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.

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

Data regarding the safety and efficacy of Holoclar in children and adolescents aged 0 to 18 years is limited. 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.

Before administration, it must be confirmed that the patient's identity matches the unique patient information on the Holoclar label and accompanying documentation.

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 cultured tissue 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, excluding the use of lidocaine local anaesthesia or anaesthetics containing adrenaline.

Post-operative treatment

Following implantation, an appropriate regimen of topical and systemic anti- inflammatory and prophylactic antibiotic treatment must be given.

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 detailed instructions on preparation, measures to take in case of accidental exposure and disposal of Holoclar, see 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 after expiry date of the product.

Autologous use

Holoclar is intended solely for autologous use and must not, under any circumstances, be administered to other patients. Holoclar must not be administered if the information on the product labels and lot number do not match the patient's identity.

Hypersensitivity reactions

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).

Transmission of an infectious agent

Holoclar could contain potentially infected biological material. Although Holoclar is tested for sterility and mycoplasma, a risk of transmission of infectious agents exists. Healthcare professionals administering Holoclar must, therefore, monitor patients for signs and symptoms of infections after treatment and treat appropriately, if needed.

Precautions for use

A thorough evaluation of the patient should be done taking into consideration not only the clinical need of the candidate, but also the biological and pathophysiologic alterations in the wound bed environment, to define the timing of any procedure and allow the proper engraftment and growth of the stem cells of the living tissue that constitute Holoclar. Concomitant surgeries should be excluded and anticipated or deferred to Holoclar implantation.

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. Concomitant eye problems should be corrected prior to Holoclar implantation.

At any of the steps of the treatment with Holoclar, topical lidocaine or anaesthetics containing adrenaline must be avoided.

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

No interaction studies have been performed.

The concomitant use of topical lidocaine or anaesthetics containing adrenaline must be avoided as they reduce the colony forming efficiency.

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 corneal epithelium, in particular the proliferative basal layer, exposed during the implantation procedure. 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 deferred 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 poor corneal stem cell engraftment, 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 reactions related to the surgical procedure were eye pain (4.0 %), corneal epithelium defect (3.4 %) and conjunctival haemorrhage (2.2 %), the latter appearing mostly during the first day after surgery and in most cases to be mild in intensity and disappearing within a few days without treatment.

Tabulated list of adverse reactions

Adverse reactions reported in patients implanted with Holoclar in clinical studies and post-marketing experience 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, conjunctivitis

Uncommon

Nervous system disorders

Syncope vasovagal, headache

Uncommon

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

Common

Eye disorders

Conjunctival adhesion, conjunctival granuloma, conjunctival hyperaemia, corneal oedema, corneal perforation, corneal thinning, corneal opacity, corneal hypertrophy, eye inflammation, hyphaemia, eye irritation, photophobia, entropion, trichiasis, mydriasis,

lacrimation increased

Uncommon

Gastrointestinal disorders

Nausea

Uncommon

Skin and subcutaneous tissue disorders

Haemorrhage subcutaneous, dermatitis allergic

Uncommon

General disorders and administration site conditions

Metaplasia of the implant, implant site extravasation, sensation of foreign body

Uncommon

Injury, poisoning and procedural complications

Eye operation complication

Common

Engraft failure, suture rupture, persistent

corneal epithelial defect, procedural vomiting

Uncommon

Description of selected adverse reactions

Eye pain (4.0 %), and corneal epithelium defect (3.4 %) were the most common individual adverse reactions not related to the surgical procedure. Glaucoma (1.9 %) 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 5 years of age and only limited information in patients 6 - 17 years of age. In the paediatric patients included in the studies HLSTM01 (age 13, 14 and 16 years), HLSTM02 (age 8 and 14 years) and HOLOCORE (6 to 13 years) the profile of adverse reactions was not different from the adult population.

Elderly

There is only limited information in elderly (n=16, > 65 years old) and very elderly (n= 4, 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 Yellow Card Scheme Website: www mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

No case of overdose has been reported.