Publication

ALCHIMIA

Review of research studies according to Annex X of Council Directive 93/42/EEC on medical

1. DECLARATION
The confirmation of the conformity with the requirements concerning the characteristics and performances of the RS-OIL, RS-OIL ECS, and SOP( silicone oil 1.000 and 5.000 cS in vials and syringes) under the normal conditions of use of the device and the evaluation of the undesirable side-effects and of the acceptability of the benefit/risk ratio was based on a critical evaluation of a compilation of the relevant scientific literature currently available on the intended purpose of the devices and the techniques employed, according to Annex X of Council Directive 93/42/EEC on medical devices. This choice was made considering that scientific literature provide sufficient information concerning the characteristics and performances of RS-OIL, RS-OIL ECS, and SOP (silicone oil 1.000 and 5.000 cS in vials and syringes), and their substantial equivalence with the silicone oils to which the data relates. Results of the critical evaluation of this compilation relating to the safety, performance, the design characteristics and the intended purpose of the devices are shown in the present report.

2. INTRODUCTION
A number of compounds are well-known for their use as intraocular tamponade during ophthalmic surgery. These compounds include gases, liquid perfluorocarbons (PFLC) and silicone oil (polydimethylsiloxane). In particular, the latter has been used as an intraocular medical device for more than forty years.
2.1. Physical and chemical properties of silicone oil
Silicone oils are polymers of polydimethylsiloxane made of repeating dimethylsiloxane units. They are clear colourless and non-absorbing fluids with scarce toxic potential. Their viscosity (usually reported in centistokes, cS) is directly correlated to polymer length. For instance, 1,000 cS silicone oil (MW 30,000 Daltons) is made of 403 repeating units, while 5,000 cS silicone oil (MW 50,000 Daltons) is made of 673 repeating units. Polydimethylsiloxane does not contain active chemical groups, and then it is considered chemically inert. Silicone oils have great thermal and oxidative stability due to the absence of double bonds and the inherent stability of the Si-O linkage. The chemical and physical properties of silicone oil made it a valuable help during vitreoretinal surgery: being a clear and non-absorbing fluid, it maintains visibility of the retina during surgery and vision is possible post-operatively. Silicone oil is not miscible with an aqueous solution, thus maintaining separated oil and water phases within the eye. Silicone oil has a sufficiently high interfacial surface tension such that in an aqueous environment it maintains a shape with the lowest surface area to volume ratio. This is a sphere in the absence of contact with an irregular surface. When the silicone bubble contacts an irregularity, such as a detached or torn retina, an indentation is formed and a counteractive force against the deformation is produced. This force creates the tamponade (Trask D. K., Richard-James, Inc.). Silicone oil is stable under normal usage conditions. It can react with strong oxidising agents.
2.2. Biocompatibility and toxicity of silicone oils
Experimental studies in mice sensitised dermally to polydimethylsiloxane have shown that this material is not irritant nor elicit hypersensitivity under these experimental conditions (NTP Report Number: IMM90006).
AL.CHI.MI.A. S.R.L. Viale Austria 14 – 35020 Ponte San Nicolò (PD) – ITALY Ph. +39.049.896.2074 – +39.049.896.2064 – fax +39.049.896.2071
P.IVA IT 00063370282 – C.C.I.A.A. 43409 Cap. Sociale 88.400,00 € int. Versati -e-mail info@alchimiasrl.com
Design, manufacturing and sale of medical devices. Design and supply of consulting services in the field of product quality and safety Albo Laboratori di Ricerca del M.U.R.S.T. N. 41 del 24/07/2000
ALCHIMIA
In addition, inflammatory reactions were not observed in rabbit eyes injected with medical-grade silicone oil (Pastor et. al. Acta Ophthalmologica 1992 70: 651-658), and no adverse immunologic effects were reported in the various tests undergone by silicone oil (Food and Drug Administration Sharon Snider (301) 443-3285). Recently, two papers have been published reporting the appearance of immunoproteins in the tissue in contact with silicone after intraocular silicone oil. In both cases, the intended use of silicone oil was as a permanent vitreous substitute, not as a temporary intraocular tamponade. In the first study, the presence of immunoproteins was attributed in part to the surgery (Versura et al. Ophthalmologica 2001 215:276-283), whereas in the second one, where the average intraocular retention of silicone oil was 852.1 days (range 202-2,027), the clinical relevance of the immunoproteins was not elucidated since no clinical sign of immune disease was observed in patients (Pastor et al. Ophthalmic Research 2001 33: 87-90). Silicone oil has scarce toxic potential. The possible toxic effects of intraocular silicone oil, which have been reported as toxicity to the retina, have been attributed to emulsification of silicone oil. This in turn has been attributed to the presence of low-molecular-weight-components (< 2.400 Daltons, LMWC) of silicone oil. However, gas chromatographic analysis of different silicone oils has shown that LMWC are scarcely detectable in medical-grade silicone oils (Nakamura et al. Invest Ophthalmol Vis Sci 1990 31(10):2059-2069). In a general way, the emulsification of silicone oil is a phenomenon associated with the factors that control the viscosity of silicone oil, i.e. the average molecular weight, the molecular weight distribution, and the enlargement of individual strands, and it is common opinion that silicone oils with high viscosity, narrow distribution of molecular weights and low concentrations of LMWC have a good biological tolerance. In particular, polydimethylsiloxanes with molecular weight greater than 30,000 Daltons, where chain enlargement prevents the movement of polymer strands relative to each other, have a reduced emulsification (Trask D. K., Richard-James, Inc.). Highly purified silicone oils have low emulsification too (Lakits et al. Ophthalmology 1999 106(6):1091-1100). LMWC could be formed in the human eye via hydrolysis of silicone oil. However a clinical study has shown that highly purified silicone oils do not undergo chemical modification even after prolonged intraocular use (26 months). In the same study, oil emulsification has been reported to occur in the absence of LMWC (Lakits et al Ophthalmology 1999 106(6):1091-1100). Therefore the authors conclude that LMWC do not play a substantial role in the oil emulsification.
2.3. Clinical use of silicone oil
Clinical use of silicone oil includes:
• giant retinal tears;
• macular holes;
• proliferative diabetic retinopathy;
• proliferative vitreoretinopathy; ocular trauma;
• cytomegalovirus (CMV) retinitis.

Silicone oil has been proven effective in the treatments of complex retinal detachment with proliferative vitreoretinopathy (Abrams et al. Arch Ophthalmol, 115, 335-44, 1997), giant retinal tears complicated by proliferative vitreoretinopathy (Batman et al. Retina 19(3): 188-92, 1999) and macular holes (Goldbaum et al. Ophthalmology, 105:2140-2148, 1998).
AL.CHI.MI.A. S.R.L. Viale Austria 14 – 35020 Ponte San Nicolò (PD) – ITALY Ph. +39.049.896.2074 – +39.049.896.2064 – fax +39.049.896.2071
P.IVA IT 00063370282 – C.C.I.A.A. 43409 Cap. Sociale 88.400,00 € int. Versati -e-mail info@alchimiasrl.com
Design, manufacturing and sale of medical devices. Design and supply of consulting services in the field of product quality and safety Albo Laboratori di Ricerca del M.U.R.S.T. N. 41 del 24/07/2000
ALCHIMIA
Silicone oil does not resorb spontaneously and, therefore, requires a second surgery for oil removal on achievement of anatomic success (Scott et al. Ophthalmology, 106: 1399-1408, 1999). Silicone oil can stay within the eye for prolonged periods (range 2 – 7 months) (Gurelik et al. Int. Ophthalmol. 23(3): 131-5, 1999; Jiang Y., and Li X. Chung Hua Yen Ko Tsa Chih 33(1): 39-41, 1997) during which it does not pass through the hole or under retina (Goldbaum et al. Ophthalmology, 105:2140-2148, 1998) nor undergoes chemical modification (Lakits et al. Ophthalmology, 106:1091-1100, 1999).
2.4. Complications associated with the use of silicone oil during vitreoretinal surgery
The use of silicone oil can result in postoperative complications that include hypotony, increase of intraocular pressure (IOP), glaucoma, development of cataracts and keratopathy. All these conditions can be treated with medical devices, drugs or surgery (Food and Drug Administration, Sharon Snider (301) 443-3285). Hypotony (≤ 5 mmHg) occurs more frequently in eyes without retinal attachment (31% vs. 5%). In fact, decreased IOP is a well-recognized feature of retinal detachment (Scott et al. Ophthalmology 1999 106(7): 1399-1407). Hypotony is also frequent in HIV-positive patients with cytomegalovirus retinitis who have a lower preoperative IOP in general than HIV-negative patients (Henderer et al. Arch Ophthalmol 1999 117:189-195). An elevated IOP (≥ 30 mmHg) is a relatively common complication associated with the use of silicone oil, and may occur by pupillary block or even by a pre-existing condition. In particular, a pre-existing history of glaucoma or diabetes mellitus, and a high IOP on the first postoperative day are risk factors for a persistently elevated IOP (Henderer et al. Arch Ophthalmol 1999 117:189¬195). In most cases the increased IOP either normalize spontaneously (Richard-James, Inc. PMA P950008) or can be corrected with local therapy (Scholda et al. Acta Opthalmologica Scandinavica 1997 75(6):695-699) The migration of silicone oil into the anterior chamber has been associated with the appearance of corneal changes such as oedema, opacification, Descemet’s folds, or decompensation when postoperative keratopathy does not disappear spontaneously (Scholda et al. Acta Opthalmologica Scandinavica 1997 75(6):695-699). If decompensation occurs, silicone oil must be removed manually by syringe, and the patients must immediately undergo the standard practice for medical treatment of kerathopaty (Richard-James, Inc. PMA P950008). Therefore, silicone oil is not a good choice when the oil can enter in the anterior chamber through defects in the capsule or zonules (Goldbaum et al. Ophthalmology 1998 105(11):2140-2148). However, even corneal decompensation may be an acceptable complication if almost lost eyes can be saved (Gurelik et al. International Ophthalmology 2001 23: 131-135). Cataract is a relatively common complication in patients that have undergone vitrectomy with silicone oil injection for the management of retinal detachment. Cataract can be extracted contemporary to silicone oil removal or during the follow-up period (Scholda et al. Acta Opthalmologica Scandinavica 1997 75(6):695-699).
2.5. Interactions between silicone oil and other medical devices
Silicone oil can be used together with liquid perfluorocarbons (PFCL) in the treatment of complex retinal detachments. In fact, silicone oil opposes the superior retina and PFCL opposes the inferior retina. The two substances are immiscible, and the meniscus delineating them is visible during fundus examination.
AL.CHI.MI.A. S.R.L. Viale Austria 14 – 35020 Ponte San Nicolò (PD) – ITALY Ph. +39.049.896.2074 – +39.049.896.2064 – fax +39.049.896.2071
P.IVA IT 00063370282 – C.C.I.A.A. 43409 Cap. Sociale 88.400,00 € int. Versati -e-mail info@alchimiasrl.com
Design, manufacturing and sale of medical devices. Design and supply of consulting services in the field of product quality and safety Albo Laboratori di Ricerca del M.U.R.S.T. N. 41 del 24/07/2000
ALCHIMIA
Because of its greater viscosity, silicone oil is less likely to enter the anterior chamber of aphakic eyes than is PFCL and may resist the movement of PFCL into the anterior chamber (Peyman et al. Surv Ophthalmol 1995 39(5):375-95). The use of silicone oil is contra-indicated in patients with silicone intraocular lenses (IOL). It is possible that silicone oil interact with IOL; even if silicone oil does not seem to damage the IOL surface, adhesion of silicone oil droplets to the lens surface can result in a reduction of the optical quality of the lens, thus contra-indicating the use of silicone IOL in complex retinal detachment requiring intraocular silicone oil (Senn et al. Ophthalmic Surgery and Lasers 1997 28(9): 776-779).
2.6. Safety and Effectiveness of silicone oil
Based upon the results of clinical studies, silicone oil has been shown to be safe and effective for the following indications:
• as a prolonged retinal tamponade during vitreoretinal surgery in patients with primary or recurrent retinal detachment which is complicated by perforating injuries, giant retinal tears or proliferative vitreoretinopathy, cytomegalovirus retinitis;
• as eliminating the need to maintain face-down position particularly in children, mental retardation and physically handicapped;
• as facilitating an early visual rehabilitation when compared with other techniques.
• as permitting travel by air or ascend in altitude after surgery.

2.7. Risk/Benefit Analysis
Retinal detachment is a severe condition that if untreated can result in blindness. The use of silicone oil has markedly improved the patient’s prognosis, allowing successful retinal reattachment (60 to 75 percent of patients treated with oil; 96 percent in people with AIDS-related CMV retinitis), and improving visual acuity (80 percent of patients treated with oil; 57 percent in people with AIDS-related CMV retinitis) (Food and Drug Administration, Sharon Snider (301) 443-3285). Silicone oil allows a normal lifestyle during the period of tamponade and this is particularly advantageous for paediatric, young and mentally or physically handicapped patients. Other endotamponades (e.g. gas) require a facedown positioning of the patient during the postoperative period (2-4 weeks), and preclude travel by air or ascension in altitude (Goldbaum et al. Ophthalmology 1998 105(11):2140¬2148). Silicone oil is a needed adjunct to vitrectomy in complex retinal detachments because it allows the salvage of previously lost eyes; improves patient’s outcome; is associated with long-term stable outcomes, and has a good safety profile (Richard-James, Inc. PMA P950008). The clinical studies with silicone oil established that additional risks added to the surgical procedure were minor, as compared to significant benefits. The silicone oil associated risks can be treated with medical devices, drugs or surgery, and possible remnant droplets of oil in the fluid that fills the vitreous cavity after oil removal are not generally bothersome. In addition, the incidence of oil-related complications has been constantly reduced by the refinement of operating techniques as well as the development of highly viscous and highly purified oils (Scholda et al. Acta Opthalmologica Scandinavica 1997 75(6):695-699). The benefits with silicone oils outweigh risks.

3. CONCLUSIONS
Based on the above critical evaluation of the relevant scientific literature currently available we conclude that RS-OIL, RS-OIL ECS, and SOP (silicone oil 1.000 and 5.000 cS in vials and syringes) are safe and perform as intended under the normal conditions of use.
AL.CHI.MI.A. S.R.L. Viale Austria 14 – 35020 Ponte San Nicolò (PD) – ITALY Ph. +39.049.896.2074 – +39.049.896.2064 – fax +39.049.896.2071
P.IVA IT 00063370282 – C.C.I.A.A. 43409 Cap. Sociale 88.400,00 € int. Versati -e-mail info@alchimiasrl.com
Design, manufacturing and sale of medical devices. Design and supply of consulting services in the field of product quality and safety Albo Laboratori di Ricerca del M.U.R.S.T. N. 41 del 24/07/2000
ALCHIMIA

4. REFERENCES

1. Nakamura K. et. al.: Analysis and fractionation of silicone and fluorosilicone oils for intraocular use. Invest Ophthalmol Vis Sci 31(10).2059-69, 1990.

2. Lakits A. et al.: Chemical stability of silicone oil in human eye after prolonged clinical use. Ophthalmology 106(6):1091-100, 1999.

3. Trask D. K.: Silikon 1000 and Silikon 5000. Richard-James, Inc. Product information.

4. Versura P. et al.: The biocompatibility of silicone, fluorosilicone and perfluorocarbon liquids as vitreous tamponades, an ultrastructural and immunohistochemical study. Ophthalmologica 215(4):276-83, 2001.

5. NTP Report IMM90006: The immunotoxicity of Polydimethylsiloxane.

6. Pastor J. C. et. al.: Intravitreal silicone and fluorosilicone oils: pathologic findings in rabbit eyes. Acta Ophthalmol 70(5): 651-8, 1992.

7. Pastor J. C. et. al.: Antisilicone antibodies in patients with silicone implants for retinal detachment surgery. Ophthalmic Res 33(2): 87-90, 2001.

8. Senn P. et. al.: Interaction Between Silicone Oil and Silicone Intraocular Lenses. Ophthalmic Surgery and Lasers 28(9) 1997.

9. Richard-James, Inc.: Silikon 1000TM Intraocular Fluid. Richard-James, Inc. PMA P950008).

10. Peyman et. al.: Perfluorocarbon Liquids in Ophthalmology. Surv. Ophthalmol. 39(5):375¬95, 1995.

11. Gurelik G., et al.: Acute corneal decompensation after silicone oil removal. Int. Ophthalmol. 23(3): 131-5, 1999.

12. Jiang Y., and Li X.: The best timing of silicone oil removal. Chung Hua Yen Ko Tsa Chih 33(1):39-41, 1997.

13. Goldbaum M.H. et. al.: Silicone oil tamponade to seal macular holes without position restrictions. Ophthalmology 105(11):2140-7, 1998.

14. Snider S.: FDA approves silicone oil for retinal reattachment. http://www.fda.gov/bbs/topics/NEWS/NEW00499.htlm

15. Scott IU, et al.: Silicone oil in the repair of pediatric complex retinal detachments: a prospective, observational, multicenter study. Ophthalmology 106(7):1399-407, 1999.

16. Henderer J. D. et al.: Elevated intraocular pressure and hypotony following silicone oil retinal tamponade for complex retinal detachment: incidence and risk factors. Arch Ophthalm 117(2):189-95, 1999.

17. Scholda C., et al.: Silicone oil removal: results, risks and complications. Acta Ophthalmol Scand 75(6):695-9, 1997.

18. Batman C., and Cekic O.: Vitrectomy with silicone oil or long-acting gas in eyes with giant retinal tears: long-term follow-up of a randomized clinical trial. Retina 19(3):188-92, 1999.

19. Abrams GW, et al.: Vitrectomy with silicone oil or long-acting gas in eyes with severe proliferative vitreoretinopathy: results of additional and long-term follow-up. Silicone Study report 11. Arch Ophthalmol 115(3):335-44, 1997.