Review of antiviral therapy for herpes labialis,genital herpes and herpes zoster

Acyclovir (Zovirax^®) was approved for the treatment of herpesvirus infections almost two decades ago. It was the first agent in a novel group of antiviral medications that now include valacyclovir (Valtrex^®), penciclovir (Denavir^®) and famciclovir (Famvir^®). These agents have made a dramatic impact on the morbidity associated with herpes simplex virus infections and herpes zoster. Topical and oral antiviral use have shown modest but statistically significant efficacy in treating herpes labialis with most studies demonstrating a significant reduction in episode length and/or healing time. Oral acyclovir, valacyclovir and famciclovir are efficacious and safe for the treatment of the first episode and recurrent genital herpes and are useful as suppressive therapy for individuals with frequent genital herpes recurrences. In addition, high doses of oral acyclovir, valacyclovir and famciclovir have been shown to speed the healing of herpes zoster, and data suggests that these agents also decrease associated acute and chronic pain in people of 50 years of age or older. Further research is required to clarify the safety of these agents in pregnant women with genital herpes, the role of antiviral therapy in decreasing the sexual transmission of genital herpes, and the efficacy and cost-effectiveness of these agents in treating herpes zoster in people below the age of 50 years.     

Valacyclovir for the treatment of genital herpes

Genital herpes is the most prevalent sexually transmitted infection in the USA. While sometimes mild in severity, it can be a distressing and painful chronic condition. Likewise, herpes labialis and herpes zoster can be both physically and psychologically painful. While there is no cure for these conditions, treatment to alleviate symptoms, suppress recurrences and reduce transmission has been drastically improved over the past 20 years with the use of guanine nucleoside antivirals, such as valacyclovir hydrochloride (Valtrex), GlaxoSmithKline) the highly bioavailable prodrug of acyclovir (Zovirax((R)), GlaxoSmithKline), and famciclovir (Famvir, Novartis), a highly bioavailable prodrug of penciclovir (Denavir, Novartis). Clinical trials involving approximately 10,000 patients (including patients from nongenital herpes studies, such as herpes zoster) have assessed the safety and efficacy of valacyclovir in the treatment of initial genital herpes outbreaks, episodic treatment of recurrent episodes and daily suppressive therapy. It was shown that valacyclovir has similar efficacy to acyclovir in the episodic and suppressive treatment of genital herpes. Valacyclovir is the only antiviral drug approved for a once-daily dose of suppressive therapy for genital herpes, as well as the only antiviral drug US FDA approved for a 3-day regimen of episodic treatment of recurrent genital herpes. In addition, valacyclovir is also indicated in the reduction of the sexual transmission of herpes simplex virus infection and for the treatment of herpes labialis. In herpes zoster, valacyclovir is more effective than acyclovir or placebo (and as equally effective as famciclovir) in shortening the length and severity of herpes zoster-associated pain and postherpetic neuralgia. Valacyclovir has an acceptable safety profile in patients with herpes simplex and herpes zoster. The less frequent dosing regimen makes it an attractive option in the treatment of genital herpes and other viral infections, and may contribute to increased patient adherence to therapy.     

Treatment of common cutaneous herpes simplex virus infections

Herpes simplex virus infection is increasingly common in the United States. New antiviral medications have expanded treatment options for the two most common cutaneous manifestations, orolabial and genital herpes. Acyclovir therapy remains an effective and often less expensive option. Famciclovir and valacyclovir offer improved oral bioavailability and convenient oral dosing schedules but are more expensive than acyclovir. Patients who have six or more recurrences of genital herpes per year can be treated with one of the following regimens: acyclovir, 400 mg twice daily; valacyclovir, 1 g daily; or famciclovir, 250 mg twice daily. These regimens are effective in suppressing 70 to 80 percent of symptomatic recurrences. Episodic treatment of recurrent genital herpes is of questionable benefit, but it may be helpful in appropriately selected patients. There is little evidence indicating benefit from treatment of recurrent orolabial herpes, which tends to be mild and infrequent.     

Nongenital herpes simplex virus

Nongenital herpes simplex virus type 1 is a common infection usually transmitted during childhood via nonsexual contact. Most of these infections involve the oral mucosa or lips (herpes labialis). The diagnosis of an infection with herpes simplex virus type 1 is usually made by the appearance of the lesions (grouped vesicles or ulcers on an erythematous base) and patient history. However, if uncertain, the diagnosis of herpes labialis can be made by viral culture, polymerase chain reaction, serology, direct fluorescent antibody testing, or Tzanck test. Other nonoral herpes simplex virus type 1 infections include herpetic keratitis, herpetic whitlow, herpes gladiatorum, and herpetic sycosis of the beard area. The differential diagnosis of nongenital herpes simplex virus infection includes aphthous ulcers, acute paronychia, varicella-zoster virus infection, herpangina, herpes gestationis (pemphigoid gestationis), pemphigus vulgaris, and Beh?et syndrome. Oral acyclovir suspension is an effective treatment for children with primary herpetic gingivostomatitis. Oral acyclovir, valacyclovir, and famciclovir are effective in treating acute recurrence of herpes labialis (cold sores). Recurrences of herpes labialis may be diminished with daily oral acyclovir or valacyclovir. Topical acyclovir, penciclovir, and docosanol are optional treatments for recurrent herpes labialis, but they are less effective than oral treatment.     

Herpes zoster: medical and nursing management

Herpes zoster, the latent descendent of the varicella zoster virus, commonly is seen in clinical practice. Healthcare providers must recognize and treat the virus to decrease the incidence of postherpetic neuralgic pain syndrome. Treatment with an antiviral medication regimen should be initiated rapidly for patients who have had lesions for up to 72 hours. Acyclovir has been the treatment of choice for herpes zoster in the past, but newer drugs, such as valacyclovir, a prodrug of acyclovir, and famciclovir, are as effective for treating the virus and have more convenient dosing regimens and decreased incidence of postherpetic neuralgia.     

Safety of antiviral medication for the treatment of herpes during pregnancy

Question One of my patients is a pregnant woman in her first trimester with a history of recurrent genital herpes. She is concerned about whether use of her antiviral medication will adversely affect her baby. What should I tell her?Answer Studies have shown that the use of acyclovir or valacyclovir is not associated with an increase in birth defects. Limited data exist for famciclovir and therefore it would not be considered a first-line choice for treatment of herpes during pregnancy.     

Drug treatment of common STDs: part I. Herpes, syphilis, urethritis, chlamydia and gonorrhea.

In 1998, the Centers for Disease Control and Prevention released guidelines for the treatment of sexually transmitted diseases. Several treatment advances have been made since the previous guidelines were published. Part I of this two-part article describes current recommendations for the treatment of genital ulcer diseases, urethritis and cervicitis. Treatment advances include effective single-dose regimens for many sexually transmitted diseases and improved therapies for herpes infections. Two single-dose regimens, 1 g of oral azithromycin and 250 mg of intramuscular ceftriaxone, are effective for the treatment of chancroid. A three-day course of 500 mg of oral ciprofloxacin twice daily may be used to treat chancroid in patients who are not pregnant. Parenteral penicillin continues to be the drug of choice for treatment of all stages of syphilis. Three antiviral medications have been shown to provide clinical benefit in the treatment of genital herpes: acyclovir, valacyclovir and famciclovir. Valacyclovir and famciclovir are not yet recommended for use during pregnancy. Azithromycin in a single oral 1-g dose is now a recommended regimen for the treatment of nongonococcal urethritis.     

Short-course oral antiviral treatment for recurrent genital herpes

OBJECTIVE: To evaluate the literature regarding short-course oral therapy for recurrent genital herpes.DATA SOURCES: Literature was accessed through MEDLINE (1966-March 2003), IOWA Drug Information Service (1966-March 2003), and International Pharmaceutical Abstracts (1966-March 2003).DATA SYNTHESIS: Data are available describing short-course (2 or 3 d) therapy with acyclovir and valacyclovir. Short-course acyclovir therapy was superior to placebo. Three- and 5-day regimens of valacyclovir were equivalent. Early initiation of therapy may be more important than duration of therapy.CONCLUSIONS: More head-to-head studies are needed to determine the most efficacious and cost-effective short-course regimens for recurrent genital herpes.     

Herpes zoster and postherpetic neuralgia: prevention and management

Herpes zoster (shingles) is diagnosed clinically by recognition of the distinctive, painful vesicular rash appearing in a unilateral, dermatomal distribution. An estimated 1 million cases occur in the United States each year, and increasing age is the primary risk factor. Laboratory testing, including polymerase chain reaction, can confirm atypical cases. Treatment with acyclovir, famciclovir, or valacyclovir decreases the duration of the rash. Adjunct medications, including opioid analgesics, tricyclic antidepressants, or corticosteroids, may relieve the pain associated with acute herpes zoster. There is conflicting evidence that antiviral therapy during the acute phase prevents postherpetic neuralgia. Postherpetic neuralgia in the cutaneous nerve distribution may last from 30 days to more than six months after the lesions have healed. Evidence supports treating postherpetic neuralgia with tricyclic antidepressants, gabapentin, pregabalin, long-acting opioids, or tramadol; moderate evidence supports the use of capsaicin cream or a lidocaine patch as a second-line agent. Immunization to prevent herpes zoster and postherpetic neuralgia is recommended for most adults 60 years and older.     

Management of herpes zoster (shingles) and postherpetic neuralgia

Herpes zoster (commonly referred to as "shingles") and postherpetic neuralgia result from reactivation of the varicella-zoster virus acquired during the primary varicella infection, or chickenpox. Whereas varicella is generally a disease of childhood, herpes zoster and post-herpetic neuralgia become more common with increasing age. Factors that decrease immune function, such as human immunodeficiency virus infection, chemotherapy, malignancies and chronic corticosteroid use, may also increase the risk of developing herpes zoster. Reactivation of latent varicella-zoster virus from dorsal root ganglia is responsible for the classic dermatomal rash and pain that occur with herpes zoster. Burning pain typically precedes the rash by several days and can persist for several months after the rash resolves. With postherpetic neuralgia, a complication of herpes zoster, pain may persist well after resolution of the rash and can be highly debilitating. Herpes zoster is usually treated with orally administered acyclovir. Other antiviral medications include famciclovir and valacyclovir. The antiviral medications are most effective when started within 72 hours after the onset of the rash. The addition of an orally administered corticosteroid can provide modest benefits in reducing the pain of herpes zoster and the incidence of postherpetic neuralgia. Ocular involvement in herpes zoster can lead to rare but serious complications and generally merits referral to an ophthalmologist. Patients with postherpetic neuralgia may require narcotics for adequate pain control. Tricyclic antidepressants or anticonvulsants, often given in low dosages, may help to control neuropathic pain. Capsaicin, lidocaine patches and nerve blocks can also be used in selected patients.     

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

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.     

A randomized, double-blind, comparative trial comparing high- and standard-dose oral acyclovir for first-episode genital herpes infections.

Orally administered acyclovir ameliorates the clinical course and decreases the duration of viral shedding in patients with first-episode genital herpes infections. We investigated in a randomized, double-blind, comparative trial whether a higher (4 g) than standard (1 g) daily dose of oral acyclovir results in greater clinical benefit and influences the time to first recurrence. A total of 139 patients with first-episode genital herpes were randomized to receive orally 4 or 1 g of acyclovir daily. A total of 52 subjects were excluded from the efficacy analysis because most had recurrent disease. Of 87 eligible subjects, 28 (32%) had primary herpes simplex virus type 1 (HSV-1) infections, 48 (55%) had primary HSV-2 infections, and 11 (13%) had nonprimary HSV-2 infections. We did not find any statistically significant differences in the duration of symptoms or viral shedding between the two dose groups, nor did the median time to first recurrence differ between the two groups. Initiation of therapy with either dose within the first 3 days of the appearance of symptoms shortened the duration of the first episode. Adverse gastrointestinal effects developed in 8% of subjects receiving the higher dose, whereas no adverse reactions were observed among those receiving the standard dose (P = 0.10). We conclude that, in comparison with standard therapy, higher-dose oral acyclovir does not result in additional clinical benefit or modify the time to first recurrence. The present study may have implications for the development and efficacy of congeners of acyclovir which provide higher levels in blood than the standard dose of acyclovir.     

Effect of acyclovir treatment of primary genital herpes on the antibody response to herpes simplex virus.

Sera from patients with first episode primary genital herpes infections who were treated with the antiviral drug acyclovir were studied to determine the effect of therapy on the immune response to herpes simplex virus (HSV) glycoproteins and polypeptides. 63 patients were evaluated, 35 patients received acyclovir: 11 intravenously, 12 orally, and 12 topically, while 28 received placebo. Topical application of acyclovir had no effect on the immune response to HSV infection. However, both oral and intravenous acyclovir were associated with later development of antibodies to two glycoproteins (of 80,000 and 60,000 mol wt [IIg80 and gD, respectively]) and one nonglycosylated polypeptide of 66,000 mol wt (vp66). Antibody to IIg80 was present in convalescent phase serum in 13/23 systemic acyclovir recipients vs. 18/19 placebo recipients (P = 0.01) and antibody to gD was detected in 8/23 oral or intravenous acyclovir recipients vs. 11/19 placebo recipients (P = 0.06). The mean time to seroconversion to IIg80 (39.0 d) and gD (55.5 d) was significantly longer for systemic acyclovir recipients than for the placebo controls, 23.4 and 18.5 d, respectively (P less than 0.05 for each comparison). 7 (30%) of 23 systemic acyclovir recipients compared with 100% of the placebo recipients had antibody to vp66 by 30 d after onset of the primary episode (P less than 0.001). Subsequent untreated recurrences of genital herpes were associated with seroconversion to gD, IIg80, and vp66. Patients who lacked antibody to both gD and vp66 in sera taken before their first clinical recurrence of disease experienced a longer duration of the recurrent episode (10.8 d) than those who possessed antibody to both vp66 and gD (6.3 d) (P less than 0.05). In addition, the mean duration of lesions, number of lesions, and mean lesion area were greater in patients who lacked antibody to vp66 but had anti gD, as compared with those who had anti-p66 but lacked anti-gD; suggesting that antibody to vp66 correlated more closely with subsequent disease severity than did antibody to gD. Acyclovir therapy appears to influence the frequency and time of development of antibody to a number of different HSV-specific polypeptides. Further studies of the effects of antiviral therapies on the immune response to these proteins may help clarify the role of these polypeptides in the pathogenesis of disease.     

Oral antivirals for the acute treatment of recurrent herpes labialis

OBJECTIVE: To evaluate the use and benefit of oral antivirals in the acute treatment of episodic, recurrent herpes labialis. DATA SOURCES: A literature search was performed in MEDLINE (1966-August 2003) using acyclovir, famciclovir, valacyclovir, cold sores, herpes labialis, and HSV-1 as search terms. DATA SYNTHESIS: We reviewed 5 placebo-controlled and 2 comparative studies evaluating oral antivirals for acute treatment of recurrent herpes labialis. No studies directly compared different antivirals. Studies discussing the efficacy of antivirals for chronic suppression of herpes simplex virus-1 infection were not included. CONCLUSIONS: Treatment with oral antivirals decreases the duration of lesion episodes and pain by approximately one day; however, the antivirals do not abort lesions from developing. Clinical implications of these results appear relatively modest.     

Antiviral agents for non-human immunodeficiency virus infections

Several new agents for treating viral infections have been developed in recent years. All available agents are virustatic, inhibiting specific steps in the process of viral replication. No agent is active against nonreplicating or latent viruses. Acyclovir is useful in the treatment of genital herpes, herpes simplex encephalitis, mucocutaneous herpetic infection, varicella infection in the immunosuppressed host, and herpes zoster infection in the normal and the immunosuppressed host. It can also be used for prevention of herpesvirus infection in immunocompromised patients. Ganciclovir is indicated for the treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome and is effective in the treatment and prevention of cytomegalovirus infection in other immunocompromised patients. Famciclovir and valacyclovir are effective in the management of herpes simplex and varicella-zoster infection. Amantadine and rimantadine are useful therapeutically and prophylactically in the management of influenza A virus infection. Chronic hepatitis B infection can respond to lamivudine therapy, and the optimal treatment of hepatitis C is the combination of interferon alfa and ribavirin. Despite pronounced toxic effects, foscarnet and cidofovir are effective antiviral agents in specific settings.     

三叉神经带状疱疹的护理

目的探讨对累及口腔的三叉神经带状疱疹患者的护理干预。方法13例三叉神经带状疱疹患者,口腔受累,有疱疹和糜烂,给予全身抗病毒治疗以及面部、口腔皮损局部用药。护理重点在预防疱疹破溃后继发感染,并注重口腔糜烂的护理、神经痛处理以及用药监护等。结果治疗、护理10天后患者面部及口腔水疱干燥、结痂,口腔糜烂逐渐愈合,20天后所有患者基本痊愈或痊愈,无严重并发症。结论防止面部、口腔疱疹继发感染是本病的护理重点,对口腔糜烂、疼痛等护理也是不可忽视的方面。     

A double-blind, randomized study assessing the equivalence of valacyclovir 1000 mg once daily versus 500 mg twice daily in the episodic treatment of recurrent genital herpes. Genival Study Group

Valaciclovir is a prodrug of acyclovir with more favourable bioavailability. Twice daily oral administration of valacyclovir is recommended in patients with genital herpes. A double-blind, randomized, controlled, multicriteria equivalence trial was conducted to determine whether od treatment with valacyclovir 1000 mg is as effective as bd treatment with 500 mg in patients with recurrent genital herpes. A total of 922 immunocompetent outpatients were treated with either regimen for 5 days; treatment was self-initiated at the first symptoms of the next recurrence. The principal outcome measures were the percentage of lesions healed at day 6, time to healing, time to cessation of pain, discomfort or itching, the percentage of abortive episodes and safety. Equivalence was assessed by comparison of 80% confidence limits for each measure; the two regimens were regarded as equivalent if the lower confidence limit was higher than a pre-determined equivalence limit calculated to show a maximum 10% inferiority of valacyclovir 1000 mg od against valaciclovir 500 mg bd. Intention-to-treat analysis showed that the two treatments were equivalent for each outcome measure. Hence, it is concluded that valacyclovir 1000 mg od is as effective as 500 mg bd. as self-initiated therapy in patients with recurrent genital herpes.     

Clinical Science (43)

Valaciclovir: a review of its use in the management of herpes zoster. (Adis International Limited, Auckland, New Zealand) Drugs 2000;59:1317–1340. This study compared the effectiveness of valaciclovir (1000 mg 3 times daily for 7 days) and aciclovir (800 mg 5 times daily for 7 days) in controlling the symptoms of acute herpes zoster. Valaciclovir was found to alleviate zoster‐associated pain and postherpetic neuralgia significantly faster than aciclovir. A 14‐day regimen of valaciclovir showed no significant advantage over the 7‐day regimen. A smaller trial in Japanese patients focusing primarily on the cutaneous (rash) signs of herpes zoster confirmed the similar efficacy of valaciclovir and aciclovir in the 7‐day regime. Valaciclovir and aciclovir demonstrated similar efficacy for the control of cutaneous lesions and ocular complications in patients with zoster ophthalmicus. Starting treatment later than 72 h after rash onset did not significantly reduce the beneficial effect of valaciclovir on the duration of zoster‐associated pain, suggesting that valaciclovir might be effective when given later than previously thought. However, valaciclovir should ideally be given as soon as possible after symptoms appear. Valaciclovir was well tolerated with nausea and headache as being the most commonly reported adverse events. The adverse events profile of the agent was similar to that seen with aciclovir or famciclovir. Conclude that the efficacy of valaciclovir for the treatment of herpes zoster has been confirmed and extended by follow‐up studies in herpes zoster ophthalmicus, in Japanese patients, and in the wider primary care setting. Valaciclovir is at least equivalent to, and better in certain parameters than, aciclovir and appears to have similar efficacy to famciclovir 500 mg 3 times daily. Comment by Susan Anderson, MD. This is a review article on the antiviral drug valaciclovir. The varicella zoster virus (VZV) is commonly treated with the antiviral drug aciclovir. However, aciclovir has a low oral bioavailability that limits its efficacy in the treatment of herpes zoster. Valaciclovir was developed in order to have a more readily absorbed oral antiviral drug. When valaciclovir was compared to aciclovir in a large study, it was noted that valaciclovir was as effective in controlling the symptoms of acute herpes zoster. It was also noted valaciclovir alleviated zoster associated pain and postherpetic neuralgia significantly faster than aciclovir. Also, there was no significant advantage of treating valaciclovir 14 days versus 7 days; therefore, a 7‐day regimen is recommended. In a smaller trial from Japan that focused primarily on the cutaneous (rash) signs of herpes zoster, there was also confirmation of similar efficacy of aciclovir and valaciclovir in a 7‐day regimen. The similarity in efficacy was not only for cutaneous lesions but also for ocular complications in patients with zoster ophthalmicus. In a large controlled trial, they compared valaciclovir and famciclovir. This showed similar efficacy in resolution of acute herpes zoster rashes shortening the duration of postherpetic neuralgia. It was purposed in the article that the therapeutic window for beneficial treatment with valaciclovir and zoster associated pain may be wider that previously though. It is still recommended that valaciclovir be ideally given as soon as possible after symptoms appear. However, starting treatment after 72 hours after rash onset did not significantly reduce the beneficial effect of the valaciclovir on duration of zoster associated pain. Valaciclovir is known to be well tolerated with nausea and headache being the most commonly reported adverse events. The adverse events profile of valaciclovir is similar to aciclovir or famciclovir. The purpose of this review was to present an overview of the pharmacodynamic/pharmacokinetic properties and therapeutic efficacy in the assessment of pain in herpes zoster in comparison with known agents of aciclovir, famciclovir, and/or placebo. It is concluded that valaciclovir is an efficacious agent in the treatment of herpes zoster and herpes zoster ophthalmicus. It's at least as efficacious as aciclovir and has similar efficacy to famciclovir. It is well tolerated with a similar side effect profile as aciclovir and famciclovir.     

综合疗法治疗带状疱疹56例疹疗效观察

目的观察泛昔洛韦联合白介素肌肉注射配合紫外线光疗治疗带状疱疹的疗效。方法选择在本院皮肤科就诊的明确诊断为带状疱疹病患者98例,随机分为两组,分别予单独泛昔洛韦口服（对照组）和应用泛昔洛韦口服白介素肌肉注射,紫外线光疗仪联合治疗（治疗组）。结果治疗组联合治疗7d56例病人痊愈率（94．6％）高于对照组（73．8％）,差异有统计学意义（P〈0．01）。且治疗组在止痛时间、止疱时间、结痂时间三方面均明显优于对照组（P〈0．05）。结论泛昔洛韦加白介素联合紫外线光疗仪治疗带状疱疹能缩短疗程,不留后遗症,效果甚佳。     

Pharmacokinetics and Safety of Famciclovir in Children with Herpes Simplex or Varicella-Zoster Virus Infection

Two multicenter, open-label, single-arm, two-phase studies evaluated single-dose pharmacokinetics and single- and multiple-dose safety of a pediatric oral famciclovir formulation (prodrug of penciclovir) in children aged 1 to 12 years with suspicion or evidence of herpes simplex virus (HSV) or varicella-zoster virus (VZV) infection. Pooled pharmacokinetic data were generated after single doses in 51 participants (∼12.5 mg/kg of body weight [BW] for children weighing <40 kg and 500 mg for children weighing ≥40 kg). The average systemic exposure to penciclovir was similar (6- to 12-year-olds) or slightly lower (1- to <6-year-olds) than that in adults receiving a 500-mg dose of famciclovir (historical data). The apparent clearance of penciclovir increased with BW in a nonlinear manner, proportional to BW^0.696. An eight-step weight-based dosing regimen was developed to optimize exposure in smaller children and was used in the 7-day multiple-dose safety phases of both studies, which enrolled 100 patients with confirmed/suspected viral infections. Twenty-six of 47 (55.3%) HSV-infected patients who received famciclovir twice a day and 24 of 53 (45.3%) VZV-infected patients who received famciclovir three times a day experienced at least one adverse event. Most adverse events were gastrointestinal in nature. Exploratory analysis following 7-day famciclovir dosing regimen showed resolution of symptoms in most children with active HSV (19/21 [90.5%]) or VZV disease (49/53 [92.5%]). Famciclovir formulation (sprinkle capsules in OraSweet) was acceptable to participants/caregivers. In summary, we present a weight-adjusted dosing schedule for children that achieves systemic exposures similar to those for adults given the 500-mg dose.Intravenous and high-dose oral acyclovir has been the gold standard for many children requiring treatment and/or prevention of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections (3, 14, 15, 25). However, intravenous acyclovir requires hospitalization, and oral acyclovir has limited bioavailability, necessitating frequent dosing, and may not provide maximum therapeutic benefit especially in immunocompromised hosts requiring higher plasma drug levels (22). It is therefore desirable to identify more pharmacokinetically appealing therapies for children with conditions caused by HSV or VZV infections. Alternative therapies for treating herpesvirus infections have become available over the last decade, including valacyclovir and famciclovir (5, 18), but only acyclovir is currently approved for pediatric use in many countries.Penciclovir, a nucleoside analogue, possesses potent in vitro antiviral activity against HSV types 1 and 2 and VZV (21). Famciclovir, the oral prodrug of penciclovir, is currently approved for the treatment of herpes zoster and herpes labialis, treatment or suppression of genital herpes in immunocompetent adult patients, and treatment of HSV infections and herpes zoster in immunocompromised adults. Although pharmacokinetic and safety data for famciclovir have been reported for adults (7, 11, 12, 18), there has been limited pharmacokinetic information in children. Because effective treatment requires attaining a therapeutic target concentration, determination of famciclovir''s pharmacokinetic profile in pediatric patients is essential.This paper describes the findings of two studies in children, ages 1 to 12 years, with confirmed or suspected HSV or VZV infection treated with a new oral pediatric formulation of famciclovir (i.e., “sprinkle” hard gelatin capsules containing famciclovir mixed with OraSweet). The initial section of this paper describes the pharmacokinetic and safety data following a single famciclovir dose. The subsequent section summarizes the multiple-dose regimen phase in order to evaluate the safety and exploratory efficacy after administration of famciclovir for 7 days.