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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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PRODUCT MONOGRAPH

Pr

VALTREX®

valacyclovir caplets,

500 mg and 1000 mg valacyclovir

(as valacyclovir hydrochloride)

Antiviral Agent

Date of Revision:

GlaxoSmithKline Inc.

August 10, 2015

7333 Mississauga Road

Mississauga, Ontario

L5N 6L4

Submission Control No: 184897

©

2015, GlaxoSmithKline Inc., All Rights Reserved VALTREX is a registered trademark of Glaxo Group Limited, used under license by GlaxoSmithKline Inc.

ZOVIRAX is a registered trademark of GlaxoSmithKline Inc.

Page 1 of 39 Table of Contents PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

ADVERSE REACTIONS

DRUG INTERACTIONS

DOSAGE AND ADMINISTRATION

OVERDOSAGE

ACTION AND CLINICAL PHARMACOLOGY

STORAGE AND STABILITY

DOSAGE FORMS, COMPOSITION AND PACKAGING

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

CLINICAL TRIALS

DETAILED PHARMACOLOGY

MICROBIOLOGY

TOXICOLOGY

REFERENCES

PART III: CONSUMER INFORMATION

–  –  –

INDICATIONS AND CLINICAL USE

VALTREX®, valacyclovir caplets (as valacyclovir hydrochloride), is indicated:

• For the treatment of herpes zoster (shingles).

• For the treatment or suppression of genital herpes in immunocompetent individuals and for the suppression of recurrent genital herpes in HIV infected individuals.

• To reduce the risk of transmission of genital herpes with the use of suppressive therapy. Safer sex practices should be used with suppressive therapy.

• For the treatment of cold sores (herpes labialis).

Geriatrics ( 65 years of age): Use in the geriatric population may be associated with differences in safety due to age-related changes in renal function and a brief discussion can be found in the appropriate sections (see WARNINGS AND PRECAUTIONS).

Pediatrics ( 12 years old): No data is available.

CONTRAINDICATIONS

VALTREX® is contraindicated in patients with a known hypersensitivity or intolerance to valacyclovir, acyclovir, or any component of the formulation. For a complete listing of ingredients, see DOSAGE FORMS, COMPOSITION AND PACKAGING section.

–  –  –

General Care should be taken to ensure adequate fluid intake in patients who are at risk of dehydration particularly in geriatric patients.

The safety and efficacy of VALTREX® have not been established for the treatment of disseminated herpes zoster.

The safety and efficacy of VALTREX® have not been established in immunocompromised patients other than for the suppression of ano-genital herpes in HIV-infected patients. The safety and efficacy of VALTREX® for the suppression of recurrent ano-genital herpes in patients with advanced HIV disease (CD4 cell count 100 cells/mm3) have not been established.

Patients should be informed that VALTREX® is not a cure for genital herpes.

Safer sex practices should be used in combination with suppressive therapy.

VALTREX® alone should not be used for reducing the risk of transmitting genital herpes.

Because genital herpes is a sexually transmitted infection, patients should, in order to further reduce the risk of infecting partners, avoid contact with lesions, damaged skin/mucosa, and also avoid intercourse when lesions and/or symptoms are present.

Genital herpes is frequently transmitted in the absence of symptoms through asymptomatic viral shedding; therefore patients should be counselled to use safer sex practices. The effect of VALTREX® on transmission of sexually transmitted infections other than herpes (including HIV, gonorrhea, syphilis and Chlamydia) is unknown.

The efficacy of VALTREX® for reducing transmission of genital herpes has not been established in individuals with multiple partners, non-heterosexual couples, and couples not counselled to use safer sex practices.

Central Nervous System Central nervous system adverse reactions (e.g., agitation, hallucinations, confusion, and encephalopathy): May occur in both adult and pediatric ( 12 years of age) patients (with or without reduced renal function) and in patients with underlying renal disease who receive higher than recommended doses of VALTREX® for their level of renal function.

Elderly patients are more likely to have central nervous system adverse reactions. Use with caution in elderly patients and reduce dosage in patients with renal impairment.

Hepatic/Biliary/Pancreatic Dose modification is not required in patients with mild or moderate cirrhosis (hepatic synthetic function maintained). Pharmacokinetic data in patients with advanced cirrhosis (impaired hepatic synthetic function and evidence of portal-systemic shunting) do not indicate the need for dosage adjustment. There are no data available on the use of higher doses of VALTREX® (4 g or more per day) in patients with liver disease. Caution should therefore be exercised when administering higher doses of VALTREX® to these patients.





–  –  –

Acyclovir, the active metabolite of valacyclovir, is eliminated by renal clearance, therefore the dose of VALTREX® must be reduced in patients with renal impairment (see DOSAGE AND ADMINISTRATION, Patients with Acute or Chronic Renal Impairment). Geriatric patients are likely to have reduced renal function and therefore the need for dose reduction must be considered in this group of patients. Both geriatric patients and patients with a history of renal impairment are at increased risk of developing neurological side effects and should be closely monitored for evidence of these effects. In the reported cases, these reactions were generally reversible on discontinuation of treatment (see ADVERSE REACTIONS).

Cases of acute renal failure have been reported in patients without adequate hydration.

Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. Adequate hydration should be maintained for all patients.

Caution should be exercised when administering VALTREX® to patients with significant renal impairment or those receiving potentially nephrotoxic agents, since this may increase the risk of renal dysfunction (see DOSAGE AND ADMINISTRATION, Patients with Acute or Chronic Renal Impairment) and/or the risk of reversible central nervous system symptoms such as those that occur infrequently in patients treated with intravenous acyclovir.

Given the dosage recommendations for treatment of cold sores, special attention should be paid when prescribing VALTREX® for cold sores in patients who are geriatric or who have impaired renal function (see DOSAGE AND ADMINISTRATION, Patients with Acute or Chronic Renal Impairment, Table 8). Treatment should not exceed 1 day (2 doses of 2000 mg in 24 hours). Therapy beyond 1 day does not provide additional clinical benefit.

In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored.

Thrombotic Thrombocytopenic Purpura/ Hemolytic Uremic Syndrome (TTP/HUS) Thrombotic Thrombocytopenic Purpura/ Hemolytic Uremic Syndrome (TTP/HUS), in some cases resulting in death, has occurred in patients with advanced HIV-1 disease, and also in allogenic bone marrow transplant and renal transplant recipients participating in clinical trials of VALTREX® at a dose of 8000 mg per day. Treatment with VALTREX® should be stopped immediately if clinical signs, symptoms, and laboratory abnormalities consistent with TTP/HUS occur.

Page 5 of 39 Special Populations Pregnant Women: There are no adequate and well-controlled studies with either acyclovir or VALTREX® in pregnant women. In a study of the pharmacokinetics of valacyclovir and acyclovir during late pregnancy, the steady-state daily acyclovir AUC (area under plasma concentration-time curve) following valacyclovir 1000 mg was approximately 2 times greater than that observed with oral acyclovir at 1200 mg daily.

VALTREX® caplets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnancy registries have documented the pregnancy outcomes in women exposed to VALTREX® or to any formulation of acyclovir (the active metabolite of valacyclovir);

111 and 1246 outcomes (29 and 756 exposed during the first trimester of pregnancy), respectively, were obtained from women prospectively registered. The findings of the acyclovir pregnancy registry have not shown an increase in the number of birth defects amongst acyclovir-exposed subjects compared with the general population, and any birth defects showed no uniqueness or consistent pattern to suggest a common cause. Given the small number of women enrolled into the valacyclovir pregnancy registry, reliable and definitive conclusions could not be reached regarding the safety of VALTREX® in pregnancy.

Valacyclovir hydrochloride was not teratogenic in rats or rabbits given 400 mg/kg (which results in 10 and 7 times human plasma levels, respectively) during the period of major organogenesis. However, in a non-standard test in rats given three subcutaneous doses of 100 mg/kg acyclovir (20 times human plasma levels) on gestation day 10, there were fetal abnormalities, such as head and tail anomalies, and maternal toxicity.

Nursing Women: Acyclovir, the principal metabolite of valacyclovir, is excreted in breast milk. Following oral administration of a 500 mg dose of valacyclovir, peak acyclovir concentrations (Cmax) in breast milk ranged from 0.5 to 2.3 (median 1.4) times the corresponding maternal acyclovir serum concentrations. The acyclovir breast milk to maternal serum AUC ratios ranged from 1.4 to 2.6 (median 2.2).

The median acyclovir concentration in breast milk was 2.24 μg/mL (9.95 μM). With a maternal valacyclovir dosage of 500 mg twice daily, this level would expose a nursing infant to a daily oral acyclovir dosage of about 0.61 mg/kg/day. The elimination half-life of acyclovir from breast milk was similar to that for serum.

Unchanged valacyclovir was not detected in maternal serum, breast milk, or infant urine.

Caution should be exercised when VALTREX® is administered to a nursing woman.

Consideration should be given to temporary discontinuation of nursing, as the safety of VALTREX® has not been established in infants.

Pediatrics: Safety and efficacy in children have not been established.

Page 6 of 39 Geriatrics: Of the total number of patients included in clinical studies of VALTREX®, more than 800 were age 65 or older, and more than 300 were age 75 or older. A total of 34 volunteers age 65 or older completed a pharmacokinetic trial of valacyclovir hydrochloride. The pharmacokinetics of acyclovir following single- and multiple-dose oral administration of VALTREX® caplets in geriatric volunteers varied with renal function. The possibility of renal impairment in geriatric patients must be considered and the dosage should be adjusted accordingly (see WARNINGS AND PRECAUTIONS, Renal, and DOSAGE AND ADMINISTRATION, Patients with Acute or Chronic Renal Impairment). Adequate hydration should be maintained.

ADVERSE REACTIONS

Serious Adverse Drug Reactions The following serious adverse reactions are discussed in greater detail in WARNINGS

AND PRECAUTIONS:

• Thrombotic Thrombocytopenic Purpura/ Hemolytic Uremic Syndrome

• Acute Renal Failure

• Central Nervous System Effects Adverse Drug Reaction Overview The most frequent adverse reactions associated with the use of VALTREX® are headache and nausea.

Neurological side effects have also been reported in rare instances. Geriatric patients and patients with a history of renal impairment are at increased risk of developing these effects. In the reported cases, these reactions were generally reversible on discontinuation of treatment (see WARNINGS AND PRECAUTIONS; and ADVERSE REACTIONS, Post-Market Adverse Drug Reactions).

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Herpes Zoster: Adverse drug reactions were not significantly different in recipients of VALTREX® compared to placebo or acyclovir in the two double-blind, randomized clinical trials of treatment of herpes zoster (shingles) in immunocompetent patients. The most frequent adverse drug reactions reported in recipients of VALTREX® are listed in Table 1.

–  –  –

Genital Herpes: In two double-blind, randomized trials of treatment of recurrent genital herpes in immunocompetent patients, adverse drug reactions were not significantly different in recipients of VALTREX® compared to placebo. The most frequent adverse reactions are listed in Table 2.

–  –  –

In two recurrent genital herpes suppression studies of immunocompetent patients, adverse drug reactions were not significantly different in recipients of VALTREX® 1000 mg once daily or VALTREX® 500 mg once daily, compared to placebo or ZOVIRAX® (acyclovir) 400 mg twice daily. The most frequent adverse reactions are reported in Table 3.

–  –  –

In one multicenter, double-blind, randomized study of immunocompetent patients for the treatment of an initial episode of genital herpes, the frequency of adverse events,

regardless of attributability to study medication, was similar in both treatment groups:

VALTREX® 1000 mg twice daily (n=318) compared to acyclovir 200 mg five times a day (n=318). The most frequent adverse events were headache (13% with VALTREX® versus 10% with ZOVIRAX®) and nausea (6% with both treatments). All other adverse events were reported by 3% or less of patients.



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