What are the side effects of Valacyclovir (Valtrex)?

Valacyclovir Side Effects

Valacyclovir is generally well-tolerated with headache and nausea being the most common side effects, occurring in over 10% of patients, though serious complications including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), acute renal failure, and central nervous system toxicity can occur, particularly in patients with renal impairment or immunocompromise. 1

Common Side Effects (>10% incidence)

• Headache is the most frequently reported adverse effect, occurring in 13-38% of patients across various indications including genital herpes suppression, cold sores, and herpes zoster 1
• Nausea occurs in 11-15% of patients, particularly in those treated for herpes zoster 1
• Abdominal pain affects approximately 11% of patients on suppressive therapy for genital herpes 1

Moderate Frequency Side Effects (1-10% incidence)

• Dizziness (2-4%), vomiting (3-6%), dysmenorrhea (5-8%), depression (5-7%), and arthralgia (4-6%) occur with moderate frequency 1
• In HIV-infected patients, fatigue (8%) and rash (8%) are commonly reported 1
• Diarrhea has been identified in postmarketing surveillance 1

Serious Adverse Effects Requiring Immediate Discontinuation

Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome (TTP/HUS)

• TTP/HUS has occurred in immunocompromised patients, particularly those with advanced HIV-1 disease, allogeneic bone marrow transplant recipients, and renal transplant recipients receiving high-dose valacyclovir (8 grams/day) 1
• This life-threatening complication has resulted in death in some cases and requires immediate cessation of valacyclovir 1
• At standard therapeutic doses for genital herpes, this risk appears minimal in immunocompromised patients 2, 3

Acute Renal Failure

• Acute kidney injury can occur through crystal-induced nephropathy, tubular dysfunction, or tubulointerstitial nephritis 4
• High-risk populations include elderly patients (with or without baseline renal dysfunction), patients with underlying renal disease receiving higher-than-recommended doses, those on concurrent nephrotoxic drugs, and inadequately hydrated patients 1
• Precipitation of acyclovir crystals in renal tubules occurs when intratubular fluid concentration exceeds 2.5 mg/mL 1
• Hemodialysis may be required in cases of acute renal failure with anuria 1

Central Nervous System Toxicity

• CNS adverse reactions include agitation, hallucinations, confusion, delirium, seizures, encephalopathy, aggressive behavior, ataxia, coma, decreased consciousness, dysarthria, mania, psychosis (including auditory and visual hallucinations), and tremors 1
• Neurotoxicity occurs more frequently in elderly patients and those with renal impairment 1, 5, 6
• The mean onset of neuropsychiatric symptoms is approximately 3.1 days after starting therapy, with most patients recovering within 7 days of discontinuation 6
• Valacyclovir should be discontinued immediately if CNS adverse reactions occur 1
• In severe cases, particularly in end-stage renal disease patients, emergent hemodialysis may be necessary to accelerate drug clearance 5

Laboratory Abnormalities

• Elevated liver enzymes (ALT >2x ULN in 1-4%, AST elevation in 1-16%) can occur 1
• Hematologic changes include decreased neutrophil counts (18% in HIV-infected patients), decreased platelet counts (1-3%), and hemoglobin decreases (particularly when combined with ribavirin) 7, 1
• No routine laboratory monitoring is required for patients on episodic or suppressive therapy unless substantial renal impairment exists 7

Special Population Considerations

Renal Impairment

• Dose adjustment is mandatory in patients with renal dysfunction to prevent accumulation and toxicity 1, 5
• In patients with end-stage renal disease, the half-life of valacyclovir can extend up to 14 hours compared to normal renal function 5
• Renal function monitoring is recommended in patients with substantial renal impairment 7
• Even normal dosing can cause acute kidney injury in patients with solitary kidneys or history of nephrectomy 4

Immunocompromised Patients

• HIV-infected patients may require higher doses but face increased risk of TTP/HUS at doses of 8 grams/day 2, 3
• At standard therapeutic doses, valacyclovir is generally safe in immunocompromised patients 3

Pediatric Patients

• In adolescents (12 to <18 years), headache (17%) and nausea (8%) are the primary adverse effects 1
• In younger children (1 month to <12 years), diarrhea (5%), pyrexia (4%), dehydration (2%), and rhinorrhea (2%) have been reported 1

Rare Postmarketing Adverse Events

• Allergic reactions including anaphylaxis, angioedema, dyspnea, pruritus, rash, and urticaria 1
• Cardiovascular effects: facial edema, hypertension, tachycardia 1
• Hematologic: thrombocytopenia, aplastic anemia, leukocytoclastic vasculitis 1
• Dermatologic: erythema multiforme, photosensitivity, alopecia 1
• Hepatobiliary: hepatitis 1
• Renal pain (may be associated with renal failure) 1
• Visual abnormalities 1

Clinical Management of Mild Side Effects

• For patients experiencing mild headache or nausea, symptomatic treatment is usually sufficient without requiring discontinuation of valacyclovir therapy 7, 3
• Adequate hydration should be maintained for all patients to prevent crystal nephropathy 1

Critical Pitfalls to Avoid

• Failure to adjust dose based on creatinine clearance is the most common cause of preventable neurotoxicity and nephrotoxicity 5, 6
• Prescribing valacyclovir at six times the recommended dose in renal impairment has resulted in severe neurological manifestations requiring hospitalization 5
• Starting treatment in elderly patients without assessing baseline renal function increases risk of accumulation 4, 6
• Inadequate patient hydration during therapy predisposes to crystal nephropathy 1