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