VALACYCLOVIR HYDROCHLORIDE- valacyclovir hydrochloride_tablet, film coated

Valacyclovir is an antiviral drug [see Clinical Pharmacology (12. 4) 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. Absorption and Bioavailability: L- max Table 3. Mean (+/-SD) Plasma Acyclovir Pharmacokinetic Parameters Following Administration of Valacyclovir Hydrochloride to Healthy Adult Volunteers a Single-Dose Administration Multiple-Dose Administration a C max AUC (+/-SD) C max AUC (+/-SD) 100 mg 0. 4) ND ND 250 mg 2. 09) 500 mg 3. 01) 750 mg 4. 54) ND ND 1,000 mg 5. 27) Distribution: L Specific Populations: Renal Impairment: [see Dosage and Administration (2. 4) Use in Specific Populations (8. 6) 2 2 3 [see Dosage and Administration (2. 6) [see Adverse Reactions (6. 2) Use in Specific Populations (8. Mean (+/-SD) Plasma Acyclovir Pharmacokinetic Parameter Estimates Following First-Dose Administration of 20 mg/kg Valacyclovir Oral Suspension to Pediatric Patients vs. 1 Gram Single Dose of Valacyclovir Hydrochloride to Adults a Parameter Pediatric Patients Adults a 1 - <2 yr 2 - <6 yr 6 - <12 yr AUC (mcghr/mL) max 14. 1) Drug Interactions: 3+ ++ max max max Mechanism of Action: in vivo Antiviral Activities: 50 50 50 50 Resistance:.

Valacyclovir hydrochloride is a nucleoside analogue DNA polymerase inhibitor indicated for: Adult Patients (1. 1) Cold Sores (Herpes Labialis) Genital Herpes Treatment in immunocompetent patients (initial or recurrent episode) Suppression in immunocompetent or HIV-infected patients Reduction of transmission Herpes Zoster Pediatric Patients (1. 2) Cold Sores (Herpes Labialis) Chickenpox Limitations of Use (1. 3) The efficacy and safety of valacyclovir tablets, USP have not been established in immunocompromised patients other than for the suppression of genital herpes in HIV-infected patients. Cold Sores (Herpes Labialis): Genital Herpes: Initial Episode: Sexually Transmitted Diseases Treatment Guidelines Herpes Zoster: Cold Sores (Herpes Labialis): [see Clinical Studies (14. 4) The efficacy and safety of valacyclovir tablets, USP have not been established in: Immunocompromised patients other than for the suppression of genital herpes in HIV-infected patients with a CD4+ cell count >=100 cells/mm 3 Patients <12 years of age with cold sores (herpes labialis). Patients <2 years of age or >=18 years of age with chickenpox. Patients <18 years of age with genital herpes. Patients <18 years of age with herpes zoster. Neonates and infants as suppressive therapy following neonatal herpes simplex virus (HSV) infection.

Valacyclovir tablets may be given without regard to meals. Valacyclovir oral suspension (25 mg/mL or 50 mg/mL) may be prepared extemporaneously from 500 mg valacyclovir tablets for use in pediatric patients for whom a solid dosage form is not appropriate [see Dosage and Administration (2. 3) Adult Dosage (2. 1) Cold Sores 2 grams every 12 hours for 1 day Genital Herpes Initial episode 1 gram twice daily for 10 days Recurrent episodes 500 mg twice daily for 3 days Suppressive therapy Reduction of transmission 500 mg once daily Herpes Zoster 1 gram 3 times daily for 7 days Pediatric Dosage (2. 2) Cold Sores (>=12 years of age) 2 grams every 12 hours for 1 day Chickenpox (2 to <18 years of age) 20 mg/kg 3 times daily for 5 days not to exceed 1 gram 3 times daily Valacyclovir oral suspension (25 mg/mL or 50 mg/mL) can be prepared from the 500 mg valacyclovir tablets. 3) Cold Sores (Herpes Labialis): Genital Herpes: Initial Episode: 3 Herpes Zoster: Cold Sores (Herpes Labialis): Chickenpox: [see Use in Specific Populations (8. 4) Clinical Pharmacology (12. 3) Clinical Studies (14. 4) Ingredients and Preparation per USP-NF: Prepare Suspension at Time of Dispensing as Follows: Prepare SSV according to the USP-NF. Using a pestle and mortar, grind the required number of valacyclovir 500 mg tablets until a fine powder is produced (5 valacyclovir tablets for 25 mg/mL suspension; 10 valacyclovir tablets for 50 mg/mL suspension). Gradually add approximately 5 mL aliquots of SSV to the mortar and triturate the powder until a paste has been produced. Ensure that the powder has been adequately wetted. Continue to add approximately 5 mL aliquots of SSV to the mortar, mixing thoroughly between additions, until a concentrated suspension is produced, to a minimum total quantity of 20 mL SSV and a maximum total quantity of 40 mL SSV for both the 25 mg/mL and 50 mg/mL suspensions. Transfer the mixture to a suitable 100 mL measuring flask. Transfer the cherry flavor* to the mortar and dissolve in approximately 5 mL of SSV. Once dissolved, add to the measuring flask. Rinse the mortar at least 3 times with approximately 5 mL aliquots of SSV, transferring the rinsing to the measuring flask between additions. Make the suspension to volume (100 mL) with SSV and shake thoroughly to mix. Transfer the suspension to an amber glass medicine bottle with a child-resistant closure. The prepared suspension should be labeled with the following information “Shake well before using. Store suspension between 2° to 8°C (36° to 46°F) in a refrigerator. Discard after 28 days. ” *The amount of cherry flavor added is as instructed by the suppliers of the cherry flavor. Dosage recommendations for adult patients with reduced renal function are provided in Table 1 [see Use in Specific Populations (8. 6) Clinical Pharmacology (12. 3) 2 Table 1. Valacyclovir Tablets Dosage Recommendations for Adults With Renal Impairment Indications Normal Dosage Creatinine Clearance (mL/min) 30-49 10-29 <10 Cold sores (Herpes labialis) treatment. Two 2 gram Two 1 gram Two 500 mg 500 mg Genital herpes: 1 gram every no reduction 1 gram every 500 mg every Genital herpes: 500 mg every no reduction 500 mg every 500 mg every Genital herpes: Herpes zoster 1 gram every 1 gram every 1 gram every 500 mg every Hemodialysis: Peritoneal Dialysis:.

The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome [see Warnings and Precautions (5. 1) Acute Renal Failure [see Warnings and Precautions (5. 2) Central Nervous System Effects [see Warnings and Precautions (5. 3) The most common adverse reactions reported in at least 1 indication by >10% of adult patients treated with valacyclovir hydrochloride and observed more frequently with valacyclovir hydrochloride compared to placebo are headache, nausea, and abdominal pain. The only adverse reaction reported in >10% of pediatric patients <18 years of age was headache. The most common adverse reactions reported in at least one indication by >10% of adult patients treated with valacyclovir hydrochloride and more commonly than in patients treated with placebo are headache, nausea, and abdominal pain. 1) The only adverse reaction occurring in >10% of pediatric patients <18 years of age was headache. 2) To report SUSPECTED ADVERSE REACTIONS, contact Citron Pharma LLC. at 1-855-5-CITRON (1-855-524-8766) or FDA at 1-800-FDA-1088 or www. gov/medwatch Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Cold Sores (Herpes Labialis): Genital Herpes: Initial Episode: Herpes Zoster: Table 2. Incidence (%) of Laboratory Abnormalities in Herpes Zoster and Genital Herpes Study Populations a Laboratory Abnormality Herpes Zoster Genital Herpes Treatment Genital Herpes Suppression Valacyclovir Placebo Valacyclovir Valacyclovir Placebo Valacyclovir Valacyclovir Placebo Hemoglobin 3 0. 2% a 0% 0% 0. 8% The safety profile of valacyclovir hydrochloride has been studied in 177 pediatric patients 1 month to <18 years of age. Sixty-five of these pediatric patients, 12 to <18 years of age, received oral tablets for 1 to 2 days for treatment of cold sores. The remaining 112 pediatric patients, 1 month to <12 years of age, participated in 3 pharmacokinetic and safety studies and received valacyclovir oral suspension. Fifty-one of these 112 pediatric patients received oral suspension for 3 to 6 days. The frequency, intensity, and nature of clinical adverse reactions and laboratory abnormalities were similar to those seen in adults. Pediatric Patients 12 to <18 Years of Age (Cold Sores): In addition to adverse events reported from clinical trials, the following events have been identified during postmarketing use of valacyclovir hydrochloride. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to valacyclovir hydrochloride. General: Allergic: [see Contraindications (4) CNS Symptoms: [see Warnings and Precautions (5. 3) Use in Specific Populations (8. 6) Eye: Gastrointestinal: Hepatobiliary Tract and Pancreas: Renal: [see Warnings and Precautions (5. 2) Use in Specific Populations (8. 6) Hematologic: [see Warnings and Precautions (5.

Valacyclovir tablets are contraindicated in patients who have had a demonstrated clinically significant hypersensitivity reaction (e. , anaphylaxis) to valacyclovir, acyclovir, or any component of the formulation [see Adverse Reactions (6. 3) ­Hypersensitivity to valacyclovir (e. , anaphylaxis), acyclovir, or any component of the formulation.

Pregnancy Category B. There are no adequate and well-controlled studies of valacyclovir hydrochloride or acyclovir in pregnant women. Based on prospective pregnancy registry data on 749 pregnancies, the overall rate of birth defects in infants exposed to acyclovir in-utero Following oral administration of a 500 mg dose of valacyclovir hydrochloride to 5 nursing mothers, peak acyclovir concentrations (C max Valacyclovir hydrochloride is indicated for treatment of cold sores in pediatric patients >=12 years of age and for treatment of chickenpox in pediatric patients 2 to <18 years of age [see Indications and Usage (1. 2) Dosage and Administration (2. 2) [see Clinical Studies (14. 1) [see Dosage and Administration (2. 2) Adverse Reactions (6. 2) Clinical Pharmacology (12. 3) Clinical Studies (14. 4) <12 years of age with cold sores <18 years of age with genital herpes <18 years of age with herpes zoster <2 years of age with chickenpox for suppressive therapy following neonatal HSV infection. The pharmacokinetic profile and safety of valacyclovir oral suspension in children <12 years of age were studied in 3 open-label studies. No efficacy evaluations were conducted in any of the 3 studies. [see Dosage and Administration (2. 4) max max Of the total number of subjects in clinical studies of valacyclovir hydrochloride, 906 were 65 and over, and 352 were 75 and over. In a clinical study of herpes zoster, the duration of pain after healing (post-herpetic neuralgia) was longer in patients 65 and older compared with younger adults. Elderly patients are more likely to have reduced renal function and require dose reduction. Elderly patients are also more likely to have renal or CNS adverse events [see Dosage and Administration (2. 4) Warnings and Precautions (5. 3) Clinical Pharmacology (12. 3) Dosage reduction is recommended when administering valacyclovir hydrochloride to patients with renal impairment [see Dosage and Administration (2.

No clinically significant drug-drug or drug-food interactions with valacyclovir hydrochloride are known [see Clinical Pharmacology (12.3)

OVERDOSAGE
Caution should be exercised to prevent inadvertent overdose [see Use in Specific Populations (8.5) (8.6) [see Dosage and Administration (2.4)
NONCLINICAL TOXICOLOGY
The data presented below include references to the steady-state acyclovir AUC observed in humans treated with 1 gram valacyclovir hydrochloride 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) in vitro
CLINICAL STUDIES
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. Initial Episode: Recurrent Episodes: Suppressive Therapy: Table 5. Recurrence Rates in Immunocompetent Adults at 6 and 12 Months a Outcome 6 Months 12 Months Valacyclovir Hydrochloride Oral acyclovir Placebo Valacyclovir Hydrochloride Oral acyclovir Placebo Recurrence free 55% 54% 7% 34% 34% 4% Recurrences 35% 36% 83% 46% 46% 85% Unknown a 10% 10% 10% 19% 19% 10% Subjects with 9 or fewer recurrences per year showed comparable results with valacyclovir hydrochloride 500 mg once daily. 10 3 3 3 3 3 Table 6. Recurrence Rates in HIV-Infected Adults at 6 Months a Outcome Valacyclovir Hydrochloride Placebo Recurrence free 65% 26% Recurrences 17% 57% Unknown a 18% 17% Reduction of Transmission of Genital Herpes: Table 7. Percentage of Susceptible Partners Who Acquired HSV-2 Defined by the Primary and Selected Secondary Endpoints a Endpoint Valacyclovir Hydrochloride a Placebo Symptomatic HSV-2 acquisition 4 (0. 2%) HSV-2 seroconversion 12 (1. 2%) Overall HSV-2 acquisition 14 (1. 6%) 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. The use of valacyclovir hydrochloride 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. max [see Use in Specific Populations (8.
PATIENT INFORMATION
Valacyclovir Tablets, USP What are valacyclovir tablets? 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/mm 3 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 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 Valacyclovir 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 tablets do not cure herpes infections What are cold sores, chickenpox, shingles, and genital herpes? Chickenpox Shingles safer sex practices 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 tablets? Do not take valacyclovir tablets if you have had a bone marrow transplant or kidney transplant, or if you have advanced HIV disease or “AIDS”. if you have kidney problems. if you are 65 years of age or older. if you are pregnant or planning to become pregnant. if you are breastfeeding. about all the medicines you take, How should I take valacyclovir tablets? Do not stop valacyclovir tablets or change your treatment without talking to your healthcare provider. Valacyclovir tablets can be taken with or without food. If you are taking valacyclovir tablets to treat cold sores, chickenpox, shingles, or genital herpes, you should start treatment as soon as possible after your symptoms start. Valacyclovir tablets may not help you if you start treatment too late. If you miss a dose of valacyclovir tablet, 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 tablets each day. Call your healthcare provider right away if you take too much valacyclovir tablets. What are the possible side effects of valacyclovir tablets? Always tell your healthcare provider if you have kidney problems before taking valacyclovir tablets. Call your doctor right away if you get a nervous system problem while you are taking valacyclovir tablets. How should I store valacyclovir tablets? Store valacyclovir tablets at Store valacyclovir oral suspension between 2 o o o o Keep valacyclovir tablets in a tightly closed container. Do not keep medicine that is out of date or that you no longer need. Keep valacyclovir tablets and all medicines out of the reach of children. General information about valacyclovir tablets Distributed by: Citron Pharma LLC

NuCare Pharmacuticals,Inc.

VALACYCLOVIR HYDROCHLORIDE- valacyclovir hydrochloride_tablet, film coated Product manual source documgent