What are the potential side effects of valacyclovir?

Valacyclovir Side Effects

Valacyclovir is generally well-tolerated with headache, nausea, and abdominal pain being the most common side effects, but serious complications including renal impairment, neurotoxicity, and thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) can occur, particularly in patients with renal dysfunction or immunocompromise. 1

Common Side Effects (>10% of patients)

• Headache is the most frequently reported adverse effect, occurring in 13-38% of patients across different indications 1
• Nausea affects 4-11% of patients depending on the treatment regimen 1
• Abdominal pain occurs in 6-11% of patients, particularly during suppressive therapy 1
• These mild symptoms typically require only symptomatic treatment without discontinuation of therapy 2, 3

Serious Adverse Effects Requiring Medical Attention

Renal Toxicity

• Acute kidney injury can occur through crystal-induced obstructive nephropathy, similar to acyclovir 4, 5
• Renal impairment typically manifests after 4 days of therapy and affects up to 20% of patients receiving intravenous acyclovir 4
• Crystalluria-induced nephropathy is rare with oral valacyclovir but can occur, especially with overdosage or in patients with pre-existing renal dysfunction 4, 5
• Patients with a single kidney or chronic kidney disease are at particularly high risk for exaggerated renal toxicity 5

Neurotoxicity

• Central nervous system effects including confusion, altered consciousness, hallucinations, agitation, and dysarthria can occur 6
• Neurotoxicity typically develops within 3.1 days of starting therapy and is most common in patients with renal impairment 6
• Visual and auditory hallucinations have been reported even at normal dosing in patients with compromised renal function 5
• Recovery time averages 9.8 days after drug discontinuation, with 74.4% of patients recovering within 7 days 6
• Hemodialysis may be required in severe cases to rapidly clear the drug, particularly in end-stage renal disease 7

Hematologic Complications

• TTP/HUS has been associated with high-dose valacyclovir (8 g/day) in immunocompromised patients, particularly those with HIV infection 4, 2, 1
• At standard therapeutic doses for genital herpes, this complication has not been reported 4, 2
• Granulocytopenia and thrombocytopenia can occur but are infrequent 4

Less Common but Notable Side Effects

• Dysmenorrhea (5-8% in suppressive therapy) 1
• Depression (5-7% during long-term suppression) 1
• Arthralgia (4-6%) 1
• Dizziness (1-4%) 1
• Elevated liver enzymes (ALT >2x ULN in 1.8% vs 0.8% placebo) 1
• Clostridium difficile colitis has been reported rarely, presenting with severe diarrhea requiring metronidazole treatment 8

Critical Risk Factors and Monitoring

Renal Impairment

• Dose adjustment is mandatory in patients with creatinine clearance <50 mL/min 4, 3
• Failure to adjust dosing in renal dysfunction is the primary cause of severe neurotoxicity, with cases reporting doses six times higher than recommended 7
• The half-life can extend to 14 hours in end-stage renal disease compared to 2.5-3.3 hours in normal renal function 7

Immunocompromised Patients

• HIV-infected patients may require higher doses (400 mg three to five times daily) but must avoid the 8 g/day threshold associated with TTP/HUS 4, 2
• At standard doses, valacyclovir is generally safe in immunocompromised patients 2

Special Populations

• Elderly patients with age-related renal decline are at increased risk for neurotoxicity 5, 6
• Pregnancy: No established safety data exists, though a registry maintained by the manufacturer shows no increased risk of major birth defects with acyclovir exposure 4
• Patients with history of nephrectomy require particularly careful dosing due to reduced renal reserve 5

Clinical Management Pitfalls

• Do not rely on a single negative symptom assessment - neurotoxicity can develop rapidly even after several days of therapy 6
• Avoid concurrent nephrotoxic drugs when prescribing valacyclovir 4
• Maintain adequate hydration to prevent crystalluria 4
• No routine laboratory monitoring is needed in patients with normal renal function on episodic or suppressive therapy 3
• If acyclovir resistance develops, valacyclovir will also be ineffective, requiring alternative therapy with foscarnet (40 mg/kg IV every 8 hours) 2