FDA label 3154f8aa-bcd9-673c-e054-00144ff8d46c

WARNINGS AND PRECAUTIONS Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS): Has occurred in patients with advanced HIV disease and in allogenic bone marrow transplant and renal transplant patients receiving 8 grams per day of valacyclovir hydrochloride 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 hydrochloride 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 ) TTP/HUS, in some cases resulting in death, has occurred in patients with advanced HIV disease and also in allogeneic bone marrow transplant and renal transplant recipients participating in clinical trials of valacyclovir hydrochloride at doses of 8 grams per day. Treatment with valacyclovir hydrochloride should be stopped immediately if clinical signs, symptoms, and laboratory abnormalities consistent with TTP/HUS occur. Cases of acute renal failure have been reported in: Elderly patients with or without reduced renal function. Caution should be exercised when administering valacyclovir hydrochloride 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 hydrochloride for their level of renal function. Dosage reduction is recommended when administering valacyclovir hydrochloride 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 hydrochloride 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) ]. 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) ].

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) ]. 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. 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 studies for the treatment of cold sores, the adverse reactions reported by patients receiving valacyclovir hydrochloride 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 (>2 x ULN) were 1.8% for patients receiving valacyclovir hydrochloride 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 study for the treatment of initial episodes of genital herpes, the adverse reactions reported by ≥5% of patients receiving valacyclovir hydrochloride 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 studies for the episodic treatment of recurrent genital herpes, the adverse reactions reported by ≥5% of patients receiving valacyclovir hydrochloride 500 mg twice daily for 3 days (n = 402), valacyclovir hydrochloride 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 study for the suppression of recurrent genital herpes infections, the adverse reactions reported by patients receiving valacyclovir hydrochloride 1 gram once daily (n = 269), valacyclovir hydrochloride 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-Infected Patients: In HIV-infected patients, frequently reported adverse reactions for valacyclovir hydrochloride (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 study for the reduction of transmission of genital herpes, the adverse reactions reported by patients receiving valacyclovir hydrochloride 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 studies for the treatment of herpes zoster, the adverse reactions reported by patients receiving valacyclovir hydrochloride 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 Study Populations Herpes Zoster Genital Herpes Treatment Genital Herpes Suppression Valacyclovir Valacyclovir Valacyclovir Valacyclovir Valacyclovir Hydrochloride Hydrochloride Hydrochloride Hydrochloride Hydrochloride 1 gram 1 gram 500 mg 1 gram 500 mg Laboratory 3 times daily Placebo twice daily twice daily Placebo once daily once daily Placebo Abnormality (n = 967) (n = 195) (n = 1,194) (n = 1,159) (n = 439) (n = 269) (n = 266) (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% * 0.5% 4.1% 3.8% 3.0% Serum creatinine (>1.5 x ULN) 0.2% 0% 0.7% 0% 0% 0% 0% 0% Sixty-five pediatric patients, 12 to <18 years of age, received oral caplets for 1 to 2 days for treatment of cold sores. 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 clinical studies for the treatment of cold sores, the adverse reactions reported by adolescent patients receiving valacyclovir hydrochloride 2 grams twice daily for 1 day, or valacyclovir hydrochloride 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%). Labeling describing additional clinical trial adverse reactions in pediatric patients (ages of 1 month to ≤12 years) is approved for GlaxoSmithKline’s Valtrex ® Caplets. However, due to GlaxoSmithKline’s marketing exclusivity rights, a description of those adverse reactions is not approved for this valacyclovir tablet product. 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: Facial edema, hypertension, tachycardia. Allergic: Acute hypersensitivity reactions including anaphylaxis, angioedema, dyspnea, pruritus, rash, and urticaria [see Contraindications (4) ]. 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: Erythema multiforme, rashes including photosensitivity, alopecia.

<table width="751"> <caption> Table 2. Incidence (%) of Laboratory Abnormalities in Herpes Zoster and Genital Herpes Study Populations</caption> <tbody> <tr> <td/> <td> Herpes Zoster</td> <td> Genital Herpes Treatment</td> <td> Genital Herpes Suppression</td> </tr> <tr> <td/> <td/> <td/> <td/> <td/> <td/> <td/> <td/> <td/> </tr> <tr> <td/> <td> Valacyclovir</td> <td/> <td> Valacyclovir</td> <td> Valacyclovir</td> <td/> <td> Valacyclovir</td> <td> Valacyclovir</td> <td/> </tr> <tr> <td/> <td> Hydrochloride</td> <td/> <td> Hydrochloride</td> <td> Hydrochloride</td> <td/> <td> Hydrochloride</td> <td> Hydrochloride</td> <td/> </tr> <tr> <td/> <td> 1 gram</td> <td/> <td> 1 gram</td> <td> 500 mg</td> <td/> <td> 1 gram</td> <td> 500 mg</td> <td/> </tr> <tr> <td> Laboratory</td> <td> 3 times daily</td> <td> Placebo</td> <td> twice daily</td> <td> twice daily</td> <td> Placebo</td> <td> once daily</td> <td> once daily</td> <td> Placebo</td> </tr> <tr> <td> Abnormality</td> <td> (n = 967)</td> <td> (n = 195)</td> <td> (n = 1,194)</td> <td> (n = 1,159)</td> <td> (n = 439)</td> <td> (n = 269)</td> <td> (n = 266)</td> <td> (n = 134)</td> </tr> <tr> <td>Hemoglobin (&lt;0.8 x LLN) </td> <td>0.8% </td> <td>0% </td> <td>0.3% </td> <td>0.2% </td> <td>0% </td> <td>0% </td> <td>0.8% </td> <td>0.8%</td> </tr> <tr> <td>White blood cells (&lt;0.75 x LLN) </td> <td>1.3% </td> <td>0.6% </td> <td>0.7% </td> <td>0.6% </td> <td>0.2% </td> <td>0.7% </td> <td>0.8% </td> <td>1.5%</td> </tr> <tr> <td>Platelet count (&lt;100,000/mm ³) </td> <td>1.0% </td> <td>1.2% </td> <td>0.3% </td> <td>0.1% </td> <td>0.7% </td> <td>0.4% </td> <td>1.1% </td> <td>1.5%</td> </tr> <tr> <td>AST (SGOT) (&gt;2 x ULN) </td> <td>1.0% </td> <td>0% </td> <td>1.0% </td> <td>* </td> <td>0.5% </td> <td>4.1% </td> <td>3.8% </td> <td>3.0%</td> </tr> <tr> <td>Serum creatinine (&gt;1.5 x ULN) </td> <td>0.2% </td> <td>0% </td> <td>0.7% </td> <td>0% </td> <td>0% </td> <td>0% </td> <td>0% </td> <td>0% </td> </tr> </tbody> </table>