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Medication Safety Issues

Sound-alike/look-alike issues:

Valtrex® may be confused with Valcyte™, Zovirax®

ValACYclovir may be confused with acyclovir, valGANCIclovir, vancomycin

Pronunciation

(val ay SYE kloe veer)

U.S. Brand Names

• Valtrex®

Index Terms

• Valacyclovir Hydrochloride

Generic Available

No

Canadian Brand Names

• Apo-Valacyclovir®
• PMS-Valacyclovir
• Riva-Valacyclovir
• Valtrex®

Pharmacologic Category

• Antiviral Agent
• Antiviral Agent, Oral

Pharmacologic Category Synonyms

• Oral Antiviral Agent

Use: Labeled Indications

Treatment of herpes zoster (shingles) in immunocompetent patients; treatment of first-episode and 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); chickenpox in immunocompetent children

Use: Dental

Treatment of herpes labialis (cold sores)

Use: Unlabeled/Investigational

Prophylaxis of cancer-related HSV, VZV, and CMV infections; treatment of cancer-related HSV, VZV infection

Pregnancy Risk Factor

B

Pregnancy Considerations

Teratogenic events were not observed in animal studies. Data from a pregnancy 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

Breast-Feeding Considerations

Peak concentrations in breast milk range from 0.5-2.3 times the corresponding maternal acyclovir serum concentration. This is expected to provide a nursing infant with a dose of acyclovir equivalent to ~0.6 mg/kg/day following ingestion of valacyclovir 500 mg twice daily by the mother. Use with caution while breast-feeding.

Contraindications

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

Warnings/Precautions

Concerns related to adverse effects:

• Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome: Has occurred in immunocompromised patients (at doses of 8 g/day).

• Urinary precipitation: Decreased precipitation in renal tubules may occur; adequately hydrate patient.

Disease-related concerns:

• Renal impairment: Use caution in patients with renal impairment, the elderly, and/or those receiving nephrotoxic agents. Acute renal failure and CNS effects have been observed in patients with renal dysfunction; dose adjustment may be required.

Special populations:

• Elderly: Use with caution in the elderly; CNS effects have been reported.

• Immunocompromised patients: Advanced HIV (CD4 <100 cells/mm³): Safety and efficacy have not been established for treatment/suppression of recurrent genital herpes or disseminated herpes in patients with profound immunosuppression.

• Pediatrics: Safety and efficacy have not been established in patients <2 years of age.

Other warnings/precautions:

• Appropriate use: For cold sores, treatment should begin with earliest symptom (tingling, itching, burning). 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 chickenpox, treatment should begin with earliest sign or symptom.

Adverse Reactions

>10%:

Central nervous system: Headache (13% to 38%)

Gastrointestinal: Nausea (5% to 15%), abdominal pain (1% to 11%)

Hematologic: Neutropenia (?18%)

Hepatic: ALT increased (?14%), AST increased (2% to 16%)

Respiratory: Nasopharyngitis (?16%)

1% to 10%:

Central nervous system: Fatigue (?8%), depression (?7%), fever (children 4%), dizziness (2% to 4%)

Dermatologic: Rash (?8%)

Endocrine: Dysmenorrhea (?1% to 8%), dehydration (children 2%)

Gastrointestinal: Vomiting (<1% to 6%), diarrhea (children 5%; adults <1%)

Hematologic: Thrombocytopenia (?3%)

Hepatic: Alkaline phosphatase increased (?4%)

Neuromuscular & skeletal: Arthralgia (<1 to 6%)

Respiratory: Rhinorrhea (children 2%)

Miscellaneous: Herpes simplex (children 2%)

<1%, postmarketing, and/or case reports: Acute hypersensitivity reactions (angioedema, anaphylaxis, dyspnea, pruritus, rash, urticaria); aggression, agitation, alopecia, anemia, aplastic anemia, ataxia, creatinine increased, coma, confusion, consciousness decreased, dysarthria, encephalopathy, erythema multiforme, facial edema, hallucinations (auditory and visual), hemolytic uremic syndrome (HUS), hepatitis, hypertension, leukocytoclastic vasculitis, leukopenia, mania, photosensitivity reaction, psychosis, renal failure, renal pain, seizure, tachycardia, thrombotic thrombocytopenic purpura (TTP), tremor, urinary precipitation, visual disturbances

Drug Interactions

Mycophenolate: Acyclovir-Valacyclovir may increase the serum concentration of Mycophenolate. Mycophenolate may increase the serum concentration of Acyclovir-Valacyclovir. Risk C: Monitor therapy

Tenofovir: Acyclovir-Valacyclovir may decrease the excretion of Tenofovir. Risk C: Monitor therapy

Zidovudine: Acyclovir-Valacyclovir may enhance the CNS depressant effect of Zidovudine. Risk C: Monitor therapy

Zoster Vaccine: Acyclovir-Valacyclovir may diminish the therapeutic effect of Zoster Vaccine. Management: When possible, discontinue antiviral agents with anti-zoster activity (i.e., acyclovir, valacyclovir, famciclovir) for at least 24 hours prior to and 14 days after receiving a live attenuated zoster vaccine. Risk X: Avoid combination

Storage

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: ~14% to 18%

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; During hemodialysis: 4 hours

Excretion: Urine, primarily as acyclovir (89%); 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:

Children 2 to <18 years: Chickenpox: 20 mg/kg/dose 3 times/day for 5 days (maximum: 1 g 3 times/day)

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

Adults:

CMV prophylaxis in allogeneic HSCT recipients (unlabeled use): 2 g 4 times/day

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

HSV, VZV in cancer patients (unlabeled use): Prophylaxis: 500 mg 2-3 times/day; Treatment: 1 g 3 times/day

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 adjustment in renal impairment:

Herpes zoster: Adults:

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

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

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

Genital herpes: Adults:

Initial episode:

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

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

Recurrent episode: Cl_cr <29 mL/minute: 500 mg every 24 hours

Suppressive therapy: Cl_cr <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:

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

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

Cl_cr <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

Dosing adjustment in hepatic impairment: No adjustment required.

Dental Usual Dosing

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

Administration: Oral

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. Use appropriate precautions to prevent spread to other persons. Take as directed, with or without food. Begin use at first sign of herpes. Maintain adequate hydration 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, or abdominal pain (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help). Immediately report difficulty swallowing or breathing; rash or hives; changes in menses; or other persistent unresolved adverse effects. Breast-feeding precaution: Consult prescriber if breast-feeding.

Geriatric Considerations

More convenient dosing and increased bioavailability, without increasing side effects, make valacyclovir a favorable choice compared to acyclovir. Has been shown to accelerate resolution of postherpetic pain. Adjust dose for renal impairment.

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

Nursing: Physical Assessment/Monitoring

Assess potential for interactions with other pharmacologic agents or herbal products patient may be taking. Assess therapeutic effectiveness (resolution of clinical symptoms) and adverse responses (eg, CNS changes [dizziness, depression], nausea, vomiting, dysmenorrhea, arthralgia). Teach patient appropriate use (eg, timing of treatment according to purpose for use), possible side effects/appropriate interventions, and adverse symptoms to report.

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Caplet:

Valtrex®: 500 mg, 1000 mg

Pricing: U.S. (www.drugstore.com)

Tablets (Valtrex)

1 g (30): $365.87

500 mg (30): $233.81

Extemporaneously Prepared

To prepare a valacyclovir 25 mg/mL oral suspension, crush five valacyclovir 500 mg caplets (10 caplets for 50 mg/mL suspension) into a fine powder in a mortar. Gradually add 5 mL aliquots of Suspension Structured Vehicle USP-NF (SSV) to powder and triturate until a paste is formed. Continue adding 5 mL aliquots of SSV to the mortar until a suspension is formed (minimum 20 mL SSV and maximum 40 mL SSV). Transfer to 100 mL bottle. Add the cherry flavor (amount recommended on package) to the mortar and dissolve in ~5 mL of SSV. Add to bottle once dissolved. Rinse the mortar at least 3 times with ~5 mL of SSV, transferring contents between additions of SSV. Continue to add the SSV to bring final volume to 100 mL. The preparation is stable for 28 days under refrigeration; shake well before using. (Refer to manufacturer's current labeling.)

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.

National Comprehensive Cancer Network® (NCCN), “Clinical Practice Guidelines in Oncology™: Prevention and Treatment of Cancer-Related Infections,” Version 1.2008. Available at http://www.nccn.org/professionals/physician_gls/PDF/infections.pdf.

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 Prodrug Valaciclovir After Escalating Single- and Multiple-Dose Administration to Normal Volunteers,” Clin Pharmacol Ther, 1993, 54(6):595-605.

International Brand Names

• Herclov (ID)
• Lizhuwei (CL)
• Rapivir (MX, UY)
• Talavir (IT)
• Valcivir (IN)
• Valcyclor (CO)
• Valtrex (AE, AR, AT, AU, BB, BD, BG, BH, BM, BR, BS, BZ, CH, CL, CN, CO, CR, CY, CZ, DE, DO, EC, EE, EG, ES, FI, GB, GT, GY, HK, HN, ID, IE, IL, IN, IQ, IR, JM, JO, JP, KP, KW, LB, LY, MY, NI, NL, NO, OM, PA, PH, PK, PT, PY, QA, SA, SE, SG, SR, SV, SY, TH, TT, TW, VE, YE)
• Valvir (ID)
• Viranet (AR)
• Zelitrex (BE, DK, FR, NL)
• Zosvir (EC)

Lexi-Comp.com

Last full review/revision September 2009

Content last modified September 2009