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Drugs

, Volume 50, Issue 2, pp 396–415 | Cite as

Famciclovir

A Review of its Pharmacological Properties and Therapeutic Efficacy in Herpesvirus Infections
  • Caroline M. Perry
  • Antona J. Wagstaff
Drug Evaluation

Abstract

Synopsis

Famciclovir, a synthetic acyclic guanine derivative, is a prodrug which, after oral administration, is rapidly metabolised to the highly bioavailable antiviral compound penciclovir. Penciclovir is active in vitro against the herpesviruses herpes simplex virus (HSV)-1, HSV-2 and varicella zoster virus (VZV).

Famciclovir is an effective treatment of immunocompetent patients with acute herpes zoster (shingles) caused by VZV. Comparative studies have demonstrated that famciclovir has therapeutic efficacy similar to that of oral aciclovir (acyclovir) in attenuating the acute signs and symptoms of infection (including pain during the acute phase of infection). In a placebo-controlled study, famciclovir significantly reduced the duration of postherpetic neuralgia; this effect was more pronounced (almost a 3-fold reduction) in patients aged ≥50 years.

In immunocompetent patients with recurrent genital herpes infection, suppressive treatment with oral famciclovir effectively prolonged the time to recurrence of symptomatic episodes of infection compared with placebo. In addition, famciclovir significantly reduced the duration of viral shedding, accelerated healing of genital herpes lesions and reduced the duration of symptoms. Famciclovir is reported to be the first antiviral agent to significantly reduce symptoms associated with multiple genital herpes lesions.

Famciclovir is a well-tolerated drug with a tolerability profile similar to that of placebo and aciclovir.

Thus, famciclovir is now established as an effective treatment of immunocompetent patients with herpes zoster or genital herpes infection, particularly as famciclovir is administered in a convenient dosage regimen that may improve compliance compared with aciclovir.

Antiviral Activity

After oral administration famciclovir is metabolised to penciclovir, an antiviral compound with activity against herpes simplex virus (HSV) and varicella zoster virus (VZV). Penciclovir is selectively phosphorylated (initially by viral thymidine kinase) in herpesvirus-infected cells (in preference to uninfected host cells) to yield high intracellular concentrations of penciclovir triphosphate. Thereafter, by interacting with viral DNA polymerases, penciclovir triphosphate inhibits viral replication. The descending order of viral susceptibility to penciclovir in plaque reduction assays is HSV-1, HSV-2 and VZV. After removal of penciclovir, a prolonged antiviral effect has been demonstrated in HSV-1, HSV-2 and VZV infected cell cultures. For antiviral agents, intracellular pharmacokinetics is a key factor in their efficacy. The prolonged intracellular half-life of penciclovir triphosphate in cells infected with HSV (10–20 hours) and VZV (7–14 hours), compared with aciclovir triphosphate (≤1 hour), may contribute to the demonstrated clinical efficacy of famciclovir despite its less frequent oral administration than aciclovir.

Combinations of penciclovir with aciclovir or ganciclovir exhibited additive in vitro activity against HSV-1 and HSV-2, and synergistic activity occurred with combinations of penciclovir and human interferon-α, interferon-β or interferon-γ against the same viruses. Combination of penciclovir with foscarnet produced synergistic activity against HSV-1 and additive effects against HSV-2 in vitro. In in vitro cross-resistance studies, most aciclovir-resistant strains of HSV and VZV were also resistant to penciclovir. The aciclovir-resistant strains that were susceptible to penciclovir had altered thymidine kinase and DNA polymerase substrate specificity.

Oral famciclovir and oral, intravenous and subcutaneous penciclovir were effective inhibitors of HSV-1 and HSV-2 in mice; topical penciclovir was an effective inhibitor of HSV-1 in guinea-pigs.

Pharmacokinetic Properties

After oral administration, famciclovir is rapidly metabolised in the intestine and liver to yield penciclovir. Penciclovir (from oral famciclovir) is highly bioavailable (77%) and has a linear dose-proportional pharmacokinetic profile over the 125 to 750mg dose range. In healthy volunteers or patients with uncomplicated herpes zoster infection, maximum plasma concentrations of penciclovir ranged from 2.73 to 3.97 mg/L within 1 hour of a single oral 500mg dose of famciclovir. Penciclovir is excreted primarily by the renal route, and elimination of famciclovir was found to decrease in patients with varying degrees of renal impairment. Following administration of single doses of famciclovir 125, 500, and 750mg to healthy volunteers, plasma elimination half-life values for penciclovir ranged from 2.06 to 2.66 hours. In formal interaction studies, no clinically significant pharmacokinetic interactions have been observed between famciclovir and allopurinol, digoxin, cimetidine, theophylline or zidovudine.

Therapeutic Efficacy

Clinical trials of famciclovir have included approximately 1200 immunocompetent patients (aged ≥18 years) with herpes zoster (shingles). A double-blind, placebo-controlled clinical trial demonstrated that famciclovir, initiated within 72 hours of the onset of zoster rash, was significantly more effective than placebo in attenuating symptoms of the zoster rash and, in patients with >50 lesions at enrolment, in resolving acute phase zoster pain. In addition, the duration of post-herpetic neuralgia was significantly less in recipients of famciclovir 500 and 750mg administered 3 times a day for 7 days than in placebo recipients. This benefit was more pronounced in a subgroup of patients aged ≥50 years, in whom the duration of postherpetic neuralgia was reduced by almost 3-fold. Randomised double-blind comparisons of famciclovir with aciclovir demonstrated equal efficacy in healing cutaneous lesions and in attenuating acute phase pain (while the zoster rash was present). Famciclovir 250, 500 or 750mg 3 times daily for 7 days significantly reduced the duration of zoster-associated pain (measured as a continuum from onset to complete cessation of pain) by about 1.5-fold compared with aciclovir 800mg 5 times a day, when patients received treatment within 48 hours of rash onset.

Data are accumulating on the therapeutic efficacy of famciclovir in immuno-competent patients with genital herpes infection, although studies published to date have been in abstract form only. A randomised double-blind placebo-controlled study of suppressive famciclovir treatment reported a significant prolongation of the time to recurrence of symptomatic episodes of genital herpes. Other placebo-controlled studies of short term treatment demonstrated that famciclovir was significantly more effective than placebo in reducing the time to cessation of viral shedding, healing cutaneous lesions, and reducing the time to cessation of symptoms. Oral famciclovir and aciclovir appear to be equally effective in treating the acute symptoms of patients with symptomatic episodes of genital herpes. Famciclovir has been reported to be the first antiviral agent to significantly reduce symptoms associated with multiple genital herpes lesions.

Tolerability

Preliminary tolerability data indicate that famciclovir is a well-tolerated drug with a profile similar to that of placebo and aciclovir. Headache, nausea and diarrhoea were the most commonly observed adverse events. Higher total daily doses of famciclovir did not appear to correlate with an increased incidence of adverse events compared with lower doses of the drug.

Dosage and Administration

Famciclovir treatment should be initiated as soon as signs and symptoms of herpes zoster infection become apparent and within 72 hours of the onset of zoster rash. The recommended oral dosage of the drug is 250 or 500mg 3 times daily (depending on different country recommendations) for 7 days. Dosage modification is not required in elderly patients. In patients with moderate to severe renal impairment, prolongation of the dosage interval is necessary to avoid penciclovir accumulation.

In the treatment of first episode genital herpes, the recommended oral dosage of famciclovir is 250mg 3 times a day for 5 days; for acute recurrent genital herpes infection the dosage is 125mg twice a day for 5 days.

Keywords

Herpes Zoster Varicella Zoster Virus Genital Herpes Postherpetic Neuralgia Famciclovir 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Boyd MR, Safrin S, Kern ER. Penciclovir: a review of its spectrum of activity, selectivity, and cross-resistance pattern. Antiviral Chem Chemother 1993; 4 Suppl 1: 3–11Google Scholar
  2. 2.
    Vere Hodge RA, Cheng Y-C. The mode of action of penciclovir. Antiviral Chem Chemother 1993; 4 Suppl 1: 13–24Google Scholar
  3. 3.
    Bacon TH, Schinazi RF. An overview of the further evaluation of penciclovir agianst herpes simplex virus and varicellazoster virus in cell culture highlighting contrasts with acyclovir. Antiviral Chem Chemother 1993; 4 Suppl 1: 25–36Google Scholar
  4. 4.
    Boyd MR, Bacon TH, Sutton D, et al. Antiherpesvirus activity of 9-(4-hydroxy-3-hydroxy-methylbut-1-yl) guanine (BRL 39123) in cell culture. Antimicrob Agents Chemother 1987; 31: 1238–42PubMedCrossRefGoogle Scholar
  5. 5.
    Weinberg AA, Bate BJ, Masters HB. In vitro activities of penciclovir and acyclovir against herpes simplex virus types 1 and 2. Antimicrob Agents Chemother 1992; 36 (9): 2037–8PubMedCrossRefGoogle Scholar
  6. 6.
    Earnshaw DL, Bacon TH, Darlison SJ, et al. Mode of antiviral action of penciclovir in MRC-5 cells infected cells with herpes simplex virus type 1 (HSV-1), HSV-2, and varicellazoster virus. Antimicrob Agents Chemother 1992; 36: 2747–57PubMedCrossRefGoogle Scholar
  7. 7.
    Vere Hodge RA, Perkins RM. Mode of action of 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (BRL 39123) against herpes simplex virus in MRC-5 cells. Antimicrob Agents Chemother 1989 Feb; 33 (2): 223–9CrossRefGoogle Scholar
  8. 8.
    Sacks S et al. Virus-specified phosphorylation of penciclovir (PCV) in a human Schwannoma continuous cell line (SW) infected with varicella zoster virus (VZV) [abstract no. H55]. 34th International Conference on Antimicrobial Agents and Chemotherapy. 1994Google Scholar
  9. 9.
    Bebault GM, Wall RA, Rennie BA, et al. Qualitative and quantitative differences between intracellular penciclovir triphosphate and acyclovir triphosphate in a human Schwannoma cell line infected with varicella zoster virus [abstract no. 213]. Eighth International Conference on Antiviral Research, Santa Fe, New Mexico, USA, 1995 April 23–28.Google Scholar
  10. 10.
    Standring-Cox R, Bacon TH, Howard BA. Prolonged activity of penciclovir in cell culture against varicella-zoster virus (VZV). Antiviral Res 1994; 23 Supp J. 1Google Scholar
  11. 11.
    Hamzeh FM, Schaad HJ, Lietman PS. A pharmacokinetic/ pharmacodynamic approach for the comparison of penciclovir and acyclovir: utilization of an in vitro model which simulates in vivo pharmacokinetics [abstract no. 214]. Eighth International Conference on Antiviral Research, Santa Fe, New Mexico, USA, 1995 April 23–28.Google Scholar
  12. 12.
    Sutton S, Taylor J, Bacon TH. Activity of penciclovir in combination with azido-thymidine, ganciclovir, acyclovir, foscarnet and human interferons against herpes simplex virus replication in cell culture. Antiviral Chem Chemother 1992; 3 (2): 85–94Google Scholar
  13. 13.
    Sutton D, Kern ER. Activity of famciclovir and penciclovir in HSV-infected animals: a review. Antiviral Chem Chemother 1993; 4 Suppl 1: 37–46Google Scholar
  14. 14.
    Harnden MR, Jarvest RL, Boyd MR, et al. Prodrugs of the selective antiherpesvirus agent 9-[4-hydroxy-3-(hydroxy-methyl)but-1-yl]guanine (BRL 39123) with improved gastrointestinal absorption properties. J Med Chem 1989 Aug; 32: 1738–43PubMedCrossRefGoogle Scholar
  15. 15.
    Ashton RJ, Abbott KH, Smith GM, et al. Antiviral activity of famciclovir and acyclovir in mice infected intraperitoneally with herpes simplex virus type 1 SCI6. J Antimicrob Chemother 1994 Aug; 34: 287–90PubMedCrossRefGoogle Scholar
  16. 16.
    Sutton D, Ashton RJ, Bacon TH. Activity of famciclovir and penciclovir in HSV-infected animals [Poster]. 6th International Congress for Infectious Diseases. Prague, Czech Republic April 26–30 1994.Google Scholar
  17. 17.
    Field HJ, Tewari D, Sutton D, et al. Comparison of efficacies of famciclovir and valaciclovir against herpes simplex virus type 1 in a murine immunosuppression model. Antimicrob Agents Chemother 1995 May; 39 (5): 1114–9PubMedCrossRefGoogle Scholar
  18. 18.
    Field HJ, Thackray AM. The effects of delayed-onset chemotherapy using famciclovir or valaciclovir in a murine immunosuppression model for HSV-1. Antiviral Chem Chemother [In press] 6 (4): 210-6Google Scholar
  19. 19.
    Thackray AM, Field HJ. Comparative effects of famciclovir and valaciclovir on cutaneous and neurological HSV-1 infection in normal and immunocompromised mice [abstract no. 193]. Eighth International Conference on Antiviral Research, Santa Fe, New Mexico, USA 1995 April 23–28Google Scholar
  20. 20.
    Pue MA, Benet LZ. Pharmacokinetics of famciclovir in man. Antiviral Chem Chemother 1993; 4 Suppl 1: 47–55Google Scholar
  21. 21.
    Boike SC, Pue MA, Freed MI, et al. Pharmacokinetics of famciclovir in subjects with varying degrees of renal impairment. Clin Pharmacol Ther 1994 Apr; 55: 418–26PubMedCrossRefGoogle Scholar
  22. 22.
    Filer CW, Allen GD, Brown TA, et al. Metabolic and pharmacokinetic studies following oral administration of 14C-famciclovir to healthy subjects. Xenobiotica 1994 Apr; 24: 357–68PubMedCrossRefGoogle Scholar
  23. 23.
    Fowles SE, Pue MA, Pierce D, et al. Pharmacokinetics of penciclovir in healthy elderly subjects following a single oral administration of 750 mg famciclovir [abstract]. Br J Clin Pharmacol 1992 Nov; 34: 450PGoogle Scholar
  24. 24.
    Pratt SK, Pue MA, Fairless AJ. High bioavailability and rapid distribution of penciclovir following an oral dose of famciclovir. VIIth International Antiviral Symposium. Acropolis, 1994 (Poster)Google Scholar
  25. 25.
    Pue MA, Boike SC, Freed MI, et al. Pharmacokinetics of penciclovir in subjects with hepatic insufficiency following oral famciclovir [abstract]. Br J Clin Pharmacol 1994 May; 37: 494PGoogle Scholar
  26. 26.
    Pue MA, Pratt SK, Fairless AJ, et al. Linear pharmacokinetics of penciclovir following administration of single oral doses of famciclovir 125, 250, 500 and 750 mg to healthy volunteers. J Antimicrob Chemother 1994 Jan; 33: 119–27PubMedCrossRefGoogle Scholar
  27. 27.
    Boike SC, Pue M, Audet PR, et al. Pharmacokinetics of famciclovir in subjects with chronic hepatic disease. J Clin Pharmacol 1994; 34 (12): 1199–207PubMedGoogle Scholar
  28. 28.
    Pratt SK, Beerahee M, Pue MA. The pharmacokinetics of penciclovir following oral administration of 500mg famciclovir to patients with uncomplicated herpes zoster infection. 3rd Congress of the European Acadamy of Dermatology and Venereology 1993.Google Scholar
  29. 29.
    Pratt SK, Pue MA, Fairless AJ, et al. Lack of an effect of gender on the pharmacokinetics of penciclovir following single oral doses of famciclovir [abstract]. Br J Clin Pharmacol 1994 May; 37: 493Google Scholar
  30. 30.
    Daniels S, Schentag JJ. Drug interaction studies and safety of famciclovir in healthy volunteers: a review. Antiviral Chem Chemother 1993; 4 Suppl 1: 57–64Google Scholar
  31. 31.
    Fowles SE, Pratt SK, Laroche J, et al. Lack of a pharmacokinetic interaction between oral famciclovir and allopurinol in healthy volunteers. Eur J Clin Pharmacol 1994; 46 (4): 355–9PubMedCrossRefGoogle Scholar
  32. 32.
    Pue MA, Saporito M, Laroche J, et al. An investigation of the potential interaction between digoxin and oral famciclovir in healthy male volunteers [abstract]. Br J Clin Pharmacol 1993 Aug; 36: 177PGoogle Scholar
  33. 33.
    Pratt SK, Fowles SE, Pierce DM, et al. An investigation of the potential interaction between cimetidine and famciclovir in non-patient volunteers [abstract]. Br J Clin Pharmacol 1991 Nov; 32: 656P–7PGoogle Scholar
  34. 34.
    Rousseau F, Scott S, Pratt S, et al. Safe coadministration of famciclovir and zidovudine [abstract]. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy. 1994:83Google Scholar
  35. 35.
    Fairless AJ, Pratt SK, Pue MA, et al. An investigation into the potential interaction between theophylline and oral famciclovir in healthy male volunteers [abstract]. Br J Clin Pharmacol 1992 Aug; 34: 171P–2PGoogle Scholar
  36. 36.
    Carrington D. Prospects for improved efficacy with antiviral prodrugs: will valaciclovir and famciclovir meet the clinical challenge? Int Antiviral News 1994 Apr; 2: 50–3Google Scholar
  37. 37.
    Siederer SK, Pue MA, Fairless AJ, et al. High bioavailability and rapid distribution of penciclovir following an oral dose of famciclovir [abstract no. 216]. Eighth International Conference on Antiviral Research, Santa Fe, New Mexico, USA 1995 April 23–28.Google Scholar
  38. 38.
    SmithKline Beecham Pharmaceuticals. Famciclovir prescribing information. Philadelphia, Pennsylvania, US 1994.Google Scholar
  39. 39.
    Fowles SE, Fairless AJ, Pierce DM, et al. A further study of the effect of food on the bioavailability and pharmacokinetics of penciclovir after oral administration of famciclovir [abstract]. Br J Clin Pharmacol 1991 Nov; 32: 657PGoogle Scholar
  40. 40.
    Fowles SE, Pierce DM, Prince WT, et al. Effect of food on bioavailability and pharmacokinetics of penciclovir, a novel antiherpes agent, following oral administration of the pro-drug, famciclovir [abstract]. Br J Clin Pharmacol 1990 May; 29: 620P–1PGoogle Scholar
  41. 41.
    Pratt SK, Standring-Cox R, Writer D, et al. Penciclovir pharmacokinetics in fed and fasted subjects following oral famciclovir in relation to in-vitro antiviral activity [abstract]. Proc 6th International Congress for Infectious Diseases (ICID) 1994 April 26–30Google Scholar
  42. 42.
    Spruance SL, Rowe N, Raborn GW. Oral famciclovir in the treatment of experimental ultraviolet radiation (UVR)-induced herpes labialis: a double-blind, dose-ranging, placebo-controlled, multi-center trial [abstract]. 35th ICAAC, San Francisco, California, US 1995Google Scholar
  43. 43.
    Nikkeis AF, Piérard GE. Recognition and Treatment of Shingles. Drugs 1994; 48 (4): 528–48CrossRefGoogle Scholar
  44. 44.
    Tyring S, Barbarash RA, Nahlik JE, et al. Famciclovir for the treatment of acute herpes zoster: effects on acute disease and postherpetic neuralgia [In Press]. Ann Intern Med 1995Google Scholar
  45. 45.
    Candaele M, Candaele D. Famciclovir: confirmed efficacy of 250mg t.i.d. for the treatment of herpes zoster infection [abstract]. Antiviral Res 1994; 23 Suppl. 1: 98Google Scholar
  46. 46.
    Degreef H, Famciclovir HZCSG. Famciclovir, a new oral anti-herpes drug: results of the first controlled clinical study demonstrating its efficacy and safety in the treatment of uncomplicated herpes zoster in immunocompetent patients. Int J Antimicrob Agents 1994 Nov; 4: 241–6PubMedCrossRefGoogle Scholar
  47. 47.
    Boon R, Griffin D, Bishop S. Famciclovir: effect on pain in herpes zoster [abstract H12]. 7th European Congress of Clinical Microbiology and Infectious Diseases, Vienna, Austria, 1995 March 26–30.Google Scholar
  48. 48.
    McKendrick MW, McGill JI, Wood MJ. Lack of effect of acyclovir of postherpetic neuralgia. BMJ 1989; 298: 431PubMedCrossRefGoogle Scholar
  49. 49.
    Wood MJ. Current experience with antiviral therapy for acute herpes zoster. Ann Neurol 1994; 35: S65–8PubMedCrossRefGoogle Scholar
  50. 50.
    Wood MJ, Johnson RW, McKendrick MW, et al. A randomised trial of aciclovir for 7 days or 21 days with and without prednisolone for treatment of acute herpes zoster. N Engl J Med 1994; 330: 896–900PubMedCrossRefGoogle Scholar
  51. 51.
    Sacks SL. The role of acyclovir in the management of genital herpes simplex. Can Med Assoc J 1987; 136: 701–7Google Scholar
  52. 52.
    Mertz GJ, Loveless MO, Kraus SJ, et al. Famciclovir for suppression of recurrent genital herpes [abstract]. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy. 1994: 11Google Scholar
  53. 53.
    Murphy SM, Ruck F, Kitchin VS, et al. Oral famciclovir (FCV) a new antiherpes agent: comparative study with acyclovir in clinic initiated treatment of first episode genital herpes (FGH) [abstract] EADV/Triaena Congress, Athens, 1991Google Scholar
  54. 54.
    Loveless M, Harris W, Sacks S. Treatment of first episode genital herpes with famciclovir [abstract H12]. 35th ICAAC, San Francisco, California, US 1995Google Scholar
  55. 55.
    Sacks SL, Martel A, Aoki F, et al. Early, clinic-initiated treatment of recurrent genital herpes using famciclovir: results of a Canadian, multicenter study [abstract]. Clin Res 1994 Apr; 42: 300AGoogle Scholar
  56. 56.
    Sacks SL, Martel A, Aoki F. Early clinic-initiated treatment of recurrent genital herpes with famciclovir: results of a Canadian multicenter study [Poster]. 1994 (Dermatology Update, Vancouver)Google Scholar
  57. 57.
    Sacks SL, Aoki FY, Diaz-Mitoma F, et al. Patient-initiated treatment (Tx) of recurrent genital herpes with oral famciclovir (FCV): a Canadian, multicenter, placebo-controlled, dose-ranging study [abstract]. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy. 1994: 11Google Scholar
  58. 58.
    Murphy SM, Ruck F, Kitchin VS. Clinic initiated treatment of recurrent genital herpes (RGH) with famciclovir (FCV) [abstract]. EADV/Triaena Congress, Athens, 1991Google Scholar
  59. 59.
    Sacks SL, Aoki F, Diaz-Mitoma F, et al. Patient and clinic-initiated treatment of recurrent genital herpes with twice-daily oral famciclovir [abstract no. 866A]. 7th European Congress of Clinical Microbiology and Infectious Diseases. Vienna 1995 Mar 26–30.Google Scholar
  60. 60.
    Saltzman R, Jurewicz R, Boon R. Safety of famciclovir in patients with herpes zoster and genital herpes. Antimicrob Agents Chemother 1994 Oct; 38: 2454–7PubMedCrossRefGoogle Scholar
  61. 61.
    Sacks SL, Bishop AM, Fox R, et al. A double-blind, placebo (PLB)-controlled trial of the effect of chronically administered oral famciclovir (FCV; BRL 42810) on sperm production in men with recurrent genital herpes (RGH) infection [abstract]. Antiviral Res 1994; 23 Suppl. 1: 72Google Scholar
  62. 62.
    SmithKline Beecham Pharmaceuticals. Famciclovir prescribing information. Welwyn Garden City, Herts, UK 1995.Google Scholar
  63. 63.
    Bacon TH. Moving forward: research and development of a novel antiviral agent. Research and Clinical Forums 1995; 17 (3): 35–44Google Scholar
  64. 64.
    Weiler S, Blum MR, Doucette M, et al. Pharmacokinetics of the aciclovir pro-drug valaciclovir after escalating single- and multiple-dose administration to normal volunteers. Clin Pharmacol Ther 1993; 54: 595–605CrossRefGoogle Scholar

Copyright information

© Adis International Limited 1995

Authors and Affiliations

  • Caroline M. Perry
    • 1
  • Antona J. Wagstaff
    • 1
  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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