Valaciclovir: Side Effects
Valaciclovir is the L-valyl ester of aciclovir. After oral administration, it is rapidly and extensively converted to aciclovir by first-pass metabolism, resulting in plasma aciclovir concentrations previously only attainable with intravenous administration. Like aciclovir, valaciclovir is generally well tolerated. Compared with oral aciclovir, the systemic availability of aciclovir from oral valaciclovir is markedly improved.
Valaciclovir is highly active against Herpes simplex and Herpes zoster. It is also effective in suppressing recurrent episodes of genital herpes. Prophylactic administration of high doses of valaciclovir to prevent CMV disease was effective in patients with AIDS and in liver transplant recipients.
Observational studies
In a double-blind comparison of two regimens of valaciclovir 500 mg bd for recurrent genital herpes, a 5-day course and a 3-day course, there were no significant differences in therapeutic outcome or adverse events between the two regimens. The most common adverse events were headache (10%), nausea (4%), diarrhea (3%), and fatigue (1.5%).
Comparative studies
The effects of aciclovir and valaciclovir for anogenital herpes have been studied in HIV-infected individuals in two controlled trials. In the first study, 1062 patients with CD4+ counts over 100 x 106/1 received valaciclovir or aciclovir for 1 year and were assessed monthly. In the second study, 467 patients were treated episodically for at least 5 days with valaciclovir or aciclovir and were assessed daily. Valaciclovir was as effective as aciclovir for suppression and episodic treatment of herpesvirus infections. Hazard ratios for the time to recurrence with valaciclovir 500 mg bd and 1000 mg od compared with aciclovir were 0.73 (95% CI = 0.50) and 1.31 (0.94). Valaciclovir 1000 mg bd and aciclovir had similar effects on the duration of infective episodes (HR — 0.92; CI = 0.75). The most common adverse events, which occurred at similar rates with all regimens, were diarrhea, headache, infections, rashes, nausea, rhinitis, pharyngitis, abdominal pain, fever, depression, and cough.
Placebo-controlled studies
In large, placebo-controlled comparisons of the efficacy of valaciclovir and aciclovir in treating or suppressing recurrent genital Herpes simplex infections in immuno-competent people, dosages up to 2 g/day were well tolerated, with safety profiles comparable to aciclovir. In a comparison of high-dose valaciclovir (8 g/day) with two doses of aciclovir (0.8 and 3.2 g/day) for prophylaxis of cytomegalovirus disease in patients with advanced human immunodeficiency virus infection, intention-to-treat analysis showed a trend toward earlier mortality in those who received valaciclovir. In those who actually received valaciclovir, survival was significantly shorter. In view of the unexplained trend toward earlier mortality, as well as higher frequencies of renal toxicity (see the section on Urinary tract) and premature treatment discontinuation, the authors concluded that the dose of valaciclovir was too high and that better tolerated doses, which maintain a protective effect on cytomegalovirus disease, need to be identified.
Valaciclovir: Organs and Systems
Second-Generation Effects
Fetotoxicity
In a phase I trial, valaciclovir administered in the third trimester of pregnancy was well tolerated.
Susceptibility Factors
Renal disease
Adverse effects of valaciclovir, the L-valyl ester of aciclovir, can be associated with increased drug concentrations when the dose is not adjusted for reduced renal function. For example, aseptic meningitis has been associated with valaciclovir in a patient with renal insufficiency.
An 88-year-old man with renal insufficiency took valaciclovir 1000 mg tds. After the first dose, he became disoriented and incontinent. Valaciclovir was withdrawn, but the symptoms continued and progressed to drowsiness and nuchal rigidity. After an extensive work-up, aseptic meningitis was diagnosed.
Given the patient’s age and renal dysfunction, it is likely that excessive valaciclovir accumulation was responsible for this presentation.
Drug-Drug Interactions
Cimetidine
In an open, single-dose study of the effects of probenecid and cimetidine on the pharmacokinetics of valaciclovir and its metabolite aciclovir in 12 healthy men, valaciclovir 1 g, valaciclovir plus probenecid 1 g, valaciclovir plus cimetidine 800 mg, and valaciclovir with a combination of probenecid and cimetidine were studied. At three subsequent administrations, drug regimens were alternated among groups so that each group received each regimen. Probenecid and cimetidine respectively increased the mean Cmax of valaciclovir by 23 and 53% and its AUC by 22 and 73%. Probenecid and cimetidine also respectively increased the mean aciclovir Cmax by 22 and 8% and its AUC by 48 and 27%. The combination had a greater effect than either drug alone. Neither cimetidine nor probenecid affected the absorption of valaciclovir.
Probenecid
In an open, single-dose study of the effects of probenecid and cimetidine on the pharmacokinetics of valaciclovir and its metabolite aciclovir in 12 healthy men, valaciclovir 1 g, valaciclovir plus probenecid 1 g, valaciclovir plus cimetidine 800 mg, and valaciclovir with a combination of probenecid and cimetidine were studied. At three subsequent administrations, drug regimens were alternated among groups so that each group received each regimen. Probenecid and cimetidine respectively increased the mean Cmax of valaciclovir by 23 and 53% and its AUC by 22 and 73%. Probenecid and cimetidine also respectively increased the mean aciclovir Cmax by 22 and 8% and its AUC by 48 and 27%. The combination had a greater effect than either drug alone. Neither cimetidine nor probenecid affected the absorption of valaciclovir.