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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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In a 6-month study of suppression of recurrent genital herpes in HIV-infected patients, adverse drug reactions were similar in nature and incidence in the groups receiving VALTREX® 500 mg twice daily and placebo when duration of exposure was considered.

Adverse reactions reported with an incidence ≥ 1% during the double-blind phase are detailed in Table 4.

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Adverse reactions reported by patients receiving VALTREX® 500 mg once daily (n=743) or placebo once daily (n=741) in a clinical study for the reduction of transmission of genital herpes are listed below in Table 5.

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Of the 1484 patients enrolled in the reduction of transmission study, 1018 entered the open-label phase of the study (≤ 12 months), 499 from the placebo group and 519 from the VALTREX® group. The nature and incidence of events in the open-label phase were similar to those observed during the double-blind phase of the study (Table 6).

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Cold Sores: Adverse drug reactions reported by patients receiving VALTREX® 2000 mg twice daily for one day (n=609) or placebo (n=609) in clinical studies for the treatment of cold sores are listed below in Table 7.

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Abnormal Hematologic and Clinical Chemistry Findings In herpes zoster trials, the frequencies of white blood cells abnormality ( 0.75 times the lower limit of normal) were 1.3% for patients receiving VALTREX® compared with 0.6% for patients receiving placebo. This difference was not clinically or statistically significant.

–  –  –

In clinical studies for the treatment of cold sores, the frequencies of abnormal ALT values ( 2 times the upper limit of normal) were 1.8% for patients receiving VALTREX® at the recommended clinical dose and 0.8% for placebo. Other laboratory abnormalities (hemoglobin, white blood cells, alkaline phosphatase, and serum creatinine) occurred with similar frequencies in the 2 groups.

Post-Market Adverse Drug Reactions The following events have been reported voluntarily during post-approval use of VALTREX® in clinical practice. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, causal connection to VALTREX®, or a combination of these factors. Post-market adverse events are reported spontaneously from a population of unknown size, thus estimates of frequency cannot be made.

Allergic: Acute hypersensitivity reactions including anaphylaxis, angioedema, dyspnea, pruritus, rash and urticaria.

Central Nervous System Symptoms: Headache. Reports of neurological reactions including dizziness, confusion, hallucinations (auditory and visual), aggressive behaviour, decreased consciousness, tremor, ataxia, dysarthria, convulsions, encephalopathy, coma, mania, and seizures. Agitation and psychotic symptoms have also been reported. These events are generally reversible and usually seen in patients with renal impairment or with other predisposing factors (see WARNINGS AND PRECAUTIONS).

General: Facial edema, hypertension, tachycardia.

Gastrointestinal: Nausea, abdominal discomfort, vomiting and diarrhea.

Hematological: Reports of thrombocytopenia, aplastic anemia, leukocytoclastic vasculitis, thrombotic thrombocytopenic purpura / hemolytic uremic syndrome (TTP/HUS). Leukopenia, mainly reported in immunocompromised patients.

Hepatobiliary Tract and Pancreas: Reports of reversible increases in liver function test, hepatitis.

Ophthalmologic: Visual abnormalities.

Renal: Reports of renal impairment, elevated blood creatinine and blood urea nitrogen (BUN) Acute renal failure, renal pain and hematuria. Renal pain may be associated with renal failure (see WARNINGS AND PRECAUTIONS).

Skin: Erythema multiforme, rashes including photosensitivity.

Page 12 of 39 Other: There have been reports of renal insufficiency, microangiopathic hemolytic anemia and thrombocytopenia (sometimes in combination) in severely immunocompromised patients, particularly those with advanced HIV disease, receiving high doses (8000 mg daily) of valacyclovir for prolonged periods in clinical trials. These findings have also been observed in patients not treated with valacyclovir who have the same underlying or concurrent conditions.

DRUG INTERACTIONS

Drug-Drug Interactions No clinically significant interactions have been identified.

No dosage adjustment is recommended when VALTREX® is co-administered with digoxin, antacids, thiazide diuretics, cimetidine, or probenecid in subjects with normal renal function (see Part II, DETAILED PHARMACOLOGY).

Acyclovir is eliminated primarily unchanged in the urine via active renal tubular secretion. Any drugs administered concurrently that compete with this mechanism may increase acyclovir plasma concentrations following valacyclovir administration.

Following administration of valacyclovir 1000 mg, cimetidine and probenecid increase the area under the curve (AUC) of acyclovir by this mechanism, and reduce acyclovir renal clearance. However, no dosage adjustment is necessary at this dose because of the wide therapeutic index of acyclovir (see Part II, DETAILED PHARMACOLOGY).

Care is also required (with monitoring for changes in renal function) if administering higher-doses of VALTREX® (4 g or more/day) with drugs which affect other aspects of renal physiology (e.g. cyclosporin, tacrolimus).





Drug-Food Interactions There is no known interaction with food (see Part II, DETAILED PHARMACOLOGY).

Drug-Herb Interactions Interactions with herbal products have not been established.

Drug-Laboratory Test Interactions Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Dosing Considerations

• The dosage of VALTREX® should be reduced in patients with impaired renal function (see Table 8).

–  –  –

• The recommended dose and duration of use is dependent on the indication.

• The safety and tolerability of VALTREX® 500 mg once daily has been established for up to 20 months (see CLINICAL TRIALS and ADVERSE REACTIONS).

Recommended Dose and Dosage Adjustment VALTREX® caplets may be given without regard to meals.

Herpes Zoster(shingles): The recommended dosage of VALTREX® caplets for the treatment of herpes zoster is 1000 mg orally three times daily for 7 days. Treatment with VALTREX® should be initiated within 72 hours of the onset of rash.

Initial Episode of Genital Herpes: The recommended dosage of VALTREX® caplets for the treatment of an initial episode of genital herpes is 1000 mg orally twice daily for 10 days. There are no data on the effectiveness of treatment with VALTREX® when initiated more than 72 hours after the onset of signs and symptoms. Therapy was most effective when administered within 48 hours of the onset of signs and symptoms.

Recurrent Episodes of Genital Herpes: The recommended dosage of VALTREX® caplets for the treatment of recurrent episodes of genital herpes is 500 mg orally twice daily for 3 days. Therapy should be initiated at the earliest sign or symptom of recurrence. VALTREX® can prevent lesion development when taken at the first signs and symptoms of a genital herpes recurrence.

Suppression of Genital Herpes: The recommended dosage of VALTREX® caplets for chronic suppressive therapy of recurrent genital herpes is 1000 mg orally once daily in patients with normal immune function. The safety and efficacy of VALTREX® 1000 mg once daily beyond 1 year have not been established. In patients with a history of 9 or fewer recurrences per year, an alternative dose is 500 mg orally once daily. The safety and tolerability of VALTREX® 500 mg once daily have been established for up to 20 months (see CLINICAL TRIALS and ADVERSE REACTIONS).

In patients with HIV infection with CD4 cell count 100 cells/mm3, the recommended dosage of VALTREX® caplets for chronic suppressive therapy of recurrent genital herpes is 500 mg orally twice daily. The safety and efficacy of therapy with VALTREX® beyond 6 months in patients with HIV infection have not been established.

Reduction of Transmission of Genital Herpes: The recommended dosage of VALTREX® caplets for reduction of transmission of genital herpes in patients with a history of 9 or fewer recurrences per year is 500 mg orally once daily for the source partner. The efficacy of reducing transmission beyond 8 months in couples discordant for HSV-2 infection has not been established. The safety and tolerability of VALTREX® Page 14 of 39 500 mg once daily has been established for up to 20 months (see CLINICAL TRIALS and ADVERSE REACTIONS).

Cold Sores (Herpes Labialis): The recommended dosage of VALTREX® for the treatment of cold sores (herpes labialis) is 2000 mg orally twice daily for 1 day (24-hour period). The second dose should be taken approximately 12 hours after the first dose, but not less than 6 hours after the first dose. Therapy should be initiated at the earliest symptom of a cold sore (e.g., tingling, itching, or burning). There are no data on the efficacy of treatment initiated after the development of clinical signs of a cold sore (e.g., papule, vesicle or ulcer).

Patients with Acute or Chronic Renal Impairment: Caution is advised when administering valacyclovir to patients with impaired renal function. Adequate hydration should be maintained.

Pharmacokinetic and safety evaluations following administration of oral valacyclovir hydrochloride have been performed in patients with renal impairment and volunteers with end-stage renal disease (ESRD) managed by hemodialysis. Based on these studies and extensive experience with acyclovir, the following dosage adjustments are recommended (data are not available for the use of VALTREX® in pediatric patients with a creatinine

clearance less than 50 mL/min/1.73m2):

Table 8 Dosage Adjustments for Adults Renal Impairment

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Page 15 of 39 Intermittent Hemodialysis: During hemodialysis, the half-life of acyclovir after administration of valacyclovir hydrochloride is approximately 4 hours. About 1/3 of acyclovir in the body is removed by dialysis during a 4-hour hemodialysis session. These patients should receive the daily dose of VALTREX® recommended (Table 8), the dose administered after hemodialysis on the days it is performed.

Peritoneal Dialysis: There is no information specific to administration of VALTREX®.

The effect of continuous ambulatory peritoneal dialysis (CAPD) and continuous arteriovenous hemofiltration/dialysis (CAVHD) on acyclovir pharmacokinetics has been studied. The removal of acyclovir after CAPD and CAVHD is less pronounced than with hemodialysis, and the pharmacokinetic parameters closely resemble those observed in patients with ESRD not receiving hemodialysis. Therefore, supplemental doses of VALTREX® should not be required following CAPD or CAVHD.

Missed Dose If a dose of VALTREX® is missed, the patient should be advised to take it as soon as he/she remembers, and then continue with the next dose at the proper time interval.

OVERDOSAGE For management of a suspected drug overdose, contact your regional Poison Control Centre.

Activated charcoal may be administered to aid in the removal of unabsorbed drug.

General supportive measures are recommended.

Acute renal failure and neurological symptoms, including confusion, hallucinations, agitation, decreased consciousness and coma, have been reported in patients receiving overdoses of VALTREX®. Nausea and vomiting may also occur. Caution is required to prevent inadvertent overdose. Many of the reported cases involved renally impaired and geriatric patients receiving repeated overdoses, due to lack of appropriate dosage reduction (see WARNINGS AND PRECAUTIONS, Renal; and ADVERSE REACTIONS).

Patients should be observed closely for signs of toxicity. Hemodialysis significantly enhances the removal of acyclovir from the blood and may, therefore be considered a management option in the event of symptomatic overdose. However, it is known that precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored (see DOSAGE AND ADMINISTRATION).

Page 16 of 39ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action VALTREX® is the L-valyl ester and a pro-drug of the antiviral drug acyclovir.

Valacyclovir hydrochloride is rapidly converted to acyclovir, which has in vitro and in vivo inhibitory activity against human herpes viruses including herpes simplex virus types 1 (HSV-1) and 2 (HSV-2), and varicella-zoster virus (VZV).

The inhibitory activity of acyclovir is highly selective due to its unique affinity for the thymidine kinase (TK) encoded by HSV and VZV. This viral enzyme converts acyclovir into acyclovir monophosphate, a nucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. In vitro, acyclovir triphosphate terminates growing chains of viral DNA. Once incorporated, acyclovir irreversibly binds to viral DNA polymerase, effectively inactivating the enzyme. Acyclovir triphosphate is a potent inhibitor of all of the human herpes virus DNA polymerases studied.

Acyclovir is virtually inactive in uninfected cells, since it is preferentially taken up and selectively converted to the active triphosphate form by herpes virus-infected cells.

Additionally, the enzyme thymidine kinase of uninfected cells does not effectively use acyclovir as a substrate and cellular α-DNA polymerase is less sensitive than viral DNA polymerase to the effects of acyclovir.

A combination of the thymidine kinase specificity, competitive inhibition of DNA polymerase and incorporation and termination of the growing viral DNA chain results in inhibition of herpes virus replication. No effect on latent non-replicating virus has been demonstrated. Inhibition of viral replication reduces the period of viral shedding, limits the degree of spread and level of pathology, and thereby facilitates healing. The pain of shingles is related to viral damage to neurons which takes place during viral replication.

Pharmacokinetics



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