Valacyclovir Hydrochloride (Page 3 of 9)

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 for their level of renal function. Elderly patients are more likely to have central nervous system adverse reactions. Valacyclovir should be discontinued if central nervous system adverse reactions occur [ see Adverse Reactions (6.3),Use in Specific Populations (8.5,8.6)].

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 greater than 10% of adult subjects treated with valacyclovir and observed more frequently with valacyclovir 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.

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 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 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 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 500 mg twice daily for 3 days (n = 402), valacyclovir 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 1 gram once daily (n = 269), valacyclovir 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 (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 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 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

Laboratory Abnormality Herpes Zoster Genital Herpes Treatment Genital Herpes Suppression
Valacyclovir 1 gram 3 times daily (n=967) Placebo (n=195) Valacyclovir 1 gram twice daily (n=1,194) Valacyclovir 500 mg twice daily (n=1,159) Placebo (n=439) Valacyclovir 1 gram once daily (n=269) Valacyclovir 500 mg once daily (n=266) Placebo (n=134)
Hemoglobin (<0.8xLLN) 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% a 0.5% 4.1% 3.8% 3.0%
Serum creatinine (>1.5 x ULN) 0.2% 0% 0.7% 0% 0% 0% 0% 0%

a Data were not collected prospectively.
LLN = Lower limit of normal.
ULN = Upper limit of normal.

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