VALACYCLOVIR HYDROCHLORIDE

Valacyclovir hydrochloride is a white to off-white powder with the molecular formula C₁₃H₂₀N₆O₄•HCl and a molecular weight of 360.80. The maximum solubility in water at 25°C is 174 mg/mL. The pk_as for valacyclovir hydrochloride are 1.90, 7.47, and 9.43.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Valacyclovir is an antiviral drug [see Clinical Pharmacology (12.4)].

12.2 Pharmacodynamics

12.3 Pharmacokinetics

The pharmacokinetics of valacyclovir and acyclovir after oral administration of valacyclovir hydrochloride have been investigated in 14 volunteer studies involving 283 adults and in 3 studies involving 112 pediatric subjects from 1 month to < 12 years of age.

Pharmacokinetics in Adults: Absorption and Bioavailability: After oral administration, valacyclovir hydrochloride is rapidly absorbed from the gastrointestinal tract and nearly completely converted to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism.

The absolute bioavailability of acyclovir after administration of valacyclovir hydrochloride is 54.5% ± 9.1% as determined following a 1 gram oral dose of valacyclovir hydrochloride and a 350 mg intravenous acyclovir dose to 12 healthy volunteers. Acyclovir bioavailability from the administration of valacyclovir hydrochloride is not altered by administration with food (30 minutes after an 873 Kcal breakfast, which included 51 grams of fat).

Acyclovir pharmacokinetic parameter estimates following administration of valacyclovir hydrochloride to healthy adult volunteers are presented in Table 3. There was a less than dose-proportional increase in acyclovir maximum concentration (C_max) and area under the acyclovir concentration-time curve (AUC) after single-dose and multiple-dose administration (4 times daily) of valacyclovir hydrochloride from doses between 250 mg to 1 gram.

There is no accumulation of acyclovir after the administration of valacyclovir at the recommended dosage regimens in adults with normal renal function.

Distribution: The binding of valacyclovir to human plasma proteins ranges from 13.5% to 17.9%. The binding of acyclovir to human plasma proteins ranges from 9% to 33%.

Metabolism: Valacyclovir is converted to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism. Acyclovir is converted to a small extent to inactive metabolites by aldehyde oxidase and by alcohol and aldehyde dehydrogenase. Neither valacyclovir nor acyclovir is metabolized by cytochrome P450 enzymes. Plasma concentrations of unconverted valacyclovir are low and transient, generally becoming non-quantifiable by 3 hours after administration. Peak plasma valacyclovir concentrations are generally less than 0.5 mcg/mL at all doses. After single-dose administration of 1 gram of valacyclovir hydrochloride, average plasma valacyclovir concentrations observed were 0.5, 0.4, and 0.8 mcg/mL in patients with hepatic dysfunction, renal insufficiency, and in healthy volunteers who received concomitant cimetidine and probenecid, respectively.

Elimination: The pharmacokinetic disposition of acyclovir delivered by valacyclovir is consistent with previous experience from intravenous and oral acyclovir. Following the oral administration of a single 1 gram dose of radiolabeled valacyclovir to 4 healthy subjects, 46% and 47% of administered radioactivity was recovered in urine and feces, respectively, over 96 hours. Acyclovir accounted for 89% of the radioactivity excreted in the urine. Renal clearance of acyclovir following the administration of a single 1 gram dose of valacyclovir hydrochloride to 12 healthy volunteers was approximately 255 ± 86 mL/min which represents 42% of total acyclovir apparent plasma clearance.

The plasma elimination half-life of acyclovir typically averaged 2.5 to 3.3 hours in all studies of valacyclovir hydrochloride in volunteers with normal renal function.

Specific Populations: Renal Impairment: Reduction in dosage is recommended in patients with renal impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.5), (8.6)].

Following administration of valacyclovir hydrochloride to volunteers with ESRD, the average acyclovir half-life is approximately 14 hours. During hemodialysis, the acyclovir half-life is approximately 4 hours. Approximately one third of acyclovir in the body is removed by dialysis during a 4-hour hemodialysis session. Apparent plasma clearance of acyclovir in dialysis patients was 86.3 ± 21.3 mL/min/1.73 m² compared with 679.16 ± 162.76 mL/min/1.73 m² in healthy volunteers.

Hepatic Impairment: Administration of valacyclovir hydrochloride to patients with moderate (biopsy-proven cirrhosis) or severe (with and without ascites and biopsy-proven cirrhosis) liver disease indicated that the rate but not the extent of conversion of valacyclovir to acyclovir is reduced, and the acyclovir half-life is not affected. Dosage modification is not recommended for patients with cirrhosis.

HIV Disease: In 9 patients with HIV disease and CD4+ cell counts <150 cells/mm³ who received valacyclovir hydrochloride at a dosage of 1 gram 4 times daily for 30 days, the pharmacokinetics of valacyclovir and acyclovir were not different from that observed in healthy volunteers.

Geriatrics: After single-dose administration of 1 gram of valacyclovir hydrochloride in healthy geriatric volunteers, the half-life of acyclovir was 3.11 ± 0.51 hours, compared with 2.91 ± 0.63 hours in healthy younger adult volunteers. The pharmacokinetics of acyclovir following single-and multiple-dose oral administration of valacyclovir hydrochloride in geriatric volunteers varied with renal function. Dose reduction may be required in geriatric patients, depending on the underlying renal status of the patient [see Dosage and Administration (2.4), Use in Specific Populations (8.5), (8.6)].

Pediatrics: Acyclovir pharmacokinetics have been evaluated in a total of 98 pediatric patients (1 month to < 12 years of age) following administration of the first dose of an extemporaneous oral suspension of valacyclovir [see Adverse Reactions (6.2), Use in Specific Populations (8.4)]. Acyclovir pharmacokinetic parameter estimates following a 20 mg/kg dose are provided in Table 4.

Drug Interactions: When valacyclovir hydrochloride is coadministered with antacids, cimetidine and/or probenicid, digoxin, or thiazide diuretics in patients with normal renal function, the effects are not considered to be of clinical significance (see below). Therefore, when valacyclovir hydrochloride is coadministered with these drugs in patients with normal renal function, no dosage adjustment is recommended.

Antacids: The pharmacokinetics of acyclovir after a single dose of valacyclovir hydrochloride (1 gram) were unchanged by coadministration of a single dose of antacids (Al³⁺or Mg⁺⁺).

Cimetidine: Acyclovir C_max and AUC following a single dose of valacyclovir hydrochloride (1 gram) increased by 8% and 32%, respectively, after a single dose of cimetidine (800 mg).

Cimetidine Plus Probenecid: Acyclovir C_max and AUC following a single dose of valacyclovir hydrochloride (1 gram) increased by 30% and 78%, respectively, after a combination of cimetidine and probenecid, primarily due to a reduction in renal clearance of acyclovir.

Digoxin: The pharmacokinetics of digoxin were not affected by coadministration of valacyclovir hydrochloride 1 gram 3 times daily, and the pharmacokinetics of acyclovir after a single dose of valacyclovir hydrochloride (1 gram) was unchanged by coadministration of digoxin (2 doses of 0.75 mg).

Probenecid: Acyclovir C_max and AUC following a single dose of valacyclovir hydrochloride (1 gram) increased by 22% and 49%, respectively, after probenecid (1 gram).

Thiazide Diuretics: The pharmacokinetics of acyclovir after a single dose of valacyclovir hydrochloride (1 gram) were unchanged by coadministration of multiple doses of thiazide diuretics.

12.4 Microbiology

Mechanism of Action: Valacyclovir is a nucleoside analogue DNA polymerase inhibitor. Valacyclovir hydrochloride is rapidly converted to acyclovir which has demonstrated antiviral activity against HSV types 1 (HSV-1) and 2 (HSV-2) and VZV both in cell culture and in vivo.

The inhibitory activity of acyclovir is highly selective due to its affinity for the enzyme 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 biochemical assays, acyclovir triphosphate inhibits replication of herpes viral DNA. This is accomplished in 3 ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporation and termination of the growing viral DNA chain, and 3) inactivation of the viral DNA polymerase. The greater antiviral activity of acyclovir against HSV compared with VZV is due to its more efficient phosphorylation by the viral TK.

Antiviral Activities: The quantitative relationship between the cell culture susceptibility of herpesviruses to antivirals and the clinical response to therapy has not been established in humans, and virus sensitivity testing has not been standardized. Sensitivity testing results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell culture (EC₅₀), vary greatly depending upon a number of factors. Using plaque-reduction assays, the EC₅₀ values against herpes simplex virus isolates range from 0.09 to 60 μM (0.02 to 13.5 mcg/mL) for HSV-1 and from 0.04 to 44 μM (0.01 to 9.9 mcg/mL) for HSV-2. The EC₅₀ values for acyclovir against most laboratory strains and clinical isolates of VZV range from 0.53 to 48 μM (0.12 to 10.8 mcg/mL). Acyclovir also demonstrates activity against the Oka vaccine strain of VZV with a mean EC₅₀ of 6 μM (1.35 mcg/mL).

Resistance: Resistance of HSV and VZV to acyclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of VZV with reduced susceptibility to acyclovir have been recovered from patients with AIDS. In these cases, TK-deficient mutants of VZV have been recovered.

Resistance of HSV and VZV to acyclovir occurs by the same mechanisms. While most of the acyclovir-resistant mutants isolated thus far from immunocompromised patients have been found to be TK-deficient mutants, other mutants involving the viral TK gene (TK partial and TK altered) and DNA polymerase have also been isolated. TK-negative mutants may cause severe disease in immunocompromised patients. The possibility of viral resistance to valacyclovir (and therefore, to acyclovir) should be considered in patients who show poor clinical response during therapy.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The data presented below include references to the steady-state acyclovir AUC observed in humans treated with 1 gram valacyclovir hydrochloride tablets given orally 3 times a day to treat herpes zoster. Plasma drug concentrations in animal studies are expressed as multiples of human exposure to acyclovir [see Clinical Pharmacology (12.3)].

Valacyclovir was noncarcinogenic in lifetime carcinogenicity bioassays at single daily doses (gavage) of valacyclovir giving plasma acyclovir concentrations equivalent to human levels in the mouse bioassay and 1.4 to 2.3 times human levels in the rat bioassay. There was no significant difference in the incidence of tumors between treated and control animals, nor did valacyclovir shorten the latency of tumors.

Valacyclovir was tested in 5 genetic toxicity assays. An Ames assay was negative in the absence or presence of metabolic activation. Also negative were an in vitro cytogenetic study with human lymphocytes and a rat cytogenetic study.

In the mouse lymphoma assay, valacyclovir was not mutagenic in the absence of metabolic activation. In the presence of metabolic activation (76% to 88% conversion to acyclovir), valacyclovir was mutagenic.

Valacyclovir was mutagenic in a mouse micronucleus assay.

Valacyclovir did not impair fertility or reproduction in rats at 6 times human plasma levels.

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

14.1 Cold Sores (Herpes Labialis)

Two double-blind, placebo-controlled clinical trials were conducted in 1,856 healthy adults and adolescents (≥12 years old) with a history of recurrent cold sores. Patients self-initiated therapy at the earliest symptoms and prior to any signs of a cold sore. The majority of patients initiated treatment within 2 hours of onset of symptoms. Patients were randomized to valacyclovir hydrochloride 2 grams twice daily on Day 1 followed by placebo on Day 2, valacyclovir hydrochloride 2 grams twice daily on Day 1 followed by 1 gram twice daily on Day 2, or placebo on Days 1 and 2.

The mean duration of cold sore episodes was about 1 day shorter in treated subjects as compared with placebo. The 2 day regimen did not offer additional benefit over the 1- day regimen.

No significant difference was observed between subjects receiving valacyclovir hydrochloride or placebo in the prevention of progression of cold sore lesions beyond the papular stage.

14.2 Genital Herpes Infections

Initial Episode: Six hundred and forty-three immunocompetent adults with first-episode genital herpes who presented within 72 hours of symptom onset were randomized in a double-blind trial to receive 10 days of valacyclovir hydrochloride 1 gram twice daily (n = 323) or oral acyclovir 200 mg 5 times a day (n = 320). For both treatment groups: the median time to lesion healing was 9 days, the median time to cessation of pain was 5 days, the median time to cessation of viral shedding was 3 days.

Recurrent Episodes: Three double-blind trials (2 of them placebo-controlled) in immunocompetent adults with recurrent genital herpes were conducted. Patients self-initiated therapy within 24 hours of the first sign or symptom of a recurrent genital herpes episode.

In 1 study, patients were randomized to receive 5 days of treatment with either valacyclovir hydrochloride 500 mg twice daily (n = 360) or placebo (n = 259). The median time to lesion healing was 4 days in the group receiving valacyclovir hydrochloride 500 mg versus 6 days in the placebo group, and the median time to cessation of viral shedding in patients with at least 1 positive culture (42% of the overall study population) was 2 days in the group receiving valacyclovir hydrochloride 500 mg versus 4 days in the placebo group. The median time to cessation of pain was 3 days in the group receiving valacyclovir hydrochloride 500 mg versus 4 days in the placebo group. Results supporting efficacy were replicated in a second trial.

In a third study, patients were randomized to receive valacyclovir hydrochloride 500 mg twice daily for 5 days (n = 398) or valacyclovir hydrochloride 500 mg twice daily for 3 days (and matching placebo twice daily for 2 additional days) (n = 402). The median time to lesion healing was about 4½ days in both treatment groups. The median time to cessation of pain was about 3 days in both treatment groups.

Suppressive Therapy: Two clinical studies were conducted, one in immunocompetent adults and one in HIV-infected adults.

A double-blind, 12-month, placebo-and active-controlled study enrolled immunocompetent adults with a history of 6 or more recurrences per year. Outcomes for the overall study population are shown in Table 5.

Subjects with 9 or fewer recurrences per year showed comparable results with valacyclovir hydrochloride 500 mg once daily.

In a second study, 293 HIV-infected adults on stable antiretroviral therapy with a history of 4 or more recurrences of ano-genital herpes per year were randomized to receive either valacyclovir hydrochloride 500 mg twice daily (n = 194) or matching placebo (n = 99) for 6 months. The median duration of recurrent genital herpes in enrolled subjects was 8 years, and the median number of recurrences in the year prior to enrollment was 5. Overall, the median prestudy HIV-1 RNA was 2.6 log₁₀ copies/mL. Among patients who received valacyclovir hydrochloride, the prestudy median CD4+ cell count was 336 cells/mm³; 11% had <100 cells/mm³, 16% had 100 to 199 cells/mm³, 42% had 200 to 499 cells/mm³, and 31% had ≥500 cells/mm³. Outcomes for the overall study population are shown in Table 6.

Reduction of Transmission of Genital Herpes: A double-blind, placebo-controlled study to assess transmission of genital herpes was conducted in 1,484 monogamous, heterosexual, immunocompetent adult couples. The couples were discordant for HSV-2 infection. The source partner had a history of 9 or fewer genital herpes episodes per year. Both partners were counseled on safer sex practices and were advised to use condoms throughout the study period. Source partners were randomized to treatment with either valacyclovir hydrochloride 500 mg once daily or placebo once daily for 8 months. The primary efficacy endpoint was symptomatic acquisition of HSV-2 in susceptible partners. Overall HSV-2 acquisition was defined as symptomatic HSV-2 acquisition and/or HSV-2 seroconversion in susceptible partners. The efficacy results are summarized in Table 7.

14.3 Herpes Zoster

Two randomized double-blind clinical trials in immunocompetent adults with localized herpes zoster were conducted. Valacyclovir hydrochloride was compared with placebo in patients less than 50 years of age, and with oral acyclovir in patients greater than 50 years of age. All patients were treated within 72 hours of appearance of zoster rash. In patients less than 50 years of age, the median time to cessation of new lesion formation was 2 days for those treated with valacyclovir hydrochloride compared with 3 days for those treated with placebo. In patients greater than 50 years of age, the median time to cessation of new lesions was 3 days in patients treated with either valacyclovir hydrochloride or oral acyclovir. In patients less than 50 years of age, no difference was found with respect to the duration of pain after healing (post-herpetic neuralgia) between the recipients of valacyclovir hydrochloride and placebo. In patients greater than 50 years of age, among the 83% who reported pain after healing  (post-herpetic neuralgia), the median duration of pain after healing [95% confidence interval] in days was: 40 [31, 51], 43 [36, 55], and 59 [41, 77] for 7-day valacyclovir hydrochloride, 14-day valacyclovir hydrochloride, and 7-day oral acyclovir, respectively.

14.4 Chickenpox

The use of valacyclovir hydrochloride tablets for treatment of chickenpox in pediatric patients 2 to < 18 years of age is based on single-dose pharmacokinetic and multiple-dose safety data from an open-label trial with valacyclovir and supported by safety and extrapolated efficacy data from 3 randomized, double-blind, placebo-controlled trials evaluating oral acyclovir in pediatric patients.

The single-dose pharmacokinetic and multiple-dose safety study enrolled 27 pediatric patients 1 to < 12 years of age with clinically suspected VZV infection. Each subject was dosed with valacyclovir oral suspension, 20 mg/kg 3 times daily for 5 days. Acyclovir systemic exposures in pediatric patients following valacyclovir oral suspension were compared with historical acyclovir systemic exposures in immunocompetent adults receiving the solid oral dosage form of valacyclovir or acyclovir for the treatment of herpes zoster. The mean projected daily acyclovir exposures in pediatric patients across all age-groups (1 to < 12 years of age) were lower (C_max: ↓13%, AUC: ↓30%) than the mean daily historical exposures in adults receiving valacyclovir 1 gram 3 times daily, but were higher (daily AUC: ↑50%) than the mean daily historical exposures in adults receiving acyclovir 800 mg 5 times daily. The projected daily exposures in pediatric patients were greater (daily AUC approximately 100% greater) than the exposures seen in immunocompetent pediatric patients receiving acyclovir 20 mg/kg 4 times daily for the treatment of chickenpox. Based on the pharmacokinetic and safety data from this study and the safety and extrapolated efficacy data from the acyclovir studies, oral valacyclovir 20 mg/kg 3 times a day for 5 days (not to exceed 1 gram 3 times daily) is recommended for the treatment of chickenpox in pediatric patients 2 to < 18 years of age. Because the efficacy and safety of acyclovir for the treatment of chickenpox in children < 2 years of age have not been established, efficacy data cannot be extrapolated to support valacyclovir treatment in children < 2 years of age with chickenpox. Valacyclovir is also not recommended for the treatment of herpes zoster in children because safety data up to 7 days’ duration are not available [see Use in Specific Populations (8.4)].

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

Valacyclovir hydrochloride tablets are blue, film-coated, capsule-shaped tablets containing valacyclovir hydrochloride equivalent to 1 g valacyclovir debossed with "W153" on one side and partial bisect on both sides.

Bottle of 4 - 68788-9554-4

Bottle of 6 - 68788-9554-0

Bottle of 10 - 68788-9554-1

Bottle of 20 - 68788-9554-2

Bottle of 30 - 68788-9554-3

Storage:

Store at 20° to 25°C (68° to 77°F). [See USP controlled room temperature] Dispense in a well-closed container as defined in the USP.

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling.

17.1 Importance of Adequate Hydration

Patients should be advised to maintain adequate hydration.

17.2 Cold Sores (Herpes Labialis)

Patients should be advised to initiate treatment at the earliest symptom of a cold sore (e.g., tingling, itching, or burning). There are no data on the effectiveness of treatment initiated after the development of clinical signs of a cold sore (e.g., papule, vesicle, or ulcer). Patients should be instructed that treatment for cold sores should not exceed 1 day (2 doses) and that their doses should be taken about 12 hours apart. Patients should be informed that valacyclovir hydrochloride is not a cure for cold sores.

17.3 Genital Herpes

Patients should be informed that valacyclovir hydrochloride is not a cure for genital herpes. Because genital herpes is a sexually transmitted disease, patients should avoid contact with lesions or intercourse when lesions and/or symptoms are present to avoid infecting partners. Genital herpes is frequently transmitted in the absence of symptoms through asymptomatic viral shedding. Therefore, patients should be counseled to use safer sex practices in combination with suppressive therapy with valacyclovir hydrochloride. Sex partners of infected persons should be advised that they might be infected even if they have no symptoms. Type-specific serologic testing of asymptomatic partners of persons with genital herpes can determine whether risk for HSV-2 acquisition exists.

Valacyclovir hydrochloride has not been shown to reduce transmission of sexually transmitted infections other than HSV-2.

If medical management of a genital herpes recurrence is indicated, patients should be advised to initiate therapy at the first sign or symptom of an episode.

There are no data on the effectiveness of treatment initiated more than 72 hours after the onset of signs and symptoms of a first episode of genital herpes or more than 24 hours after the onset of signs and symptoms of a recurrent episode.

There are no data on the safety or effectiveness of chronic suppressive therapy of more than 1 year’s duration in otherwise healthy patients. There are no data on the safety or effectiveness of chronic suppressive therapy of more than 6 months’ duration in HIV-infected patients.

17.4 Herpes Zoster

There are no data on treatment initiated more than 72 hours after onset of the zoster rash. Patients should be advised to initiate treatment as soon as possible after a diagnosis of herpes zoster.

17.5 Chickenpox

Patients should be advised to initiate treatment at the earliest sign or symptom of chickenpox.

Repackaged by Preferred Pharmaceuticals, Inc.

Manufactured by:

Wockhardt Limited

Mumbai, India.

Distributed by:

Wockhardt USA LLC.

20 Waterview Blvd.

Parsippany, NJ 07054

USA.

Rev.080213

PHARMACIST: Dispense the patient information leaflet with the drug product

PATIENT INFORMATION

Valacyclovir Hydrochloride Tablets

Rx only

Read the Patient Information that comes with valacyclovir hydrochloride tablets before you start using it and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. Ask your healthcare provider or pharmacist if you have questions.

What are valacyclovir hydrochloride tablets?

Valacyclovir hydrochloride tablets are prescription antiviral medicine. Valacyclovir hydrochloride tablet lowers the ability of herpes viruses to multiply in your body.

Valacyclovir hydrochloride tablets are used in adults:

• •to treat cold sores (also called fever blisters or herpes labialis)
• •to treat shingles (also called herpes zoster)
• •to treat or control genital herpes outbreaks in adults with normal immune systems
• •to control genital herpes outbreaks in adults infected with the human immunodeficiency virus (HIV) with CD4+ cell count greater than 100 cells/mm³
• •with safer sex practices to lower the chances of spreading genital herpes to others. Even with safer sex practices, it is still possible to spread genital herpes.

Valacyclovir hydrochloride tablets used daily with the following safer sex practices can lower the chances of passing genital herpes to your partner.

• • Do not have sexual contact with your partner when you have any symptom or outbreak of genital herpes.
• • Use a condom made of latex or polyurethane whenever you have sexual contact.

Valacyclovir hydrochloride tablets are used in children:

• •to treat cold sores (for children ≥12 years of age)
• •to treat chickenpox (for children 2 to < 18 years of age).

Valacyclovir hydrochloride tablet does not cure herpes infections (cold sores, chickenpox, shingles, or genital herpes).

The efficacy of valacyclovir hydrochloride tablets have not been studied in children who have not reached puberty.

What are cold sores, chickenpox, shingles, and genital herpes?

Cold sores are caused by a herpes virus that may be spread by kissing or other physical contact with the infected area of the skin. They are small, painful ulcers that you get in or around your mouth. It is not known if valacyclovir hydrochloride tablets can stop the spread of cold sores to others.

Chickenpox is caused by a herpes virus. It causes an itchy rash of multiple small, red bumps that look like pimples or insect bites usually appearing first on the abdomen or back and face. It can spread to almost everywhere else on the body and may be accompanied by flu-like symptoms.

Shingles is caused by the same herpes virus that causes chickenpox. It causes small, painful blisters that happen on your skin. Shingles occurs in people who have already had chickenpox. Shingles can be spread to people who have not had chickenpox or the chickenpox vaccine by contact with the infected areas of the skin. It is not known if valacyclovir hydrochloride tablets can stop the spread of shingles to others.

Genital herpes is a sexually transmitted disease. It causes small, painful blisters on your genital area. You can spread genital herpes to others, even when you have no symptoms. If you are sexually active, you can still pass herpes to your partner, even if you are taking valacyclovir hydrochloride tablets. Valacyclovir hydrochloride tablets, taken every day as prescribed and used with the following safer sex practices, can lower the chances of passing genital herpes to your partner.

• •Do not have sexual contact with your partner when you have any symptom or outbreak of genital herpes.
• •Use a condom made of latex or polyurethane whenever you have sexual contact.

Ask your healthcare provider for more information about safer sex practices.

Who should not take valacyclovir hydrochloride tablets?

Do not take valacyclovir hydrochloride tablets if you are allergic to any of its ingredients or to acyclovir. The active ingredient is valacyclovir. See the end of this leaflet for a complete list of ingredients in valacyclovir hydrochloride tablets.

Before taking valacyclovir hydrochloride tablets, tell your healthcare provider:

About all your medical conditions, including:

• • if you have had a bone marrow transplant or kidney transplant, or if you have advanced HIV disease or "AIDS". Patients with these conditions may have a higher chance for getting a blood disorder called thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS). TTP/HUS can result in death.
• • if you have kidney problems. Patients with kidney problems may have a higher chance for getting side effects or more kidney problems with valacyclovir hydrochloride tablets. Your healthcare provider may give you a lower dose of valacyclovir hydrochloride tablets.
• • if you are 65 years of age or older. Elderly patients have a higher chance of certain side effects. Also, elderly patients are more likely to have kidney problems. Your healthcare provider may give you a lower dose of valacyclovir hydrochloride tablets.
• • if you are pregnant or planning to become pregnant. Talk with your healthcare provider about the risks and benefits of taking prescription drugs (including valacyclovir hydrochloride tablets) during pregnancy.
• • if you are breastfeeding. Valacyclovir hydrochloride tablets may pass into your milk and it may harm your baby. Talk with your healthcare provider about the best way to feed your baby if you are taking valacyclovir hydrochloride tablets.
• • about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Valacyclovir hydrochloride tablets may affect other medicines, and other medicines may affect valacyclovir hydrochloride tablets. It is a good idea to keep a complete list of all the medicines you take. Show this list to your healthcare provider and pharmacist any time you get a new medicine.

How should I take valacyclovir hydrochloride tablets?

Take valacyclovir hydrochloride tablets exactly as prescribed by your healthcare provider. Your dose of valacyclovir hydrochloride tablets and length of treatment will depend on the type of herpes infection that you have and any other medical problems that you have.

• •Do not stop valacyclovir hydrochloride tablets or change your treatment without talking to your healthcare provider.
• •Valacyclovir hydrochloride tablets can be taken with or without food.
• •If you are taking valacyclovir hydrochloride tablets to treat cold sores, chickenpox, shingles, or genital herpes, you should start treatment as soon as possible after your symptoms start. Valacyclovir hydrochloride tablets may not help you if you start treatment too late.
• •If you miss a dose of valacyclovir hydrochloride tablets, take it as soon as you remember and then take your next dose at its regular time. However, if it is almost time for your next dose, do not take the missed dose. Wait and take the next dose at the regular time.
• •Do not take more than the prescribed number of valacyclovir hydrochloride tablets each day. Call your healthcare provider right away if you take too much valacyclovir hydrochloride tablets.

What are the possible side effects of valacyclovir hydrochloride tablets?

Kidney failure and nervous system problems are not common, but can be serious in some patients taking valacyclovir hydrochloride tablets. Nervous system problems include aggressive behavior, unsteady movement, shaky movements, confusion, speech problems, hallucinations (seeing or hearing things that are really not there), seizures, and coma. Kidney failure and nervous system problems have happened in patients who already have kidney disease and in elderly patients whose kidneys do not work well due to age. Always tell your healthcare provider if you have kidney problems before taking valacyclovir hydrochloride tablets. Call your doctor right away if you get a nervous system problem while you are taking valacyclovir hydrochloride tablets.

Common side effects of valacyclovir hydrochloride tablets in adults include headache, nausea, stomach pain, vomiting, and dizziness. Side effects in HIV-infected adults include headache, tiredness, and rash. These side effects usually are mild and do not cause patients to stop taking valacyclovir hydrochloride tablets.

Other less common side effects in adults include painful periods in women, joint pain, depression, low blood cell counts, and changes in tests that measure how well the liver and kidneys work.

The most common side effect seen in children <18 years of age was headache.

Talk to your healthcare provider if you develop any side effects that concern you.

These are not all the side effects of valacyclovir hydrochloride. For more information ask your healthcare provider or pharmacist.

How should I store valacyclovir hydrochloride tablets?

• •Store at 20° to 25°C (68° to 77°F). [See USP controlled room temperature]
• •Store valacyclovir hydrochloride suspension between 2° to 8°C (36° to 46°F) in a refrigerator. Discard after 28 days.
• •Keep valacyclovir hydrochloride tablets in a tightly closed container.
• •Do not keep medicine that is out of date or that you no longer need.
• •Keep valacyclovir hydrochloride tablets and all medicines out of the reach of children.

General information about valacyclovir hydrochloride tablets

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use valacyclovir hydrochloride tablets for a condition for which it was not prescribed. Do not give valacyclovir hydrochloride tablets to other people, even if they have the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about valacyclovir hydrochloride tablets. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about valacyclovir hydrochloride tablets that is written for health professionals.

What are the ingredients in valacyclovir hydrochloride tablets?

Active Ingredient: valacyclovir hydrochloride

Inactive Ingredients: croscarmellose sodium, FD&C Blue No. 2 aluminium lake, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone, talc and titanium dioxide.

Repackaged by Preferred Pharmaceuticals, Inc.

Manufactured by:

Wockhardt Limited

Mumbai, India.

Distributed by:

Wockhardt USA LLC.

20 Waterview Blvd.

Parsippany, NJ 07054

USA.

Rev.080213