Valacyclovir

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Valacyclovir quick reference

Valacyclovir
Valacyclovir general drug information
 Pronunciation val ay SYE kloe veer (.wav file)
 Trade Name(s) Valtrex
 How Supplied Oral caplets: 500 mg, 1000 mg
 Generic Availability No generics available
 Patent Expiry Date June 2009
 Classification antiviral
 Schedule Rx
 Pregnancy Category B
 Breast-feeding Use with caution and only when indicated.
Valacyclovir chemical information
 IUPAC Name L-valine,2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester, monohydrochloride
 Empirical Formula C13H20N6O4•HCl
 Molecular Weight 360.80 g/mol
pharmacokinetic information  |  pharmacogenomic information

Description

Valacyclovir is the L-valyl ester of acyclovir and is an oral antiviral agent that is supplied as a 500 mg and 1 gram caplet. It was approved by the FDA for the treatment of herpes zoster (shingles) in immunocompetent patients, the treatment of initial and recurrent herpes genitalis infections, maintenance (suppression) of herpes genitalis, the suppression of recurrent genital herpes in patients with HIV, and herpes labialis.[1] [2]

Acyclovir was the first antiviral considered the gold standard for the treatment of herpes infections. As such, all other anti-herpesvirus medications are compared to it. Valacyclovir has a better oral bioavailability than acyclovir. This allows for a reduction in the number of required doses per day for successful treatment, thus increasing patient compliance.[3]

Mechanism of Action

Valacyclovir is rapidly converted to the active form, acyclovir, by hepatic metabolism. Acyclovir is then converted to acyclovir monophosphate by virus specific thymidine kinase and then ultimately converted to acyclovir triphosphate via cellular enzymes. Acyclovir triphosphate inhibits viral DNA synthesis by competing with deoxyguanosine triphosphate for viral DNA polymerase, gaining incorporation into and termination of the growing viral DNA chain, or inactivating the viral DNA polymerase.[2]

Time Required for Therapeutic Response

  • Initial: 3-5 days
  • Maximum: N/A

Pharmacokinetics

Absorption
After oral administration of valacyclovir, the prodrug is rapidly metabolized to its active counterpart, acyclovir. Acyclovir is then rapidly absorbed with an absolute bioavailability of 54.5%.[2][4][5] The bioavailability of acyclovir after the administration of valacyclovir is not affected by food consumption.[2] The Cmax and AUC are dose-dependent and show no proportionality.[2][4] In one study, after single doses of valacyclovir 100 mg, 250 mg, 500 mg, 750 mg, and 1 gram to 8 healthy volunteers, the mean Cmax (± SD) was 0.83 (± 0.14), 2.15 (± 0.50), 3.28 (± 0.83), 4.17 (± 1.14), and 5.65 (± 2.37) mcg/mL, respectively; and the mean AUC (± SD) was 2.28 (± 0.40), 5.76 (± 0.60), 11.59 (± 1.79), 14.11 (± 3.54), and 19.52 (± 6.04) hr•mcg/mL, respectively.[2] No accumulation of the drug was found in several studies, when normal therapeutic dosing was administered.[2][4]

Distribution
The protein binding of valacyclovir ranges from 13.5% to 17.9%,[2][5] and distributes into most body tissues.[5]

Metabolism
Valacyclovir is hepatically metabolized to acyclovir (active metabolite) and L-valine by first-pass metabolism. Acyclovir undergoes minimal hepatic metabolism by aldehyde oxidase, alcohol dehydrogenase, and aldehyde dehydrogenase to form inactive metabolites.[2] It is suspected that the metabolism of valacyclovir to acyclovir occurs in the gut lumen before it is absorbed. It could also take place in the small intestine after uptake has occurred, but prior to its entry into the portal blood system. The minimal hepatic metabolism occurs before entry into the systemic circulation.[5]

Excretion
Acyclovir is primarily eliminated by the kidneys via glomerular filtration and tubular secretion and found unchanged in the urine.[2][5] The plasma elimination half-life of acyclovir after administration of valacyclovir ranges from 2.5 to 3.3 hours in patients with normal renal function.[2]

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Special Population Pharmacokinetics

  • Renal insufficiency: The elimination half-life of acyclovir following valacyclovir administration in patients with end stage renal disease (ESRD) is approximately 14 hours. Patients with renal dysfunction should follow a modified dosing regimen.[2]
  • Hepatic insufficiency: Studies have shown that the rate of conversion from valacyclovir to acyclovir is reduced in patients with moderate to severe hepatic insufficiency. However, the elimination half-life is not changed and no dosing changes are required.[2]
  • Hemodialysis: During hemodialysis, the elimination half-life of acyclovir following valacyclovir administration is approximately 4 hours and about one-third of the dose is removed from the blood during hemodialysis. Patients receiving hemodialysis should receive their dose of valacyclovir following their dialysis session.[2]
  • Geriatric: The elimination half-life of acyclovir following administration of valacyclovir was slightly longer in healthy geriatric patients when compared to healthy volunteers (3.11 ± 0.51 hours vs. 2.91 ± 0.63 hours). The pharmacokinetics depended on the patient's renal function. Therefore, dose adjustments may be necessary and should be based on the patient's current renal status.[2]
  • Pediatric: Valacyclovir pharmacokinetics has not been evaluated in this population.
  • Gender: No dosage adjustment is needed.

Indications and Dosages

FDA Approved Indications

Herpes genitalis[3][6][7]

  • Starting dose (first episode):
    • 1 g twice daily for 10 days starting at the first sign or symptom of lesions, preferably within 48 hours of onset.
  • Maintenance dose (recurrent episodes):
    • 500 mg twice daily for 3 days starting at the first sign or symptom of lesions, preferably within 24 hours of onset.

Herpes zoster (shingles)[3][6][7]

  • Starting dose:
    • 1 g three times a day for 7 days starting at the first sign or symptom of herpes zoster, preferably within 48 hours of onset.

Herpes labialis[3][6][7]

  • Starting dose:
    • 2 g every 12 hours for 2 doses starting at the first sign or symptom of lesions.

Herpes genitalis prophylaxis[3][6][7]
Herpes simplex virus type 1[3][6][7]
Herpes simplex virus type 2[3][6][7]
Varicella-zoster virus[3][6][7]

Non-FDA Approved Indications

  • Bell's palsy [8]
  • Cytomegalovirus (CMV)[3][6][7]
  • Cytomegalovirus (CMV) infection prophylaxis[3][6][7]
  • Epstein-Barr Virus infection prophylaxis[3][6][7]
  • Herpes simplex infection prophylaxis

Dosage Adjustment

Renal insufficiency:

  • CrCl 30—49 ml/min: For regimens of 1 g orally every 8 hours, change to 1 g orally every 12 hours. For treatment of herpes labialis, give 1 g orally every 12 hours for 2 doses.
  • CrCl 10—29 ml/min: For regimens of 1 g orally every 8—12 hours, reduce dose to 1 g orally every 24 hours. For regimens of 1 g orally per day, reduce dose to 500 mg orally per day. For regimens of 500 mg per day, change dose to 500 mg every 48 hours. For one-day treatment of herpes labialis, give 500 mg orally every 12 hours for 2 doses.
  • CrCl <10 ml/min: For regimens of 1 g orally every 8—24 hours or 500 mg orally every 12 hours, reduce dose to 500 mg once daily. For regimens of 500 mg once daily, change dose to 500 mg every 48 hours. For one-day treatment of herpes labialis, give 500 mg PO for 1 dose.

Hemodialysis: Approximately one-third of the valacyclovir dose is removed from the body during hemodialysis. The patient should receive the appropriate dose after the hemodialysis session.
Geriatric: No age specific data available, however renal function should be considered.
Pediatric: No data available.

Dosage Limits

  • Adults: 3 g/day
  • Elderly: 3 g/day
  • Adolescents and children ≥10 years: Information is not available
  • Children <10 years: Information is not available


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Administration

  • Route: Oral
  • Method:
    • May be taken without regard to meals. If GI upset occurs, take with a meal.

Monitoring Parameters

  • Serum creatinine/BUN: baseline
  • Urinalysis
  • Liver enzymes
  • CBC

Contraindications/Precautions

Contraindications

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

Precautions

  • Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) has occurred in advanced HIV patients as well as allogeneic bone marrow transplant and renal transplant recipients who were receiving high doses (8 grams per day) of valacyclovir. This can be fatal.
  • Dosage reduction is recommended when administering valacyclovir to patients with renal impairment.

Pregnancy indications

Category B [2]

There are no adequate well-controlled trials in pregnant women. Valacyclovir was not teratogenic in rats or rabbits at 10 and 7 times human plasma levels.

Breast-feeding indications

Secretion into breast milk: valacyclovir should be administered to a nursing mother with caution and only when indicated. In a study of five nursing mothers, a 500 mg dose of valacyclovir was given. The peak acyclovir concentrations (Cmax) in the breast milk ranged from 0.5 to 2.3 times (median 1.4) the corresponding maternal acyclovir serum concentrations, however this equaled to an oral acyclovir dosage of approximately 0.6 mg/kg/day. This exposure would be less than 2% of the standard dose for a neonate, which is 30 mg/kg/day given intravenously.[2]

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Drug-Drug, -Food, -Herb Interactions

Click the link above to go to the drug interactions page.

Adverse Reactions/Side Effects

Valacyclovir Adverse Reactions Chart[2][9][10] [11] [12]
Incidence Body System Adverse Reactions
>10% All Headache (14-35%)
1-10% CNS Dizziness (2-4%), Depression (0-7%)
GI Abdominal pain (2-11%), vomiting (<1-6%), nausea (6-15%)
Neuromuscular/skeletal Arthralgia (<1-6%)
Misc Dysmenorrhea (<1-8%), AST increased (1-4%)
<1% All Acute hypersensitivity reactions (angioadema, anaphylaxis, dyspnea, pruritis, rash, urticaria), aggression, agitation, alopecia, aplastic anemia, ataxia, coma, confustion, dysarthria, encephalopathy, erythema multiforme, hallucinations, hemolytic uremic syndrome, hepatitis, leukocytoclastic vasculitis, leukopenia, mania, photosensitivity, psychosis, rash, renal failure, seizure, thrombocytopenia, thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, tremor

Overdosage Measures

Precipitation of acyclovir in renal tubules may occur when the solubility is exceeded in the intratubular fluid.
Treatment (in the event of acute renal failure and anuria):

  • Hemodialysis should be considered until renal function is restored.
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Product Information and Distribution

Note: appearance only available for brand-name product
Dose/form Drug color(s) Drug shape Markings or odor/flavor
500 mg tablet blue oval VALTREX 500 mg
1 g tablet blue oval VALTREX 1 gram
  • Inactive ingredients for tablets: carnauba wax, colloidal silicon dioxide, crospovidone, FD&C Blue No. 2, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone, titanium dioxide

Patient Information

  • Take as directed, with or without food.
  • Maintain adequate hydration unless otherwise restricted.
  • Begin use at the first sign of a herpes outbreak.
  • Remember that this is not a cure for herpes, and spread is possible even when no symptoms are present.
  • May cause dizziness (use caution while driving or operating heavy machinery).
  • May cause headache, nausea, vomiting, and abdominal pain. If GI upset occurs, take with a meal.
  • Immediately report difficulty of breathing or swallowing, hives or rash, or changes in menses.
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References

  1. ↑ Food and Drug Administration. Drugs@FDA Data Files. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm 2007.
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 GlaxoSmithKline. Valtrex (valacyclovir) Prescribing Information. Research Triangle Park, NC 2006.
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 <Perry CM, Faulds D. Valaciclovir. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in herpesvirus infections. Drugs 1996;52(5):754-72.
  4. ↑ 4.0 4.1 4.2 Beutner KR. Valacyclovir: a review of its antiviral activity, pharmacokinetic properties, and clinical efficacy. Antiviral Res 1995;28(4):281-90.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 MacDougall C, Guglielmo BJ. Pharmacokinetics of valaciclovir. J Antimicrob Chemother 2004;53(6):899-901.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 6.9 Wu JJ, Brentjens MH, Torres G, Yeung-Yue K, Lee P, Tyring SK. Valacyclovir in the treatment of herpes simplex, herpes zoster, and other viral infections. J Cutan Med Surg 2003;7(5):372-81.
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 Weller S, Blum MR, Doucette M, Burnette T, Cederberg DM, de Miranda P, 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.
  8. ↑ Hato N, Yamada H, Kohno H, Matsumoto S, Honda N, Gyo K, et al. Valacyclovir and Prednisolone Treatment for Bell's Palsy: A Multicenter, Randomized, Placebo-Controlled Study. Otol Neurotol 2007;28(3):408-13.
  9. ↑ Saiag P, Praindhui D, Chastang C. A double-blind, randomized study assessing the equivalence of valacyclovir 1000 mg once daily versus 500 mg twice daily in the episodic treatment of recurrent genital herpes. Genival Study Group. J Antimicrob Chemother 1999;44(4):525-31.
  10. ↑ Ormrod D, Scott L, Perry C. Valaciclovir: A review of its long term utility in the management of genital herpes simplex virus and cytomegalovirus infections. Drugs 2000;59(4):839-63.
  11. ↑ Corey L, Wald A, Patel R, Sacks SL, Tyring SK, Warren T, et al. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med 2004;350(1):11-20.
  12. ↑ Tyring SK, Douglas JM, Jr., Corey L, Spruance SL, Esmann J. A randomized, placebo-controlled comparison of oral valacyclovir and acyclovir in immunocompetent patients with recurrent genital herpes infections. The Valaciclovir International Study Group. Arch Dermatol 1998;134(2):185-91

PUBMED References

Efficacy Trial Articles

  1. Beutner KR. Valacyclovir: a review of its antiviral activity, pharmacokinetic properties, and clinical efficacy. Antiviral Res 1995;28(4):281-90
  2. Saiag P, Praindhui D, Chastang C. A double-blind, randomized study assessing the equivalence of valacyclovir 1000 mg once daily versus 500 mg twice daily in the episodic treatment of recurrent genital herpes. Genival Study Group. J Antimicrob Chemother 1999;44(4):525-31
  3. Ormrod D, Scott L, Perry C. Valaciclovir: A review of its long term utility in the management of genital herpes simplex virus and cytomegalovirus infections. Drugs 2000;59(4):839-63
  4. Corey L, Wald A, Patel R, Sacks SL, Tyring SK, Warren T, et al. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med 2004;350(1):11-20
  5. Wu JJ, Brentjens MH, Torres G, Yeung-Yue K, Lee P, Tyring SK. Valacyclovir in the treatment of herpes simplex, herpes zoster, and other viral infections. J Cutan Med Surg 2003;7(5):372-81.
  6. Hato N, Yamada H, Kohno H, Matsumoto S, Honda N, Gyo K, et al. Valacyclovir and Prednisolone Treatment for Bell's Palsy: A Multicenter, Randomized, Placebo-Controlled Study. Otol Neurotol 2007;28(3):408-13.
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Therapeutic Class Comparison Articles

  1. Tyring SK, Douglas JM, Jr., Corey L, Spruance SL, Esmann J. A randomized, placebo-controlled comparison of oral valacyclovir and acyclovir in immunocompetent patients with recurrent genital herpes infections. The Valaciclovir International Study Group. Arch Dermatol 1998;134(2):185-91

Pharmacokinetics Articles

  1. Beutner KR. Valacyclovir: a review of its antiviral activity, pharmacokinetic properties, and clinical efficacy. Antiviral Res 1995;28(4):281-90
  2. MacDougall C, Guglielmo BJ. Pharmacokinetics of valaciclovir. J Antimicrob Chemother 2004;53(6):899-901
  3. Perry CM, Faulds D. Valaciclovir. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in herpesvirus infections. Drugs 1996;52(5):754-72.
  4. Weller S, Blum MR, Doucette M, Burnette T, Cederberg DM, de Miranda P, 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.
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Drug Interaction Articles

  1. DeBony F, Tod M, Bidault M, et al. Multiple interactions of cimetidine and probenecid with valacyclovir and its metabolite acyclovir. Antimicrob Agents Chemother 2002;46:458—63
  2. Parmeggiani A, Riva R, Posar A, et al. Possible interaction between acyclovir and antiepileptic treatment. Ther Drug Monit 1995;17:312—5

Adverse Effects Articles

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Compliance Articles

Pharmacoeconomic Articles

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External Links

Clinical treatment guidelines

Patient information pages

Other resources

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