Multivariate guard-bands and total risk assessment on multiparameter evaluations with correlated and uncorrelated measured values

Abstract The quality, efficacy, and safety of medicines are usually verified by analytical results. Measurement uncertainty is a critical aspect for the reliability of these analytical results. The pharmacopeial compendia usually adopt a simple acceptance rule that does not consider information from measurement uncertainty. In this work, we compared decision-making using simple acceptance and decision rules with the use of guard-band for multiparameter evaluation of ofloxacin ophthalmic solution and acyclovir topical cream. Ciprofloxacin ophthalmic solution and acyclovir topical cream samples were subject to pharmacopeial tests and assays. Multivariate guard-band widths were calculated by multiplying the standard uncertainty (u) by an appropriate multivariate coverage factor (k'). The multivariate coverage factor (k') was obtained by the Monte Carlo method. According to the simple acceptance rule, all the results obtained for ciprofloxacin ophthalmic solution and acyclovir topical cream are within the specification limits. However, the risk of false conformity decisions increases for ciprofloxacin tests. Decisions made using the simple acceptance rule and decision rules with the use of guard-band may differ. The simple acceptance rule may increase the risk of false conformity decisions when the measured value is close to the regulatory specification limits and/or when the measurement uncertainty value is inappropriately high. Nevertheless, the guard-band decision rule will always reduce the risk of false conformity decisions. Therefore, using information on measurement uncertainty in conformity assessment is highly recommended to ensure the proper efficacy, safety, and quality of medicines.

FV-100 versus valacyclovir for the prevention of post-herpetic neuralgia and the treatment of acute herpes zoster-associated pain: A randomized-controlled trial.

This prospective, parallel-group, randomized, double-blind, multicenter study compared the efficacy and safety of FV-100 with valacyclovir for reducing pain associated with acute herpes zoster (HZ). Patients, ≥50 years of age, diagnosed with HZ within 72 h of lesion appearance who had HZ-associated pain, were randomized 1:1:1 to a 7-day course of either FV-100 200 mg QD (n = 117), FV-100 400 mg QD (n = 116), or valacyclovir 1000 mg TID (n =117). Efficacy was evaluated on the basis of the burden of illness (BOI; Zoster Brief Pain Inventory scores); incidence and duration of clinically significant pain (CSP); pain scores; incidence and severity of post-herpetic neuralgia (PHN); and times to full lesion crusting and to lesion healing. Safety was evaluated on the basis of adverse event (AE)/SAE profiles, changes in laboratory and vital signs values, and results of electrocardiograms. The burden of illness scores for pain through 30 days were 114.5, 110.3, and 118.0 for FV-100 200 mg, FV-100 400 mg, and valacyclovir 3000 mg, respectively. The incidences of PHN at 90 days for FV-100 200 mg, FV-100 400 mg, and valacyclovir 3000 mg were 17.8%, 12.4%, and 20.2%, respectively. Adverse event and SAE profiles of the two FV-100 and the valacyclovir groups were similar and no untoward signals or trends were evident. These results demonstrate a potential for FV-100 as an antiviral for the treatment of shingles that could both reduce the pain burden of the acute episode and reduce the incidence of PHN compared with available treatments.

The efficacy and cost-effectiveness of valacyclovir in cytomegalovirus prevention in solid organ transplantation.

Prevention of cytomegalovirus infection using antiviral prophylaxis or the pre-emptive therapy approach is an integral part of management of patients after solid organ transplantation. Regarding renal transplantation, valacyclovir is currently the only antiviral agent recommended for prophylaxis as an alternative to valganciclovir. This review article discusses studies documenting the efficacy and safety of valacyclovir prophylaxis as well as those comparing valacyclovir with other prophylactic regimens or with pre-emptive therapy. Also addressed are the economic aspects supporting the cost-effectiveness of valacyclovir prophylaxis and demonstrating lower costs compared with other cytomegalovirus preventive strategies.

Efficacy and tolerability assessment of a topical formulation containing copper sulfate and hypericum perforatum on patients with herpes skin lesions: a comparative, randomized controlled trial.

BACKGROUND: Topical Acyclovir has moderate efficacy on recurrent HSV symptoms, requiring repeat applications for several days. Topical Dynamiclear, which requires only a single dose application, may provide a more effective and convenient treatment option for symptomatic management of HSV. OBJECTIVES: The study assessed the comparative efficacy and tolerability of a single use, topical formulation containing copper sulfate pentahydrate and Hypericum perforatum that is marketed as Dynamiclear™ to a topical 5% Acyclovir cream standard preparation and use. METHODS: A prospective, randomized, multi-centered, comparative, open-label clinical study was conducted. A total of 149 participants between 18 and 55 years of age with active HSV-1 and HSV-2 lesions were recruited for the 14-day clinical trial. Participants were randomized into two groups: A (n=61), those receiving the Dynamiclear formulation, and B (n=59), those receiving 5% Acyclovir. Efficacy parameters were assessed via physical examination at baseline (day 1), day 2, 3, 8, and 14. Laboratory safety tests were conducted at baseline and on day 14. RESULTS: Use of the Dynamiclear formulation was found to have no significant adverse effects and was well tolerated by participants. All hematological and biochemical markers were within normal range for the Dynamiclear group. Statistically, odds for being affected by burning and stinging sensation were 1.9 times greater in the Acyclovir group in comparison to the Dynamiclear group. Similarly, the odds of being affected by symptoms of acute pain, erythema and vesiculation were 1.8, 2.4, and 4.4 times higher in the Acyclovir group in comparison to the Dynamiclear group. CONCLUSIONS: The Dynamiclear formulation was well tolerated, and efficacy was demonstrated in a number of measured parameters, which are helpful in the symptomatic management of HSV-1 and HSV-2 lesions in adult patients. Remarkably, the effects seen from this product came from a single application.

Silica gel is as effective as acyclovir cream in patients with recurrent herpes labialis: results of a randomized, open-label trial.

OBJECTIVE: To compare silica gel with acyclovir cream in the treatment of recurrent herpes labialis. METHODS: In this randomized, open-label, comparator-controlled trial, 74 patients with recurrent herpes labialis applied silica gel or acyclovir cream respectively over a period of 10 days. The treatment started within 24 hours of the first symptoms of a new recurrence. Patients rated five symptoms (tautness, tingling, itching, burning sensation, pain), lesion stage, efficacy, tolerability, and duration until the onset of improvement. Their willingness-to-pay was assessed. Physicians rated the severity of the herpes recurrence and efficacy. RESULTS: There was no significant difference between silica gel and acyclovir cream in the overall patients' assessment. There is evidence that silica gel relieved all investigated symptoms earlier than acyclovir cream. The efficacy and tolerability of both medications were rated as good to very good. CONCLUSIONS: Silica gel was as effective in the treatment of recurrent herpes labialis as acyclovir and equally well tolerated and tended to take effect more quickly. Therefore, silica gel could prove a useful alternative to topical acyclovir.

Prospective comparison of valacyclovir and oral ganciclovir for prevention of cytomegalovirus disease in high-risk renal transplant recipients.

AIMS: To compare the efficacy, costs and safety of oral ganciclovir and valacyclovir in the prophylaxis of cytomegalovirus (CMV) disease in renal transplant (RTx) recipients at high risk of CMV disease. METHODS: A total of 83 patients were prospectively randomized to 3-month treatment with either oral ganciclovir (3 g/day) or oral valacyclovir (8 g/day). A 3rd group received no prophylaxis. Forty-nine patients were considered to be at high risk of CMV disease due to D+R- serologic status, OKT3/ATG treatment and/or acute rejection within 12 months after RTx. Twenty-three high-risk patients were treated with ganciclovir (GAN group), 17 patients with valacyclovir (VAL group), and 9 patients received no prophylaxis (C group). RESULTS: No significant differences were found among the groups in their demographic characteristics, immunosuppressive protocols, D/R CMV serology, or CMV risk factors. The 12-month incidence of CMV disease was 89% in the C group compared with 9% in the GAN group and 6% in the VAL group (p < 0.001, GAN or VAL vs. C; p = 0.713, GAN vs. VAL). Treatment failure (death, graft loss, CMV disease or withdrawal from study) occurred in 17, 6, and 89% in the GAN, VAL, and C groups, respectively (p < 0.001, GAN or VAL vs. C; p = 0.285, GAN vs. VAL). The average CMV-associated costs per patient were EUR 3,161, 3,757, and 7,247 in the GAN, VAL, and C groups, respectively (p = 0.027). CONCLUSION: Valacyclovir and oral ganciclovir are equally effective in the prophylaxis of CMV disease in high-risk RTx patients. Both regimens are cost-effective and help reduce CMV-associated costs by nearly 50% compared with patients without prophylaxis.

Monitoring pregnancy outcomes after prenatal drug exposure through prospective pregnancy registries: a pharmaceutical company commitment.

OBJECTIVE: Glaxo Wellcome becomes aware of prenatal exposures to its medications as early as the clinical trial phase of development. An international process for monitoring prenatal exposure to all Glaxo Wellcome medicines has been developed. For specific products there are prospective pregnancy registries. STUDY DESIGN: The registries are observational, case-registration, and follow-up studies designed to detect evidence of teratogenicity associated with specific medications. After prenatal exposure to the registry medication, pregnancies are registered prospectively, through voluntary reports by health care providers. An advisory committee of independent scientists for each registry reviews data and advises in dissemination of information. Risk of birth defects, as defined by the Centers for Disease Control and Prevention, is compared with published risks both in women in the general population and in women with the underlying condition being treated, if available. RESULTS: The following data show results from the prospective first-trimester exposures registered since establishment of each registry. The published risk of birth defects in the general population range is 3% to 5%, and the risk in women with epilepsy is 6% to 9%. The proportions of outcomes with birth defects are as follows: in the Acyclovir (antiviral medication) Pregnancy Registry (1984-1998) (19/581), 3.3% (95% confidence interval, 2.0%-5.2%); in the Lamotrigine (monotherapy and polytherapy antiepileptic medication) Pregnancy Registry (1992-September 1998) (8/123), 6.5% (95% confidence interval, 3.1%-12.8%); in the Sumatriptan (migraine medication) Pregnancy Registry (1996-October 1998) (7/183), 3.8% (95% confidence interval, 1.7%-8.0%). The Valacyclovir, Bupropion, and Naratriptan registries have insufficient data for analysis. CONCLUSION: None of the registries has provided a risk estimate exceeding that expected in the disorder treated, and no pattern of defects has been observed. Whereas information from the larger registries is reassuring regarding risk, these studies cannot rule out possible small excess risks from use of these drugs in pregnancy. Data obtained through these registries are shared with the medical community as a supplement to animal toxicology studies to assist in weighing potential risks and benefits of treatment for individual patients. The success of the registries depends on the continued willingness of the obstetrics and gynecology community to notify the registries of prenatal exposures.

Valaciclovir in herpes zoster ophthalmicus: new indication. An empty clinical assessment file.

(1) Valaciclovir, a metabolic precursor of aciclovir, improves the bioavailability of the active compound. It is licensed for the prevention of ocular complications of herpes zoster ophthalmicus in immunocompetent subjects. (2) The clinical file on valaciclovir in this indication is very thin. Only two (uninterpretable) trials have been done, both versus aciclovir. Note that oral aciclovir has also been assessed inadequately in this indication. (3) Over 10% of patients treated with valaciclovir in the two trials had nausea or headache.

American Academy of Pediatrics Committee on Infectious Diseases: The use of oral acyclovir in otherwise healthy children with varicella.

UNLABELLED: Oral acyclovir therapy initiated within 24 hours of illness for otherwise healthy children with varicella typically will result in a 1-day reduction of fever and approximately a 15% to 30% reduction in the severity of cutaneous and systemic signs and symptoms. Therapy has not been shown to reduce the rate of acute complications, pruritus, spread of infection,or duration of absence from school. Its long-term effect on the rate of occurrence of zoster is unknown. To date, no significant adverse effects of oral acyclovir therapy in otherwise healthy children have been demonstrated. In adults, delay of therapy beyond the first 24 hours of illness results in loss of therapeutic effect. The cost-benefit ratio of therapy is currently unknown, and its determination is extremely complex. RECOMMENDATIONS: 1. Oral acyclovir therapy is not recommended routinely for the treatment of uncomplicated varicella in otherwise healthy children. This recommendation is based on the marginal therapeutic effect, the cost of the drug, feasibility of drug delivery in the first 24 hours of illness. Such a decision should be based on an informed discussion among the physician, parent, and patient. 2. For certain groups at increased risk of severe varicella or its complications, oral acyclovir therapy for varicella, if it can be initiated within the first 24 hours after the onset of rash, should be considered. These groups include the following: a. Otherwise healthy, nonpregnant individuals 13 years of age or older. b. Children older than 12 months with a chronic cutaneous or pulmonary disorder and those receiving long-term salicylate therapy, although in the latter instance a reduced risk for Reye syndrome has not been shown to result from oral acyclovir therapy nor from milder illness with varicella.(ABSTRACT TRUNCATED AT 250 WORDS)

Disseminated herpes zoster in the immunocompromised host: a comparative trial of acyclovir and vidarabine. The NIAID Collaborative Antiviral Study Group.

Seventy-three immunocompromised patients with disseminated herpes zoster were evaluated in a double-blind controlled trial of acyclovir (n = 37) versus vidarabine (n = 36) therapy. Acyclovir was administered at 30 mg/kg/day at 8-h intervals and vidarabine was given as a continuous 12-h infusion at 10 mg/kg/day for 7 days (longer if resolution of cutaneous or visceral disease was incomplete). No demographic differences existed between treatment groups. No deaths attributable to varicella-zoster virus infection occurred within 1 month of treatment. Neither rates of cutaneous healing, resolution of acute neuritis, and frequency of postherpetic neuralgia nor adverse clinical and laboratory events differed between treatment groups. Acyclovir recipients were discharged from the hospital more promptly than vidarabine recipients (P = .04, log rank test). These data indicate that disseminated herpes zoster is amenable to therapy with either acyclovir or vidarabine; resultant mortality is low.

Monitoring the safety of antivirals. The example of the acyclovir experience.

The obligation to monitor the safety of newly introduced medicines is as old as the medical epidemiologic obligations of medicine itself. But society's expectations, the resources and methodologies for such monitoring, and the practices of the pharmacologic community have all evolved rapidly over the past decade. This report describes an extensive program of scientific epidemiologic monitoring of the safety of acyclovir during the first five years following approval. The presentation highlights the emerging field of pharmacoepidemiology, describes new and important resources and approaches for investigators concerned about drug safety monitoring, and presents safety data from the first five years of monitoring. The data thus far provide no reason for new safety concerns regarding this important antiviral; however, it is cautioned that, as in all such areas of public health protection, continued vigilance is needed.