Valacyclovir

Pronunciation

(val ay SYE kloe veer)

U.S. Brand Names

Valtrex®

Synonyms

Valacyclovir Hydrochloride

Generic Available

Canadian Brand Names

Valtrex®

Use

Treatment of herpes zoster (shingles) in immunocompetent patients; treatment of first-episode genital herpes; episodic treatment of recurrent genital herpes; suppression of recurrent genital herpes and reduction of heterosexual transmission of genital herpes in immunocompetent patients; suppression of genital herpes in HIV-infected individuals; treatment of herpes labialis (cold sores)

Pregnancy Risk Factor

Pregnancy Implications

Teratogenicity registry has shown no increased rate of birth defects than that of the general population; however, the registry is small and use during pregnancy is only warranted if the potential benefit to the mother justifies the risk of the fetus.

Lactation

Enters breast milk/use caution

Contraindications

Hypersensitivity to valacyclovir, acyclovir, or any component of the formulation

Warnings/Precautions

Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome has occurred in immunocompromised patients (at doses of 8 g/day); use caution and adjust the dose in elderly patients or those with renal insufficiency and in patients receiving concurrent nephrotoxic agents. For genital herpes, treatment should begin as soon as possible after the first signs and symptoms (within 72 hours of onset of first diagnosis or within 24 hours of onset of recurrent episodes). For herpes zoster, treatment should begin within 72 hours of onset of rash. For cold sores, treatment should begin at with earliest symptom (tingling, itching, burning). Safety and efficacy in prepubertal patients have not been established.

Adverse Reactions

>10%: Central nervous system: Headache (14% to 35%)

1% to 10%:

Central nervous system: Dizziness (2% to 4%), depression (0% to 7%)

Endocrine: Dysmenorrhea ( 1% to 8%)

Gastrointestinal: Abdominal pain (2% to 11%), nausea (6% to 15%), vomiting (<1% to 6%)

Hematologic: Leukopenia ( 1%), thrombocytopenia ( 1%)

Hepatic: AST increased (1% to 4%)

Neuromuscular & skeletal: Arthralgia ( 1 to 6%)

<1%: Anemia

Postmarketing and/or case reports: Acute hypersensitivity reactions (angioedema, anaphylaxis, dyspnea, pruritus, rash, urticaria); aggression, agitation, alopecia, aplastic anemia, ataxia, creatinine increased, coma, confusion, consciousness decreased, diarrhea, dysarthria, encephalopathy, facial edema, erythema multiforme, hallucinations (auditory and visual), hemolytic uremic syndrome (HUS), hepatitis, hypertension, leukocytoclastic vasculitis, mania, photosensitivity reaction, psychosis, rash, renal failure, seizure, tachycardia, thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, tremor, visual disturbances

Overdosage/Toxicology

Precipitation in renal tubules may occur. Treatment is symptomatic and includes hemodialysis, especially if compromised renal function develops.

Drug Interactions

Cimetidine: Decreased renal clearance of acyclovir; no dosage adjustment needed in patients with normal renal function

Probenecid: Decreased renal clearance of acyclovir; no dosage adjustment needed in patients with normal renal function

Stability

Store at 15°C to 25°C (59°F to 77°F).

Mechanism of Action

Valacyclovir is rapidly and nearly completely converted to acyclovir by intestinal and hepatic metabolism. Acyclovir is converted to acyclovir monophosphate by virus-specific thymidine kinase then further converted to acyclovir triphosphate by other cellular enzymes. Acyclovir triphosphate inhibits DNA synthesis and viral replication by competing with deoxyguanosine triphosphate for viral DNA polymerase and being incorporated into viral DNA.

Pharmacodynamics/Kinetics

Absorption: Rapid

Distribution: Acyclovir is widely distributed throughout the body including brain, kidney, lungs, liver, spleen, muscle, uterus, vagina, and CSF

Protein binding: 13.5% to 17.9%

Metabolism: Hepatic; valacyclovir is rapidly and nearly completely converted to acyclovir and L-valine by first-pass effect; acyclovir is hepatically metabolized to a very small extent by aldehyde oxidase and by alcohol and aldehyde dehydrogenase (inactive metabolites)

Bioavailability: ~55% once converted to acyclovir

Half-life elimination: Normal renal function: Adults: Acyclovir: 2.5-3.3 hours, Valacyclovir: ~30 minutes; End-stage renal disease: Acyclovir: 14-20 hours

Excretion: Urine, primarily as acyclovir (88%); Note: Following oral administration of radiolabeled valacyclovir, 46% of the label is eliminated in the feces (corresponding to nonabsorbed drug), while 47% of the radiolabel is eliminated in the urine.

Dosage

Oral:

Adolescents and Adults: Herpes labialis (cold sores): 2 g twice daily for 1 day (separate doses by ~12 hours)

Adults:

Herpes zoster (shingles): 1 g 3 times/day for 7 days

Genital herpes:

Initial episode: 1 g twice daily for 10 days

Recurrent episode: 500 mg twice daily for 3 days

Reduction of transmission: 500 mg once daily (source partner)

Suppressive therapy:

Immunocompetent patients: 1000 mg once daily (500 mg once daily in patients with <9 recurrences per year)

HIV-infected patients (CD4 100 cells/mm³ ): 500 mg twice daily

Dosing interval in renal impairment:

Herpes zoster: Adults:

Clcr 30-49 mL/minute: 1 g every 12 hours

Clcr 10-29 mL/minute: 1 g every 24 hours

Clcr<10 mL/minute: 500 mg every 24 hours

Genital herpes: Adults:

Initial episode:

Clcr 10-29 mL/minute: 1 g every 24 hours

Clcr<10 mL/minute: 500 mg every 24 hours

Recurrent episode: Clcr<10-29 mL/minute: 500 mg every 24 hours

Suppressive therapy: Clcr<10-29 mL/minute:

For usual dose of 1 g every 24 hours, decrease dose to 500 mg every 24 hours

For usual dose of 500 mg every 24 hours, decrease dose to 500 mg every 48 hours

HIV-infected patients: 500 mg every 24 hours

Herpes labialis: Adolescents and Adults:

Clcr 30-49 mL/minute: 1 g every 12 hours for 2 doses

Clcr 10-29 mL/minute: 500 mg every 12 hours for 2 doses

Clcr<10 mL/minute: 500 mg as a single dose

Hemodialysis: Dialyzable (~33% removed during 4-hour session); administer dose postdialysis

Chronic ambulatory peritoneal dialysis/continuous arteriovenous hemofiltration dialysis: Pharmacokinetic parameters are similar to those in patients with ESRD; supplemental dose not needed following dialysis

Administration

If GI upset occurs, administer with meals.

Monitoring Parameters

Urinalysis, BUN, serum creatinine, liver enzymes, and CBC

Dietary Considerations

May be taken with or without food.

Patient Education

This medication is not a cure for genital herpes; it is not known if it will prevent transmission to others. Take as directed, with or without food. Begin use at first sign of herpes. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. May cause headache, dizziness (use caution when driving or engaging in potentially hazardous tasks until response to drug is known); or nausea, vomiting, abdominal pain (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help). Immediately report respiratory difficulty difficulty swallowing, rash, or hives. Breast-feeding precaution: Consult prescriber if breast-feeding.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May cause aggression, agitation, confusion, encephalopathy, hallucinations, mania, psychosis

Mental Health: Effects on Psychiatric Treatment

Use caution in patients with renal impairment; CNS symptoms have been reported in these patients

Dosage Forms

Caplet: 500 mg, 1000 mg

References

Acosta EP and Fletcher CV, "Valacyclovir," Ann Pharmacother , 1997, 31(2):185-91.

Alrabiah FA and Sacks SL, "New Antiherpesvirus Agents. Their Targets and Therapeutic Potential," Drugs , 1996, 52(1):17-32.

Beutner KR, Friedman DJ, Forszpaniak C, et al, "Valacyclovir Compared With Acyclovir for Improved Therapy for Herpes Zoster in Immunocompetent Adults," Antimicrob Agents Chemother , 1995, 39(7):1546-53.

Bodsworth NJ, Crooks RJ, Borelli S, et al, "Valaciclovir Versus Aciclovir in Patients Initiated Treatment of Recurrent Genital Herpes: A Randomized, Double-Blind Clinical Trial. International Valaciclovir HSV Study Group," Genitourin Med , 1997, 73(2):110-6.

Grant DM, Mauskopf JA, Bell L, et al, "Comparison of Valaciclovir and Acyclovir for the Treatment of Herpes Zoster in Immunocompetent Patients Over 50 Years of Age: A Cost-Consequence Model," Pharmacotherapy , 1997, 17(2):333-41.

Patel R, Bodsworth NJ, Woolley P, et al, "Valaciclovir for the Suppression of Recurrent Genital HSV Infection: A Placebo Controlled Study of Once Daily Therapy. International Valaciclovir HSV Study Group," Genitourin Med , 1997, 73(2):105-9.

Perry CM and Faulds D, "Valaciclovir. A Review of Its Antiviral Activity, Pharmacokinetic Properties and Therapeutic Efficacy in Herpesvirus Infections," Drugs , 1996, 52(5):754-72.

Reitano M, Tyring S, Lang W, et al, "Valaciclovir for the Suppression of Recurrent Genital Herpes Simplex Virus Infection: A Large-Scale Dose Range-Finding Study. International Valaciclovir HSV Study Group," J Infect Dis , 1998, 178(3):603-10.

Tyring SK, Douglas JM Jr, Corey L, et al, "A Randomized, Placebo-Controlled Comparison of Oval Valacyclovir and Acyclovir in Immunocompetent Patients With Recurrent Genital Herpes Infections. The Valaciclovir International Study Group," Arch Dermatol , 1998, 134(2):185-91.

"Valacyclovir," Med Lett Drugs Ther , 1996, 38(965):3-4.

Weller S, Blum MR, 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(6):595-605.

International Brand Names

Valtrex® (CA)

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