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REFERENCIAS BIBLIOGRÁFICAS / BIBLIOGRAPHICAL REFERENCES

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VALACICLOVIR 

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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 

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FAMCICLOVIR 

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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 

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VALACICLOVIR 

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1.) Valaciclovir. A review of its antiviral activity, pharmacokinetic  properties and therapeutic efficacy in herpesvirus infections. 

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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. 

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2.) Valaciclovir versus aciclovir in patient initiated treatment of  recurrent genital herpes: a randomised, double blind clinical trial.  International Valaciclovir HSV Study Group. 

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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. 

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3.) Valaciclovir for the suppression of recurrent genital herpes simplex  virus infection: a large-scale dose range-finding study. 

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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. 

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4.) A large-scale, placebo-controlled, dose-ranging trial of peroral  valaciclovir for episodic treatment of recurrent herpes genitalis.  Valaciclovir HSV Study Group. 

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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. 

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5.) Valaciclovir for the suppression of recurrent genital HSV infection: a  placebo controlled study of once daily therapy. International Valaciclovir  HSV Study Group. 

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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. 

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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. 

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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. 

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7.) Management of genital herpes. 

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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. 

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8.) Valaciclovir compared with acyclovir for improved therapy for herpes  zoster in immunocompetent adults. 

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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. 

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9.) Valacyclovir. New indication: for genital herpes, simpler administration. 

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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. 

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10.) Valacyclovir. 

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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. 

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11.) Antiviral therapy of acute herpes zoster in older patients. 

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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. 

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12.) A randomized, placebo-controlled comparison of oval valacyclovir and  acyclovir in immunocompetent patients with recurrent genital herpes  infections. The Valaciclovir International Study Group. 

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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. Tyring@flash.net 

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. 

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13.) Comparison of valaciclovir and acyclovir for the treatment of herpes  zoster in immunocompetent patients over 50 years of age: a cost-consequence  model. 

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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. 

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14.) Valacyclovir: a review of its antiviral activity, pharmacokinetic  properties, and clinical efficacy. 

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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. 

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15.) Lessons from the natural history of cytomegalovirus. 

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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) 

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16.) VALACYCLOVIR (Systemic), The product 

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INN: Valaciclovir2 

VA CLASSIFICATION (Primary/Secondary);AM800 

Commonly used brand name(s): 

Valtrex. 

Note: For a listing of dosage forms and brand names by country 

availability, see Dosage Forms section(s). 

Not commercially available in Canada. 

Category 

Antiviral (systemic). 

Indications 

Accepted 

Herpes zoster (treatment);Valacyclovir 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: 

Source;Valacyclovir is the hydrochloride salt of the L-valyl ester of  acyclovir1,8. 

Molecular weight; 

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: 

Valacyclovir;Low (13 to 18%).1 

Acyclovir;Low (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: 

Valacyclovir; 

Less than 30 minutes.8 

Acyclovir; 

After administration of valacyclovir: Normal renal function;2.5 to 3.3 hours.1,8,9 

End-stage renal disease;Approximately 14 hours.1 

Geriatric patients (65 to 83 years of age);3.3 to 3.7 hours.10 

Time to peak concentration: 

1.6 to 2.1 hours.7,8,9,10 

Peak plasma concentrations 

Valacyclovir; 

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 

Acyclovir; 

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: 

Valacyclovir; 

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. 

Acyclovir; 

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: 

Hemodialysis;During 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 dialysis;Chronic 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 

Fertility;Valacyclovir did not impair fertility in rats given a dose of 200  mg/kg per day (6 times human plasma levels).1 

Pregnancy;Acyclovir 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);not 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 

Probenecid1,11;(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);not 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 transplantation1;(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 impairment1;(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 acyclovir1; 

>> Renal function impairment1;(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);not 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) 

sup3;50/0.83 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 

Antiviral; 

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.; 

500 mg (base) (Rx)[Valtrex]. 

Canada; 

Not commercially available. 

Packaging and storage: 

Store between 15 and 25 deg;C (59 and 77; deg;F), in a tight container. Protect  from light.1,6 

Auxiliary labeling: 

middot; Continue medicine for full time of treatment. 

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FAMCICLOVIR 

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17.) Famciclovir. A review of its pharmacological properties and  therapeutic efficacy in herpesvirus infections. 

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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. 

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18.) Famciclovir: review of clinical efficacy and safety. 

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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. 

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19.) Efficacy of famciclovir in the treatment of herpes zoster. 

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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. 

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20.) Safety of famciclovir in patients with herpes zoster and genital herpes. 

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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. 

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21.) Famciclovir for treatment of herpesvirus infections. 

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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. 

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22.) The pharmacological profile of famciclovir. 

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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. 

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23.) Advances in the treatment of herpesvirus infection: the role of  famciclovir. 

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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. 

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24.) Genital herpes simplex virus and its treatment: focus on famciclovir. 

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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. 

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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. 

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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. gmertz@medusa.unm.edu 

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. 

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26.) Oral famciclovir for the suppression of recurrent genital herpes: a  randomized controlled trial. Collaborative Famciclovir Genital Herpes  Research Group. 

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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. diaz@cheo.on.ca 

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. 

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27.) Famciclovir: a new systemic antiviral agent for herpesvirus infections. 

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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. 

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28.) Patient-initiated, twice-daily oral famciclovir for early recurrent  genital herpes. A randomized, double-blind multicenter trial. Canadian  Famciclovir Study Group. 

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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. 

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29.) A review of famciclovir in the management of genital herpes. 

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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. 

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30.) Antivirals for the treatment of herpesvirus infections. 

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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. 

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31.) Pharmacology of new antiherpes agents: famciclovir and valacyclovir. 

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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. 

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32.) Economic evaluation of famciclovir in reducing the duration of  postherpetic neuralgia. 

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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. 

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33.) Conversion of recurrent delta-positive hepatitis B infection to  seronegativity with famciclovir after liver transplantation. 

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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. 

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34.) Treatment of hepatitis B-related polyarteritis nodosa with famciclovir  and interferon alfa-2b. 

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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. 

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35.) Famciclovir for the treatment of acute retinal necrosis (ARN) syndrome. 

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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. 

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36.) Pretransplant famciclovir as prophylaxis for hepatitis B virus  recurrence after liver transplantation. 

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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. 

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37.) Famciclovir therapy for recurrent hepatitis B virus infection after  liver transplantation. 

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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. 

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38.) Penciclovir cream for the treatment of herpes simplex labialis. A randomized,  multicenter, double-blind, placebo-controlled trial. Topical Penciclovir  Collaborative Study Group. 

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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. 

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39.) FAMICLOVIR (Systemic), The product 

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VA CLASSIFICATION (Primary/Secondary);AM800 

Commonly used brand name(s): 

Famvir. 

Note: For a listing of dosage forms and brand names by country  availability, see Dosage Forms section(s). 

Not commercially available in Canada. 

Category 

Antiviral (systemic). 

Indications 

Accepted 

Herpes zoster (treatment);Famciclovir 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 weight; 

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 function; 

2.1 to 3 hours.1,3,4,5,6,11 

Severe renal failure (creatinine clearance < 30 mL/min [0.33 mL/sec]);  10 to 13 hours.1,7 

Intracellular half-life of penciclovir triphosphate;  In HSV-1-infected cells;Approximately 10 hours.1 

In HSV-2-infected cells;Approximately 20 hours.1,8 

In VZV-infected cells;Approximately 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 dialysis;It 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 

Fertility;Testicular 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 

Pregnancy;No 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);not necessarily inclusive (>> = major  clinical significance): 

Note: Combinations containing any of the following medications, depending  on the amount present, may also interact with this medication. 

Probenecid1;(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);not necessarily inclusive (>> = major  clinical significance). 

Risk-benefit should be considered when the following medical problem exists 

>> Renal function impairment1;(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-feeding;Because of the potential for tumorigenicity seen in rats, it  is recommended that either breast-feeding or famciclovir be discontinued 

Use in children;Safety 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) 

sup3;60/1.0 500 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 

Antiviral; 

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.; 

500 mg (Rx)[Famvir]. 

Canada; 

Not commercially available. 

Packaging and storage: 

Store between 15 and 25 &deg;C (59 and 77 &deg;F), in a tight container, unless  otherwise specified by manufacturer. 

Auxiliary labeling: 

middot; Continue medicine for full time of treatment. 

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DATA-MÉDICOS/DERMAGIC-EXPRESS No (68) 01/09/99 DR. JOSÉ LAPENTA R. 

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Produced by Dr. José Lapenta R. Dermatologist

Venezuela 1.998-2.025

Producido por Dr. José Lapenta R. Dermatólogo Venezuela 1.998-2.025

Tlf: 0414-2976087 - 04127766810