Valacyclovir Hydrochloride

5 WARNINGS AND PRECAUTIONS Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS): Has occurred in patients with advanced HIV-1 disease and in allogenic bone marrow transplant and renal transplant patients receiving 8 grams per day of valacyclovir tablets in clinical trials. Discontinue treatment if clinical symptoms and laboratory findings consistent with TTP/HUS occur. ( 5.1 ) Acute renal failure: May occur in elderly patients (with or without reduced renal function), patients with underlying renal disease who receive higher-than-recommended doses of valacyclovir tablets for their level of renal function, patients who receive concomitant nephrotoxic drugs, or inadequately hydrated patients. Use with caution in elderly patients and reduce dosage in patients with renal impairment. ( 2.4 , 5.2 ) Central nervous system adverse reactions (e.g., agitation, hallucinations, confusion, and encephalopathy): May occur in both adult and pediatric patients (with or without reduced renal function) and in patients with underlying renal disease who receive higher-than-recommended doses of valacyclovir tablets 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. ( 2.4 , 5.3 ) Severe cutaneous adverse reactions (SCARs): Including acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), toxic epidermal necrolysis (TEN), and Stevens-Johnson syndrome (SJS) have been reported during the postmarketing experience with valacyclovir. Discontinue valacyclovir tablets immediately if a painful rash with mucosal involvement or a progressive severe rash develops, and closely monitor clinical status. ( 5.4 ) 5.1 Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome (TTP/HUS) TTP/HUS, in some cases resulting in death, has occurred in patients with advanced HIV-1 disease and also in allogeneic bone marrow transplant and renal transplant recipients participating in clinical trials of valacyclovir tablets at doses of 8 grams per day. Treatment with valacyclovir tablets should be stopped immediately if clinical signs, symptoms, and laboratory abnormalities consistent with TTP/HUS occur. 5.2 Acute Renal Failure Cases of acute renal failure have been reported in: Elderly patients with or without reduced renal function. Caution should be exercised when administering valacyclovir tablets to geriatric patients, and dosage reduction is recommended for those with impaired renal function [see Dosage and Administration (2.4) , Use in Specific Populations (8.5) ]. Patients with underlying renal disease who received higher-than-recommended doses of valacyclovir tablets for their level of renal function. Dosage reduction is recommended when administering valacyclovir tablets to patients with renal impairment [see Dosage and Administration (2.4) , Use in Specific Populations (8.6) ]. Patients receiving other nephrotoxic drugs. Caution should be exercised when administering valacyclovir tablets to patients receiving potentially nephrotoxic drugs. 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. In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored [see Dosage and Administration (2.4) , Adverse Reactions (6.3) ] . 5.3 Central Nervous System Effects Central nervous system adverse reactions, including agitation, hallucinations, confusion, delirium, seizures, and encephalopathy, have been reported in both adult and pediatric patients with or without reduced renal function and in patients with underlying renal disease who received higher-than-recommended doses of valacyclovir tablets for their level of renal function. Elderly patients are more likely to have central nervous system adverse reactions. Valacyclovir tablets should be discontinued if central nervous system adverse reactions occur [see Adverse Reactions (6.3) , Use in Specific Populations (8.5 , 8.6) ]. 5.4 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions (SCARs), including acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) have been reported during postmarketing experience with valacyclovir [see Contraindications (4) and Adverse Reactions (6.3) ] . Discontinue valacyclovir tablets immediately if a painful rash with mucosal involvement or a progressive severe rash develops. Closely monitor clinical status and initiate appropriate therapy. Valacyclovir tablets are contraindicated in patients who have developed SCARs with the use of valacyclovir or acyclovir, or any component of the formulation [see Contraindications (4) , Adverse Reactions (6.3) ] .

6 ADVERSE REACTIONS 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) ] . Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.4) ] . The most common adverse reactions reported in at least 1 indication by greater than 10% of adult subjects treated with valacyclovir tablets and observed more frequently with valacyclovir tablets compared with placebo are headache, nausea, and abdominal pain. The only adverse reaction reported in greater than 10% of pediatric subjects aged less than 18 years was headache. The most common adverse reactions reported in at least one indication by greater than 10% of adult subjects treated with valacyclovir tablets and more commonly than in subjects treated with placebo are headache, nausea, and abdominal pain. ( 6.1 ) The only adverse reaction occurring in greater than 10% of pediatric subjects aged less than 18 years was headache. ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Viatris at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience in Adult Subjects 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) In clinical trials for the treatment of cold sores, the adverse reactions reported by subjects receiving valacyclovir tablets 2 grams twice daily (n = 609) or placebo (n = 609) for 1 day, respectively, included headache (14%, 10%) and dizziness (2%, 1%). The frequencies of abnormal ALT (greater than 2 x ULN) were 1.8% for subjects receiving valacyclovir tablets compared with 0.8% for placebo. Other laboratory abnormalities (hemoglobin, white blood cells, alkaline phosphatase, and serum creatinine) occurred with similar frequencies in the 2 groups. Genital Herpes Initial Episode In a clinical trial for the treatment of initial episodes of genital herpes, the adverse reactions reported by greater than or equal to 5% of subjects receiving valacyclovir tablets 1 gram twice daily for 10 days (n = 318) or oral acyclovir 200 mg 5 times daily for 10 days (n = 318), respectively, included headache (13%, 10%) and nausea (6%, 6%). For the incidence of laboratory abnormalities see Table 2. Recurrent Episodes In 3 clinical trials for the episodic treatment of recurrent genital herpes, the adverse reactions reported by greater than or equal to 5% of subjects receiving valacyclovir tablets 500 mg twice daily for 3 days (n = 402), valacyclovir tablets 500 mg twice daily for 5 days (n = 1,136), or placebo (n = 259), respectively, included headache (16%, 11%, 14%) and nausea (5%, 4%, 5%). For the incidence of laboratory abnormalities see Table 2. Suppressive Therapy: Suppression of Recurrent Genital Herpes in Immunocompetent Adults In a clinical trial for the suppression of recurrent genital herpes infections, the adverse reactions reported by subjects receiving valacyclovir tablets 1 gram once daily (n = 269), valacyclovir tablets 500 mg once daily (n = 266), or placebo (n = 134), respectively, included headache (35%, 38%, 34%), nausea (11%, 11%, 8%), abdominal pain (11%, 9%, 6%), dysmenorrhea (8%, 5%, 4%), depression (7%, 5%, 5%), arthralgia (6%, 5%, 4%), vomiting (3%, 3%, 2%), and dizziness (4%, 2%, 1%). For the incidence of laboratory abnormalities see Table 2. Suppression of Recurrent Genital Herpes in HIV-1 - Infected Subjects In HIV-1-infected subjects, frequently reported adverse reactions for valacyclovir tablets (500 mg twice daily; n = 194, median days on therapy = 172) and placebo (n = 99, median days on therapy = 59), respectively, included headache (13%, 8%), fatigue (8%, 5%), and rash (8%, 1%). Post-randomization laboratory abnormalities that were reported more frequently in valacyclovir subjects versus placebo included elevated alkaline phosphatase (4%, 2%), elevated ALT (14%, 10%), elevated AST (16%, 11%), decreased neutrophil counts (18%, 10%), and decreased platelet counts (3%, 0%), respectively. Reduction of Transmission In a clinical trial for the reduction of transmission of genital herpes, the adverse reactions reported by subjects receiving valacyclovir tablets 500 mg once daily (n = 743) or placebo once daily (n = 741), respectively, included headache (29%, 26%), nasopharyngitis (16%, 15%), and upper respiratory tract infection (9%, 10%). Herpes Zoster In 2 clinical trials for the treatment of herpes zoster, the adverse reactions reported by subjects receiving valacyclovir tablets 1 gram 3 times daily for 7 to 14 days (n = 967) or placebo (n = 195), respectively, included nausea (15%, 8%), headache (14%, 12%), vomiting (6%, 3%), dizziness (3%, 2%), and abdominal pain (3%, 2%). For the incidence of laboratory abnormalities see Table 2. Table 2. Incidence (%) of Laboratory Abnormalities in Herpes Zoster and Genital Herpes Trial Populations LLN = Lower limit of normal. ULN = Upper limit of normal. Laboratory Abnormality Herpes Zoster Genital Herpes Treatment Genital Herpes Suppression Valacyclovir Tablets 1 gram 3 Times Daily (n = 967) Placebo (n = 195) Valacyclovir Tablets 1 gram Twice Daily (n = 1,194) Valacyclovir Tablets 500 mg Twice Daily (n = 1,159) Placebo (n = 439) Valacyclovir Tablets 1 gram Once Daily (n = 269) Valacyclovir Tablets 500 mg Once Daily (n = 266) Placebo (n = 134) Hemoglobin (< 0.8 x LLN) 0.8% 0% 0.3% 0.2% 0% 0% 0.8% 0.8% White blood cells (< 0.75 x LLN) 1.3% 0.6% 0.7% 0.6% 0.2% 0.7% 0.8% 1.5% Platelet count (< 100,000/mm 3 ) 1.0% 1.2% 0.3% 0.1% 0.7% 0.4% 1.1% 1.5% AST (SGOT) (> 2 x ULN) 1.0% 0% 1.0% Data were not collected prospectively. 0.5% 4.1% 3.8% 3.0% Serum creatinine (> 1.5 x ULN) 0.2% 0% 0.7% 0% 0% 0% 0% 0% 6.2 Clinical Trials Experience in Pediatric Subjects The safety profile of valacyclovir tablets has been studied in 177 pediatric subjects aged 1 month to less than 18 years. Sixty-five of these pediatric subjects, aged 12 to less than 18 years, received oral tablets for 1 to 2 days for treatment of cold sores. The remaining 112 pediatric subjects, aged 1 month to less than 12 years, participated in 3 pharmacokinetic and safety trials and received valacyclovir oral suspension. Fifty-one of these 112 pediatric subjects 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 Subjects Aged 12 to Less than 18 Years (Cold Sores) In clinical trials for the treatment of cold sores, the adverse reactions reported by adolescent subjects receiving valacyclovir tablets 2 grams twice daily for 1 day, or valacyclovir tablets 2 grams twice daily for 1 day followed by 1 gram twice daily for 1 day (n = 65, across both dosing groups), or placebo (n = 30), respectively, included headache (17%, 3%) and nausea (8%, 0%). Pediatric Subjects Aged 1 Month to Less than 12 Years Adverse events reported in more than 1 subject across the 3 pharmacokinetic and safety trials in children aged 1 month to less than 12 years were diarrhea (5%), pyrexia (4%), dehydration (2%), herpes simplex (2%), and rhinorrhea (2%). No clinically meaningful changes in laboratory values were observed. 6.3 Postmarketing Experience In addition to adverse events reported from clinical trials, the following events have been identified during postmarketing use of valacyclovir tablets. 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 tablets. General Facial edema, hypertension, tachycardia. Allergic Acute hypersensitivity reactions including anaphylaxis, angioedema, dyspnea, pruritus, rash, and urticaria [see Contraindications (4) ] . Central Nervous System (CNS) Symptoms Aggressive behavior; agitation; ataxia; coma; confusion; decreased consciousness; dysarthria; encephalopathy; mania; and psychosis, including auditory and visual hallucinations, seizures, tremors [see Warnings and Precautions (5.3) , Use in Specific Populations (8.5 , 8.6) ]. Eye Visual abnormalities. Gastrointestinal Diarrhea. Hepatobiliary Tract and Pancreas Liver enzyme abnormalities, hepatitis. Renal Renal failure, renal pain (may be associated with renal failure) [see Warnings and Precautions (5.2) , Use in Specific Populations (8.5 , 8.6) ] . Hematologic Thrombocytopenia, aplastic anemia, leukocytoclastic vasculitis, TTP/HUS [see Warnings and Precautions (5.1) ] . Skin and Subcutaneous Tissue Disorders Acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), erythema multiforme (EM), rashes including photosensitivity, alopecia [see Contraindications (4) , Warnings and Precautions (5.4) ] .

<table cellpadding="5.75pt" width="100%"><caption>Table 2. Incidence (%) of Laboratory Abnormalities in Herpes Zoster and Genital Herpes Trial Populations</caption><col width="15%"/><col width="13%"/><col width="9%"/><col width="12%"/><col width="12%"/><col width="8%"/><col width="12%"/><col width="12%"/><col width="8%"/><tfoot><tr><td align="left" colspan="9" valign="top">LLN = Lower limit of normal. ULN = Upper limit of normal. </td></tr></tfoot><tbody><tr><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Laboratory Abnormality</content></paragraph></td><td align="center" colspan="2" styleCode="Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Herpes Zoster</content></paragraph></td><td align="center" colspan="3" styleCode="Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Genital Herpes Treatment</content></paragraph></td><td align="center" colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Genital Herpes Suppression</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"><paragraph><content styleCode="bold">Valacyclovir Tablets</content></paragraph><paragraph><content styleCode="bold">1 gram</content></paragraph><paragraph><content styleCode="bold">3 Times Daily</content></paragraph><paragraph><content styleCode="bold">(n = 967)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">(n = 195)</content></paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="bottom"><paragraph><content styleCode="bold">Valacyclovir Tablets</content></paragraph><paragraph><content styleCode="bold">1 gram</content></paragraph><paragraph><content styleCode="bold">Twice Daily</content></paragraph><paragraph><content styleCode="bold">(n = 1,194)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"><paragraph><content styleCode="bold">Valacyclovir Tablets</content></paragraph><paragraph><content styleCode="bold">500 mg</content></paragraph><paragraph><content styleCode="bold">Twice Daily</content></paragraph><paragraph><content styleCode="bold">(n = 1,159)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">(n = 439)</content></paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="bottom"><paragraph><content styleCode="bold">Valacyclovir Tablets</content></paragraph><paragraph><content styleCode="bold">1 gram</content></paragraph><paragraph><content styleCode="bold">Once Daily</content></paragraph><paragraph><content styleCode="bold">(n = 269)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"><paragraph><content styleCode="bold">Valacyclovir Tablets</content></paragraph><paragraph><content styleCode="bold">500 mg</content></paragraph><paragraph><content styleCode="bold">Once Daily</content></paragraph><paragraph><content styleCode="bold">(n = 266)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">(n = 134)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hemoglobin</paragraph><paragraph>(&lt; 0.8 x LLN)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.8%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0%</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>0.3%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.2%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0%</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>0%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.8%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.8%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>White blood cells</paragraph><paragraph>(&lt; 0.75 x LLN)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.3%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.6%</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>0.7%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.6%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.2%</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>0.7%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.8%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.5%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Platelet count</paragraph><paragraph>(&lt; 100,000/mm ³) </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.0%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.2%</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>0.3%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.1%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.7%</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>0.4%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.1%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.5%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>AST (SGOT)</paragraph><paragraph>(&gt; 2 x ULN)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.0%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0%</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>1.0%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><footnote ID="_Ref31103349">Data were not collected prospectively.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.5%</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>4.1%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3.8%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3.0%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Serum creatinine</paragraph><paragraph>(&gt; 1.5 x ULN)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>0.2%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>0%</paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph>0.7%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>0%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>0%</paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph>0%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>0%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>0%</paragraph></td></tr></tbody></table>