AHFS Class:

• Nucleosides and Nucleotides 8:18.32

Generic Name(s):

• valACYclovir Hydrochloride

Valacyclovir, the l-valine ester of acyclovir, is an antiviral agent1,2,3,4,5,6,7,8,9 that is a prodrug of acyclovir and is active against herpes viruses.1,2,5,6,7

Oral valacyclovir is used for the treatment of initial and recurrent episodes of genital herpes infections in immunocompetent adults and adolescents1,24,29,30 and for the suppression of recurrent episodes of genital herpes in immunocompetent adults and adolescents and individuals infected with human immunodeficiency virus (HIV).1,33 Valacyclovir also is used for the episodic treatment of herpes labialis (perioral herpes, cold sores, fever blisters) in adults and adolescents1,34 and for the treatment of acute, localized herpes zoster (shingles, zoster) in adults and adolescents.1,4,10,11,30

The manufacturer states that safety and efficacy of valacyclovir in immunocompromised patients have not been established for any use other than suppression of genital herpes and safety and efficacy of the drug have not been established for any use in prepubertal pediatric patients.1

Genital Herpes

Treatment of First Episodes

Oral valacyclovir is used in the treatment of initial episodes of genital herpes simplex virus (HSV-2) infection in immunocompetent adults and adolescents.1,24,29,30 Because many patients with first episodes of genital herpes present with mild clinical symptoms but later develop severe or prolonged symptoms, the US Centers for Disease Control and Prevention (CDC) states that most patients with initial genital herpes should receive antiviral therapy.24 The CDC and some clinicians recommend that first episodes of genital herpes be treated with a regimen of oral acyclovir (400 mg 3 times daily or 200 mg 5 times daily for 7-10 days), oral famciclovir (250 mg 3 times daily for 7-10 days), or oral valacyclovir (1 g twice daily for 7-10 days).24,29,30

Oral valacyclovir appears to be as effective as oral acyclovir in the treatment of first episodes of genital herpes.1 Efficacy of oral valacyclovir (1 g twice daily for 10 days) was compared with that of oral acyclovir (200 mg 5 times daily for 10 days) in a randomized, double-blind trial in immunocompetent adults who presented for treatment within 72 hours of the onset of symptoms.1 Results of this study indicate that, for both drugs, the median time to lesion healing was 9 days, the median time to cessation of pain was 5 days, and the median time to cessation of viral shedding was 3 days.1

Episodic Treatment of Recurrent Episodes

Oral valacyclovir is used in the treatment of recurrent episodes of genital herpes in immunocompetent adults and adolescents.1,24,29,30 Antiviral therapy for recurrent genital herpes can be given episodically to ameliorate or shorten the duration of lesions or can be given continuously as suppressive therapy to reduce the frequency of recurrences.24 For episodic treatment of recurrent genital herpes, the CDC and some clinicians recommend oral acyclovir (400 mg 3 times daily for 5 days, 800 mg twice daily for 5 days, or 800 mg 3 times daily for 2 days), oral famciclovir (125 mg twice daily for 5 days or 1 g twice daily for 1 day), or oral valacyclovir (500 mg twice daily for 3 days or 1 g once daily for 5 days).24,29,30 Episodic antiviral therapy should be initiated within 1 day of lesion onset or during the prodrome that precedes some outbreaks.24 The manufacturer states that patients should be advised to initiate oral valacyclovir at the first sign or symptoms of an episode and that there are no data on the effectiveness of the drug initiated more than 24 hours after the onset of signs and symptoms of a recurrent episode.1

Efficacy of oral valacyclovir in the treatment of recurrent episodes of genital herpes has been evaluated in 3 double-blind (2 of them placebo-controlled) studies in which immunocompetent adults self-initiated therapy within 24 hours of the first sign or symptom of a recurrent genital herpes episode.1 In one study, the median time to lesion healing and cessation of pain was 4 and 3 days, respectively, in those randomized to receive oral valacyclovir (500 mg twice daily for 5 days) compared with 6 and 4 days, respectively, in those randomized to receive placebo.1 The median time to cessation of viral shedding was 2 days in those who received valacyclovir versus 4 days in those who received placebo.1 Results of this study were duplicated in a second study.1

There is evidence that a 3-day regimen of oral valacyclovir is as effective as a 5-day regimen of the drug for the episodic treatment of recurrent genital herpes.1,32 In a double-blind study, patients were randomized to receive valacyclovir 500 mg twice daily for 3 or 5 days (patients receiving the 3-day regimen received placebo on days 4 and 5).1,32 The median time to lesion healing was about 4.5 days and the median time to cessation of pain was about 3 days in both treatment groups.1,32

Suppressive Therapy of Recurrent Episodes

Valacyclovir is used for chronic suppressive therapy of recurrent genital herpes in immunocompetent and HIV-infected adults and adolescents.1,24,29,30,33 The CDC states that suppressive antiviral therapy can reduce the frequency of genital herpes recurrences by 70-80% in patients who have frequent recurrences (i.e., 6 or more per year) and many patients report no symptomatic outbreaks during such therapy.24 For chronic suppressive therapy of recurrent genital herpes, the CDC and some clinicians recommend a regimen of oral acyclovir (400 mg twice daily), oral famciclovir (250 mg twice daily), or oral valacyclovir (500 mg or 1 g once daily).24,29,30 The CDC states that data suggest that famciclovir and valacyclovir are as effective as acyclovir in terms of clinical outcome, although the 500 mg once-daily valacyclovir regimen might be less effective than the acyclovir regimen or other valacyclovir regimens in patients who have very frequent recurrences (i.e., 10 or more episodes per year).24

Efficacy of oral valacyclovir for chronic suppressive therapy of recurrent genital herpes infections has been evaluated in a double-blind, placebo-controlled study in immunocompetent adults with a history of frequent recurrences (6 or more per year).1 Patients were randomized to receive oral valacyclovir (1 g once daily), oral acyclovir (400 mg twice daily), or placebo.1 At 6 months, 55% of those receiving valacyclovir and 54% of those receiving acyclovir were free of recurrences compared with only 7% of those receiving placebo; at 12 months, 34% of patients in both groups receiving antiviral therapy were still free of recurrences.1 When valacyclovir is used for suppressive therapy in immunocompetent individuals, the risk of heterosexual transmission to susceptible partners is reduced.1,35 (See Reduction of Transmission under Uses: Genital Herpes.)

Efficacy of oral valacyclovir for suppressive therapy of recurrent genital herpes has been evaluated in HIV-infected adults 18 years of age or older (median HIV-1 RNA level 2.6 log₁₀ copies/mL and median CD4⁺ T-cell count 336/mm³ at study entry) with a history of frequent recurrences (4 or more per year).1,33 At 6 months, 65% of those receiving valacyclovir were free of recurrences compared with 26% of those receiving placebo.1,33 Safety and efficacy of valacyclovir for suppression of recurrent genital herpes in patients with advanced HIV disease (CD4⁺ T-cell counts less than 100/mm³) have not been established.1

Safety and efficacy of oral valacyclovir for suppressive therapy of recurrent genital herpes infections have been established in immunocompetent patients receiving daily therapy for up to 1 year; safety and efficacy for this indication have been established in HIV-infected patients receiving daily therapy for up to 6 months.1,24,33

Reduction of Transmission

When valacyclovir is used for suppressive therapy of genital herpes in immunocompetent individuals, the risk of heterosexual transmission to susceptible partners is reduced.1,35 Transmission of genital herpes was assessed in a double-blind, placebo-controlled study in monogamous, heterosexual, immunocompetent couples discordant for HSV-2 infection; the infected partner received valacyclovir (500 mg once daily) or placebo for 8 months.1,35 Clinically symptomatic HSV-2 infection developed in 0.5% of susceptible individuals whose partner received valacyclovir and in 2.2% of those whose partner received placebo.1,35 Acquisition of HSV-2 was observed in 1.9% of susceptible individuals whose partner received valacyclovir and in 3.6% of those whose partner received placebo.1,35 Efficacy for reducing transmission of HSV-2 has not been established in individuals with multiple partners or in non-heterosexual couples.1

HIV-infected Individuals

Immunocompromised individuals may have prolonged or severe episodes of genital, perianal, or oral herpes; HSV-2 lesions are common in those with human immunodeficiency virus (HIV) infection and may be severe, painful, and atypical.24 (See Uses: Mucocutaneous Herpes Simplex Virus Infections.)

The CDC states that episodic treatment or suppressive therapy with oral antiviral agents often is beneficial in HIV-infected individuals with genital herpes.24 While the drugs of choice for episodic treatment or suppressive therapy of genital herpes in HIV-infected individuals are the same as those in immunocompetent individuals, higher dosages and/or more prolonged therapy may be necessary.24 Although safety and efficacy of valacyclovir for treatment of genital herpes have not been established in immunocompromised patients,1 CDC recommends valacyclovir for the treatment of genital herpes in HIV-infected individuals†.24 For episodic treatment of recurrences of genital herpes in HIV-infected individuals, the CDC recommends a 5- to 10-day regimen of oral acyclovir (400 mg 3 times daily), oral famciclovir (500 mg twice daily), or oral valacyclovir (1 g twice daily).24 Valacyclovir is used for suppression of recurrent genital herpes in HIV-infected individuals.1 For chronic suppressive therapy of recurrent genital herpes, CDC recommends oral acyclovir (400-800 mg 2-3 times daily), oral famciclovir (500 mg twice daily), or oral valacyclovir (500 mg twice daily).24

Patient Counseling and Management of Sexual Partners

Counseling of infected individuals and their sex partners is critical to management of genital herpes.24 The goals of such counseling are to help patients understand and cope with the infection and to prevent sexual and perinatal transmission of the virus.24 Antiviral therapy offers clinical benefit to most symptomatic patients and is the mainstay of management; however, genital herpes is a recurrent, life-long viral infection.24 Use of valacyclovir for suppressive therapy in immunocompetent individuals is associated with reduced risk of heterosexual transmission to susceptible partners.1,35 However, antiviral therapy does not eradicate latent HSV-2 or affect the risk, frequency, or severity of recurrences of genital herpes following discontinuance of therapy.24

The majority of genital herpes infections are transmitted by individuals unaware that they have the infection or by individuals who are asymptomatic when transmission occurs.24 Patients should be advised that valacyclovir is not a cure for genital herpes.1 While use of valacyclovir for suppressive therapy is associated with a reduced risk of heterosexual transmission, safer sex practices should be used even in patients receiving suppressive therapy.1 Because genital herpes is a sexually transmitted disease, patients should be advised to avoid sexual contact with uninfected partners when lesions and/or prodromal symptoms are present.1,24 In addition, patients should be advised that sexual transmission of the virus can occur during asymptomatic periods1,24 and that suppressive antiviral therapy reduces, but does not eliminate, subclinical viral shedding.24

Sex partners of individuals with genital herpes should be advised that they may be infected even if they have no symptoms.24 Asymptomatic partners of patients with genital herpes should be questioned regarding a history of genital lesions, educated to recognize symptoms of genital herpes, and offered type-specific serologic testing to determine whether risk for HSV-2 acquisition exists.24 Antiviral therapy is not recommended for sex partners who do not have clinical manifestations of infection, but symptomatic sex partners of individuals with genital herpes should be evaluated and treated.24

The risk for neonatal HSV-2 infection should be discussed with all genital herpes patients, including men.24 Pregnant women and women of childbearing age who have genital herpes should inform their providers who care for them during pregnancy as well as those who will care for their neonate.24

Information to assist patients and clinicians in counseling regarding genital herpes is available at [Web] and [Web].24 For further information on treatment of initial or recurrent episodes of genital herpes or suppression of recurrent infections, see Uses: Genital Herpes in Acyclovir 8:18.32.

Herpes Labialis

Valacyclovir is used for the episodic treatment of herpes labialis (perioral herpes, cold sores, fever blisters) in adults and adolescents.1,34

Efficacy of a short-duration regimen of valacyclovir was evaluated in healthy adults and adolescents 12 years of age or older with a history of recurrent cold sores (at least 3 episodes in the past year).1,34 Patients were randomized to 1-day treatment (valacyclovir 2 g twice daily), 2-day treatment (valacyclovir 2 g twice daily on day 1 then valacyclovir 1 g twice daily on day 2), or placebo; patients self-initiated therapy at the earliest prodromal symptom and before clinical signs of a cold sore (most initiated treatment within 2 hours of symptom onset).1,34 The mean duration of the cold sore episode was reduced by about 1 day in patients receiving valacyclovir compared with those given placebo; the 2-day regimen was not more effective than the 1-day regimen.1,34 The proportion of valacyclovir-treated patients with prevented and/or blocked cold sore lesions (44-46%) was essentially the same as the proportion of patients given placebo (38%).34

The manufacturer states that safety and efficacy of valacyclovir for the treatment of cold sores in immunocompromised patients have not been established.1

Mucocutaneous Herpes Simplex Virus Infections

Oral valacyclovir has been used for the treatment of recurrent mucocutaneous HSV-1 infections in HIV-infected adults†26 and for chronic suppressive or maintenance therapy (secondary prophylaxis) against HSV-1 disease in HIV-infected individuals†.25,26

In patients with advanced HIV infection, reactivation of HSV-1 frequently occurs and can result in chronic, persistent mucocutaneous disease that may be severe.25,26 The Prevention of Opportunistic Infections Working Group of the US Public Health Service and the Infectious Diseases Society of America (USPHS/IDSA) has established guidelines for the prevention of opportunistic infections in HIV-infected individuals that include recommendations concerning prevention of exposure to opportunistic pathogens, prevention of first disease episodes, and prevention of disease recurrence.25 The USPHS/IDSA does not currently recommend primary prophylaxis against initial episodes of HSV-1 infection in HIV-infected adults, adolescents, or children.25 In addition, the USPHS/IDSA does not recommend routine chronic suppressive or maintenance therapy (secondary prophylaxis) against HSV-1 disease in HIV-infected individuals since acute episodes generally can be treated successfully with acyclovir.25 However, long-term prophylaxis against recurrence of HSV-1 can be considered for adults, adolescents, and children who have frequent or severe recurrences.25,26 If secondary prophylaxis of HSV-1 disease is indicated in HIV-infected adults or adolescents, the USPHS/IDSA recommends oral acyclovir or oral famciclovir as the drugs of choice and oral valacyclovir as an alternative.25 If indicated in infants and children, the USPHS/IDSA recommends oral acyclovir.25 If acyclovir-resistant HSV-1 is suspected, IV foscarnet or IV cidofovir can be used to treat the infection.25

Herpes Zoster

Oral valacyclovir is used for the treatment of acute, localized herpes zoster (shingles, zoster) in immunocompetent adults.1,4,10,11,30 Some clinicians suggest that the drugs of choice for the treatment of herpes zoster in immunocompetent adults are oral acyclovir, oral famciclovir, or oral valacyclovir.30

Efficacy of oral valacyclovir in the treatment of acute, localized herpes zoster has been evaluated in a randomized, double-blind, placebo-controlled trial in immunocompetent adults younger than 50 years of age and in a double-blind trial in immunocompetent adults 50 years of age or older who were randomized to receive oral valacyclovir (1 g every 8 hours for 7 or 14 days) or oral acyclovir (800 mg 5 times daily for 7 days).1,4,5,10,11 Results of these studies indicate that valacyclovir may prevent the appearance of new lesions,1,4 decrease viral shedding,4,5 decrease the duration of pain,1,4,5 and promote healing and crusting of lesions4,5,11 in immunocompetent adults with localized herpes zoster, at least when given within 72 hours of onset of rash.1,4,5,11 In one study, there was no evidence of additional benefit on pain duration when valacyclovir was initiated within 48 hours versus between 48-72 hours of rash onset;4,5 however, the effect of time on other clinical endpoints (e.g., appearance of new lesions, viral shedding) was not determined,4 and antiviral therapy for herpes zoster generally is most effective when initiated within 48 hours of rash onset.1 Like acyclovir,1,4 valacyclovir does not appear to prevent the development of postherpetic neuralgia;1,4 the drug may decrease the median duration of neuralgia, particularly in patients older than 50 years of age.1,4 In comparative studies, 7 or 14 days of oral valacyclovir (1 g 3 times daily) was as effective as 7 days of oral acyclovir (800 mg 5 times daily) in reducing the duration of virus shedding and accelerating the resolution of herpes zoster-associated pain and cutaneous healing in patients 50 years of age or older, and the drugs exhibited comparable safety profiles.1,4,5 Although there was a trend toward a shorter median duration of postherpetic pain with the valacyclovir regimens compared with the acyclovir regimen in patients 50 years of age or older, the difference was not statistically significant.1,4,5 The principal potential benefits relative to acyclovir are valacyclovir's improved oral bioavailability and resultant more convenient dosing regimen.1,4,5 In these studies, there were no gender-related differences in safety or efficacy.4

Valacyclovir has been used for the treatment of localized dermatomal herpes zoster in HIV-infected adults or adolescents†.38 If cutaneous lesions are extensive or there is clinical evidence of visceral involvement, IV acyclovir should be used for initial treatment.38

The manufacturer states that the efficacy of valacyclovir in the treatment of disseminated herpes zoster or for the treatment of herpes zoster in immunocompromised patients has not been established.1

Prevention of Cytomegalovirus Disease

HIV-infected Individuals

Although some evidence indicates that use of valacyclovir for prophylaxis of cytomegalovirus (CMV) disease in HIV-infected individuals† reduces the incidence of CMV disease in these patients,28 the USPHS/IDSA states that valacyclovir should not be used for primary prophylaxis against CMV in HIV-infected individuals because an unexplained trend toward increased mortality has been observed in HIV-infected patients receiving the drug for such prophylaxis.25,28

Transplant Recipients

Valacyclovir has been evaluated for the prevention of CMV disease in renal transplant recipients† considered at risk for the disease.27 Results of a randomized placebo-controlled study in renal transplant recipients at risk of developing CMV infection (i.e., CMV-seropositive or -seronegative recipients of a kidney from a CMV-seropositive donor) indicate that in patients who received valacyclovir (2 g four times daily, dosage reduced for those with a creatinine clearance less than 75 mL/minute) the probability of CMV disease was reduced compared with those receiving placebo.27

Although valacyclovir is being investigated for prophylaxis of CMV disease in hematopoietic stem cell transplant (HSCT) recipients†, the CDC, IDSA, and American Society of Blood and Marrow Transplantation (ASBMT) state the valacyclovir currently is not recommended for this use since it is presumed to be less effective against CMV than ganciclovir.31

Administration

Valacyclovir hydrochloride is administered orally without regard to meals.1 Food does not affect systemic bioavailability of the drug.1

Patients should maintain adequate hydration during valacyclovir treatment.1

Extemporaneously Compounded Oral Liquid

Extemporaneously compounded oral liquid formulations of valacyclovir containing 50 mg/mL have been prepared using the commercially available caplets and commonly used syrups.40

Standardize 4 Safety

Standardized concentrations for an extemporaneously prepared oral liquid formulation of valacyclovir have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 252Multidisciplinary expert panels were convened to determine recommended standard concentrations. 252Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. 252 For additional information on S4S (including updates that may be available), see [Web].252

Dosage

Dosage of valacyclovir hydrochloride is expressed in terms of valacyclovir.1

Valacyclovir dosage modification according to renal function may be necessary in geriatric patients, depending on the underlying renal status of the patient.1,23 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Genital Herpes

Treatment of First Episodes

For the treatment of initial episodes of genital herpes simplex virus (HSV-2) infection in immunocompetent adults and adolescents, the dosage of oral valacyclovir recommended by the manufacturer, the US Centers for Disease Control and Prevention (CDC), and other clinicians is 1 g twice daily for 7-10 days.1,24,29,30 The manufacturer recommends a duration of 10 days;1 the CDC states that the usual duration of treatment is 7-10 days but that this may be extended if healing is incomplete after 10 days.24

In HIV-infected adults and adolescents†, the CDC and other experts recommend 1 g twice daily for 7-14 days for the treatment of initial episodes of genital herpes.38

Valacyclovir has been most effective when administered within 48 hours of the onset of signs and symptoms of genital herpes; efficacy of the drug initiated more than 72 hours after the onset of signs and symptoms has not been established.1

Episodic Treatment of Recurrent Episodes

For the episodic treatment of recurrent genital herpes in immunocompetent adults and adolescents, the manufacturer and some clinicians recommend that oral valacyclovir be given in a dosage of 500 mg twice daily for 3 days.1,29,30 The CDC states that oral valacyclovir can be given in a dosage of 500 mg twice daily for 3 days or 1 g once daily for 5 days for the episodic treatment of recurrent genital herpes in immunocompetent adults and adolescents.24

In HIV-infected adults and adolescents†, the CDC recommends a dosage of 1 g twice daily for 5-10 days for the episodic treatment of recurrent genital herpes.24 Alternatively, treatment may be continued for 7-14 days in these patients.38

Patients should be advised to initiate valacyclovir therapy at the first sign or symptom of an episode.1 Data are not available concerning efficacy of oral valacyclovir initiated more than 24 hours after the onset of signs or symptoms of a recurrent episode of genital herpes.1

Suppressive Therapy of Recurrent Episodes

For chronic suppression of recurrent episodes of genital herpes in immunocompetent adults and adolescents, the usual dosage of oral valacyclovir is 1 g once daily; however, a dosage of 500 mg once daily may be used in patients with infrequent recurrences.1,24,30 The manufacturer states that those with a history of 9 or fewer recurrences per year may receive 500 mg once daily for chronic suppressive therapy;1 the CDC cautions that the 500 mg once daily regimen might be less effective in those who have very frequent recurrences (i.e., 10 or more per year).24

In HIV-infected adults and adolescents, the usual dose of oral valacyclovir for chronic suppression of recurrent episodes of genital herpes is 500 mg twice daily.1,24,33

Data are not available to date concerning efficacy and safety of oral valacyclovir administered for more than 1 year in immunocompetent patients1 or for more than 6 months in HIV-infected patients for chronic suppressive therapy of recurrent genital herpes infections.1

Because the frequency of recurrent episodes diminishes over time in many patients, the CDC recommends that suppressive antiviral therapy be discontinued periodically (e.g., once yearly) to assess the need for continued therapy.24,29,30

Reduction of Transmission

For reduction of transmission of genital herpes in patients with a history of 9 or fewer recurrences per year, the recommended dosage of oral valacyclovir for the infected partner is 500 mg once daily.1,35 Valacyclovir is used in conjunction with safer sex practices.1

Efficacy for reducing transmission in discordant couples has not been established beyond 8 months.1

Herpes Labialis

For the treatment of herpes labialis (perioral herpes, cold sores, fever blisters) in immunocompetent adults and adolescents, the recommended dosage of oral valacyclovir is 2 g every 12 hours for 1 day; initiate at the first prodromal symptom of a cold sore (e.g., tingling, itching, burning).1 Efficacy has not been established if initiated after development of clinical signs of a cold sore (e.g., papule, vesicle, ulcer).1

Mucocutaneous Herpes Simplex Virus Infections

If oral valacyclovir is used for chronic suppressive or maintenance prophylaxis (secondary prophylaxis) of HSV† in HIV-infected adults and adolescents who have frequent or severe recurrences of HSV disease, a dosage of 500 mg twice daily has been recommended by the Prevention of Opportunistic Infections Working Group of the US Public Health Service and the Infectious Diseases Society of America (USPHS/IDSA).25

Herpes Zoster (Shingles, Zoster)

For the treatment of acute, localized herpes zoster (shingles, zoster) in immunocompetent adults and adolescents, the recommended dosage of oral valacyclovir is 1 g 3 times daily at 8-hour intervals for 7 days.1,4,30

Therapy should be initiated at the earliest sign or symptom of herpes zoster, preferably within 48 hours of rash onset.1,4 Efficacy of oral valacyclovir initiated longer than 72 hours after rash onset has not been established.1 Limited evidence indicates that extending the valacyclovir regimen to 14 days in immunocompetent adults with acute, localized herpes zoster does not provide additional clinical benefit.4

For the treatment of local dermatomal herpes zoster in HIV-infected adults or adolescents†, the CDC and others recommend 1 g of valacyclovir 3 times daily for 7-10 days.38

Dosage in Renal and Hepatic Impairment

The manufacturer states that valacyclovir should be used with caution in patients receiving potentially nephrotoxic agents because this may increase the risk of renal dysfunction and/or reversible CNS manifestations.1 In patients with impaired renal function, doses and/or frequency of administration of valacyclovir must be modified in response to the degree of impairment.1

For the treatment of first episodes of genital herpes in immunocompetent adults with impaired renal function, the manufacturer states that patients with creatinine clearances of 30 mL/minute per 1.73 m² or greater may receive the usual oral valacyclovir dosage of 1 g every 12 hours; however, those with creatinine clearances of 10-29 or less than 10 mL/minute per 1.73 m² should receive 1 g or 500 mg, respectively, once every 24 hours.1 For the episodic treatment of recurrent genital herpes in immunocompetent adults with impaired renal function, patients with creatinine clearances of 30 mL/minute per 1.73 m² may receive the usual dosage of 500 mg every 12 hours, but those with clearances of 29 mL/minute per 1.73 m² or less should receive 500 mg once every 24 hours.1

For chronic suppression of recurrent episodes of genital herpes in immunocompetent adults with renal impairment, those with creatinine clearances of 30 mL/minute per 1.73 m² or greater may receive the usually recommended dosage of oral valacyclovir.1 Patients with creatinine clearances less than 30 mL/minute per 1.73 m² should receive 500 mg once every 24 hours; alternatively, those with a history of 9 or fewer recurrences per year may receive 500 mg once every 48 hours.1

For chronic suppression of recurrent episodes of genital herpes in HIV-infected adults with renal impairment, those with creatinine clearances of 30 mL/minute per 1.73 m² or greater may receive the usually recommended dosage of oral valacyclovir and those with creatinine clearances less than 30 mL/minute per 1.73 m² should receive 500 mg once every 24 hours.1

For the treatment of herpes labialis (cold sores) in patients with renal impairment, patients with creatinine clearances of 50 mL/minute or greater per 1.73 m² may receive the usual oral valacyclovir dosage of 2 g every 12 hours for 1 day.1 Those with creatinine clearances of 30-49 mL/minute per 1.73 m² should receive 1 g every 12 hours for 1 day, those with creatinine clearances of 10-29mL/minute per 1.73 m² should receive 500 mg every 12 hours for 1 day, and those with creatinine clearances less than 10 mL/minute per 1.73 m² should receive a single 500-mg dose.1

For the treatment of acute, localized herpes zoster in adults, the manufacturer states that patients with creatinine clearances of 50 mL/minute or greater per 1.73 m² may receive the usual oral valacyclovir dosage of 1 g every 8 hours.1 Those with creatinine clearances of 30-49 mL/minute per 1.73 m² should receive 1 g every 12 hours, and those with creatinine clearances of 10-29 or less than 10 mL/minute per 1.73 m² should receive 1 g or 500 mg, respectively, once every 24 hours.1

Because acyclovir is removed by hemodialysis, the manufacturer states that patients undergoing hemodialysis may require a supplemental dose of valacyclovir after each dialysis period.1,23 However, if usual dosing coincides with a valacyclovir dose being administered soon after hemodialysis and subsequent dialysis takes place toward the end of the dosing interval, a supplemental dose would not be necessary.23

Information regarding use of valacyclovir in patients undergoing peritoneal dialysis is not available.1 Based on experience with acyclovir, the manufacturer states that supplemental doses of valacyclovir do not appear to be necessary following peritoneal dialysis, either continuous ambulatory peritoneal dialysis (CAPD) or continuous arteriovenous hemofiltration/dialysis (CAVHD).1

The rate but not the extent of conversion of valacyclovir to acyclovir may be reduced in patients with moderate (biopsy-proven cirrhosis) or severe (with and without ascites and biopsy-proven cirrhosis) hepatic impairment.1 Therefore, the manufacturer states that dosage modification is not necessary for patients with cirrhosis.1

Contraindications

Known hypersensitivity or intolerance to valacyclovir, acyclovir, or any component of the formulation.1

Warnings/Precautions

Warnings

Hematologic Effects

Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (sometimes fatal) reported in patients with advanced HIV infection and in allogeneic bone marrow or renal transplant recipients receiving high dosages (8 g daily).1,23

General Precautions

Renal Effects

Use of inappropriately high dosage for the level of renal function has resulted in acute renal failure in patients with underlying renal disease.1 Acyclovir may precipitate in renal tubules if solubility exceeds 2.5 mg/mL in intratubular fluid.1

Adequate hydration should be maintained during therapy.1

If acute renal failure and anuria occur, hemodialysis recommended until normal renal function returns.1

CNS Effects

Use of inappropriately high dosage for the level of renal function has resulted in CNS symptoms in patients with underlying renal disease.1

Genital Herpes

Valacyclovir is not a cure for genital herpes.1 Patients should avoid sexual contact while lesions and/or symptoms are present due to risk of infecting sexual partners.1 Infection can be transmitted in the absence of symptoms through asymptomatic viral shedding.1 Although use of valacyclovir for suppressive therapy in immunocompetent individuals with genital herpes decreases the risk for heterosexual transmission, safer sex practices also should be used.1 Efficacy for reducing transmission not established in individuals with multiple partners or in non-heterosexual couples.1 Type-specific serologic testing of asymptomatic partners of individuals with genital herpes can determine whether risk for HSV-2 acquisition exists.1 Valacyclovir has not been shown to reduce transmission of sexually transmitted infections other than HSV-2.1

Although recommended by CDC and others for episodic treatment of genital herpes or chronic suppressive therapy of recurrent episodes in HIV-infected adults and adolescents,25,26 manufacturer says efficacy not established for treatment of genital herpes in HIV-infected individuals and safety and efficacy not established for chronic suppressive therapy in those with advanced HIV disease (CD4⁺ T-cell count <100/mm³).1

Herpes Labialis

Valacyclovir is not a cure for cold sores.1 Treatment should not exceed a single day; therapy beyond 1 day does not provide additional clinical benefits.1 Because of high dosage, use caution when prescribing valacyclovir for treatment of cold sores in geriatric individuals or those with renal impairment.1

Herpes Zoster

Safety and efficacy not established for treatment of disseminated herpes zoster or for treatment of herpes zoster in immunocompromised individuals.1

Specific Populations

Pregnancy

Category B.1

Lactation

Acyclovir distributed into human milk following oral administration of valacyclovir.1 Use valacyclovir with caution.30

Pediatric Use

Safety and efficacy not established in prepubertal children.1

Geriatric Use

Increased risk of adverse renal or CNS effects.30 CNS effects reported more frequently in geriatric adults than in younger adults include agitation, hallucinations, confusion, delirium, and encephalopathy.1 In herpes zoster, longer duration of pain after healing (post-herpetic neuralgia) than in younger adults.1 Consider age-related decreases in renal function when selecting dosage and adjust dosage if necessary.1,23 (See Renal Impairment under Dosage and Administration.)

Renal Impairment

Decreased clearance; increased risk of adverse renal and CNS effects in patients with underlying renal disease receiving high dosages.30 Adjust dosage as necessary.1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Headache,1 nausea,1 vomiting.1

Antacids

Concomitant use of valacyclovir and aluminum- or magnesium-containing antacids does not affect the pharmacokinetics of acyclovir; no dosage adjustments are necessary.1

Cimetidine

Concomitant use of valacyclovir and cimetidine may increase peak plasma concentrations and AUC of acyclovir.1 This pharmacokinetic interaction is not considered clinically important in patients with normal renal function; no dosage adjustments are necessary in these patients.1

Digoxin

Concomitant use of valacyclovir and digoxin does not affect the pharmacokinetics of acyclovir or digoxin; no dosage adjustments are necessary.1

Probenecid

Concomitant use of valacyclovir and probenecid may increase peak plasma concentrations and AUC of acyclovir.1 This pharmacokinetic interaction is not considered clinically important in patients with normal renal function and no dosage adjustments are necessary in these patients.1

Thiazide Diuretics

Concomitant use of valacyclovir and thiazide diuretics does not affect the pharmacokinetics of acyclovir; no dosage adjustments are necessary.1

Pharmacokinetics

Absorption

Bioavailability

Valacyclovir hydrochloride, a prodrug of acyclovir, is rapidly absorbed following oral administration and almost completely converted to acyclovir andl-valine by first-pass intestinal and/or hepatic metabolism.1,37

Absolute bioavailability of acyclovir approximately 54% following oral administration of valacyclovir hydrochloride;1,37 peak acyclovir plasma concentrations attained within 1.7 hours.37

Food

Administration of valacyclovir with food does not alter acyclovir bioavailability.1

Distribution

Extent

Although there are no adequate studies using valacyclovir in pregnant women, acyclovir crosses the placenta.1

Following oral administration of valacyclovir to the mother, peak plasma concentrations of acyclovir in breast milk generally are similar to corresponding maternal plasma concentrations.1

Plasma Protein Binding

13.5-17.9% bound to plasma proteins.1

Elimination

Metabolism

Valacyclovir hydrochloride rapidly converted to acyclovir and l-valine by first-pass intestinal and/or hepatic metabolism.1 Acyclovir converted to acyclovir monophosphate, diphosphate, and triphosphate in cells infected with herpesviruses.1

Neither valacyclovir nor acyclovir metabolized by CYP enzymes.1

Elimination Route

Valacyclovir principally eliminated as acyclovir;1 46 and 47% of an oral dose eliminated in urine and feces, respectively.1,37

Half-life

Plasma elimination half-life of acyclovir after oral administration of valacyclovir averages 2.5-3.3 hours.1,37

Special Populations

Renal clearance and elimination half-life decreased in patients with renal impairment;1 half-life averages 14 hours in end-stage renal disease.1

Pharmacokinetics in geriatric patients vary depending on renal function.1

Description

Valacyclovir, the l-valine ester of acyclovir, is an antiviral agent.1,2,3,4,5,6,7,8,9 Valacyclovir is a prodrug and exhibits no antiviral activity until hydrolyzed in the intestinal wall and/or liver to acyclovir and subsequently to its active metabolite (acyclovir triphosphate).1,2,5,6,7 Valacyclovir is commercially available as the hydrochloride salt and differs structurally from acyclovir by the presence of the l-amino acid, valine, attached to the 5'-hydroxyl group of the nucleoside and by the presence of the monohydrochloride salt.1,3 These structural modifications result in substantially increased GI absorption of valacyclovir and resultant plasma acyclovir concentrations compared with those achieved orally with the parent drug acyclovir, which is poorly absorbed from the GI tract.1,2,3,4,5,6,7,8

Valacyclovir is rapidly converted to acyclovir in vivo and subsequently to the pharmacologically active triphosphate metabolite, which has in vitro and in vivo inhibitory activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2), varicella-zoster virus (VZV), and cytomegalovirus (CMV).1 Acyclovir triphosphate exerts its antiviral effect on HSV and VZV by interfering with DNA synthesis and inhibiting viral replication.1 The inhibitory activity of acyclovir triphosphate is highly selective because of its affinity for the enzyme thymidine kinase encoded by HSV and VZV;1 however, other mechanisms may be involved since the drug exhibits activity against viruses that apparently do not code for this enzyme.12,13,14,15,16,17,18,19,20 Virus-coded thymidine kinase converts acyclovir into acyclovir monophosphate, a nucleotide analog.1 The monophosphate is further converted to the diphosphate via cellular guanylate kinase and then to the triphosphate via other cellular enzymes.1 In vitro, acyclovir triphosphate stops replication of herpes viral DNA by competitive inhibition of viral DNA polymerase, incorporation and termination of the growing viral DNA chain, and inactivation of the viral DNA polymerase.1 For additional information, see Mechanism of Action in Acyclovir 8:18.32.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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