implantation into your eye. The cells are kept alive in a small 
sterile container. The medicine is put in several layers of packaging which protect the medicine 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


28 

from bacteria and ensures that Holoclar is kept at a stable temperature for 36 hours, if stored at 
room temperature. 
 
Each package contains an individual treatment dose which is large enough to cover your cornea. 
 
Marketing Authorisation Holder and Manufacturer 
Holostem Terapie Avanzate s.r.l. 
Via Glauco Gottardi 100, Modena, 41125, Italy 
Phone: +39 059 2058070 
Fax: +39 059 2058115 
 
This leaflet was last revised in  
 
This medicine has been given ‘conditional approval’. This means that there is more evidence to come 
about this medicine. 
The European Medicines Agency will review new information on this medicine at least every year and 
this leaflet will be updated as necessary. 
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	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
	E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION
	A. LABELLING
	B. PACKAGE LEAFLET