Valacyclovir (Systemic)



INN:

Valaciclovir {02}

VA CLASSIFICATION
Primary: AM820

Commonly used brand name(s): Valtrex.

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



Category:


Antiviral (systemic)—

Indications

Accepted

Herpes genitalis, initial episode (treatment)1—Valacyclovir is indicated in the treatment of initial episodes of genital herpes in immunocompetent adults {01}.

Herpes genitalis, recurrent episodes (suppression)1—Valacyclovir is indicated in the suppression of recurrent episodes of genital herpes in immunocompetent adults {01}.

Herpes genitalis, recurrent episodes (treatment)—Valacyclovir is indicated in the treatment of recurrent episodes of genital herpes in immunocompetent adults {01} {15}.

Herpes zoster (treatment)—Valacyclovir is indicated in the treatment of herpes zoster (shingles) infections caused by varicella-zoster virus (VZV) in immunocompetent adults {01} {15}. In patients older than 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 {01}. There are no data on the safety and effectiveness of valacyclovir in children, immunocompromised patients, or patients with disseminated zoster {01}.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Valacyclovir is the hydrochloride salt of the L-valyl ester of acyclovir {01} {08}.
Molecular weight—
    Valacyclovir: 324.34 {09}
    Valacyclovir hydrochloride: 360.8 {01} {02}

Mechanism of action/Effect:

Valacyclovir is a prodrug that is nearly completely converted to acyclovir and L-valine {01}. 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) {01} {03} {06}, Epstein-Barr virus (EBV), and cytomegalovirus (CMV) {03} {06}.

Acyclovir is phosphorylated by thymidine kinase to acyclovir monophosphate, which is then converted into acyclovir diphosphate and triphosphate by cellular enzymes {01}. Acyclovir is selectively converted to the active triphosphate form by cells infected with herpes viruses {03}. Acyclovir triphosphate inhibits herpes viral DNA replication by competitive inhibition of viral DNA polymerase, and by incorporation into and termination of the growing viral DNA chain {01}.

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 {01} {07}. Administration of valacyclovir with food was not found to alter the bioavailability of acyclovir {01}.

The bioavailability of acyclovir following administration of valacyclovir is approximately 54% {01} {12}, which is three to five times greater than its bioavailability following oral administration of acyclovir {13}. 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 {08} {09}.

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 {03} {04} {05} {06}. Highest concentrations are found in the kidneys, liver, and intestines. Acyclovir concentrations in the CSF are approximately 50% of plasma concentrations {03}. In addition, acyclovir crosses the placenta {03} {04} {05} {06}.

Protein binding:

Valacyclovir—Low (13 to 18%) {01}.

Acyclovir—Low (9 to 33%) {03}.

Biotransformation:

Valacyclovir is rapidly and nearly completely (99%) {06} converted to the active compound, acyclovir, and L-valine by first-pass intestinal and hepatic metabolism {01} {07} {08} {09} by enzymatic hydrolysis {08} {09}. Acyclovir is converted to inactive metabolites by alcohol and aldehyde dehydrogenase and, to a small extent, by aldehyde oxidase {01}. The metabolism of valacyclovir and acyclovir is not associated with hepatic microsomal enzyme systems {01}.

Half-life:


Valacyclovir:

Less than 30 minutes {08}.



Acyclovir:


After administration of valacyclovir—

Normal renal function—2.5 to 3.3 hours {01} {08} {09}.

End-stage renal disease—Approximately 14 hours {01}.

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 {07} {08} {09} {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. {01} {08} {09}



Acyclovir:

Peak plasma concentrations are not proportional to the dose.


After a single dose of valacyclovir—

500 mg: Approximately 3.3 mcg/mL {01} {08}.

1 gram: 4.8 to 5.6 mcg/mL {01} {08} {09}.



After multiple doses of valacyclovir—

500 mg: Approximately 3.7 mcg/mL {01} {08}.

1 gram: 5 to 5.5 mcg/mL {01} {08} {09}.



Elimination:


Valacyclovir—
        Less than 1% of valacyclovir is recovered unchanged in the urine over 24 hours {07} {08}.


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 {01} {08}. There was no accumulation of acyclovir after repeated administration of valacyclovir in patients with normal renal function {01}.


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. {01}
        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. {01}




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. {01}

Mutagenicity

An in vitro cytogenetic study with human lymphocytes, a rat cytogenetic study after a single oral dose of 3000 mg/kg (eight to nine times human plasma concentrations), and Ames tests 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 and 51 times human plasma concentrations, respectively). {01}

Pregnancy/Reproduction
Fertility—
Valacyclovir did not impair fertility in rats given a dose of 200 mg/kg per day (six times human plasma concentrations). {01}

Pregnancy—
Acyclovir crosses the placenta {03} {04} {05} {06}. 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 April 1999 has documented 749 pregnancies that were followed in women with live births who were exposed to systemic acyclovir during the first trimester of pregnancy resulting in 756 outcomes. 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. {01}{17}

FDA Pregnancy Category B {01}.

Breast-feeding

It is not known whether valacyclovir is distributed into breast milk {01}. Acyclovir has been found to pass into breast milk at concentrations ranging from 0.6 to 4.1 times the corresponding plasma concentration {01}. At these concentrations, a nursing infant could potentially be exposed to a dose of acyclovir as high as 0.3 mg/kg per day {01}. However, problems in humans have not been documented.

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. {01}


Geriatrics


Studies performed to date have not demonstrated geriatrics-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. {01} {10}In addition, elderly patients are at high risk of dehydration and care should be taken to ensure that these patients have adequate fluid intake.{16}

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.

Cimetidine {01} {11} and
Probenecid {01} {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 is 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 {01} or
» Human immunodeficiency virus (HIV) infection, advanced {01} or
» Renal transplantation {01}    (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 time {14}; 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 impairment {01}    (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 acyclovir {01}
» Renal function impairment {01}    (because valacyclovir is renally excreted, patients with renal function impairment or a history of renal impairment may be at increased risk of toxicity, including enhanced risk of adverse neurological effects{16}; 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 administration of valacyclovir in immunocompetent adults. {01}

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
Incidence less frequent
    
Dysmenorrhea {01}painful menstruation, including (abdominal cramps; diarrhea; nausea)(abdominal cramps; diarrhea; nausea)



Incidence rare
    
Aplastic anemia {16}(chest pain; chills; cough; fever; headache; shortness of breath)
    
decreased consciousness {16}(reduced mental alertness)— in patients with renal insufficiency
    
hepatitis with liver function test abnormalities {16}(flu-like symptoms; unusual tiredness; yellow eyes or skin)
    
renal insufficiency {16}(lower back/side pain; decreased frequency/amount of urine)— manifested by increased serum creatinine
    
thrombocytopenia {16}(black, tarry stools; chest pain; chills; cough; fever)



Incidence not determined
—Observed during clinical practice; estimates of frequency cannot be determined {16}     
Acute hypersensitivity reactions and anaphylaxis {16}(fast heartbeat; swelling of face; wheezing; difficulty in breathing or swallowing; skin rash; itching)
    
aggressive behavior {16}( changes in behavior, especially in interactions with other people)
    
facial edema {16}(swelling or puffiness of face)
    
hallucinations {16}(seeing, hearing, or feeling things that are not there)
    
hemolytic anemia, microangiopathic {16}(back, leg, or stomach pains; chills; difficulty breathing; swelling of face, hands, legs, or feet)
    
hypertension {16}(high blood pressure)
    
skin reactions such as erythema multiforme, photosensitivity, or rash {16}(redness of the skin)
    
tachycardia (fast, pounding, or irregular heartbeat; lightheadedness when getting up from a lying or sitting position )



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Headache {01} {08} {09}
    
nausea {01} {08} {09} {13}

Incidence less frequent
    
Arthralgia {01}(joint pain)
    
dizziness {01}{08}
    
fatigue (unusual tiredness or weakness){01}{09}
    
gastrointestinal disturbances (constipation; diarrhea; loss of appetite; stomach pain; vomiting){01}{08}{09}



Incidence not determined
—Observed during clinical practice; estimates of frequency cannot be determined {16}    
Agitation {16}(anxiety; dry mouth ; irritability; nervousness; restlessness)
    
confusion {16}(mood or mental changes)
{16}




Overdose
For specific information on the agents used in the management of Valacyclovir overdose, see:    • Charcoal, Activated (Oral-Local) monograph.

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

Note: To date, there is limited information on overdosage with valacyclovir {01}{16}. However, precipitation of acyclovir in the renal tubules has occurred with rapid or high intravenous doses of acyclovir {03}. No significant adverse effects have been seen with oral overdoses of acyclovir of up to 20 grams {06}. Confusion headache, nausea, and vomiting have been associated with repeated overdoses of oral acyclovir.{16}

The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Effects of Overdosage with Intravenous Acyclovir
    
Agitation {16} ( anxiety; dry mouth; irritability; nervousness; restlessness )
    
coma {16} (loss of consciousness)
    
elevated serum creatinine with subsequent renal failure{16} (lower back/side pain; decreased urine output; decreased frequency of urination)
    
hallucinations{16} (seeing, hearing, or feeling things that are not there)
    
seizures{16} (convulsions)


Treatment of overdose
To decrease absorption—Activated charcoal may be used to aid removal of unabsorbed valacyclovir.{16}

Treatment is symptomatic and supportive.

If acute renal failure or anuria occurs, hemodialysis may be helpful until renal function is restored {01} {03}{16}.


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





Use in the elderly—Increased risk of dehydration
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; within 48 hours of the onset of rash, pain, or burning when used to treat shingles or an initial episode of genital herpes, or within 24 hours of onset when used to treat recurrent genital herpes

Valacyclovir may be taken with meals

» Compliance with full course of therapy; not using more often or for longer than prescribed

» Proper dosing
Missed 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
Signs of dysmenorrhea, aplastic anemia, decreased consciousness, hepatitis with liver function test abnormalities, renal insufficiency, thrombocytopenia, acute hypersensitivity reactions and anaphylaxis, aggressive behavior, facial edema, hallucinations, microangiopathic hemolytic anemia, hypertension, skin reactions such as erythema multiforme, photosensitivity, rash, or tachycardia


General Dosing Information
For treatment of initial or recurrent episodes of genital herpes, valacyclovir therapy should be initiated as soon as possible following the onset of signs and symptoms. In clinical studies, therapy for an initial episode was most effective when initiated within 48 hours of the onset of signs and symptoms; therapy for recurrent episodes was most effective when initiated within 24 hours. {01}

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 effective if started within 48 hours. {01}

Valacyclovir may be taken with meals since absorption has not been shown to be significantly affected by food. {01}

Adults with impaired renal function may require a change in dosing, as follows: {01}

  Creatinine clearance
(mL/min)/(mL/sec) 
Indication  ³ 50/0.83  30–49/0.5–0.82  10–29/0.16–0.49  < 10/0.16 
Genital herpes, treatment of initial episode  1 gram
every 12 hours 
1 gram
every 12 hours 
1 gram
every 24 hours 
500 mg
every 24 hours 
Genital herpes, treatment of recurrent episodes  500 mg
every 12 hours 
500 mg
every 12 hours 
500 mg
every 24 hours 
500 mg
every 24 hours 
Genital herpes, suppression  500 mg
every 24 hours * 
500 mg
every 24 hours * 
500 mg
every 48 hours * 
500 mg
every 48 hours * 
1 gram
every 24 hours 
1 gram
every 24 hours 
500 mg
every 24 hours 
500 mg
every 24 hours 
Herpes zoster treatment  1 gram
every 8 hours 
1 gram
every 12 hours 
1 gram
every 24 hours 
500 mg
every 24 hours 
Hemodialysis patients  Patients requiring hemodialysis should receive the recommended dose after hemodialysis. 
Peritoneal dialysis patients   Supplemental doses should not be required. 
* Recommended for patients with a history of nine or fewer recurrent episodes of herpes genitalis per year.


Patients should maintain adequate fluid intake during valacyclovir therapy, especially elderly patients who are at increased risk of dehydration.{16}


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

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
Herpes genitalis, treatment of initial episode1
Oral, 1 gram (base) two times a day for ten days{01}.

Herpes genitalis, treatment of recurrent episodes1
Oral, 500 mg (base) two times a day for three days.{17}

[Herpes genitalis, treatment of recurrent episodes]
Oral, 500 mg (base) two times a day for five days{01} {15}.

Herpes genitalis, suppression of recurrent episodes1
Oral, 1 gram (base) once a day{01}.
Note: For patients with a history of nine or fewer recurrent episodes per year, 500 mg once a day may be given{01}.



Herpes zoster, treatment
Oral, 1 gram (base) three times a day for seven days{01} {15}.


Usual pediatric dose
Safety and efficacy in patients younger than 18 years of age have not been established{01}.

Usual geriatric dose
See Usual adult dose.{01}

Strength(s) usually available
U.S.—


500 mg (base) (Rx) [Valtrex]{01}


1 gram (base) (Rx) [Valtrex]{01}

Canada—


500 mg (base) (Rx) [Valtrex]{15}

Packaging and storage:
Store between 15 and 25 °C (59 and 77 °F), in a tight container. Protect from light.{01}{06}

Auxiliary labeling:
   • Continue medicine for full time of treatment.



Developed: 05/28/1996
Revised: 08/16/2001



References
  1. Valtrex package insert (Glaxo Wellcome—US), New 6/95, Rec 9/95; Rev 9/97, Rec 10/97.
  1. Fleeger CA, editor. USP dictionary of USAN and international drug names 1996. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1995: 737.
  1. Acyclovir sterile powder (Zovirax, Burroughs Wellcome). In: PDR Physicians" desk reference. 49th ed. 1995. Montvale, NJ: Medical Economics Data Production Company, 1995: 831-4.
  1. O'Brien JJ, Campoli-Richards DM. Acyclovir. Drugs 1989; 37(3): 233-309.
  1. Hung SO, Patterson A, Rees PJ. Pharmacokinetics of oral acyclovir (Zovirax) in the eye. Br J Ophthalmol 1984; 68: 192-5.
  1. Valtrex (valacyclovir) fact sheet (Glaxo Wellcome), Rev 8/25/95, Rec 9/95.
  1. Easterbrook P, Wood MJ. Successors to acyclovir. J Antimicrob Chemother 1994; 34: 307-11.
  1. Weller S, Blum R, Doucette M, et al. Pharmacokinetics of the acyclovir pro-drug valaciclovir after escalating single- and multiple-dose administration to normal volunteers. Clin Pharmacol Ther 1993; 54: 595-605.
  1. Jacobson MA, Gallant J, Wang LH, et al. Phase I trial of valacyclovir, the L-valyl ester of acyclovir, in patients with advanced human immunodeficiency virus disease. Antimicrob Agents Chemother 1994; 38(7): 1534-40.
  1. Wang LH, Schultz M, Weller S, et al. Pharmacokinetics and safety of valaciclovir, an acyclovir prodrug, in geriatric volunteers with and without concomitant diuretic therapy [abstract P16]. J Am Geriatr Soc 1993; 41(Suppl 10): SA23.
  1. Rolan PE, Maillot F, On NT, et al. The effects of cimetidine and probenecid on the conversion of a valine ester of acyclovir, 256U, to acyclovir and acyclovir renal clearance in healthy volunteers [abstract]. Br J Clin Pharmacol 1993; 33(5): 533.
  1. Coakley D, Weller S, Blum MR, et al. Valtrex (valaciclovir) administration achieves increased acyclovir concentrations in multiple populations [abstract 176]. Pharmacotherapy 1994; 14(3): 373.
  1. Beutner KR, Friedman DJ, Forszpaniak C, et al. Valaciclovir compared with acyclovir for improved therapy for herpes zoster in immunocompetent adults. Antimicrob Agents Chemother 1995; 39(7): 1546-53.
  1. Panel comment, 11/95.
  1. Valacyclovir product monograph (Valtrex—Glaxo Wellcome, Canada), Rev 9/96, Rec 1/97.
  1. Product Information: Valtrex®, valacyclovir hydrochloride caplets. Glaxo Wellcome Inc., Mississauga, Ontario, Canada, (PI revised 3/2000) reviewed 5/2000.
  1. Product Information: Valtrex®, valacyclovir hydrochloride caplets. GlaxoSmithKline, Research Triangle Park, NC (PI revised 6/2001) reviewed 8/2001.
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