Valaciclovir and famciclovir / Valaciclovir y famciclovir

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Valaciclovir and Famciclovir./ Valaciclovir y Famciclovir. Data-Medicos Dermagic/Express No. 71 01 Septiembre 1.999. 01 September 1.999. ~ Valaciclovir y /and Famciclovir ~ EDITORIAL ESPANOL ================= Hola Amigos, DERMAGIC de nuevo en la red. El tema de hoy: VALACICLOVIR Y FAMCICLOVIR. El Valciclovir ( Valtrex) es realmente una prodroga del ACICLOVIR, (L-valil ester) el cual al ser administrado oralmente se convierte rapidamente en Aciclovir y su aminoacido esencial ( L-valina) cuya biodisponibilidad es SUPERIOR (dosis 2-3 veces al dia) a la del ACICLOVIR oral (dosis 5 veces al dia): 500 MGRS de valaciclovir dos veces al dia son similares a 200 mgrs cinco veces al dia de aciclovir. Muy efectivo contra los virus del herpes simple, varicela-zoster y tambien Citomegalovirus. El FAMCICLOVIR (FAMVIR) es tambien una prodroga, en este caso del antiviral PENCICLOVIR, el FAMVIR al ser administrado oralmente se convierte en el metabolito activo PENCICLOVIR-TRIFOSFATO que posee una vida media intracelular bastante prolongada (9-10 horas), tambien mayor biodisponibilidad que el ACICLORVIR: 500 MGRS de FAMCICLOVIR 3 veces al dia vs 200 mgrs de ACICLOVIR cinco veces al dia. Altamente efectivo contra los virus del herpes simple (HSV-1, HSV-2), y varicela-zoster (VZV), Pero encuentro que tambien es efectivo en la NEURALGIA POSTHERPETICA, y contra el virus de la HEPATITIS B. Esta ultima caracteristica lo diferencia TOTALMENTE del Aciclovir y Valaciclovir. En estas 39 referencias quedan plasmados los hechos. Espero que las disfruten Bienvenido a DERMAGIC Dr. Dr. Stephen G Wiener (USA) Saludos a todos !!! Dr. Jose Lapenta R.,,, EDITORIAL ENGLISH ================= Hello Friends, DERMAGIC again in the net. Today's topic: VALACICLOVIR AND FAMCICLOVIR. The Valciclovir (Valtrex) it is really a prodrug of the ACICLOVIR, (L-valyl ester) which becomes in aciclovir and their essential amino acid quickly when being administered oral (L-valine) whose bioavailability is SUPERIOR (dose 2-3 times a day) to that of the oral ACICLOVIR (dose 5 times a day): 500 MGRS of valaciclovir twice a day they are similar to 200 mgrs five times a day of aciclovir. Very effective against the virus of the herpes simplex, varicella-zoster and also citomegalovirus. The FAMCICLOVIR (FAMVIR) it is also a prodrug, in this case of the antiviral PENCICLOVIR, the FAMVIR when being administered oral becomes in the active metabolite penciclovir-triphosphate that has a prolonged intracellular half-life (9-10 hours), also bigger bioavailability than the ACICLORVIR: 500 MGRS of FAMCICLOVIR 3 times a day vs 200 mgrs of ACICLOVIR five times a day. Highly effective against the virus of the herpes simplex (HSV-1, HSV-2), and varicella-zoster (VZV), But I find that is also effective in the POSTHERPETIC NEURALGIA , and against the virus of the HEPATITIS B. This characteristic differentiates it TOTALLY of the Aciclovir and Valaciclovir. In these 39 references the facts are captured. I hope you enjoy it. Welcome to DERMAGIC Dr. Stephen G Wiener (USA) Greetings to ALL, !! Dr. Jose Lapenta R.,,, =================================================================== REFERENCIAS BIBLIOGRAFICAS / BIBLIOGRAPHICAL REFERENCES =================================================================== =================================================================== VALACICLOVIR =================================================================== 1.) Valaciclovir. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in herpesvirus infections. 2.) Valaciclovir versus aciclovir in patient initiated treatment of recurrent genital herpes: a randomised, double blind clinical trial. International Valaciclovir HSV Study Group. 3.) Valaciclovir for the suppression of recurrent genital herpes simplex virus infection: a large-scale dose range-finding study. 4.) A large-scale, placebo-controlled, dose-ranging trial of peroral valaciclovir for episodic treatment of recurrent herpes genitalis. Valaciclovir HSV Study Group. 5.) Valaciclovir for the suppression of recurrent genital HSV infection: a placebo controlled study of once daily therapy. International Valaciclovir HSV Study Group. 6.) Valaciclovir versus acyclovir in the treatment of first-episode genital herpes infection. Results of an international, multicenter, double-blind, randomized clinical trial. The Valaciclovir International Herpes Simplex Virus Study Group. 7.) Management of genital herpes. 8.) Valaciclovir compared with acyclovir for improved therapy for herpes zoster in immunocompetent adults. 9.) Valacyclovir. New indication: for genital herpes, simpler administration. 10.) Valacyclovir. 11.) Antiviral therapy of acute herpes zoster in older patients. 12.) A randomized, placebo-controlled comparison of oval valacyclovir and acyclovir in immunocompetent patients with recurrent genital herpes infections. The Valaciclovir International Study Group. 13.) Comparison of valaciclovir and acyclovir for the treatment of herpes zoster in immunocompetent patients over 50 years of age: a cost-consequence model. 14.) Valacyclovir: a review of its antiviral activity, pharmacokinetic properties, and clinical efficacy. 15.) Lessons from the natural history of cytomegalovirus. 16.) VALACYCLOVIR (Systemic), The product ==================================================================== FAMCICLOVIR ==================================================================== 17.) Famciclovir. A review of its pharmacological properties and therapeutic efficacy in herpesvirus infections. 18.) Famciclovir: review of clinical efficacy and safety. 19.) Efficacy of famciclovir in the treatment of herpes zoster. 20.) Safety of famciclovir in patients with herpes zoster and genital herpes. 21.) Famciclovir for treatment of herpesvirus infections. 22.) The pharmacological profile of famciclovir. 23.) Advances in the treatment of herpesvirus infection: the role of famciclovir. 24.) Genital herpes simplex virus and its treatment: focus on famciclovir. 25.) Oral famciclovir for suppression of recurrent genital herpes simplex virus infection in women. A multicenter, double-blind, placebo-controlled trial. Collaborative Famciclovir Genital Herpes Research Group. 26.) Oral famciclovir for the suppression of recurrent genital herpes: a randomized controlled trial. Collaborative Famciclovir Genital Herpes Research Group. 27.) Famciclovir: a new systemic antiviral agent for herpesvirus infections. 28.) Patient-initiated, twice-daily oral famciclovir for early recurrent genital herpes. A randomized, double-blind multicenter trial. Canadian Famciclovir Study Group. 29) A review of famciclovir in the management of genital herpes. 30.)Antivirals for the treatment of herpesvirus infections. 31.) Pharmacology of new antiherpes agents: famciclovir and valacyclovir. 32.) Economic evaluation of famciclovir in reducing the duration of postherpetic neuralgia. 33.) Conversion of recurrent delta-positive hepatitis B infection to seronegativity with famciclovir after liver transplantation. 34) Treatment of hepatitis B-related polyarteritis nodosa with famciclovir and interferon alfa-2b. 35) Famciclovir for the treatment of acute retinal necrosis (ARN) syndrome. 36.) Pretransplant famciclovir as prophylaxis for hepatitis B virus recurrence after liver transplantation. 37.) Famciclovir therapy for recurrent hepatitis B virus infection after liver transplantation. 38.) Penciclovir cream for the treatment of herpes simplex labialis. A randomized, multicenter, double-blind, placebo-controlled trial. Topical Penciclovir Collaborative Study Group. 39.) FAMICLOVIR (Systemic) , The product ==================================================================== VALACICLOVIR ==================================================================== 1.) Valaciclovir. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in herpesvirus infections. ==================================================================== Drugs 1996 Nov;52(5):754-72 Perry CM, Faulds D Adis International Limited, Auckland, New Zealand. Valaciclovir, the L-valyl ester of aciclovir (acyclovir), is an oral prodrug that undergoes rapid and extensive first-pass metabolism to yield aciclovir and the essential amino acid L-valine. Aciclovir, the active antiviral component of valaciclovir, shows good in vitro activity against the herpesviruses herpes simplex virus (HSV)-1, HSV-2 and varicella zoster virus. The bioavailability of aciclovir from oral valaciclovir is considerably greater than that achieved after oral aciclovir administration. Thus, valaciclovir delivers \\therapeutic aciclovir concentrations when administered in a less frequent oral dosage regimen than is required for aciclovir. Valaciclovir is an effective treatment for herpes zoster in immunocompetent adults. In a large comparative study that included patients > or = 50 years of age, valaciclovir (1000mg 3 times daily for 7 or 14 days) and oral aciclovir (800mg 5 times daily) were equally effective in achieving resolution of cutaneous zoster lesions. Importantly, valaciclovir was significantly more effective than aciclovir in reducing the duration of zoster-associated pain. Preliminary results of several studies indicate that valaciclovir (500 to 1000mg twice daily for 5 to 10 days) is as effective as aciclovir (200mg 5 times a day for 5 to 10 days) in the treatment of genital herpes. In patients with first or recurrent episodes of genital herpes, valaciclovir reduced the duration of viral shedding, hastened lesion healing and decreased lesion-associated pain. Valaciclovir was also effective in suppressing recurrent episodes of genital herpes and significantly prolonged the time to a recurrent episode of infection compared with placebo. Valaciclovir is a well tolerated drug; in herpes zoster and HSV studies its tolerability profile was similar to that of aciclovir or placebo. Valaciclovir represents and advance in antiherpes drug therapy and is a useful treatment option for patients with herpes zoster or genital herpes. It is at least as effective as aciclovir and is administered in a more convenient oral dosage regimen. Thus, valaciclovir may ultimately succeed aciclovir as a first-line treatment for genital herpes or herpes zoster. ==================================================================== 2.) Valaciclovir versus aciclovir in patient initiated treatment of recurrent genital herpes: a randomised, double blind clinical trial. International Valaciclovir HSV Study Group. ==================================================================== Genitourin Med 1997 Apr;73(2):110-6 Bodsworth NJ, Crooks RJ, Borelli S, Vejlsgaard G, Paavonen J, Worm AM, Uexkull N, Esmann J, Strand A, Ingamells AJ, Gibb A Sydney Sexual Health Centre, Sydney Hospital, New South Wales, Australia. OBJECTIVE: To compare the efficacy and safety of twice daily valaciclovir with five times daily aciclovir in the treatment of an episode of recurrent genital herpes simplex virus (HSV) infection in immunocompetent individuals. METHODS: 739 patients with a history of recurrent genital HSV infection received either oral valaciclovir (500 mg twice daily) or aciclovir (200 mg five times daily) for 5-days for treatment of their next recurrent episode in a controlled, randomised, double blind trial. Patients self initiated therapy at the first signs and/or symptoms of the HSV recurrence, then were assessed in clinic on five occasions over 7 days, and twice weekly thereafter until lesions had healed. Safety was evaluated through adverse experience reports and haematology and biochemistry monitoring. RESULTS: No significant differences were detected between valaciclovir and aciclovir for the primary endpoint, the duration of all signs and symptoms which included lesion healing and pain/discomfort. The hazard ratio [95% confidence interval] for valaciclovir v aciclovir was 0.93 [0.79, 1.08]. Lesion healing time was similar in each treatment group (hazard ratio valaciclovir v aciclovir 0.96 [0.80, 1.14]). The odds ratio of valaciclovir v aciclovir in preventing the development of vesicular/ulcerative lesions was 1.08 [0.82, 1.42]. Percentages of patients in whom all HSV cultures were negative were similar in the valaciclovir and aciclovir groups at 59% and 54% respectively; for patients having equal to or more than one positive culture result after treatment initiation, cessation of virus shedding was similarly rapid for the two treatments (hazard ratio 0.98 [0.75, 1.27]). The safety profiles of valaciclovir and aciclovir were comparable with adverse experiences being infrequent and generally mild. CONCLUSION: This study has demonstrated that valaciclovir 500 mg twice daily is equivalent in efficacy to aciclovir 200 mg five times daily as episodic treatment of recurrent genital HSV infection. Valaciclovir maintains the established efficacy and safety of aciclovir but offers a much more convenient twice daily dosing regimen. ==================================================================== 3.) Valaciclovir for the suppression of recurrent genital herpes simplex virus infection: a large-scale dose range-finding study. ==================================================================== International Valaciclovir HSV Study Group. J Infect Dis 1998 Sep;178(3):603-10 Reitano M, Tyring S, Lang W, Thoming C, Worm AM, Borelli S, Chambers LO, Robinson JM, Corey L Reitano and Stern Research, New York, USA. A randomized, double-blind study of valaciclovir for suppression of recurrent genital herpes was conducted among 1479 immunocompetent patients. Patients were randomized to receive valaciclovir (250 mg, 500 mg, or 1 g once daily, or 250 mg twice daily), acyclovir (400 mg twice daily), or placebo, for 1 year. All valaciclovir dosages were significantly more effective than placebo at preventing or delaying recurrences (P < .0001). There was a dose-response relationship (P < .0001) across the once-daily valaciclovir regimens. Twice-daily valaciclovir and acyclovir were similar in effectiveness. Subgroup analysis showed that patients with a history of < 10 recurrences per year were effectively managed with 500 mg of valaciclovir once daily. One gram of valaciclovir once daily, 250 mg of valaciclovir twice daily, or 400 mg of acyclovir twice daily were more effective in patients with > or = 10 recurrences per year. Safety profiles of all treatments were comparable. Thus, valaciclovir is highly effective and well tolerated for suppression of recurrent genital herpes. Once-daily regimens offer a useful option for patients who require suppressive therapy for management of genital herpes. ==================================================================== 4.) A large-scale, placebo-controlled, dose-ranging trial of peroral valaciclovir for episodic treatment of recurrent herpes genitalis. Valaciclovir HSV Study Group. ==================================================================== Arch Intern Med 1996 Aug 12-26;156(15):1729-35 Spruance SL, Tyring SK, DeGregorio B, Miller C, Beutner K Salt Lake City County Health Department, USA. BACKGROUND: Valaciclovir, the 1-valyl ester of acyclovir, has provided a peroral acyclovir bioavailability 3 to 5 times that of acyclovir itself and is rapidly and completely converted to acyclovir by the liver. Accordingly, valaciclovir has the same antiviral activity as acyclovir, but the potential for enhanced clinical activity and/or less frequent administration because of its superior pharmacokinetics. METHODS: We conducted a double-blind, placebocontrolled, patient-initiated clinical trial of peroral valaciclovir, 500 or 1000 mg, or matching placebo tablets twice daily for 5 days for the acute treatment of 1 episode of recurrent herpes genitalis among 987 otherwise healthy volunteers. RESULTS: Both doses of valaciclovir were equally effective. Patients receiving the lower dose of valaciclovir experienced a median episode length of 4.0 days compared with 5.9 days for those receiving placebo treatment (hazard ratio, 1.9; 95% confidence interval [Cl], 1.6-2.3). Valaciclovir therapy increased the proportion of patients in whom the development of vesicular and ulcerative lesions was prevented in comparison with placebo treatment: 31% vs 21% (relative risk, 1.5; 95% CI, 1.1-1.9). Valaciclovir therapy accelerated the resolution of pain (hazard ratio, 1.8; 95% CI, 1.5-2.1) and the time to cessation of viral shedding (hazard ratio, 2.9; 95% CI, 2.1-3.9). Adverse reactions among the valaciclovir groups were comparable with those of the placebo group. CONCLUSIONS: Valaciclovir therapy provided a clinically significant benefit to patients that included shortening of the duration of lesions, the duration of pain or discomfort, and the duration of virus shedding. In addition, this study, to our knowledge, provides the first convincing demonstration that antiviral therapy can prevent lesion development. These results should prompt a reconsideration of the role that episodic treatment plays in the management of recurrent herpes genitalis. ==================================================================== 5.) Valaciclovir for the suppression of recurrent genital HSV infection: a placebo controlled study of once daily therapy. International Valaciclovir HSV Study Group. ==================================================================== Genitourin Med 1997 Apr;73(2):105-9 Patel R, Bodsworth NJ, Woolley P, Peters B, Vejlsgaard G, Saari S, Gibb A, Robinson J Royal South Hants Hospital, Southampton, UK. OBJECTIVE: To determine the efficacy and safety of once daily valaciclovir for the suppression of recurrent genital herpes simplex virus (HSV) infection in immunocompetent patients. METHODS: 382 otherwise healthy patients with a history of frequently recurring genital HSV infection (eight recurrences per year) were randomly allocated to receive either oral valaciclovir (500 mg once daily) or placebo (3:1 ratio) for 16 weeks or until the first genital HSV recurrence, whichever occurred first. Patients were clinically assessed at regular intervals and also if they experienced a recurrence. Safety was evaluated through adverse experience reporting and monitoring of haematology and biochemistry variables. On completion of the double blind phase, patients were eligible for follow up to a maximum of 48 weeks' treatment with open label valaciclovir (500 mg once daily) for further safety monitoring. The results from the double blind phase of the study are reported here. RESULTS: A significant difference was detected between valaciclovir and placebo in the time to first recurrence of genital HSV infection. The hazard ratio [95% confidence interval] for valaciclovir v placebo was 0.155 [0.112, 0.214], p < 0.0001. Valaciclovir prevented or delayed 85% of the recurrences that would have occurred with placebo. After 16 weeks (day 112) with treatment, 69% of patients receiving valaciclovir were recurrence free compared with only 9.5% of patients assigned to placebo. The safety profiles of valaciclovir and placebo were comparable, with adverse experiences being infrequent and generally mild. CONCLUSION: This study has demonstrated that once daily valaciclovir (500 mg), is highly effective and well tolerated for the suppression of recurrent genital HSV infection. Once daily dosing with valaciclovir provides a more convenient dosing regimen than the more frequent aciclovir regimens. ==================================================================== 6.) Valaciclovir versus acyclovir in the treatment of first-episode genital herpes infection. Results of an international, multicenter, double-blind, randomized clinical trial. The Valaciclovir International Herpes Simplex Virus Study Group. ==================================================================== Sex Transm Dis 1997 Sep;24(8):481-6 Fife KH, Barbarash RA, Rudolph T, Degregorio B, Roth R Department of Medicine, Indiana University School of Medicine, Indianapolis, USA. BACKGROUND AND OBJECTIVES: Valaciclovir, the L-valine ester prodrug of acyclovir, is much better absorbed than acyclovir and produces acyclovir exposures three to five times those attainable with the parent drug. GOALS: To determine whether the improved bioavailability of valaciclovir and a more convenient, less frequent dose regimen can maintain the clinical efficacy previously demonstrated for acyclovir. STUDY DESIGN: This was an international, multicenter, randomized, double-blind clinical trial comparing 10-day regimens of valaciclovir (1000 mg, twice daily) and acyclovir (200 mg, 5 times daily) in the treatment of 643 otherwise healthy adults (> or = 18 years of age) with first-episode genital herpes. Patients were evaluated clinically and lesions were staged and cultured on days 1, 2, 3, 5, 7, 10, 14, and then twice weekly until healed. Blood for herpes serology tests was obtained on days 1 and 14; hematology and chemistry toxicity screening was done on days 1 and 7. RESULTS: Valaciclovir and acyclovir did not differ significantly in efficacy with respect to duration of viral shedding (hazard ratio, 1.00; 95% confidence interval [CI], 0.84-1.18), time to healing (hazard ratio, 1.08; 95% CI, 0.92-1.27), duration of pain (hazard ratio, 1.0; 95% CI, 0.85-1.18), and time to loss of all symptoms (hazard ratio, 1.02; 95% CI, 0.85-1.22). Patients with primary genital herpes (no preexisting antibody to either herpes simplex virus type at enrollment with seroconversion at day 14) had longer times to healing and longer duration of viral shedding and pain than patients with nonprimary first genital episodes. Adverse experiences were generally infrequent and mild and were comparable in the two treatment groups. CONCLUSIONS: Twice-daily valaciclovir proved as effective and well tolerated in the treatment of first-episode genital herpes as five-times-daily acyclovir. Valaciclovir provides a useful alternative to acyclovir with the advantage of a more convenient dosing regimen and the potential for improved compliance. ==================================================================== 7.) Management of genital herpes. ==================================================================== Adv Exp Med Biol 1996;394:1-10 Mertz GJ University of New Mexico School of Medicine, Albuquerque, USA. Oral acyclovir is the therapy of choice for treatment of first-episode genital herpes, for suppression of frequently recurrent genital herpes, and, in selected patients, for episodic treatment of recurrent genital herpes. Topical acyclovir therapy is relatively or totally ineffective and is therefore discouraged. Indications for intravenous acyclovir therapy of mucocutaneous HSV infections include patients hospitalized with severe first-episode genital herpes and immunocompromised patients who have severe infections or who cannot swallow the oral preparation. The most promising investigational drugs are the oral prodrugs valaciclovir and famciclovir. Famciclovir is licensed in the U.S. for treatment of zoster but not for treatment of mucocutaneous genital herpes. When used for episodic therapy of recurrent genital herpes, both famciclovir and valaciclovir effectively reduce the duration of viral shedding, lesion healing times, and the duration of symptoms. Suppressive therapy with famciclovir has also been shown to be effective in reducing the frequency of episodes in women with frequently recurring genital herpes. Although these drugs can be given less frequently than oral acyclovir, there is yet no clear indication that they are more effective or better tolerated than oral acyclovir. ==================================================================== 8.) Valaciclovir compared with acyclovir for improved therapy for herpes zoster in immunocompetent adults. ==================================================================== Antimicrob Agents Chemother 1995 Jul;39(7):1546-53 Beutner KR, Friedman DJ, Forszpaniak C, Andersen PL, Wood MJ Department of Dermatology, University of California at San Francisco, Vallejo 94589, USA. Acyclovir treatment of acute herpes zoster speeds rash healing and decreases pain and ocular complications. The limited oral bioavailability of acyclovir necessitates frequent dosing. Valaciclovir, the l-valyl ester of acyclovir, is rapidly and almost completely converted to acyclovir in vivo and gives three- to fivefold increases in acyclovir bioavailability. In a randomized, double-blind, multicenter study, the safety and efficacy of oral valaciclovir given at a dosage of 1,000 mg three times daily for 7 or 14 days and oral acyclovir given at a dosage of 800 mg five times daily for 7 days were compared in immunocompetent adults aged > or = 50 years with herpes zoster. Patients were evaluated for 6 months. The intent-to-treat analysis (1,141 patients) showed that valaciclovir for 7 or 14 days significantly accelerated the resolution of herpes zoster-associated pain (P = 0.001 and P = 0.03, respectively) compared with acyclovir; median pain durations were 38 and 44 days, respectively, versus 51 days for acyclovir. Treatment with valaciclovir also significantly reduced the duration of postherpetic neuralgia and decreased the proportion of patients with pain persisting for 6 months (19.3 versus 25.7%). However, there were no differences between treatments in pain intensity or quality-of-life measures. Cutaneous manifestations resolved at similar rates in all groups. Adverse events were similar in nature and prevalence among groups, and no clinically important changes occurred in hematology or clinical chemistry parameters. ==================================================================== 9.) Valacyclovir. New indication: for genital herpes, simpler administration. ==================================================================== Can Fam Physician 1999 Jul;45:1698-700, 1703-5 Valacyclovir, the metabolic precursor of acyclovir, is now approved for treatment and prevention of genital infection with herpes simplex viruses. The clinical file is bulky and methodologically sound. For treatment of a first episode of genital herpes, a large comparative trial has shown that valacyclovir (1 g twice a day) is as effective as acyclovir (200 mg five times a day) when given for 10 days. For treating recurrences, two trials show that valacyclovir is as effective as acyclovir (200 mg five times a day) with a treatment period of 5 days. A daily dose of 1 g of valacyclovir is as effective as 2 g daily. Valacyclovir can be administered once a day. For prevention among patients with frequent recurrences, the efficacy of valacyclovir (500 mg/d in a single dose) has been proven in a placebo-controlled trial lasting 4 months. In these trials, valacyclovir and acyclovir were both well tolerated, with no major differences between the two drugs. ==================================================================== 10.) Valacyclovir. ==================================================================== Ann Pharmacother 1997 Feb;31(2):185-91 Acosta EP, Fletcher CV Department of Pharmacy Practice, College of Pharmacy, University of Minnesota 55455, USA. OBJECTIVE: To discuss the clinical pharmacology, antiviral activity, clinical efficacy, and other therapeutic issues associated with valacyclovir use for the treatment of herpesvirus infections. DATA SOURCE: Literature searches using MEDLINE were prospectively designed to include relevant articles and abstracts between January 1982 and March 1996. The searches focused on valacyclovir pharmacology, clinical efficacy, and issues associated with herpesvirus infections. STUDY SELECTION: Selection of clinical and basic science studies were limited to those focusing on valacyclovir. All articles with pertinent information relevant to the scope of this article were reviewed. DATA SYNTHESIS: Valacyclovir is an amino acid ester prodrug of acyclovir. It is currently approved for the treatment of herpes zoster infections in immunocompetent adults (1 g p.o. tid for 7 d) and recurrent episodes of genital herpes in immunocompetent adults (500 mg bid for 5 d). Valacyclovir is rapidly and almost completely hydrolyzed to acyclovir prior to systemic exposure. The bioavailability of valacyclovir is 54% compared to approximately 20% for oral acyclovir. At higher dosages (2 g qid), the plasma AUC of acyclovir following oral valacyclovir administration approximates that seen after intravenous administration of 10 mg/kg every 8 hours. Clinical data indicate that valacyclovir is at least as effective as acyclovir in decreasing the duration of pain associated with postherpetic neuralgia, and in reducing time to genital lesion healing and the length of the episode. CONCLUSIONS: Valacyclovir has improved bioavailability over acyclovir and is at least as efficacious. The favorable safety profile of acyclovir and increased systemic exposure make it a particularly ideal candidate for further studies of herpes group viral infections in immunocompromised patients. ==================================================================== 11.) Antiviral therapy of acute herpes zoster in older patients. ==================================================================== Drugs Aging 1996 Feb;8(2):97-112 Herne K, Cirelli R, Lee P, Tyring SK Department of Microbiology/Immunology, University of Texas Medical Branch, Galveston 77555, USA. Although herpes zoster (shingles) can occur in anyone with a history of chickenpox, it is more prevalent and usually more severe in older patients (i.e. persons over 50 years of age). While the cutaneous manifestations of shingles usually resolve in approximately 4 weeks, the pain can persist for several months, or even years in the untreated patient. This pain following healing of the skin, termed post-herpetic neuralgia (PHN), can be very severe. Three well tolerated and effective antiviral drugs are available for the therapy of acute herpes zoster. The nucleoside analogues, aciclovir, famciclovir and valaciclovir, appear to shorten the duration of PHN to a similar degree, but none affects the incidence of PHN. Aciclovir is taken 5 times daily for 7 days, while famciclovir is taken 3 times daily for 7 days. Valaciclovir, the L-valyl ester of aciclovir, when taken orally, produces plasma levels of aciclovir equivalent to those seen following intravenous administration of aciclovir. Valaciclovir has not only been proved to be more efficient than aciclovir (i.e. 3 times daily administration) but also more effective than aciclovir in shortening the duration of PHN. Current studies are determining the relative efficacy of valaciclovir versus famciclovir. Presently, a fourth drug, sorivudine, is being compared with aciclovir for the therapy of acute herpes zoster in older patients, but data from these trials are not yet available. Corticosteroids have been used to treat herpes zoster for much longer than the antiviral drugs, but the effect of corticosteroids on PHN does not appear to be consistent. Corticosteroids plus aciclovir did not provide an added benefit over aciclovir alone in one study but this combination did appear to improve the quality of life of older patients in another investigation. The recent availability of the varicella zoster vaccine may cause shingles to be an uncommon and/or mild disease by the mid twenty-first century. Meanwhile, the search continues for more effective and efficient therapies for acute herpes zoster with the primary goal in older patients to affect the most important sequela of zoster in this population, PHN. ==================================================================== 12.) A randomized, placebo-controlled comparison of oval valacyclovir and acyclovir in immunocompetent patients with recurrent genital herpes infections. The Valaciclovir International Study Group. ==================================================================== Arch Dermatol 1998 Feb;134(2):185-91 Tyring SK, Douglas JM Jr, Corey L, Spruance SL, Esmann J Department of Dermatology, University of Texas Medical Branch, Galveston, USA. [email protected] OBJECTIVE: To compare valacyclovir hydrochloride with acyclovir in the treatment of recurrent genital herpes infection. DESIGN: A multicenter, double-blind, placebo-controlled, randomized, parallel-design study. SETTING: University clinics (dermatology, gynecology, and infectious diseases) and private practices. PATIENTS: One thousand two hundred patients with recurrent genital herpes simplex infections. INTERVENTIONS: Patients self-initiated oral therapy with 1000 mg of valacyclovir hydrochloride twice daily, 200 mg of acyclovir 5 times daily, or placebo for 5 days. MAIN OUTCOME MEASURES: Resolution of all signs and symptoms of recurrent genital herpes infection. RESULTS: Both drugs were significantly more effective than placebo in speeding resolution of herpetic episodes (median duration, 4.8, 4.8, and 5.9 days, respectively); the hazards ratios for valacyclovir and acyclovir vs placebo were 1.66 (95% confidence interval [CI], 1.38-2.01) and 1.71 (95% CI, 1.41-2.06) (both P < .001). Similarly, valacyclovir and acyclovir significantly hastened lesion healing (hazards ratios vs placebo were 1.88 [95% CI, 1.53-2.32] and 1.90 [95% CI, 1.55-2.34], respectively; P < .001). Pain duration was shorter in valacyclovir- and acyclovir-treated patients (median, 2 vs 3 days). Viral shedding stopped 2.55 times faster in patients treated with valacyclovir and 2.24 times faster in patients treated with acyclovir than in patients treated with placebo. Aborted episodes, in which lesions did not progress beyond the macule or papule stage, tended to occur in more patients treated with valacyclovir (25.9%) or acyclovir (24.8%) than in patients treated with placebo (19.8%). Valacyclovir and acyclovir did not differ significantly with regard to their respective effects on any of the above efficacy parameters. The nature, severity, and frequency of adverse events did not differ among the 3 treatment groups. CONCLUSIONS: Twice-daily valacyclovir was as effective and well tolerated in the treatment of recurrent genital herpes simplex virus infection as 5-times-daily acyclovir. Therefore, valacyclovir could prove a useful alternative to acyclovir when convenience of dosing or compliance issues are the prime considerations in treatment. ==================================================================== 13.) Comparison of valaciclovir and acyclovir for the treatment of herpes zoster in immunocompetent patients over 50 years of age: a cost-consequence model. ==================================================================== Pharmacotherapy 1997 Mar-Apr;17(2):333-41 Grant DM, Mauskopf JA, Bell L, Austin R GlaxoWellcome Research and Development, Greenford, United Kingdom. A method was developed for modeling the costs and consequences of treating varicella zoster viral infections to clinical data generated in a pivotal phase III clinical trial of valaciclovir versus acyclovir for the treatment of acute herpes zoster in immunocompetent patients over 50 years of age. Direct medical costs and indirect costs (productivity losses) were modeled using unit costs applicable in the United States. Compared with acyclovir, valaciclovir reduced average direct medical costs per patient by 17% ($60.01) and indirect costs by an average of 25% ($46.54). Median duration of pain was reduced by 13 days for valaciclovir compared with acyclovir in the intent-to-treat population or by 19 days in patients with pain after rash healing. The cost variables described in the model (drug costs, cost of treating long-term pain, physician visits, hospitalization, treatment of severe ocular involvement, productivity losses) were tested by sensitivity analysis. Total costs associated with valaciclovir treatment remained lower than those with acyclovir over the range of the analysis. ==================================================================== 14.) Valacyclovir: a review of its antiviral activity, pharmacokinetic properties, and clinical efficacy. ==================================================================== Antiviral Res 1995 Dec;28(4):281-90 Beutner KR Department of Dermatology, University of California at San Francisco, USA. Oral administration of the prodrug valacyclovir results in enhanced bioavailability and significantly greater plasma concentrations of acyclovir than can be achieved with oral doses of acyclovir itself. The results of clinical trials with valacyclovir have demonstrated significant benefits in the resolution of pain associated with herpes zoster infection. Efficacy parameters were similar for valacyclovir and acyclovir in the treatment of herpes simplex; however the results were achieved with lower and less-frequent doses of valacyclovir. The cost of a course of therapy with valacyclovir is expected to be similar to that of other antivirals. The potential clinical benefits of valacyclovir will likely be apparent in the case of acyclovir-resistant herpesvirus infections, where high-dose intravenous treatment with acyclovir has been necessary. Most of these resistant viruses have been encountered in immunocompromised patients, and the resistance has been attributed to inadequate exposure to the drug. Because optimal levels of acyclovir are achieved with a simpler dosing regimen of valacyclovir, compliance may be improved in many patients, thus reducing the incidence of resistant virus. ==================================================================== 15.) Lessons from the natural history of cytomegalovirus. ==================================================================== Bowen EF; Griffiths PD; Davey CC; Emery VC; Johnson MA Department of Virology, Royal Free Hospital, London, UK. AIDS (UNITED STATES) Nov 1996 10 Suppl 1 pS37-41 ISSN: 0269-9370 Language: ENGLISH Document Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL Journal Announcement: 9706 Subfile: INDEX MEDICUS BACKGROUND: More than 90% of patients with HIV have been infected at some time with cytomegalovirus (CMV) and up to 40% of those with advanced HIV will develop CMV disease. The incidence of CMV disease is increasing but the prognosis for the patient remains poor. MONITORING FOR CMV: It is therefore important to monitor patients with low CD4+ counts in order to identify those most at risk of developing CMV disease and to treat them before the disease becomes established. Polymerase chain reaction (PCR) is probably the most effective and sensitive method of detecting CMV and a positive result is predictive for development of CMV disease; more than 80% of patients with CMV retinitis are CMV PCR-positive at the time of diagnosis. PCR can also detect the presence of CMV up to 14 months before the development of retinitis. TREATMENT OF CMV RETINITIS: In patients with detectable CMV, but no evidence of active infection, pre-emptive treatment with ganciclovir or valaciclovir has been shown to reduce the risk of developing retinitis in these high-risk patients. Such oral therapy, which is generally better tolerated than intravenous therapy and results in a better quality of life for the patient, is likely to be more effective at this stage whilst viral loads are low. CONCLUSIONS: CMV PCR can be used to prospectively monitor patients in order to identify those most at risk of developing CMV retinitis. If CMV infection is diagnosed early, while viral loads are still low, pre-emptive oral therapy can be instituted which will reduce the chances of developing retinitis in those patients most at risk. (14 References) ==================================================================== 16.) VALACYCLOVIR (Systemic), The product ==================================================================== INN: Valaciclovir2 VA CLASSIFICATION (Primary/Secondary)¾AM800 Commonly used brand name(s): Valtrex. Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s). bNot commercially available in Canada. Category Antiviral (systemic). Indications Accepted Herpes zoster (treatment)¾Valacyclovir is indicated in the treatment of herpes zoster (shingles) infections caused by varicella-zoster virus (VZV) in immunocompetent adults.1 In patients over 50 years of age, valacyclovir significantly reduced the duration of zoster-associated pain and the duration of postherpetic neuralgia lasting greater than 6 months when compared to acyclovir.13 Therapy is most effective when started within 48 hours of the onset of rash.1 There are no data on the safety and effectiveness of valacyclovir in children, immunocompromised patients, or patients with disseminated zoster.1 Pharmacology/Pharmacokinetics Physicochemical characteristics: Source¾Valacyclovir is the hydrochloride salt of the L-valyl ester of acyclovir1,8. Molecular weight¾ Valacyclovir: 324.349 Valacyclovir hydrochloride: 360.801,2 Mechanism of action/Effect: Valacyclovir is a prodrug that is nearly completely converted to acyclovir and L-valine.1 Due to its more efficient phosphorylation by viral thymidine kinase, acyclovir's antiviral activity is greatest against herpes simplex virus type 1 (HSV-1), followed by herpes simplex virus type 2 (HSV-2), varicella-zoster virus (VZV)1,3,6, Epstein-Barr virus (EBV), and cytomegalovirus (CMV).3,6 Acyclovir is phosphorylated by thymidine kinase to acyclovir monophosphate, which is then converted into acyclovir diphosphate and triphosphate by cellular enzymes.1 Acyclovir is selectively converted to the active triphosphate form by cells infected with herpes viruses.3 Acyclovir triphosphate inhibits herpes viral DNA replication by competitive inhibition of viral DNA polymerase, and incorporation and termination of the growing viral DNA chain.1 Absorption: Valacyclovir is rapidly absorbed in the gastrointestinal tract; it is then converted to the active compound, acyclovir, by first-pass intestinal and hepatic metabolism.1,7 Administration of valacyclovir with food was not found to alter the bioavailability of acyclovir.1 The bioavailability of acyclovir following administration of valacyclovir is approximately 54%1,12, which is three to five times greater than its bioavailability following oral administration of acyclovir13. After administration of 1 gram of valacyclovir given four times a day, the area under the plasma concentration-time curve (AUC) of acyclovir is approximately that obtained after intravenous administration of 5 mg per kg of body weight of acyclovir every 8 hours.8,9 Distribution: Acyclovir is widely distributed to tissues and body fluids, including brain, kidneys, lungs, liver, aqueous humor, tears, intestines, muscle, spleen, breast milk, uterus, vaginal mucosa, vaginal secretions, semen, amniotic fluid, cerebrospinal fluid (CSF), and herpetic vesicular fluid.3,4,5,6 Highest concentrations are found in the kidneys, liver, and intestines. Acyclovir concentrations in the CSF are approximately 50% of plasma concentrations.3 In addition, acyclovir crosses the placenta.3,4,5,6 Protein binding: Valacyclovir¾Low (13 to 18%).1 Acyclovir¾Low (9 to 33%).3 Biotransformation: Valacyclovir is rapidly and nearly completely (99%)6 converted to the active compound, acyclovir, and L-valine by first-pass intestinal and hepatic metabolism1,7,8,9 by enzymatic hydrolysis.8,9 Acyclovir is converted to inactive metabolites by alcohol and aldehyde dehydrogenase and, to a small extent, by aldehyde oxidase.1 The metabolism of valacyclovir and acyclovir is not associated with hepatic microsomal enzyme systems.1 Half-life: Valacyclovir¾ Less than 30 minutes.8 Acyclovir¾ After administration of valacyclovir: Normal renal function¾2.5 to 3.3 hours.1,8,9 End-stage renal disease¾Approximately 14 hours.1 Geriatric patients (65 to 83 years of age)¾3.3 to 3.7 hours.10 Time to peak concentration: 1.6 to 2.1 hours.7,8,9,10 Peak plasma concentrations Valacyclovir¾ Plasma concentrations of unconverted valacyclovir are low, with peak concentrations of less than 0.5 mcg per mL (mcg/mL) after any dose. Plasma concentrations are nonquantifiable within 3 hours after administration.1,8,9 Acyclovir¾ Peak plasma concentrations are not proportional to the dose. The following peak plasma concentrations have been found: After a single dose of valacyclovir: 500 mg: Approximately 3.3 mcg/mL.1,8 1 gram: 4.8 to 5.6 mcg/mL.1,8,9 After multiple doses of valacyclovir: 500 mg: Approximately 3.7 mcg/mL.1,8 1 gram: 5 to 5.5 mcg/mL.1,8,9 Elimination: Valacyclovir¾ Less than 1% of valacyclovir is recovered unchanged in the urine over 24 hours.7,8 In dialysis: It is not known if peritoneal dialysis removes valacyclovir from the blood. Acyclovir¾ Renal; acyclovir accounts for 80 to 89% of the total urinary recovery.1,8 There was no accumulation of acyclovir after repeated administration of valacyclovir in patients with normal renal function.1 In dialysis: Hemodialysis¾During a 4-hour hemodialysis session, approximately one-third of acyclovir in the body is removed. The half-life of acyclovir is approximately 4 hours during hemodialysis.1 Peritoneal dialysis¾Chronic ambulatory peritoneal dialysis (CAPD) and continuous arteriovenous hemofiltration/dialysis (CAVHD) do not substantially remove acyclovir, with pharmacokinetic parameters resembling those observed in patients with end-stage renal disease not receiving hemodialysis.1 Precautions to Consider Carcinogenicity/Tumorigenicity Valacyclovir was found to be noncarcinogenic in lifetime carcinogenicity bioassays at single daily doses of up to 120 mg per kg of body weight (mg/kg) per day for mice and 100 mg/kg per day for rats. There was no significant difference in the incidence of tumors between mice and rats treated with valacyclovir and control animals; also, valacyclovir did not shorten the latency of tumors. Plasma concentrations of acyclovir were equivalent to human levels in the mouse bioassay and 1.4 to 2.3 times human levels in the rat bioassay.1 Mutagenicity An in vitro cytogenetic study with human lymphocytes, a rat cytogenetic study after a single oral dose of 3000 mg/kg (8 to 9 times human plasma levels), and Ames assays in the presence or absence of metabolic activation were all negative. Valacyclovir was also negative in the mouse lymphoma assay in the absence of metabolic activation. In the presence of metabolic activation (76 to 88% conversion to acyclovir), valacyclovir was weakly mutagenic. A mouse micronucleus assay was negative at 250 mg/kg, but weakly positive at 500 mg/kg (acyclovir concentrations of 26 to 51 times human plasma levels, respectively).1 Pregnancy/Reproduction Fertility¾Valacyclovir did not impair fertility in rats given a dose of 200 mg/kg per day (6 times human plasma levels).1 Pregnancy¾Acyclovir crosses the placenta3,4,5,6. No adequate and well-controlled studies have been done with either valacyclovir or acyclovir in pregnant women. A prospective epidemiologic registry of acyclovir use during pregnancy from 1984 to December 1994 has documented 380 women with live births who were exposed to systemic acyclovir during the first trimester of pregnancy. The rate of birth defects in this group approximates that found in the general population. However, it is thought that the small size of the registry is insufficient to evaluate the risk for less common defects or to make definitive conclusions about the safety of acyclovir in developing fetuses.1 FDA Pregnancy Category B. Breast-feeding It is not known whether valacyclovir is distributed into breast milk. However, acyclovir has been found to pass into breast milk at concentrations ranging from 0.6 to 4.1 times the corresponding plasma concentration.1At these concentrations, a nursing infant could potentially be exposed to a dose of acyclovir as high as 0.3 mg/kg per day.1 Pediatrics No information is available on the relationship of age to the effects of valacyclovir in pediatric patients. Safety and efficacy have not been established.1 Geriatrics Studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of valacyclovir in the elderly. However, elderly patients are more likely to have an age-related decrease in renal function, which may require an adjustment of valacyclovir dosage or dosing interval.1,10 Drug interactions and/or related problems The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)¾not necessarily inclusive (>> = major clinical significance): Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication. Cimetidine1,11 and Probenecid1,11¾(cimetidine and probenecid have been found to decrease the rate, but not the extent, of conversion of valacyclovir to acyclovir; the renal clearance of acyclovir was reduced by approximately 24 and 33% by cimetidine and probenecid, respectively, resulting in an increase in the peak plasma concentration of acyclovir by approximately 8 and 22%, respectively; combined use of cimetidine and probenecid resulted in a reduced renal clearance of acyclovir by approximately 46% and an increase in the peak plasma concentration by approximately 30%) Medical considerations/Contraindications The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)¾not necessarily inclusive (>> = major clinical significance). Risk-benefit should be considered when the following medical problems exist >> Bone marrow transplantation or1 >> Human immunodefiency virus (HIV) infection, advanced or1 >> Renal transplantation1¾(thrombotic thrombocytopenic purpura/hemolytic uremic syndrome [TTP/HUS] has been reported in patients with these conditions who were taking high doses of valacyclovir for prolonged periods of time14; in rare cases, death has occurred; therefore, valacyclovir is not indicated in immunocompromised patients; however, TTP/HUS has not been seen in immunocompetent patients treated with valacyclovir) Hepatic function impairment1¾(the rate, but not the extent, of conversion of valacyclovir to acyclovir is reduced in patients with moderate or severe liver disease [biopsy-proven cirrhosis]; however, the half-life of acyclovir is not affected and dosage modification is not recommended for patients with cirrhosis) >> Hypersensitivity to valacyclovir or acyclovir1¾ >> Renal function impairment1¾(because valacyclovir is renally excreted, patients with renal function impairment may be at increased risk of toxicity; patients with a creatinine clearance of < 50 mL/min [< 0.83 mL/sec] require a reduction in dose) Side/Adverse Effects Note: No serious side effects have been noted to date with the adminstration of valacyclovir in immunocompetent adults.1 The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)¾not necessarily inclusive: Those indicating need for medical attention only if they continue or are bothersome Incidence more frequent Headache1,8,9; nausea1,8,9,13 Incidence less frequent Dizziness1,8; fatigue (unusual tiredness or weakness)1,9; gastrointestinal disturbances (constipation; diarrhea; loss of appetite; stomach pain; vomiting)1,8,9 Overdose For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing). Clinical effects of overdose To date, there have been no reports of overdosage with valacyclovir.1 However, precipitation of acyclovir in the renal tubules has occurred with rapid or high intravenous doses of acyclovir3. No significant adverse effects have been seen with oral overdoses of acyclovir of up to 20 grams.6 If acute renal failure or anuria occurs, hemodialysis may be helpful until renal function is restored.1,3 Patient Consultation As an aid to patient consultation, refer to Advice for the Patient, Valacyclovir (Systemic). In providing consultation, consider emphasizing the following selected information (>> = major clinical significance): Before using this medication >> Conditions affecting use, especially: Hypersensitivity to valacyclovir or acyclovir Other medical problems, especially advanced human immunodeficiency virus infection, bone marrow transplantation, renal function impairment, or renal transplantation Proper use of this medication >> Initiating use of valacyclovir at the earliest sign or symptom; it is most effective when started within 48 hours of the onset of rash, pain, or burning Valacyclovir may be taken with meals >> Compliance with full course of therapy; not using more often or for longer than prescribed >> Proper dosingMissed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses >> Proper storage Precautions while using this medication Checking with physician if no improvement within a few days Keeping affected areas as clean and dry as possible; wearing loose-fitting clothing to avoid irritating the lesions Side/adverse effects No side/adverse effects that indicate the need for prompt medical attention have been reported General Dosing Information Therapy should be initiated as soon as possible following the onset of signs and symptoms of varicella-zoster infection. In clinical studies, treatment was started within 72 hours of the onset of rash; however, valacyclovir was found to be more useful if started within 48 hours.1 Valacyclovir may be taken with meals since absorption has not been shown to be significantly affected by food.1 Adults with impaired renal function may require a change in dosing, as follows:1 Creatinine Clearance Recommended dose (mL/min)/(mL/sec) ³50/0.83 1 gram every 8 hours 30-49/0.50-0.82 1 gram every 12 hours 10-29/0.17-0.48 1 gram every 24 hours <10/0.17 500 mg every 24 hours Oral Dosage Forms Note: The dosing and strengths of the dosage forms available are expressed in terms of valacyclovir base (not the hydrochloride salt). VALACYCLOVIR HYDROCHLORIDE TABLETS Usual adult dose Antiviral¾ Oral, 1 gram (base) three times a day for seven days.1 Usual pediatric dose Safety and efficacy have not been established.1 Usual geriatric dose See Usual adult dose.1 Strength(s) usually available U.S.¾ 500 mg (base) (Rx)[Valtrex]. Canada¾ Not commercially available. Packaging and storage: Store between 15 and 25 °C (59 and 77 °F), in a tight container. Protect from light.1,6 Auxiliary labeling: · Continue medicine for full time of treatment. ==================================================================== FAMCICLOVIR ==================================================================== 17.) Famciclovir. A review of its pharmacological properties and therapeutic efficacy in herpesvirus infections. ==================================================================== Drugs 1995 Aug;50(2):396-415 Perry CM, Wagstaff AJ Adis International Limited, Auckland, New Zealand. 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 > or = 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. ==================================================================== 18.) Famciclovir: review of clinical efficacy and safety. ==================================================================== Antiviral Res 1996 Mar;29(2-3):141-51 Cirelli R, Herne K, McCrary M, Lee P, Tyring SK Department of Microbiology/Immunology, University of Texas Medical Branch, Galveston 77555, USA. Famciclovir is the well-absorbed oral form of penciclovir, an antiviral agent with potent activity against varicella-zoster virus (VZV) and herpes simplex virus (HSV-1) and 2 (HSV-2). After oral administration, famciclovir is rapidly converted to penciclovir with a bioavailability of 77%. penciclovir is efficiently phosphorylated to the active metabolite, penciclovir-triphosphate, and has a prolonged intracellular half-life of approximately 9-10 h in VZV-infected cells, and 10 and 20 h in cells infected with HSV-1 and HSV-2, respectively. Two multicenter clinical trials have shown that famciclovir given during the acute zoster phase accelerated healing of cutaneous lesions. More importantly, in a placebo-controlled study, famciclovir reduced the duration of postherpetic neuralgia (PHN), particularly in elderly patients. Famciclovir has also been proven effective in treating recurrent genital herpes, as demonstrated by a reduction in times to cessation of viral shedding, complete healing, and loss of all symptoms. One study showed that suppressive therapy with famciclovir was effective in reducing genital herpes episodes in patients with frequent recurrences. A promising new area of investigation for famciclovir is controlling virus replication in patients with chronic hepatitis B virus (HBV) or HBV reinfections after liver transplant. Results from a double-blind, placebo-controlled, pilot study and several case reports have shown that famciclovir, alone or in combination with other agents, decreased HBV-DNA levels and was tolerated with long-term treatment. Available clinical data indicate that famciclovir is an effective agent for treating herpes and holds significant promise for the treatment of chronic HBV infection HBV reinfection after liver transplantation. ==================================================================== 19.) Efficacy of famciclovir in the treatment of herpes zoster. ==================================================================== Semin Dermatol 1996 Jun;15(2 Suppl 1):27-31 Tyring SK University of Texas Medical Branch, Galveston 77555, USA. Although vidarabine was the first systemic antiviral drug for the treatment of acute herpes zoster, the agent now used most frequently is acyclovir, a far safer drug that became available a decade ago. However, even with widespread use of acyclovir, postherpetic neuralgia (PHN) remains a principal cause of postinfectious morbidity. Newer antiviral agents, such as famciclovir and valacyclovir, have recently been introduced for the treatment of uncomplicated herpes zoster. In a double-blind, randomized study, 500 mg of famciclovir three times daily for 7 days was compared with placebo; in a second study, 500 mg of famciclovir three times daily for 7 days was compared with 800 mg of acyclovir five times daily for 7 days. Famciclovir significantly reduced duration of viral shedding (P = 0.0001) and accelerated lesion resolution compared with placebo. Famciclovir was comparable to acyclovir for these acute parameters. Most importantly, famciclovir recipients lost PHN two times faster than those receiving placebo (P = 0.02 all patients; P = 0.004 patients > or = 50 years) resulting in a reduction in the median duration of PHN (56 days all patients; 100 days patients > or = 50 years). This reduction translated to a 3.5-month reduction in the median duration of PHN for patients 50 years or older, those at greatest risk for developing the most common complication of herpes zoster. Famciclovir 500 mg administered three times a day for 7 days is an effective and well-tolerated treatment for acute herpes zoster, and is the only oral antiviral agent proven to reduce the duration of PHN when administered during acute zoster infection. ==================================================================== 20.) Safety of famciclovir in patients with herpes zoster and genital herpes. ==================================================================== Antimicrob Agents Chemother 1994 Oct;38(10):2454-7 Saltzman R, Jurewicz R, Boon R SmithKline Beecham Pharmaceuticals, Philadelphia, Pennsylvania. Safety reporting from individual ongoing and completed clinical studies has demonstrated that famciclovir, the well-absorbed oral form of the antiherpesvirus agent penciclovir, has been well tolerated by more than 3,000 individuals worldwide. An integrated safety evaluation has been performed and includes over 1,600 patients from 11 completed, randomized, double-blind clinical trials and 2 open trials. The famciclovir population consisted of 816 herpes zoster patients (four trials), 409 patients with acute genital herpesvirus infections (seven trials), and 382 patients from two genital herpes suppression studies. Overall, the famciclovir-treated patient population was 57.7% female and ranged in age from 15 to 102 years (mean, 42.6 years), with 31.2% aged 50 years or more and 15.7% aged 65 years or more. The mean duration of exposure to famciclovir was 28.8 days (5.8 days excluding suppression studies). The total daily doses ranged from 125 mg to 2.25 g. The most common adverse experiences reported as related to study medication (famciclovir and placebo) were headache, nausea, and diarrhea. The frequencies of adverse experiences and laboratory abnormalities (hematology, clinical chemistry, and urinalysis parameters) were similar in both famciclovir and placebo recipients. Thus, safety data from the analysis of 13 completed clinical studies demonstrate that famciclovir is tolerated well by patients with either herpes zoster or genital and has a safety profile comparable to that of placebo. ==================================================================== 21.) Famciclovir for treatment of herpesvirus infections. ==================================================================== Ann Pharmacother 1996 Sep;30(9):978-85 Luber AD, Flaherty JF Jr School of Pharmacy, University of California, San Francisco 94143, USA. OBJECTIVE: To discuss the antiviral activity, pharmacokinetics, clinical efficacy, and adverse effect profile of famciclovir, the oral prodrug of penciclovir (PCV), and to compare these features of famciclovir with those of acyclovir in the treatment of herpesvirus infections. DATA SOURCES: Literature was identified by MEDLINE search, and abstracts from recent meetings were included where relevant. Data provided by the manufacturer were also used. STUDY SELECTION: Data regarding antiviral activity were included if accepted and widely used methods were followed. Clinical trials in which a comparison with acyclovir or placebo was performed were given the highest priority. DATA SYNTHESIS: In comparison with acyclovir, PCV has similar antiviral activity although its mode of action is not identical. When administered orally, faMciclovir, the oral prodrug of PCV, is better absorbed than acyclovir, yielding an absolute bioavailability of PCV of 77%. The predominant route of PCV elimination is via the kidneys, with a half-life of approximately 2.5 hours. In trials comparing famciclovir with acyclovir for the treatment of herpes zoster in immunocompetent individuals, comparable results were obtained. Famciclovir is also effective as therapy for recurrent episodes of genital herpes and may prove useful for chronic suppressive therapy. The most common adverse effects of famciclovir are headache and gastrointestinal upset. The dosage of famciclovir for herpes zoster in immunocompetent individuals is 500 mg po tid for 7 days; for recurrent genital herpes a dosage of 125 mg po bid for 5 days is recommended. Dosage adjustments are necessary in patients with renal dysfunction. CONCLUSIONS: Given its comparable efficacy, similar adverse effect profile, and less frequent dosing schedule than acyclovir, famciclovir represents a viable alternative for treatment of herpes zoster and for episodic therapy of recurrent genital herpes in immunocompetent adults. Specific recommendations for other uses of famciclovir await the publication of recent clinical trial results. ==================================================================== 22.) The pharmacological profile of famciclovir. ==================================================================== Semin Dermatol 1996 Jun;15(2 Suppl 1):14-26 Crumpacker C Division of Infectious Diseases, Beth Israel Hospital, Boston, MA 02215, USA. Famciclovir is the well-absorbed oral form of penciclovir, a potent and selective antiviral agent, with activity against members of the herpesvirus family, including varicella-zoster virus (VZV), and herpes simplex virus-1 (HSV-1) and HSV-2. Famciclovir is rapidly absorbed and converted to penciclovir. Penciclovir has excellent bioavailability (77%) after oral administration of 500 mg of famciclovir. Similar to acyclovir, famciclovir is converted by phosphorylation to its active metabolite, penciclovir-triphosphate. Penciclovir-triphosphate has a prolonged in vitro intracellular half-life of 10 to 20 hours in HSV-1-and HSV-2-infected cells, respectively, and 9 to 14 hours in VZV-infected cells. In contrast, the in vitro intracellular half-life of acyclovir is substantially shorter at 0.7 and 1 hours in HSV-1- and HSV-2-infected cells, respectively, and 0.8 hours in VZV-infected cells. Famciclovir is eliminated primarily via the kidneys. Dosage adjustment is not required for famciclovir in elderly patients with normal or mildly impaired renal function, and the extent of penciclovir availability is not affected by food. The excellent bioavailability ensures that adequate drug reaches virus-infected cells, and the prolonged intracellular half-life of the active form of famciclovir results in persistent antiviral activity. ==================================================================== 23.) Advances in the treatment of herpesvirus infection: the role of famciclovir. ==================================================================== Clin Ther 1998 Jul-Aug;20(4):661-70 Tyring SK Department of Microbiology/Immunology, University of Texas Medical Branch, Galveston 77555, USA. Shingles (herpes zoster) is the result of reactivation of varicella-zoster virus after years of latency. The acute phase is self-limiting but is often associated with moderate-to-severe pain; postherpetic neuralgia is the most frequent and debilitating complication of shingles, occurring in 3.4 per 1000 individuals per year. In the case of genital herpes, herpes simplex virus can reactivate to cause recurrent episodes as often as several times a year, sometimes for the remainder of a person's life. Antiviral agents such as famciclovir, valacyclovir, and acyclovir can be used to shorten the course and decrease the severity of these diseases and may suppress the virus itself, thereby preventing future outbreaks of genital herpes. This article presents a brief synopsis of the etiology of herpes zoster and genital herpes and reviews 12 key studies that demonstrate the efficacy of famciclovir in the management of these two conditions. ==================================================================== 24.) Genital herpes simplex virus and its treatment: focus on famciclovir. ==================================================================== Semin Dermatol 1996 Jun;15(2 Suppl 1):32-6 Sacks SL Department of Medicine, University of British Columbia, Vancouver, Canada. The incidence of genital herpes continues to increase worldwide. Primary first-episode genital herpes are commonly associated with severe systemic symptoms. Primary first-episode lesions are usually bilateral and may from over a period of 10 days. Nonprimary first-episode genital herpes are often associated with less severe systemic symptoms and lesion formation. Although recurrent genital herpes episodes are generally limited to localized lesions without systemic symptoms, the frequent recurrence and chronicity may have a substantial psychosocial impact on a patient's well-being. Presently, there are no available treatments capable of abating the latent virus in human beings. Current management of genital herpes focuses on treatment with antiviral agents, which are effective in reducing the course of genital herpes. ==================================================================== 25.) Oral famciclovir for suppression of recurrent genital herpes simplex virus infection in women. A multicenter, double-blind, placebo-controlled trial. Collaborative Famciclovir Genital Herpes Research Group. ==================================================================== Arch Intern Med 1997 Feb 10;157(3):343-9 Mertz GJ, Loveless MO, Levin MJ, Kraus SJ, Fowler SL, Goade D, Tyring SK Department of Internal Medicine, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, USA. [email protected] OBJECTIVE: To evaluate the efficacy and safety of oral famciclovir in the suppression of genital herpes. METHODS: In this randomized, double-blind, placebo-controlled trial that was performed at 11 university and 9 private ambulatory care referral centers, 375 women who were 18 years of age or older and had a history of 6 or more episodes of genital herpes during 12 of the last 24 months in the absence of suppressive therapy were treated for 4 months with oral famciclovir, 125 mg once daily or twice daily, 250 mg once daily or twice daily, 500 mg once daily, or placebo. The primary outcome measures included the time to first clinically and virologically confirmed recurrences, and safety as measured by clinical laboratory tests and adverse experiences. RESULTS: The median time to first recurrence was 82 days in the placebo group, 114 days in those receiving famciclovir, 125 mg once daily, and more than 120 days in the other treatment groups. When compared with placebo recipients, the time to the first clinical recurrence was significantly prolonged in subjects who received famciclovir, 125 mg twice daily (hazard ratio, 1.8; 95% confidence interval, 1.0-3.0; P = .03), and in those who received famciclovir, 250 mg twice daily (hazard ratio, 3.6; 95% confidence interval, 1.9-6.9; P < .001). Treatment was well tolerated, and there was no evidence of emergence of resistance during or after suppressive famciclovir therapy. CONCLUSIONS: Oral famciclovir, 250 mg, given twice daily for 4 months is an effective, well-tolerated treatment for the suppression of genital herpes in women with frequent recurrences, but single daily doses produced less complete suppression of genital herpes. ==================================================================== 26.) Oral famciclovir for the suppression of recurrent genital herpes: a randomized controlled trial. Collaborative Famciclovir Genital Herpes Research Group. ==================================================================== JAMA 1998 Sep 9;280(10):887-92 Diaz-Mitoma F, Sibbald RG, Shafran SD, Boon R, Saltzman RL Children's Hospital of Eastern Ontario, Ottawa, Canada. [email protected] CONTEXT: Recurrent genital herpes simplex virus (HSV) may be treated episodically, but this may not be sufficient for patients with frequent recurrences. OBJECTIVE: To determine the efficacy and safety of famciclovir in the suppression of recurrent genital HSV infection. DESIGN: A randomized, double-blind, placebo-controlled, parallel-group study. SETTING: Thirty university, hospital, or private outpatient referral centers in Canada and Europe. PATIENTS: A total of 455 patients (223 men, 232 women) aged 18 years or older with a history of 6 or more episodes of genital herpes during 12 of the most recent 24 months, in the absence of suppressive therapy, received study medication. INTERVENTION: Oral famciclovir, 125 mg or 250 mg 3 times daily or 250 mg twice daily, or placebo for 52 weeks. MAIN OUTCOME MEASURES: Time to the first recurrence of genital HSV infection; the proportion of patients remaining free of HSV recurrence at 6 months; frequency of adverse events. RESULTS: In an intent-to-treat analysis, famciclovir significantly delayed the time to the first recurrence of genital herpes at all dose regimens (hazard ratios, 2.9-3.3; P<.001); median time to recurrence for famciclovir recipients was 222 to 336 days compared with 47 days for placebo recipients. The proportion of patients remaining free of HSV recurrence was approximately 3 times higher in famciclovir recipients (79%-86%) than in placebo recipients (27%) at 6 months (relative risks, 2.9-3.1; P<.001); efficacy was maintained at 12 months. Famciclovir was well tolerated with an adverse experience profile comparable to placebo. CONCLUSIONS: Oral famciclovir (125 mg or 250 mg 3 times daily or 250 mg twice daily) is an effective, well-tolerated treatment for the suppression of genital HSV infection in patients with frequent recurrences. ==================================================================== 27.) Famciclovir: a new systemic antiviral agent for herpesvirus infections. ==================================================================== Am Fam Physician 1997 May 15;55(7):2501-4 Stott GA Department of Family Medicine, York Hospital, Pennsylvania, USA. Acyclovir was the first antiviral drug approved for the treatment of herpes zoster. Several new antiviral agents have since been introduced, one of which is famciclovir. The pharmacokinetics of famciclovir allow a more convenient dosing schedule than the schedule used with acyclovir. Famciclovir is metabolized in the liver, but the P450 cytochrome system is not involved. Both acyclovir and famciclovir accelerate cutaneous healing, but studies suggest that famciclovir may reduce the severity of postherpetic neuralgia when compared with placebo. Famciclovir is currently approved only for use in immunocompetent patients, but clinical trials involving immunocompromised patients are in progress. ==================================================================== 28.) Patient-initiated, twice-daily oral famciclovir for early recurrent genital herpes. A randomized, double-blind multicenter trial. Canadian Famciclovir Study Group. ==================================================================== JAMA 1996 Jul 3;276(1):44-9 Sacks SL, Aoki FY, Diaz-Mitoma F, Sellors J, Shafran SD Division of Infectious Diseases, Vancouver Hospital and Health Sciences Centre, University of British Columbia, Canada. OBJECTIVE--To compare the efficacy and safety of episodic patient-initiated oral famciclovir with placebo in recurrent genital herpes. DESIGN--Randomized, double-blind, frequent-observation, dose-ranging study comparing twice-daily 125-mg, 250-mg, or 500-mg oral famciclovir with placebo. Patients initiated therapy after self-culturing, reported to the clinic within 12 hours, and were assessed twice daily for at least 5 days. SETTING--Fifteen Canadian university, private practice, or public outpatient clinics. PATIENTS--A total of 692 patients with culture-proven recurrent genital herpes were randomized; 467 patients experienced a symptomatic episode and commenced treatment. MAIN OUTCOME MEASURE--Time to complete healing of all lesions. RESULTS--Famciclovir (all doses) was significantly more effective than placebo in reducing time to healing, time to cessation of viral shedding, and durations of lesion edema, vesicles, ulcers, and crusts. Times to cessation of all symptoms and of moderate to severe lesion tenderness, pain, and burning were also reduced. Patients who initiated famciclovir prior to viral shedding were more likely to not shed virus throughout. All doses were equally effective, safe, and well tolerated. CONCLUSIONS--Oral famciclovir reduced the onset and duration of viral shedding, lesion persistence, and uncomfortable symptoms. Several individual symptoms and lesion stages were also reduced in duration by this episodic therapy. Additionally, our twice-daily observation trial design proved to be a helpful tool for studying recurrent disease. Episodic oral famciclovir provides a convenient and effective alternative for those patients with recurrent genital herpes whose frequency rates do not require continuous antiviral suppression. ==================================================================== 29.) A review of famciclovir in the management of genital herpes. ==================================================================== Infect Dis Obstet Gynecol 1998;6(1):38-43 Faro S Department of Obstetrics and Gynecology, Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL 60612-3833, USA. The frequent occurrence of genital herpes continues to be a serious clinical problem. Although not life threatening, the physical symptoms of the disease, and the ensuing psychosocial complications, can be overwhelming to patients. The life cycle of the herpes simplex virus is complex, comprising multiple stages. Following infection, the virus establishes life-long latency in its host and can reactivate at any time as a recurrent infection. Successful management of genital herpes simplex infections involves patient education and psychological support, as well as antiviral agents. The antiviral agent famciclovir has been shown to shorten the course and decrease the severity of episodes of recurrent genital herpes. In addition, famciclovir has been shown to be effective in suppressing recurrent genital herpes. A review of the clinical experience with famciclovir in the treatment of genital herpes is presented. ==================================================================== 30.) Antivirals for the treatment of herpesvirus infections. ==================================================================== J Antimicrob Chemother 1993 Jul;32 Suppl A:121-32 De Clercq E Rega Institute for Medical Research, K.U. Leuven, Belgium. Agents available to treat herpesvirus infections include idoxuridine, trifluridine, vidarabine and acyclovir for the topical treatment of herpetic eye infections; vidarabine and acyclovir for the systemic (intravenous) treatment of herpes encephalitis; acyclovir for the topical and systemic (oral) treatment of genital herpes; acyclovir for the systemic (intravenous, oral) treatment of HSV or varicella-zoster (VZV) infections in immunosuppressed patients; brivudin for the systemic (oral) treatment of HSV-1 or VZV infections in immunosuppressed patients; and ganciclovir and foscarnet for the systemic (intravenous) treatment of cytomegalovirus (CMV) retinitis in AIDS patients. Brivudin is also effective in the treatment of herpetic eye infections that no longer respond to idoxuridine, trifluridine, vidarabine or acyclovir; and foscarnet is effective in the treatment of infections with acyclovir-resistant, thymidine kinase-deficient (TK-) HSV or VZV mutants. Other antiviral agents considered for use in herpesvirus infections include brovavir, penciclovir (and its prodrug famciclovir), desciclovir (a prodrug of acyclovir), bishydroxymethylcyclobutylguanine (BHCG) and, in particular, 1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC). The latter is more active than either acyclovir or ganciclovir in the chemotherapy and prophylaxis of various HSV-1, HSV-2, TK- HSV, VZV or CMV infections in animal models. ==================================================================== 31.) Pharmacology of new antiherpes agents: famciclovir and valacyclovir. ==================================================================== J Am Pharm Assoc (Wash) 1997 Mar-Apr;NS37(2):157-63 Stein GE Department of Medicine, Michigan State University, Lansing, USA. Limitations of acyclovir in treating infections caused by herpes simplex virus include the development of resistant isolates and relatively poor oral bioavailability. Penciclovir and famciclovir may have added clinical utility in the treatment of herpes virus infections in humans. Intracellular pharmacokinetics differ for valacyclovir and famciclovir, but the importance of these differences is unknown. Animal studies suggest that famciclovir (but not valacyclovir) can affect subsequent latent infection with HSV-1; the relevance of these findings to humans requires further investigation. Famciclovir and valacyclovir appear to decrease time to resolution of pain compared with acyclovir in patients with herpes zoster infections. ==================================================================== 32.) Economic evaluation of famciclovir in reducing the duration of postherpetic neuralgia. ==================================================================== Huse DM; Schainbaum S; Kirsch AJ; Tyring S Medical Research International, Burlington, MA 01803, USA. Am J Health Syst Pharm (UNITED STATES) May 15 1997 54 (10) p1180-4 ISSN: 1079-2082 Language: ENGLISH Document Type: CLINICAL TRIAL; JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL Journal Announcement: 9710 Subfile: INDEX MEDICUS The economic impact of famciclovir therapy for postherpetic neuralgia (PHN) in patients with acute herpes zoster was studied. A decision- analytic model of the treatment of herpes zoster and PHN was used to compare the cost of PHN between patients treated with oral famciclovir 500 mg three times daily for seven days and patients not receiving any antiviral therapy. The effects of famciclovir on PHN in the model were based on the results of a randomized, double-blind trial in 419 adult outpatients. The cost of the course of famciclovir therapy (21 tablets) was estimated as the sum of the drug's wholesale acquisition cost and the pharmacy dispensing cost. The cost of treating PHN (physician visits, medications, and miscellaneous nondrug therapy) was estimated by consulting a panel of physicians. According to the model, the cost of treating PHN was $85 lower per famciclovir recipient ($294 for famciclovir versus $379 for no antiviral therapy). The net cost of famciclovir therapy was $23 per patient ($108 for acquisition and dispensing minus the $85 savings). Among patients 50 years of age or older, famciclovir reduced the average cost of PHN by $155 ($414 for famciclovir versus $569 for no antiviral therapy) and yielded a net savings of $7 per patient. A model for the use of famciclovir to treat acute herpes zoster showed that the cost of such therapy was largely offset by savings in the cost of treating this complication. ==================================================================== 33.) Conversion of recurrent delta-positive hepatitis B infection to seronegativity with famciclovir after liver transplantation. ==================================================================== Klein M; Geoghegan J; Schmidt K; Bockler D; Korn K; Wittekind C; Scheele J Department of Surgery, Friedrich-Schiller University of Jena, Germany. Transplantation (UNITED STATES) Jul 15 1997 64 (1) p162-3 ISSN: 0041- 1337 BACKGROUND: Recurrent hepatitis B infection after liver transplantation is associated with poor graft and patient survival. Famciclovir is a nucleoside with virostatic action in hepatitis B infection. We report the case of a 51-year-old patient who developed recurrent delta-positive hepatitis B infection after liver transplantation. After famciclovir treatment, he became seronegative for hepatitis B early and hepatitis B surface antigens and developed protective anti-hepatitis B surface antibody titers. METHODS: After recurrent hepatitis B was confirmed, treatment with famciclovir was initiated. RESULTS: Eighteen days after starting famciclovir, the patient became seronegative for hepatitis B early antigen and delta antigen, and hepatitis B virus DNA was no longer detectable in serum. Three months later, the patient became hepatitis B surface antigen negative and remains well 16 months later with increasing anti-hepatitis B surface levels. CONCLUSIONS: Antiviral treatment with famciclovir may be useful in treatment of delta-positive hepatitis B infection following liver transplantation. Further evaluation of famciclovir in treatment and prevention of hepatitis B in these patients is warranted. ==================================================================== 34.) Treatment of hepatitis B-related polyarteritis nodosa with famciclovir and interferon alfa-2b. ==================================================================== Kruger M; Boker KH; Zeidler H; Manns MP Department of Gastroenterology and Hepatology, Medizinische Hochschule Hannover, Germany. J Hepatol (DENMARK) Apr 1997 26 (4) p935-9 ISSN: 0168-8278 Document Type: JOURNAL ARTICLE Journal Announcement: 9710 Subfile: INDEX MEDICUS BACKGROUND: The association between polyarteritis nodosa and viral hepatitis B infection is well established and still remains a therapeutic challenge. Famciclovir--a new nucleoside analog--has a broad spectrum of antiviral activity against herpes viruses and the human hepatitis B virus. CASE REPORT: A 56-year-old man with hepatitis B-related polyarteritis nodosa presented with symptoms correlating to high levels of HBV DNA. The patient did not respond to treatment with steroids (prednisolone started with 100 mg daily) and two courses of interferon alfa-2b (5 x 10(6) units 3 times per week for 6 months). Therefore, a combination therapy of interferon alfa-2b (5 x 10(6) units 3 times per week) and famciclovir (500 mg tid, orally) was started; 5 mg daily prednisolone was given at this time. Under this regimen HBV DNA rapidly declined, with a reduction of 79% after the first week (HBV DNA 53 pg/ml), and 88% after the second week (29 pg/ml), accompanied by a significant improvement in clinical symptoms. After 1 year of famciclovir treatment, HBeAg-anti-HBe seroconversion was noted; HBsAg still remained positive. Long-term famciclovir therapy has been continued at a reduced dose of 125 mg tid for 3 years now. HBV DNA values have been stable below 100 pg/ml, transaminases have normalized and clinical symptoms of polyarteritis nodosa have disappeared. CONCLUSIONS: Famciclovir has been successfully administered to a patient with hepatitis B-related polyarteritis nodosa. A reduction in viral replication and an improvement of symptoms were noted within 4 weeks of starting famciclovir. The oral nucleoside analog famciclovir is effective and well tolerated, even in long-term therapy, and might offer new treatment options in immunosuppressed patients for whom hepatitis B replication is critical for the disease process. ==================================================================== 35.) Famciclovir for the treatment of acute retinal necrosis (ARN) syndrome. ==================================================================== Figueroa MS; Garabito I; Gutierrez C; Fortun J Department of Ophthalmology, Ramon y Cajal University Hospital, Madrid, Spain. Am J Ophthalmol (UNITED STATES) Feb 1997 123 (2) p255-7 ISSN: 0002- 9394 Language: ENGLISH Document Type: JOURNAL ARTICLE Journal Announcement: 9709 Subfile: AIM; INDEX MEDICUS PURPOSE: To document a case of acute retinal necrosis syndrome in an immunocompetent patient who was successfully treated with famciclovir after unsuccessful treatment with acyclovir. METHODS: After diagnosing acute retinal necrosis syndrome in the patient's left eye, we treated him with 13 mg/kg/24 hours of intravenous acyclovir in three daily doses for 14 days, followed by 800 mg of acyclovir five times per day orally. New areas of retinitis developed within the posterior pole despite treatment with the maximum dosage of acyclovir; thus, we used a new antiviral agent, famciclovir. RESULTS: When we administered 500 mg of famciclovir orally every 8 hours for 3 months, the retinitis regressed within 1 month, leaving atrophic granular pigmented scars. CONCLUSION: Famciclovir can effectively treat acute retinal necrosis syndrome in immunocompetent patients. ==================================================================== 36.) Pretransplant famciclovir as prophylaxis for hepatitis B virus recurrence after liver transplantation. ==================================================================== Singh N; Gayowski T; Wannstedt CF; Wagener MM; Marino IR Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Veterans Affairs Medical Center, Pennsylvania 15240, USA. Transplantation (UNITED STATES) May 27 1997 63 (10) p1415-9 ISSN: Language: ENGLISH Document Type: JOURNAL ARTICLE Journal Announcement: 9708 Subfile: INDEX MEDICUS Liver transplantation in patients with detectable hepatitis B virus (HBV) DNA is associated with a high rate of HBV recurrence and detectable HBV DNA is often considered a contraindication for liver transplantation. Famciclovir, an oral form of the purine nucleoside penciclovir, has been shown to inhibit HBV replication. This pilot study was conducted to determine whether a 6-month course of famciclovir, administered before transplantation, was effective in inhibiting HBV replication in patients with end-stage liver disease caused by HBV and detectable HBV DNA and to assess the posttransplant clinical and virologic outcome of patients becoming HBV DNA negative with famciclovir prior to transplantation. All eight patients enrolled were hepatitis B surface antigen (HBsAg) positive; their HBV DNA levels at baseline ranged from 4.3 to 25,321 pg/ml (mean 3,661 pg/ml). Six of the eight patients were also seropositive for HBeAg. An initial decline in HBV DNA titers occurred in all patients; however, only 25% (two of eight) of the patients became HBV DNA negative before transplantation and underwent liver transplantation. Seroconversion to hepatitis B surface antibody (HBsAb) (and HBeAb in HBeAg-positive patient) was demonstrated at the conclusion of famciclovir in the transplanted patients. Both patients remain HBV DNA negative at nearly 2 years of follow-up after transplantation. HBV DNA remained detectable in 63% (five of eight) of the patients. The mean HBV DNA level for patients who became HBV DNA negative was 5.1 pg/ml versus 424 pg/ml in nonresponders. Adverse effects attributable to famciclovir were not observed in any of the patients. Future studies should assess the predictors of response to famciclovir so that patients likely to achieve good virologic outcome can be targeted for such a therapy. ==================================================================== 37.) Famciclovir therapy for recurrent hepatitis B virus infection after liver transplantation. ==================================================================== Haller GW; Bechstein WO; Neuhaus R; Raakow R; Berg T; Hopf U; Neuhaus P Department of Surgery, Virchow Clinic, Humboldt University of Berlin, Germany. Transpl Int (GERMANY) 1996 9 Suppl 1 pS210-2 ISSN: 0934-0874 Language: ENGLISH Document Type: JOURNAL ARTICLE Journal Announcement: 9705 Subfile: INDEX MEDICUS Between November 1993 and June 1995 18 patients received oral famciclovir (3 x 500 mg) for treatment of hepatitis B virus (HBV) reinfection after liver transplantation. Reinfection was defined as the reoccurrence of HBsAg in the serum. In the first 15 patients, famciclovir therapy was initiated after clinical signs of graft hepatitis, whereas the last 3 patients received treatment immediately after HBV-DNA was detected. Famciclovir was well-tolerated in all patients. HBV-DNA values were decreased to undetectable levels in 8 out of 18 patients. Clinical status improved in 7 patients, whereas 5 patients remained unchanged and 6 patients progressed to deteriorating graft function and death. When famciclovir was initiated early after reinfection, a response rate of approximately 66% was observed. Late onset of therapy in patients with fulminant hepatitis generally failed to provide any clinical benefit. ==================================================================== 38.) Penciclovir cream for the treatment of herpes simplex labialis. A randomized, multicenter, double-blind, placebo-controlled trial. Topical Penciclovir Collaborative Study Group. ==================================================================== Spruance SL; Rea TL; Thoming C; Tucker R; Saltzman R; Boon R Division of Infectious Diseases, University of Utah, Salt Lake City, USA. JAMA (UNITED STATES) May 7 1997 277 (17) p1374-9 ISSN: 0098-7484 Language: ENGLISH Document Type: CLINICAL TRIAL; JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL Journal Announcement: 9707 Subfile: AIM; INDEX MEDICUS OBJECTIVE: To compare the safety and efficacy of topical 1% penciclovir cream with vehicle control cream (placebo) for the treatment of a recurrent episode of herpes simplex labialis (cold sores) in immunocompetent patients. DESIGN: Randomized, double-blind, placebo-controlled, patient-initiated, 2-armed, parallel clinical trial. Patients were prospectively dispensed study medication, and treatment was self- initiated by the patient within 1 hour of the first sign or symptom of a recurrence. SETTING: A total of 31 ambulatory clinics in the United States in a variety of settings, including private practices, public health facilities, and universities. PATIENTS: Otherwise healthy individuals with a history of frequent episodes of herpes simplex labialis. A total of 2209 patients were enrolled and given study medication, and 1573 initiated treatment for a recurrence. INTERVENTIONS: Topical 1% penciclovir cream or vehicle control cream. Subjects applied treatment every 2 hours while awake for 4 consecutive days. MAIN OUTCOME MEASURES: Lesion healing was the primary efficacy variable. Secondary end points included time to loss of lesion pain and time to cessation of viral shedding. RESULTS: Healing of classical lesions (vesicles, ulcers, and/or crusts) was 0.7 day faster for penciclovir-treated patients compared with those who received vehicle control cream (median, 4.8 days vs 5.5 days; hazard ratio [HR], 1.33; 95% confidence interval [CI], 1.18-1.49; P<.001). Pain (median, 3.5 days vs 4.1 days; HR, 1.22; 95% CI, 1.09-1.36; P<.001) and lesion virus shedding (median, 3 days vs 3 days; HR, 1.35; 95% CI, 1.10-1.64; P=.003) also resolved more quickly for penciclovir-treated patients compared with patients who applied the vehicle control. The efficacy of penciclovir cream was apparent when therapy was initiated early (prodrome or erythema lesion stage) and when initiated late (papule or vesicle stage). The incidence of adverse events was comparable between penciclovir and placebo groups. CONCLUSIONS: Penciclovir cream is the first treatment to clearly demonstrate an impact on the course of recurrent herpes labialis in immunocompetent patients. Efficacy was seen in all clinical and laboratory measures of the disease (lesion healing, pain resolution, and cessation of viral shedding). Faster healing and pain resolution occurred both among patients who first applied penciclovir cream in the prodrome and erythema stages and among those who started treatment in the papule and vesicle lesion stages. ==================================================================== 39.) FAMICLOVIR (Systemic), The product ==================================================================== VA CLASSIFICATION (Primary/Secondary)¾AM800 Commonly used brand name(s): Famvir. Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s). bNot commercially available in Canada. Category Antiviral (systemic). Indications Accepted Herpes zoster (treatment)¾Famciclovir is indicated in the treatment of herpes zoster infections (shingles) caused by varicella-zoster virus (VZV).1 Famciclovir has been found to decrease the duration of post-herpetic neuralgia (defined as pain at or following healing) when compared to placebo (55 to 62 days versus 128 days, respectively). Famciclovir has also been found to be equivalent to acyclovir in decreasing the duration of acute pain.9Therapy is most effective when started within 48 hours of the onset of rash.1 Famciclovir has been studied only in healthy adults. There are no data on its safety and efficacy in children or in immunocompromised persons, or on its efficacy in the treatment of ophthalmic zoster or disseminated zoster.1 Pharmacology/Pharmacokinetics Physicochemical characteristics: Molecular weight¾ 321.31 Mechanism of action/Effect: Famciclovir is a pro-drug; it is the diacetyl 6-deoxy analog of the active antiviral compound, penciclovir. Penciclovir is phosphorylated by viral thymidine kinase to penciclovir monophosphate, which is then converted to penciclovir triphosphate by cellular kinases. Penciclovir inhibits herpes viral DNA synthesis, and, therefore, replication. Penciclovir does not inhibit DNA synthesis in uninfected cells because it is phosphorylated only in herpes-infected cells.1 Penciclovir has antiviral activity against herpes simplex virus type 1 (HSV-1), HSV-2, varicella-zoster virus (VZV), and Epstein-Barr virus.1,9 In vitro studies have shown that penciclovir triphosphate has greater intracellular stability in HSV-2-infected cells than does acyclovir triphosphate.2 Also, unlike acyclovir, the antiviral activity of penciclovir persists in the absence of extracellular drug.7,10 Absorption: Famciclovir is absorbed in the upper intestine and rapidly converted in the intestinal wall to the active compound, penciclovir.9 The bioavailability of peniciclovir after oral administration of famciclovir is approximately 77%.1,9 Famciclovir may be taken without regard to meals; although a decrease in the time to peak serum concentration and peak serum concentration of penciclovir was seen when famciclovir was taken with food or after a meal, there was no decrease in the extent of systemic availability.1,3 Distribution: The steady-state volume of distribution of penciclovir is approximately 1 liter per kilogram (L/kg).1 Protein binding: Low (20 to 25%).1,7 Biotransformation: Famciclovir is deacetylated, and then oxidized to form the active agent, penciclovir.1,10 Little or no famciclovir is detected in the plasma or urine. Inactive metabolites include 6-deoxy penciclovir, monoacetylated penciclovir, and monoacetylated 6-deoxypenciclovir, all of which account for < 1.5% of the dose.1,7 Half-life: Normal renal function¾ 2.1 to 3 hours.1,3,4,5,6,11 Severe renal failure (creatinine clearance < 30 mL/min [0.33 mL/sec])¾ 10 to 13 hours.1,7 Intracellular half-life of penciclovir triphosphate¾ In HSV-1-infected cells¾Approximately 10 hours.1 In HSV-2-infected cells¾Approximately 20 hours.1,8 In VZV-infected cells¾Approximately 7 hours.1,8 Time to peak plasma concentration 0.7 to 0.9 hours.1,3,4,5,6,11 Peak plasma concentration 3.3 to 4.2 mcg/mL [10.3 to 13.1 micromoles/L] after a single oral dose (fasting) of 500 mg.1,3,5,6,11 Elimination: Renal (glomerular filtration and tubular secretion)2; 60 to 65% of an oral dose is recovered as penciclovir in the urine3,4,5,6,11; 27% in the feces over 72 hours.1 In dialysis¾It is not known if hemodialysis removes penciclovir from the blood.1 Precautions to Consider Carcinogenicity Dietary carcinogenicity studies of famciclovir were conducted in rats and mice at the doses listed below for approximately 1.5 years. A significant increase in the incidence of mammary adenocarcinoma was seen in female rats receiving 600 mg per kg (mg/kg) per day (1.5 times the human systemic exposure at 500 mg three times a day, based on the area under the plasma-concentration-time curve [AUC] for penciclovir). Marginal increases in the incidence of subcutaneous tissue fibrosarcomas or squamous cell carcinomas of the skin were seen in female rats and male mice dosed at 600 mg/kg per day (0.4 times the human exposure, based on AUC for penciclovir). There was no increase in tumor incidence reported in male rats treated with doses of up to 240 mg/kg per day (0.9 times the human AUC), or in female mice treated with doses of up to 600 mg/kg per day (0.4 times the human AUC).1 Mutagenicity Famciclovir and penciclovir were negative in in vitro tests for gene mutations in bacteria (S. typhimurium and E. coli) and unscheduled DNA synthesis in mammalian HeLa 83 cells. Famciclovir was also negative in the L5178Y mouse lymphoma assay, the in vivo mouse micronucleus test, and rat dominant lethal study. Famciclovir induced increases in polyploidy in human lymphocytes in vitroin the absence of chromosomal damage. Penciclovir was positive in the L5178Y mouse lymphoma assay for gene mutation/chromosomal aberrations, with and without metabolic activation. In human lymphocytes, penciclovir caused chromosomal aberrations in the absence of metabolic activation. Penciclovir caused an increased incidence of micronuclei in mouse bone marrow in vivo when administered intravenously at doses highly toxic to bone marrow, but not when administered orally.1 Pregnancy/Reproduction Fertility¾Testicular toxicity was observed in rats, mice, and dogs following repeated administration of famciclovir or penciclovir. Testicular changes included atrophy of the seminiferous tubules, reduction in sperm count, and/or increased incidence of sperm with abnormal morphology or reduced motility. The degree of toxicity was related to dose and duration of exposure. In male rats, decreased fertility was observed after 10 weeks of dosing at 500 mg/kg per day (1.9 times the human AUC). Testicular toxicity was observed following chronic administration to mice (104 weeks) and dogs (26 weeks) at doses of 600 mg/kg per day (0.4 times the human AUC) and 150 mg/kg per day (107 times the human AUC), respectively.1 Famciclovir had no effect on general reproductive performance or fertility in female rats at doses up to 1000 mg/kg per day (3.6 times the human AUC).1 Pregnancy¾No adequate and well-controlled studies have been done in pregnant women.1 No adverse effects were observed on embryo-fetal development in rats and rabbits given oral famciclovir at doses up to 1000 mg/kg per day (approximately 3.6 and 1.8 times the human exposure based on AUC, respectively), and intravenous doses of 360 mg/kg per day in rats (2 times the human exposure based on body surface area [BSA]) and 120 mg/kg per day in rabbits (1.5 times the human exposure based on BSA). Also, no adverse effects were observed after intravenous administration of penciclovir to rats given 80 mg/kg per day (0.4 times the human exposure based on BSA), and rabbits given 60 mg/kg per day (0.7 times the human exposure based on BSA).1 FDA Pregnancy Category B. Breast-feeding Following oral administration of famciclovir, it is not known whether penciclovir is distributed into human breast milk. However, it has been found to pass into the milk of lactating rats at concentrations higher than those seen in the plasma.1 Also, because of the tumorigenicity seen in rats, it is recommended that either breast-feeding or administration of famciclovir to the mother be discontinued.1 Pediatrics Safety and efficacy have not been established in children up to 18 years of age.1 Geriatrics Studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of famciclovir in the elderly. However, elderly patients are more likely to have an age-related decrease in renal function, which may require an adjustment of famciclovir dosage or dosing interval.1,4 Drug interactions and/or related problems The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)¾not necessarily inclusive (>> = major clinical significance): Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication. Probenecid1¾(probenecid may compete with penciclovir for active tubular secretion, resulting in increased plasma concentrations of penciclovir) Medical considerations/Contraindications The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)¾not necessarily inclusive (>> = major clinical significance). Risk-benefit should be considered when the following medical problem exists >> Renal function impairment1¾(because penciclovir is renally excreted, patients with renal function impairment may be at increased risk of toxicity; patients with a creatinine clearance of < 60 mL/min [1 mL/sec] require a reduction in dose) Side/Adverse Effects Note: No serious side effects have been noted to date with the adminstration of famciclovir.1 Those indicating need for medical attention only if they continue or are bothersome Incidence more frequent1 Headache Incidence less frequent1 Dizziness; fatigue (unusual tiredness or weakness); gastrointestinal disturbances (diarrhea; nausea; vomiting) Patient Consultation As an aid to patient consultation, refer to Advice for the Patient, Famciclovir (Systemic). In providing consultation, consider emphasizing the following selected information (>> = major clinical significance): Before using this medication >> Conditions affecting use, especially: Breast-feeding¾Because of the potential for tumorigenicity seen in rats, it is recommended that either breast-feeding or famciclovir be discontinued Use in children¾Safety and efficacy have not been established in children up to 18 years of age Other medical problems, especially renal function impairment Proper use of this medication Initiating use of famciclovir at the earliest sign or symptom; it is most effective when started within 48 hours of the onset of rash Famciclovir may be taken with meals >> Compliance with full course of therapy; not using more often or for longer than prescribed >> Proper dosingMissed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses >> Proper storage Precautions while using this medication Checking with physician if no improvement within a few days Keeping affected areas as clean and dry as possible; wearing loose-fitting clothing to avoid irritation of lesions General Dosing Information Therapy should be initiated as soon as possible following the onset of signs and symptoms of varicella-zoster infection. Treatment was started within 72 hours of the onset of rash in clinical studies; however, famciclovir was found to be more useful if started within 48 hours.1 In clinical trials, the effect of famciclovir on the resolution of rash was most pronounced in patients over 50 years of age.1 Famciclovir tablets may be taken with meals since absorption has not been shown to be significantly affected by food.1 Adults with impaired renal function may require a change in dosing, as follows1: Creatinine Clearance Recommended dose (mL/min)/(mL/sec) ³60/1.0 500 mg every 8 hours 40-59/0.67-0.98 500 mg every 12 hours 20-39/0.33-0.65 500 mg every 24 hours There are not enough data to recommend a dosage for patients with a creatinine clearance of less than 20 mL/min (0.33 mL/sec).1 Oral Dosage Forms FAMCICLOVIR TABLETS Usual adult dose Antiviral¾ Oral, 500 mg every eight hours for seven days.1 Usual pediatric dose Safety and efficacy have not been established for patients less than 18 years of age.1 Strength(s) usually available U.S.¾ 500 mg (Rx)[Famvir]. Canada¾ Not commercially available. Packaging and storage: Store between 15 and 25 °C (59 and 77 °F), in a tight container, unless otherwise specified by manufacturer. Auxiliary labeling: · Continue medicine for full time of treatment. =================================================================== DATA-MEDICOS/DERMAGIC-EXPRESS No (71) 01/09/99 DR. JOSE LAPENTA R. ===================================================================
Produced by Dr. Jose Lapenta R. Dermatologist Maracay Estado Aragua Venezuela 1.999 Telf: 0416-6401045- 02432327287-02432328571