Imunovir®500mg TabletsInosine Acedoben Dimepranol

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Imunovir® 500mg TabletsInosine Acedoben Dimepranol

A N T I V I R A L I M M U N O T H E R A P Y

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Imunovir® 500mg TabletsInosine Acedoben Dimepranol

Imunovir® tablets contain as an active pharmaceutical ingredient, 500mg Inosine Acedoben Dimepranol (also known as Inosine Pranobex [BAN]), an immunomodulating agent with specific antiviral properties. Imunovir® is anacceptable oral solid dose therapy with a well established safety profile that is indicated for the treatment of:

• Mucocutaneous infections due to herpes simplex virus (type I and/or type II)• Genital warts as adjunctive therapy to podophyllin or carbon dioxide laser

• Subacute sclerosing panencephalitis (SSPE)

Imunovir® is a Prescription Only Medicine and is available in blister packsof 100 tablets.

PIP code 100 Tablets: 001-3987 Trade Price: £39.50

Imunovir® is marketed worldwide and is known by various trade names in different countriese.g. Delimmun® and Isoprinosine®. The active ingredient is also known in different territoriesunder different names such as Inosine Pranobex (BAN), Inosiplex and Methisoprinol.

Immunomodulation

Inosine Acedoben Dimepranol (IAD) is an immunomodulatory agent that mediates anti-viral properties. IAD supports the immune system throughmodulation of T-cell proliferation, T-cell function, natural killer cell activity and phagocytosis.

Studies have shown that IAD induced an enhanced lymphocytetransformation response to inactivated HSV antigen in patients with genitalherpes (Corey et al 1979). Lomnitzer (1988) demonstrated the in-vitro ability of IAD to enhance the proliferation of peripheral blood mononuclear cells.

IAD has also been shown to elicit a PBMC response coupled with an increasein Interferon activity in patients suffering from SSPE (Gadoth et al 1989). Miglietta et al (1980) showed that IAD brought about an increase in monocyte and neutrophil phagocytosis.

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Tsang et al (1985) observed, through in-vitro analysis in healthy elderly humans, that the presence of IAD was associated with the restoration ofConA-induced lymphocyte proliferation, natural killer cell activity, neutrophilchemotaxis and IL-2 production to normal or near normal levels in 90%,85.3%, 84.6% and 71.4% respectively of the subjects studied.

Petrova et al (2010) demonstrated that IAD, administered at a dose of 3g IADper day for five days repeated weekly for three weeks, was capable of increasing cytokine levels (IFN-γ, IL-10 and TNF-α) in healthy patients at Day 7and Day 10.

The pivotal role played by the cell-mediated immune system in controllingduration and severity of, and recovery from, viral infection provides the basisfor treatment with immunopharmacological agents such as IAD (Miller 1984).

Genital Herpes

IAD is one of the treatment options for the treatment of primary genital herpes.

In an 812 patient study Talbot and Menday (1985) found that the clinicalresponse was highly significant in favour of IAD (4g/day for seven days) inpatients with both primary lesions irrespective of stage or recurrent episodeswhen compared to placebo.

In addition the mean reduction in total “symptom score” (based on the pre-treatment and post-treatment evaluation of pain, itching and inflammationon a 4-point scale) was significantly greater in primary cases in the activegroup (p<0.01). The greatest symptomatic relief attributable to IAD was reliefof itching and reduction of inflammation. This was particularly apparent forall patients with herpes labialis treated in the prodromal stages.

In a double blind placebo controlled clinical study, IAD was shown toproduce a significant reduction in recurrence rate (Figure 1), virus sheddingand overall severity of the disease (Miller 1984). Therapy began with an initialdosage of IAD at 3g/day initiated within 24 hours of a recurrence outbreak for

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the first 5 days of each recurrence with the dosage reduced to 1g/day on day6 until the next recurrence occurred at which time the cycle was repeated for6 months. In the follow-up open phase for another 6 months, all patientsreceived Isoprinosine® at the same treatment schedule as for the first 6months. Isoprinosine® produced a significant reduction in recurrence rate,virus shedding and overall severity of the disease.A large number of concomitant medications were used with no indications ofany drug interaction with Isoprinosine®.

Miller (1984) concluded that IAD has significant therapeutic andepidemiological importance in the management and control of HSVinfections.

Recurrences / 6 months

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Figure 1: The effect of IAD on the frequency of recurrences in genital herpes (Adapted from Miller 1984)

Byrne et al (1988) in a double blind placebo controlled clinical study furthercompared episodic therapy (4g IAD per day for 5 days from the first sign ofrecurrence) to continuous therapy (4g IAD per day for 5 days from the firstsign of recurrence followed by a maintenance dose of 1g IAD per day for 1year) – the final six months was an open label study. Mean recurrence ratesremained significantly less than the pre-treatment mean during the follow-upperiod of 80 to 450 days after cessation of therapy. The results of the studypresented in Figure 2 showed that continuous treatment exhibited astatistically significant reduction in the frequency of recurrence of genitalherpes infection with the effect persisting for one year.

Number of recurrences per month Episodic treatment Continuous treatment

IAD Placebo IAD Placebo

Pre-treatment 0.92 0.77 1.13 0.96

Treatment 0.99 0.81 0.60 0.86

Changes 0.07 0.04 -0.53* -0.11

* p < 0.01 compared with pre-treatment baseline

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Figure 2: The effect of IAD on the number of recurrences of genital herpes per month(Adapted from Byrne et al 1988)

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In a 12 week double-blind placebo-controlled trial in 39 patients with a highfrequency of herpes simplex labialis recurrences (median number ofrecurrences in the year before the trial was 9.25±2), IAD was shown to affect agreater reduction of recurrences than the placebo group (p<0.02). Thedosing regime was 70mg/kg IAD for 7 days which was repeated every fourweeks for three cycles (Galli et al 1984).

Genital Warts

IAD through its immunomodulating capability represents a unique oral systemictherapy for the treatment of genital HPV infection.

In a 38 patient randomized placebo-controlled study, Georgala et al (2006)investigated the efficacy and safety of IAD (50mg/kg daily for 12 weeks) as atreatment of cervical condylomata acuminata that was resistant to at least oneconventional therapy. Results showed a statistically significant differentialbetween the treatment and placebo groups (p < 0.01) which remainedsignificant when an intention to treat analysis was performed (p < 0.01). Patientsthat exhibited complete recovery did not experience any recurrence within the12 month follow-up period.

Davidson-Parker et al (1988) conducted a UK multi-centred, randomised,placebo controlled study in 51 patients suffering from genital warts for at leastone year. Results showed that a four week course of IAD (3g per day) improvedthe clinical response to conventional treatment (primary podophyllin ortrichloroacetic acid). Of the 27 patients that attended all of the follow-up visits (2, 4, 8 and 12 weeks post study entry), the conventional therapy supplemented by IAD had a significant effect in eradicating the warts and reducing the extent of lesions compared to conventional treatment alone (Figure 3).

Conventional therapy Conventional therapy with IAD (14 patients) (13 patients)

Complete eradication of warts 5* 3

Reduction of number of warts 10 7

Reduction in extent of lesions 11** 5

General response 11 8

* p < 0.05 ** p = 0.05

Figure 3: Assessment of the effects on IAD in combination with conventional therapies(Adapted from Davidson-Parker et al 1988)Figure 3: Assessment of the effects on IAD in combination with conventional therapies(Adapted from Davidson-Parker et al 1988)

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Sadoul and Beuret (1984) studied the clinical effects of combined IAD/CO2 lasertherapy compared to CO2 laser therapy alone in 126 patients suffering fromcervical condylomata and vulvo-vaginal condylomata that were refractory tomultiple treatments (diathermic coagulation, cryotherapy and podophyllin).Results showed that combined IAD/CO2 laser therapy reduced the clinical failurerate to 6.25% after one treatment compared to 45.16% in the group thatreceived only CO2 laser therapy. The number of failures was reduced to zerofollowing three treatments with combined IAD/CO2 laser therapy (Figure 4).

In an open label 60 patient trial Jurisin et al (1986) observed higher rates of healing of genital warts in male patients that received IAD in combination with podophyllin when compared to those patient that received podophyllinalone.

Similarly Kovacs et al (1989) concluded that IAD (3g per day for 4 weeks) in combination with podophyllin compared with podophyllin only resulted in shortened healing times in female patients suffering from condylomatous lesions.

Hicks and Kelly (1997) combined the diverse clinical study data from fourteenclinical trials that evaluated IAD as a drug therapy in the management of genital HPV infections. The meta-analysis of the clinical data from the trials focused on the use of IAD as an adjunct to conventional therapy.

The clinical data shows that the use of IAD in the treatment of genital warts provides a 24-26% additional success rate over the effects of conventional

1st treatment 2nd treatment 3rd treatment

CC VC CC VC CC VC

CO2 laser therapy 12 16 2 10 2 8

(62 patients – 38 CC, 24 VC) Total: 28 Total: 12 Total: 10

CC VC CC VC CC VC

IAD CO2 laser therapy 2 2 1 1 0 0

(64 patients – 29 CC, 35 VC) Total: 4 Total: 2 Total: 0

CC: cervical condylomata VC: vulvo-vaginal condylomata

Figure 4: Assessment of the effect of IAD in combination with CO2 laser therapy –comparison of failures (Adapted from Sadoul and Beuret 1984)

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therapy alone with regard to total lesion clearance and improvement incellular morphology in surrounding tissue harbouring active HPV-infectedcells (Figure 5).

Additionally the meta-analysis of all of the clinical study data revealed that IADproduced a 22-29% greater effect over conventional or control therapy where

• the lesions are single or multiple in site or quantity

• the lesions are situated externally (limited to the perineum and not including perianal warts in either sex) or internally (including vulvovaginal or endocervical sites in females but not urethral meatal warts in males)

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Study 1 (Davidson Parker)

Study 2 (Jurisin)

Study 3 (Kovacs)

Study 4 (Sadoul and Beuret)

Pooled Data(meta-analysis)

Difference in proportionof successes frombaseline when usingadjuvant Imunivor®(% of patients withcleared lesions

Baseline control(conventionaltreatment forgenital warts)

Adjuvant use of Imunivor® improvestreatment success (measured by theclearance of external genital warts).

In Figure 5, the comparison is withconventional treatment for externalgenital warts while the bars showthe difference achieved by usingadjuvant Imunivor® in four trials;95% confidence intervals areshown (vertical lines)

Pooling the data by meta-analysis(extreme right) gives a clearer and(as the confidence intervals show) amore consistent summary of the individual studies.

Figure 5: The effect of using Imunovir® as an adjunct to conventional therapy(Adapted from Hicks and Kelly 1997)

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Subacute Sclerosing Panencephalitis (SSPE)

IAD has been used in many clinical conditions in which sub-acute or chronicviral infections have been associated with a reduced host immune response.

This is classically found in SSPE, in which a reduced immune function, characterised by reduced interferon production, is related to persisting activity of mutated measles virus.

In a 121 patient study the efficacy and safety of oral IAD alone versus combined treatment with oral IAD and intraventricular alpha interferon in patients diagnosed with SSPE was evaluated in a Phase III trial (1997-2002).There were no statistically significant differences between treatment groupson any measure of efficacy. Although there was no significant difference between the treatment groups in rates of clinically defined satisfactory outcomes the observed rates were higher than spontaneous remission ratesreported in the literature suggesting that treatment was superior to no treatment. The rate of adverse events was statistically lower in the IAD treatment group when compared to the combination treatment group (Gascon 2003).

In a retrospective study using historical controls involving 59 clinical centresin Japan, Fukuyama et al (1987) concluded that the use of IAD in the treatment of SSPE was useful, with relatively high safety, in that it improvedthe survival curve of patients with SSPE and caused a delay in the progress ofclinical symptoms. The data is entirely consistent with the expected effect ofinterferon therapy and that the benefits of Isoprinosine® appear independently of interferon therapy and are additive to it.

Fukuyama et al (1987) make the important point that clinical benefits do notappear in every case however IAD was particularly efficacious in the treatment of the slowly progressive form of the disease which accounts for70% of all SSPE cases.

Ginsberg (1989) in a clinical study comprising 98 prospectively selected patients in USA and Canada showed that the probability of long-term survival

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beyond six years was 62% in treated patients compared to 6-26% in the controlgroups albeit some doubt was raised with respect to the control groups as theywere not prospectively randomised.

Horiguchi and Ohya (1995) reported prolonged effectiveness of both neurological symptoms and life expectancy after oral inosiplex and intrathecal interferon therapy. Anlar (1998) studied a combination of subcutaneous interferon-beta and Isoprinosine® according to an open design with stabilizationor improvement observed in 3 of the 7 patients. Gokcil (1999) followed up 8 patients treated with intraventricular interferon-alpha in combination with Isoprinosine® or Isoprinosine® alone and noted that all patients receiving combined treatment had survived after 3-4 years of follow up with 3 patients improving or stabilizing.

In an 18 patient study by Gascon et al (1993) that used IAD in combination withα-interferon by intraventricular injection, an improvement in the disability indexwas found in 3 patients, with the index remaining stable in 5 constituting a response of 44% over a follow-up period of 12 to 40 months. Gascon et al (1993)recommended this combined therapy as treatment of choice in the few cases ofSSPE presenting after widespread vaccination policies.

Garg (2002) stated that a combination of oral IAD and intraventricular interferon alfa appears to be the best effective treatment for SSPE albeit patients responding to treatment need to receive it life long. The only effective solution to this disease remains immunisation against measles.

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Safety

IAD has been used for almost 40 years receiving its first approval in 1971in Argentina and its first European approval in Italy in 1979.

Since 1971 approximately 1.45 billion tablets have been prescribed worldwide.

Since 1971 there have been approximately 1500 adverse reactions reported in postmarket surveillance.

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References

Immunomodulation

Corey L., Chiang W., Reeves W., Stamm W., Brewer L. and Holmes K. (1979) Effect of Isoprinosine onthe cellular immune response in initial genital herpes virus infection. Clinical Research, 27 (1), 41A.

Gadoth N., Kott E., Levin S. and Hahn T. (1989) The interferon system in subacute sclerosing panencephalitis and its response to Isoprinosine. Brain and Development, 11 (5), 308-312.

Lomnitzer R. (1988) Isoprinosine potentiation of human peripheral blood mononuclear responseto mitogens: kinetics and effect on expression of the IL-2 receptor and the activity of interleukin-2. Journal of Clinical Laboratory Immunology, 27, 91-96.

Miglietta A., Ventura M., Ressa A. and Dammacco F. (1980) The in-vitro effect of methisoprinol onphagocytes, monocytes and neutrophilic granulocytes. 5th Congress of the Italian Society of Immunology and Immunopathology.

Miller R. D. (1984) Safety and efficacy of inosine pranobex in recurrent genital herpes simplex infections. Presented at a Clinical Meeting of the Praed Street Clinic, St. Mary's Hospital; September, London, UK, 8-11.

Petrova M., Jelev D., Ivanova A. and Krastev Z. (2010) Isoprinosine Affects Serum Cytokine Levels inHealthy Adults. Journal of Interferon and Cytokine Research, 30 (4), 5-9.

Tsang K. Y., Pan J. F., Swanger D. L. and Fudenberg H. H. (1985) In-vitro restoration of immuneresponses in aging humans by Isoprinosine. International Journal of Immunopharmacology, 7(2), 199-206.

Genital Herpes

Byrne M. A., Lawrence A. G., Walker G. D., O’Neill B. B., Csonka G. W., John J., Shanson D. C., JeffriesD. J. and Harris J. R. W. (1988) Suppression of recurrent genital herpes by inosine pranobex: effectsof episodic and continuous treatment. Current Therapeutic Research [USA], 43(4), 681-688.

Galli M., Lazzarin A., Moroni M. and Zanussi C. (1984) Treatment of recurrent viral infectious diseases by methisoprinol. In: Fudenberg H. H., Whitten H. D., Ambrogi F., eds. Immunomodulation: New Frontiers and Advances. New York, NY, USA, Plenum Press, 385-397.

Miller R. D. (1984) Safety and efficacy of inosine pranobex in recurrent genital herpes simplex infections. Presented at a Clinical Meeting of the Praed Street Clinic, St. Mary's Hospital; September, London, UK, 8-11.

Talbot D. J. and Menday A. P. (1985) Inosine pranobex in mucocutaneous herpes. The Lancet [UK],325, 877.

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Genital Warts

Davidson-Parker J., Dinsmore W., Khan M. H., Hicks D. A., Morris C. A. and Morris D. F. (1988) Immunotherapy of genital warts with inosine pranobex and conventional treatment:doubleblind, placebo-controlled study. Genitourinary Medicine, 64, 383-386.

Georgala S., Katoulis A. C., Befon A., Georgala C. and Rigopoulos D. (2006) Oral inosiplex in thetreatment of cervical condylomata acuminata: a randomised placebo-controlled trial. BJOG, 113,1088–1091.

Hicks, DA. and Kelly A. (1997) Meta—analysis of clinical studies for use of Imunovir in treatment ofgenital warts. 6th Congress of EADV, Dublin, JEADV, 9 (suppl 1),S149, [FC146] September 11-15.

Jurisin D., Isailovic G., Veljkovic M. and Djekic L. (1986) Topical use of cytostatics and immunostimulants in the treatment of genital warts. Presented at Dermatotherapeutic Days,Arandjelovac, Yugoslavia, September.

Kovacs L., Molnar G. B. and Farkas E. (1989) Experience with Isoprinosine in the treatment ofcondyloma acuminatum (in Hungarian). Presented at Roundtable Symposium on Immunology,Hungarian Immunology Congress, Szeged, Hungary, Oct 25-28.

Sadoul G. and Beuret T. (1984) Treatment of cervical and vulvar condylomata with CO2 laser combined with immunostimulant (in French). Revue Française de Gynécologie et d’Obstétrique,79 (11), 681-684.

SSPE

Anlar B., Yalaz K., Kose G. and Saygi S. (1998) Beta interferon plus inosiplex in the treatment ofSubacute sclerosing panencephalitis. Journal of Child Neurology, 13 (11), 557-59.

Fukuyama Y., Nihei K., Matsumoto S., Ebina T., Kamoshita S., Sato T., Arima M., Yabuuchi H., Ueda S., Ohtahara S., Takeshita K., Kurokawa T., Ishida N., Okuno Y., Tateishi J. and Sakuma A. (1987) Clinical effects of MND-19 (Inosiplex) on subacute sclerosing panencephalitis. Brain and Development, 9, 270-282.

Garg R. K. (2002) Subacute sclerosing panencephalitis. Postgrad Medical Journal, 78, 63–70.

Gascon G. (2003) Randomized treatment of inosiplex versus combined inosiplex and intraventricular interferon-alpha in subacute sclerosing panencephalitis (SSPE): internationalmulticentre study. Journal of Child Neurology, 18, 819-827.

Gascon G., Yamani S., Crowell J., Stigsby B., Nester B., Nester M., Kanaan I. and Jallu A. (1993) Combined oral Isoprinosine-intraventricular α-interferon therapy for subacute sclerosing panencephalitis. Brain and Development, 15(5), 346-354.

Ginsberg T. (1989) Isoprinosine in subacute sclerosing panencephalitis: Confirmation and extension of beneficial clinical results in the US and Canada by a recent study in Japan. Third International Symposium on SSPE, India.

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Gokcil Z., Odabasi Z., Demirkaya S., Eroglu E. and Vural O. (1999) Alpha-interferon and Isoprinosine in adult onset subacute sclerosing panencephalitis. Journal of Neurological Sciences, 162(1), 62-64.

Horiguchi Y. and Ohya T. (1995) Successful treatment of subacute sclerosing panencephalitis with long-term intrathecal large dose of alpha-interferon – a case report. No To Hattatsu, 27 (3), 231- 37.

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Imunovir® 500mg TabletsInosine Acedoben Dimepranol

Each tablet contains 500mg Inosine Acedoben Dimepranol (INN, also known as inosine pranobex*) which is the p-acetamidobenzoic acid salt of N,N-dimethylamino-2-propanol [DIP.PAcBA] and β-inosine in a 3:1molar ratio. *British ApprovedName (BAN) the non-proprietary designation.

PRESCRIBING INFORMATION: Pharmaceutical Form:White to off-white tablets with a faint amine odour, engraved with ascore-line on one side and 'DN' on the other. The score-line is only to facilitate breaking for ease of swallowing and not to divide into equal doses. Therapeutic indications: Imunovir® tablets are indicated in the management of:a) Mucocutaneous infections due to herpes simplex virus (type l and/or type II)b) Genital warts as adjunctive therapy to podophyllin or carbon dioxide laserc) Subacute sclerosing panencephalitis (SSPE)

Posology and method of administration: ORAL ADMINISTRATION. Adults: Mucocutaneous herpes simplex: 1g q.d.s. (4g daily),for 7-14 days. Genital warts: 1g t.d.s. (3g daily), for 14-28 days as adjunctive therapy to podophyllin or carbon dioxide laser.Subacute sclerosing panencephalitis (SSPE): 50-100mg/kg daily, in divided doses every 4 hours. Children: No information isavailable in children. Elderly: No dosage alterations are necessary in the elderly. Contraindications: There are no known contraindications to therapy with this drug.

Special Warnings and special precautions for use: As the inosine component of Imunovir® is metabolised to uric acid, itshould be used with caution in patients with renal impairment, a history of gout or hyperuricaemia.

Interaction with other medicaments and other forms of interaction: None known.

Use in pregnancy and lactation: Although animal tests have shown no teratogenic effect, the use of Imunovir® in womenwhere pregnancy is suspected or confirmed should be avoided.

Undesirable effects: The only consistently observed drug-related side effect is a transient elevation (usually remaining withinnormal range) of urine and serum uric acid levels, which usually return to baseline values a few days after the end of treatment.Side effects recorded in >1% of clinical studies of 3 months or longer and reported infrequently in postmarketing surveillance: Gastrointestinal: Nausea with or without vomiting, epigastric discomfort, Hepatic: Elevation of transaminases, alkaline phosphatase or blood urea nitrogen (BUN) level, Dermatological: Itching, skin rashes, Nervous system: Headaches, vertigo, fatigue or malaise, Other: Arthralgia.Side effects recorded in <1% of clinical studies of 3 months or longer and reported rarely in postmarketing surveillance: Gastrointestinal: Diarrhoea, constipation, Nervous system: Nervousness, drowsiness or insomnia, Genitourinary: Polyuria(increased urine volume). Overdose: There has been no experience of overdosage with Imunovir®. However serious adverseeffects apart from increased levels of uric acid in the body, seem unlikely in view of the animal toxicity studies. Treatmentshould be restricted to symptomatic and supportive measures.

Legal Category: POM (Prescription only Medicine). Product License Number: PL 39972/0001

Marketing Authorisation Holder: KoRa Corporation Ltd. t/a KoRa Healthcare, Swords Business Park, Swords, Co. Dublin, Ireland.

Trade Price: £39.50 PIP Code 100 Tablets: 001-3987 EAN Code 5702191001280

Date of issue: 11th March 2013

The cover shows a herpes simplex virus

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Imunovir® 500mg TabletsInosine Acedoben Dimepranol

A N T I V I R A L I M M U N O T H E R A P Y

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KoRa HealthcareSwords Business Park, Swords, Co. Dublin, Ireland.UK Tel: 0845-303 8631 UK Fax: 0845-303 8632www.kora-health.com

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