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Volume 2 • Number 1 • October 1996

Contents: (Full text available in print edition.)


Valacyclovir (Valtrex®, Glaxo Wellcome), the L-valyl ester of acyclovir, is an inactive oral pro-drug that is rapidly and almost completely converted to acyclovir, producing systemic acyclovir levels comparable to those achieved with intravenous acyclovir. Like acyclovir, it is active against a range of herpes viruses including herpes simplex (HSV) and varicella zoster (VZV).


Oral Treatment of Herpes Zoster

This indication for valacyclovir was approved in the USA in August 1995 and in Canada in May 1996. Zoster is treated with 1000 mg of valacyclovir three times daily for seven days.1 In a clinical trial in 1,141 patients over 50 years of age, who started therapy within 72 hours of onset of rash, the median time to cessation of pain with this dosage regimen was 38 days, compared to 51 days for oral acyclovir (800 mg five times a day for seven days) (p=0.001).2 The median duration of post-herpetic neuralgia was also significantly reduced with valacyclovir compared to acyclovir (23% reduction, 30 versus 39 days; p<=0.05).

Genital Herpes

Valacyclovir is approved in the USA for treating recurrent genital herpes, and was approved in Canada for this indication in October 1996. The dose for recurrent genital herpes episodes is 500 mg twice daily for five days.1 In clinical trials, valacyclovir has been studied in over 3,000 patients with recurrent genital herpes. A recently published clinical trial3 in 1,486 patients with recurrent genital herpes showed valacyclovir (versus placebo) provided clinically significant benefit to patients. The clinical endpoints included shortening of the healing time of lesions by 32% (p<0.001), the duration of pain or discomfort by 28% (p=0.001), and the duration of viral shedding by 50% (p=0.001). Spruance and his fellow workers feel that the results of their study offer the first conclusive demonstration that antiviral therapy can abort lesion development. In the valacyclovir treated groups, 28-31% of lesions did not progress to the vesicular stage (p=0.005).

The dosage under study for initial episodes of genital herpes is 1000 mg twice daily for ten days. In clinical trials in 643 patients with first episode disease, valacyclovir was as effective as oral acyclovir (200 mg five times daily) in eliminating symptoms, including complete healing of lesions and duration of viral shedding.4 This indication is not approved in Canada.

Treatment should begin as early as possible for both indications.

Side Effects

In immunocompetent patients, valacyclovir is very well tolerated with similar side effects to acyclovir. Acyclovir is known to have a low incidence of side effects with the most common being nausea and vomiting and headache.4 During clinical trials involving severely immunocompromised patients, some of whom were receiving high doses of oral valacyclovir (2 g four times daily) for prolonged periods of time, isolated cases of syndromes similar to thrombotic thrombocytopenic purpura and/or hemolytic uremic syndrome were reported. While some studies are still ongoing and blinded, the incidence of these syndromes in immunocompromised patients in the valacyclovir trials did not differ from those reported for patient populations with the same medical conditions that were not treated with valacyclovir.

Safety During Pregnancy and Lactation

Although there are no data on the use of valacyclovir in pregnancy, acyclovir is known to cross the placental barrier. However, the observed proportion (3.7%) of birth defects following first trimester exposure to systemic acyclovir in 515 women did not differ from the expected proportion in the general population.5 No data are available on valacyclovir excretion in breast milk, but acyclovir is readily distributed into this fluid. However, the potential exposure of infants to breast milk acyclovir is lower than the licensed treatment dose for neonates.6


Following oral administration, valacyclovir is well absorbed and undergoes rapid and almost complete conversion to acyclovir, resulting in much better bioavailability in comparison to high dose (800 mg four times a day) oral acyclovir.8 Its 54% bioavailability is not reduced by food.6 In normal adults, the plasma half-life of acyclovir after oral valacyclovir administration is 2.5 - 3.3 hours.6,8

Mechanism of Action

Once absorbed, valacyclovir is rapidly converted to acyclovir. Viral thymidine kinase then activates phosphorylation of acyclovir to the monophosphate form, while further phosphorylation results in the formation of acyclovir triphosphate (ACV-TTP), the active form. In vitro, ACV-TTP terminates growing chains of viral DNA. Once incorporated, ACV-TTP irreversibly binds to viral DNA polymerase, effectively inactivating this enzyme and preventing further chain elongation (obligate chain terminator).6

Clinical Assessment

For genital herpes, valacyclovir is equally as effective, reduces the cost of treatment, and provides a more convenient dosing format, to the parent drug acyclovir. In zoster, valacyclovir reduces the median time to cessation of pain and also reduces the duration of post-herpetic neuralgia, in comparison to acyclovir. Treatment must be started within 48-72 hours of the first symptoms.

"Valacyclovir is an attractive drug to use for the treatment of genital herpes and herpes zoster."4


  1. Olin BR, ed. Drug facts and comparisons. St. Louis: Facts and Comparisons, Inc. 1996.
  2. 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: 1546-1553.
  3. Spruance SL, Tyring SK, DeGregorio B, et al. A large scale, placebo-controlled, dose-ranging trial of peroral valaciclovir for episodic treatment of recurrent herpes genitalis. Arch Int Med 1996; 156: 1729-1735.
  4. Memar OM, Tyring SK. Antiviral agents in dermatology: current status and future prospects. Int J Dermatol 1995; 34: 597-606.
  5. Eldridge RE, White AD, Andrews EB. Monitoring birth outcomes in the acyclovir pregnancy registry. Poster presented to the 35th ICAAC, San Francisco, September 1995.
  6. Glaxo Wellcome Canada, Product Monograph, April 1996.
  7. AHFS 95 Drug Information. Bethesda, Maryland. American Society of Health-System Pharmacists. 1995.
  8. Weller S, Blum MR, Doucette M, et al. Pharmacokinetics of the acyclovir pro-drug, valacyclovir after escalating single- and multiple-dose administration to normal volunteers. Clin Pharmacol Ther 1993; 54: 595-605.
Comparative Costs of Seven Days Zoster Therapy
Drug Dose Cost*
Acyclovir Avirax®
800 mg five times daily
Famciclovir Famvir®
500 mg three times daily $142.80
Valacyclovir Valtrex®
1000 mg three times daily $126.84
*1996 list price in Canada (does not include fees, mark-ups, and discounts).

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Minocycline - Benefits and Risks in Treating Acne

Minocycline is widely used in patients with acne who fail to respond to other treatments. Minocycline can be taken with food and causes less GI upset than other tetracyclines and can reduce treatment failures due to poor compliance.1,2 Most strains of P. acnes are sensitive to minocycline, making its availability more important in light of this organism's increasing rate of resistance to tetracycline, doxycycline,1,3 and erythromycin. This year, two papers have been published warning practitioners about serious adverse reactions induced by minocycline,4,5 and the risk/benefit questions raised have been addressed by Professor Cunliffe and Dr. Chu in a widely circulated open letter.1 Reports of serious adverse effects may pose questions in the mind of the prescriber, thereby denying patients the benefit of this valuable anti-acne agent. Because acne is such a common problem, and minocycline after 30 years has proven to be such a useful drug, I feel that there is no need to change our prescribing patterns."

Dr. Stuart Maddin, Editor

Gough et al discussed 34 serious adverse reactions to minocycline reported to the Committee on Safety of Medicines in the UK, concentrating on 11 reports of hepatitis and 11 of a lupus erythematosus-like syndrome.5 Knowles et al described six patients with a serum sickness and one with symptoms consistent with drug-induced lupus.4 Their literature review identified 11 cases of hypersensitivity syndrome, one case of a serum-sickness like reaction, and 24 cases of drug-induced lupus. Shear et al are presently reviewing the adverse effects of other tetracyclines including doxycycline, and their findings will soon be published.6

Cunliffe and Chu, in reviewing Gough et al, pointed out that minocycline is used very extensively. In the UK alone, 21 million tablets are taken annually.1 They noted that two deaths have been reported in patients taking minocycline. One death may have been due to an antimalarial that was being taken concurrently and the other due to idiopathic pancytopenia rather than the minocycline.1 Many of the 25,000 patients with acne that Dr. Cunliffe treated over a 30-year period received minocycline, but there were no deaths due to the minocycline. However, there were five suicides and a further 51 patients admitted to hospital because of the anxiety and depression associated with the disease, not the medications they used for acne. Five of the overdose patients developed liver damage.1 Cunliffe et al have taken blood from more than 3,000 patients taking minocycline without finding any abnormalities in their liver function.1

Serum sickness-like reactions can occur after the ingestion of B-lactam antibiotics, sulfonamides, and propanolol. In the six cases of this reaction in patients taking minocycline reported by Knowles et al, corticosteroids were required by four, but the final outcome was said to be favourable in all patients.4 Symptoms of drug-induced LE are self-limiting once treatment is ceased but often recur on re-challenge.4

"While we should all be alert for rare but potentially serious adverse effects, with minocycline as with any other drug, I would suggest that we should not too quickly abandon a well-tested, widely-prescribed, and very effective drug."
Dr. Stuart Maddin
"I have been using minocycline for 20 years and while it's important to be aware of potential serious adverse reactions, my practical experience suggests that such events are extremely rare."
Dr. Alan Shalita, Brooklyn


  1. Cunliffe WJC, Chu T. The benefits/risks of minocycline in the treatment of acne. Letter from the Acne Support Group, Middlesex, UK, 1996.
  2. Ho V, Schachter D, Miller R, et al. Acne management for the 90s: current treatment guidelines. Canad J Diagnosis 1995; December Supplement: 1-25.
  3. Eady EA, Jones CE, Gardner KJ, et al. Tetracycline-resistant proprionibacteria from acne patients are cross-resistant to doxycycline but sensitive to minocycline. Brit J Dermatol 1993; 128: 556-560.
  4. Knowles SR, Shapiro L, Shear NH. Serious adverse reactions induced by minocycline. Report of 13 patients and review of the literature. Arch Dermatol 1996; 132: 934-939.
  5. Gough AG, Chapman S, Wagstaff K, et al. Minocycline induced autoimmune hepatitis and systemic lupus erythematosus-like syndrome. Brit Med J 1996; 312: 169-172.
  6. Shear NH. Personal communication. October 1996.

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Update on Drugs
Class Name/Company Approval Dates and Comments
Anti-allergic Quaternium-18 bentonite (bentoquatam)
Ivy Block®
Enviroderm Pharmaceuticals
Protects against poison ivy, poison oak, and poison sumac rash when applied before contact. Approved by the FDA on the 26th of August 1996.

See the article in this issue.

Antipsoriatic Calcipotriol
Dovonex® Cream
Leo Laboratories
Long approved in most other countries, Dovonex® cream is now approved by the FDA for the treatment of plaque psoriasis.

Dovonex® Scalp lotion was recently approved in Canada
(See Volume 1, Number 6).

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EDITOR: Stuart Maddin Associate Editor: David I. McLean INTERNET EDITOR: Harvey Lui PRINCIPAL MEDICAL WRITER: Susan Kingsley Manuscript Editor: Rodger Hall Editorial Advisory Board: Kenneth A. Arndt, Beth Israel Hospital & Harvard Medical School, Boston; Wilma Fowler Bergfeld, Cleveland Clinic, Cleveland; Jan D. Bos, University of Amsterdam, Amsterdam; Enno Christophers, Universitäts-Hautklinik, Kiel; Hugo Degreef, Catholic University, Leuven; Richard L. Dobson, Medical University of South Carolina, Charleston; Boni E. Elewski, Case Western Reserve University, Cleveland; Barbara A. Gilchrest, Boston University School of Medicine, Boston; W. Andrew D. Griffiths, St. Johns Institute of Dermatology, London; Vincent C.Y. Ho, University of British Columbia, Vancouver; James J. Leyden, University of Pennsylvania, Philadelphia; Howard I. Maibach, University of California Hospital, San Francisco; Larry E. Millikan, Tulane University Medical Center, Louisiana; Takeji Nishikawa, Keio University School of Medicine, Tokyo; Constantin E. Orfanos, Freie Universitäts Berlin, Universitätsklinikum Benjamin Franklin, Berlin; Stephen L. Sacks, Viridae Clinic Sciences, Vancouver; Alan R. Shalita, SUNY Health Sciences Center, Brooklyn; Stephen K. Tyring, University of Texas Medical Branch, Galveston; John Voorhees, University of Michigan, Ann Arbor; Klaus Wolff, University of Vienna, Vienna
Skin Therapy Letter®. (ISSN 1201-5989) Copyright 1996 by International Skin Therapy Newsletter Inc. All rights reserved. Reproduction in whole or in part by any process in whole or in part is strictly forbidden without prior consent of the publisher in writing.
Published six times yearly by International Skin Therapy Newsletter Inc., 835 West Tenth Avenue, Vancouver, British Columbia, Canada V5Z 4E8. Tel: (604) 874-6112. Fax: (604) 873-9919. Annual subscription: Canadian $85 individual; $155 institutional (GST included). US $60 individual; $110 institutional. Outside North America: US$80 individual; $130 institutional. Quotes on multiple subscriptions and student rates supplied upon request.
Skin Therapy Letter Editor: Dr. Stuart Maddin Vol. 2 No. 1
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