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«PRODUCT MONOGRAPH Pr VALTREX® valacyclovir caplets, 500 mg and 1000 mg valacyclovir (as valacyclovir hydrochloride) Antiviral Agent Date of ...»

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No additional signs of toxicity occurred in rats and monkeys given daily oral doses of valacyclovir hydrochloride for 1 year. Although high-dose rats (120 mg/kg/day) had obstructive nephropathy, none of the doses of valacyclovir hydrochloride given to monkeys (125, 250 and 500 mg/kg/day) produced toxicity.

Carcinogenicity Carcinogenicity bioassays were conducted in mice given 40, 80 and 120 mg/kg/day and in rats given 50, 75 and 100 mg/kg/day valacyclovir hydrochloride by gavage. The high doses were maximum tolerated doses and produced expected obstructive nephropathy.

Both bioassays were negative for tumorigenic and carcinogenic potential. Dosing was for 20 months in female mice, 18 months in male mice, 23 months in female rats and 24 months in male rats. Except for expected effects on the kidney, there were no signs of chronic toxicity.

Mutagenicity Five mutagenicity studies were performed with valacyclovir hydrochloride. An Ames test including pre-incubation was negative at concentrations up to 10,000 μg/plate (the highest concentration tested) with and without metabolic activation. An in vitro cytogenetic study in cultured human lymphocytes was negative at 500 μg/mL without metabolic activation and at 1000 μg/mL with metabolic activation. A mouse lymphoma assay was negative at 5000 μg/mL without metabolic activation and at 300 μg/mL with metabolic activation. Weak mutagenicity consistent with that previously encountered in testing acyclovir itself, occurred at 1000 μg/mL valacyclovir hydrochloride in the presence of metabolic activation where it was estimated that concentrations of acyclovir averaged 400 μg/mL over the 4-hour exposure period. There were no mutagenic effects at single doses up to and including 250 mg/kg (nephrotoxic) in a mouse micronucleus Page 29 of 39 assay. Weak mutagenicity encountered at 500 mg/kg in this assay was fully explained by Cmax acyclovir concentrations of 250 μg/mL for males and 128 μg/mL for females, as exposures in this range produced chromosomal damage when acyclovir itself was tested.

These exposures also may have produced expected toxic effects on the bone marrow as there were decreased numbers of polychromatic erythrocytes in peripheral circulation. A rat cytogenetic study was negative at all doses including the highest one tested, 3000 mg/kg.

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Reproduction and Teratology In reproductive toxicology studies, valacyclovir hydrochloride produced expected obstructive nephropathy in rats and rabbits. There were no teratogenic effects in either species. Embryotoxicity in rats consisted of post-implantation loss, decreased fetal body weight and length, and increased incidences of minor skeletal variations at the high dose.

Maternal plasma levels of approximately 50 μg/mL acyclovir were achieved. This Page 30 of 39 concentration of acyclovir is intermediate between that associated with an increased incidence of skeletal variations (but no embryolethality) in previous studies with acyclovir and that of 100 μg/mL producing overt fetal malformations in rats. Plasma levels of 50 μg/mL acyclovir are approximately 10 times those achieved in humans given the recommended oral dose (1000 mg 3 times per day) of valacyclovir to treat herpes zoster.

At high parenteral doses of acyclovir, testicular atrophy and aspermatogenesis have been observed in rats and dogs.

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1. Barry DW, Blum MR. Antiviral drugs: acyclovir. In: Turner P, Shand DG, eds.

Recent Advances in Clinical Pharmacology, ed 3. New York: Churchill Livingstone 1983; 57-80.

2. Barry DW, Nusinoff-Lehrman S. Viral resistance in clinical practice: summary of five years experience with acyclovir. In: Kono R, Nakajima A, eds. Herpes

Viruses and Virus Chemotherapy (Ex Med Int Congr Ser 667). New York:

Excerpta Medica 1985; 269-270.

3. Beutner KR, Friedman DJ, Forszpaniak C. Anderson PL, Wood MJ. Valacyclovir compared with acyclovir for improved therapy for herpes zoster in immunocompetent adults. Antimicrob Agents Chemother 1995; 39:1546-1553.

4. Bodsworth NJ, Crooks RJ, Borelli S, Vejlsgaard G, Paavonen J et al.

Valacyclovir versus acyclovir in patient initiated treatment of recurrent genital herpes: a randomised, double-blind clinical trial. Genitourin Med 1997; 73:110Boivin G, Edelman CK, Pedneault L, Talarico CL, Biron KK et al. Acyclovirresistant VZV strains from persons with AIDS: phenotypic and genotypic characterization of acyclovir-resistant varicella-zoster viruses isolated from persons with AIDS. J Infect Dis 1994; 170:68-75.

6. Burgess ED, Gill MJ. Intraperitoneal administration of acyclovir in patients receiving continuous ambulatory peritoneal dialysis. J Clin Pharmacol 1990;

30:997-1000.

7. Chulay JD, Bell AR. Long-term safety of valacyclovir for suppression of herpes simplex virus infections (Abstract). Clin Infect Dis 1996; 23:879.

8. Cole NL, Balfour HH Jr. Varicella-zoster virus does not become more resistant to acyclovir during therapy. J Infect Dis 1986; 153:605-608.

9. Collins P, Ellis MN. Sensitivity monitoring of clinical isolates of herpes simplex virus to acyclovir. J Med Virol 1993; 1:58-66.

10. Datta AK, Colby BM, Shaw JE, Pagano JS. Acyclovir inhibition of Epstein-Barr virus replication. Proc Natl Acad Sci USA 1980; 77:5163-5166.





11. de Bony F, Bidault R, Peck R, Posner J. Lack of interaction between valacyclovir, the L-valyl ester of acyclovir, and Maalox antacid. J Antimicrob Chemother 1996; 37:383-387.

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13. Dekker C, Ellis MN, McLaren C, et al. Virus resistance in clinical practice. J Antimicrob Chemother 1983; 12 (Suppl B):137-152.

14. Derse D, Cheng YC, Furman PA, St.Clair MH, Elion GB. Inhibition of purified human and herpes simplex virus-induced DNA polymerases by 9-(2hydroethoxymethyl)guanine triphosphate: effects on primer-template function. J Biol Chem 1981; 256:11447-11451.

15. Ellis MN, Keller PM, Fyfe JA, Martin JL, Rooney JF et al. Clinical isolates of herpes simplex virus type 2 that induces thymidine kinase with altered substrate specificity. Antimicrob Agents Chemother 1987; 31:1117-1125.

16. Fife KH, Barbarash RA, Rudolph T, Degregorio B, Roth R. Valaciclovir versus acyclovir in the treatment of first-episode genital herpes infection. Results of an international, multicenter, double-blind, randomized clinical trial. The Valaciclovir International Herpes Simplex Virus Study Group. Sex Transm Dis 1997; 24:481-486.

17. Furman PA, St.Clair MH, Fyfe JA, Rideout JL, Keller PM et al. Inhibition of herpes simplex virus-induced DNA polymerase activity and viral DNA replication by 9-(2-hydroxyethoxymethyl) guanine and its triphosphate. J Virol 1979; 32:72-77.

18. Jacobson MA, Berger TG, Fikrig S, Becherer P, Moohr JW et al. Acyclovirresistant varicella zoster virus infection after chronic oral acyclovir therapy in patients with the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1990; 112:187-191.

19. Jones T, Alderman C. Acyclovir clearance by CAVHD. Intensive Care Med 1991; 17:125.

20. Laskin OL, deMiranda P, King DH, Page DA, Longstreth JA et al. Effects of probenecid on the pharmacokinetics and elimination of acyclovir in humans.

Antimicrob Agents Chemother 1982; 21:804-807.

21. Lau RJ, Emery MG, Galinsky RE. Unexpected accumulation of acyclovir in breast milk with estimate of infant exposure. Obstet Gynecol 1987; 69:468-471.

22. Leone PA, Trottier S, Miller JM. Valacyclovir for Episodic Treatment of Genital Herpes: A Shorter 3-Day Treatment Course compared with 5-Day Treatment.

Clinical Infectious Diseases 2002; 34:958-962.

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O'Brien JJ, Campoli-Richards DM. Acyclovir − an updated review of its antiviral 24.

activity, pharmacokinetic properties, and therapeutic efficacy. Drugs 1989;

37:233-309.

25. Patel R, Bell AR. Valacyclovir for prevention of genital herpes simplex virus recurrences - Long-term safety (Abstract). European Congress of Clinical Microbiology and Infectious Diseases 1997; 1425.

26. Patel R, Bodsworth NJ, Peters B. Valacyclovir for the suppression of recurrent genital HSV infection: a placebo controlled study of once daily therapy.

Genitourin Med 1997; 73:105-109.

27. Perry CM, Faulds D. Valacyclovir. A review of its antiviral acitivity, pharmacokinetic properties and therapeutic efficacy in herpesvirus infections.

Drugs 1996; 52:754-772.

28. Spruance MD, Tyring SK, DeGregorio B, Miller C, Beutner K. A Large-Scale, Placebo-Controlled, Dose-Ranging Trial of Peroral Valacyclovir for Episodic Treatment of Recurrent Herpes Genitalis. Arch Intern Med 1996; 156:1729-1735.

29. Stahlmann R, Klug S, Lewandowski C, Chahoud I, Bochert G et al.

Teratogenicity of acyclovir in rats. Infection 1987; 15:261-262.

30. Strauss SE, Takiff HE, Seidlin M, Bachrach S, Lininger L et al. Suppression of frequently recurring genital herpes: a placebo-controlled double-blind trial of oral acyclovir. N Engl J Med 1984; 310:1545-1550.

31. Weller S, Blum R, Doucette M, Burnette T, Cederberg DM et al.

Pharmacokinetics of the acyclovir pro-drug valacyclovir after escalating singleand multiple-dose administration to normal volunteers. Clin Pharmacol Ther 1993; 54:595-605.

–  –  –

Reduction of Transmission: When taken every day, VALTREX® in combination with safer sex practices can also reduce the risk of transmitting genital herpes to your sexual partner.

Talk to your doctor if you have questions about treatment with VALTREX® and if you are concerned about transmitting genital herpes to your partner. Your physician will help you decide which type of therapy is best for you.

–  –  –

NOTE: Contact your health professional if you need information about how to manage your side effects. The Canada Vigilance Program does not provide medical advice.

MORE INFORMATION

This document plus the full product monograph, prepared for

health professionals can be found at:

http://www.gsk.ca or by contacting the sponsor, GlaxoSmithKline Inc.

7333 Mississauga Road Mississauga, Ontario L5N 6L4 1-800-387-7374 This leaflet was prepared by GlaxoSmithKline Inc.

Last revised: August 10, 2015 © 2015, GlaxoSmithKline Inc., All Rights Reserved VALTREX is a registered trademark of Glaxo Group Limited, used under license by GlaxoSmithKline Inc.

Page 39 of 39

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