Acyclovir cream has been available for the treatment of herpes labialis in numerous countries outside the United States for over a decade. Evidence for its efficacy comes from a few small clinical trials conducted in the 1980s. To examine more comprehensively the efficacy and safety of this formulation, we conducted two independent, identical, parallel, randomized, double-blind, vehicle-controlled, large-scale multicenter clinical trials. Healthy adults with a history of frequent herpes labialis were recruited from the general population, screened for eligibility, randomized equally to 5% acyclovir cream or vehicle control, given study medication, and told to self-initiate treatment five times daily for 4 days beginning within 1 h of the onset of a recurrent episode. The number of patients who treated a lesion was 686 in study 1 and 699 in study 2. In study 1, the mean duration of episodes was 4.3 days for patients treated with acyclovir cream and 4.8 days for those treated with the vehicle control (hazards ratio [HR] ‫؍‬ 1.23; 95% confidence interval [CI], 1.06 to 1.44; P ‫؍‬ 0.007). In study 2, the mean duration of episodes was 4.6 days for patients treated with acyclovir cream and 5.2 days for those treated with the vehicle control (HR ‫؍‬ 1.24; 95% CI, 1.06 to 1.44; P ‫؍‬ 0.006). Efficacy was apparent whether therapy was initiated "early" (prodrome or erythema lesion stage) or "late" (papule or vesicle stage). There was a statistically significant reduction in the duration of lesion pain in both studies. Acyclovir cream did not prevent the development of classical lesions (progression to vesicles, ulcers, and/or crusts). Adverse events were mild and infrequent.Acyclovir (ACV) has been found to be efficacious in the management of herpes labialis in a variety of formulations and routes of administration. ACV (5%) ointment (Zovirax ointment) accelerated healing of herpes labialis in immunocompromised patients (22). Peroral administration of 400 mg of ACV five times/day for 5 days significantly reduced virus shedding and reduced lesion healing time and the duration of lesion pain among the subgroup of patients who started treatment "early" (in the prodrome or erythema lesion stage) (19). Peroral ACV administered as prophylaxis at 400 mg two times/day significantly reduces the frequency of recurrent episodes and prevents herpes-associated erythema multiforme (4,8,11).Demonstration of the clinical efficacy of topical formulations of antiviral drugs among immunocompetent patients has been difficult because of the marked variance in lesion severity that occurs, necessitating large numbers of subjects; the rapid natural healing of lesions; and the difficulty in finding a topical drug formulation that facilitates skin penetration without causing undue skin irritation (15,16,20). Several studies with ACV ointment in immunocompetent subjects provided sparse evidence of efficacy in this population (1,6,13,17). ACV was shown to penetrate human skin more effectively in a cream than in an ointment formulation (3). According...

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SUMMARYPurpose: Nonrandomized studies of the relationship of antiepileptic drugs (AEDs) with sudden unexpected death in epilepsy (SUDEP) may be susceptible to confounding by tonic-clonic seizure frequency, polypharmacy, and other potential risk factors for SUDEP. We evaluated the risk of SUDEP with lamotrigine (LTG) compared to active comparators and placebo in randomized controlled clinical trials conducted by GlaxoSmithKline (GSK) between 1984 and 2009. Methods: Among 7,774 subjects in 42 randomized clinical trials, there were 39 all-cause deaths. Ten deaths occurred >2 weeks after discontinuation of study medication and were excluded. Narrative summaries of deaths were independently reviewed by three clinical experts (TT, LH, DF), who were blinded to randomized treatment arm. The risk of definite or probable SUDEP was compared between treatment arms for each trial type (placebo-controlled, active-comparator, crossover), using exact statistical methods. Key Findings: Of 29 on-treatment deaths, eight were definite/probable SUDEP, four were possible SUDEP, and 17 were non-SUDEP. The overall, unadjusted rate of definite/probable SUDEP for LTG was 2.2 events per 1,000-patient years (95% confidence interval [95% CI] 0.70-5.4). The odds ratios (OR) for on-treatment, definite/probable SUDEP in LTG arms relative to comparator arms, adjusted for length of exposure and trial, were the following: placebo-controlled, OR 0.22 (95% CI 0.00-3.14; p = 0.26); active-comparator, OR 2.18 (95% CI 0.17-117; p = 0.89); and placebo-controlled cross-over, OR 1.08 (95% CI 0.00-42.2; p = 1.0). Significance: There was no statistically significant difference in rate of SUDEP between LTG and comparator groups. However, the CIs were wide and a clinically important effect cannot be excluded.