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11 December 2002 PROPOSAL FOR THE INCLUSION OF VALACICLOVIR IN THE WHO MODEL LIST OF ESSENTIAL MEDICINES DEPARTMENT OF REPRODUCTIVE HEALTH AND RESEARCH STI/RTI Team NOVEMBER 2002 1. Summary statement of the proposal for inclusion, change or deletion Valaciclovir is proposed for inclusion in the World Health Organisation (WHO) Model List of Essential Medicines for the management of genital herpes simplex infections. Herpes simplex virus type 2 (HSV2) infection is the primary cause of genital herpes causing an ulcerative sexually transmitted infection (STI). Control of HSV2 is of paramount importance because of its chronicity, its complications, both physical and psycho-social and its role as cofactor for the acquisition and transmission HIV. It is also an infection that can be vertically transmitted from mother to child. HSV2 is highly prevalent in many parts of the world with a wide geographic variation. Valaciclovir, which is the L-valyl ester pro-drug of aciclovir, is converted to the antiherpes compound aciclovir and l-valine by hepatic first-pass metabolism following oral administration. It is better absorbed than aciclovir and the bioavailability of aciclovir following oral valaciclovir administration is enhanced three to five-fold compared to oral acyclovir. This renders valaciclovir properties that allow it to be taken on a twice daily dosage compared with aciclovir, which must be administered at four to six hourly intervals. The efficacy of valaciclovir equals that of acyclovir, and there is no significant difference in adverse events in the two drugs. Episodic and suppressive therapies have been recommended by WHO for the management of herpes simplex. However, compliance with acyclovir has raised concerns in clinical management settings. Therefore, valaciclovir, with its high bioavailability, is being proposed for inclusion in the WHO Model List of Essential Medicines. 2. Name of the focal point in WHO submitting or supporting the application Dr. Francis Ndowa Department of Reproductive Health and Research (RHR) STI/RTI Team 3. Name of the organisation(s) consulted and/or supporting the application World Health Organisation 4. International Nonproprietary Name (INN, generic name) of the medicine VALACICLOVIR 1 5. Whether listing is requested as an individual medicine or as an example of a therapeutic group Valaciclovir, the L-valyl ester pro-drug of aciclovir is extensively converted to the antiherpes compound aciclovir and l-valine by hepatic first-pass metabolism following oral administration. Aciclovir, the active form of the pro-drug, is highly specific for herpes virus-infected cells. It is selectively is activated by viral thymidine kinase in HSV- and varicella–zoster virus infected cells. In the active form aciclovir acts specifically to inhibit viral replication by acting as a competitive substrate for viral DNA polymerase and as an obligate chain terminator, effectively preventing any further elongation of the viral DNA chain. This proposal is for inclusion of valaciclovir as a better alternative to acyclovir on account of its improved bioavailability. 6. Information supporting the public health relevance (epidemiological information on disease burden, assessment of current use, target population) Herpes simplex infections are among the most frequent human viral infections. Herpes simplex virus type 2 (HSV2) infection is the primary cause of genital herpes causing an ulcerative sexually transmitted infection (STI). The improvement in the management of bacterial causes of genital ulcer diseases has resulted in an increase in the proportion of genital ulcer disease due to HSV2 in developing countries. The public health importance of HSV2 stems mainly from its chronicity, its complications both physical and psychosocial, and its role as cofactor for the acquisition and transmission HIV. HSV2 is highly prevalent in many parts of the world and varies according to geographic location, age, sex and behavioural practices. Prevalences in adults are low in some parts of Europe (15%), intermediate in the United States (22%), Latin American and South East Asia and high in some population in sub-Saharan Africa (50%). 1, 2 Prevalences have been shown to be higher among women than among men and increase with increasing age.3,4 Prevalence studies have shown that women are infected with HSV2 much earlier in life and that they have more episodes of disease than men. The disparity could be due to women being more biologically susceptible or younger females seeking sexual partners among older males who are more likely to be already infected. Infection has also been associated with younger age at first sex, increased years of sexual activity, lack of circumcision in men and current or recent STI.3,5, 6, 7. Neonatal Herpes simplex Neonatal herpes infection is one of the most serious outcomes of genital herpes in a pregnant woman. Intra-partum contact of the foetus with infected genital tract accounts for approximately 85% of all cases neonatal herpes. Estimates of the incidence of neonatal herpes range from 1 in 2500 to 1 in 20,000,000 live births.8 Studies have shown that 3% to 4% of gravid women have a known history of recurrent genital HSV infection.9 To avoid exposure of intrapartum HSV exposure and transmission of infection to the neonate, it has been recommended in some countries that pregnant women with 2 active genital herpes lesions at the time of labour should undergo caesarean delivery. Treatment with aciclovir during late pregnancy has been shown to decrease the frequency of recurrence of HSV disease at delivery. Natural history of HSV2 Transmission of HSV infection most frequently occurs through sexual contact with a person who is shedding virus in genital or oral secretions. Viral replication occurs locally, usually associated with ulcerations. The virus ascends the peripheral sensory nerves and enters sensory or autonomic nerve root ganglia where latency is established. The infection follows a sequence of clinical manifestations whose severity is dependent on a number of factors, including the site of the lesion and the immune status of the host. Primary infection may be followed by a clinically apparent first episode. Subsequently, there may be clinical recurrences and/or asymptomatic shedding. The rate of recurrence varies greatly between individuals and over time within the same individual. Recurrences tend to be more frequent in the first months to years after acquisition of the infection.10 The median recurrence rate after a symptomatic first episode of genital herpes is four to five episodes per year and severe first episodes are associated with even higher recurrence rates.11, 12 Asymptomatic shedding, defined as the detection of HSV in the absence of genital lesions is synonymous with subclinical reactivation and subclinical shedding. Studies have shown that HSV asymptomatic shedding does play a role in HSV transmission. Studies have also shown that after lesions have healed a person may continue to shed virus particles for a period of time.13 Though there is no known cure for genital herpes the course of symptoms can be modified if systemic therapy with aciclovir, or its analogues, is started as soon as possible following the onset of symptoms, either for a short course of five to seven days (episodic treatment) or over a prolonged period of time to prevent recurrences (suppressive treatment). 7. Treatment details (dosage regimen, duration; reference to existing WHO and other clinical guidelines; need for special diagnostic or treatment facilities and skills) The main goals of therapy of genital HSV infection are shortening the clinical course of disease, including the frequency of complications of primary infection and decreasing the transmission of the infection. Additionally, strategies are being evaluated to prevent recurrences in individual cases. Treatment methodologies include episodic and suppressive treatments. Episodic treatment decreases the severity, duration, and viral shedding of the primary episode but has less impact on recurrences.14 Treatment of recurrent genital herpes reduces the duration of lesions only by a day or two in an immunocompetent person. Its effect is enhanced when treatment is started in the prodrome or within a day of onset of lesions. Suppressive therapy decreases the frequency and duration of recurrences and viral shedding. Antiviral therapy does not eradicate the latent virus or affect the natural history, frequency, or severity of recurrences after the drugs are discontinued. 3 Thus, the main benefits of treatment are the clinical and viral shedding benefits during the first episode genital herpes. Recommendations for suppressive therapy take into account a number of criteria (i.e. the number of recurrences in the past 12 months, patient concerns on psycho-sexual and social issues and cost of medication. In individuals who are HSV2 positive but not HIV infected, reducing the severity and duration of the person’s herpes outbreaks may reduce the risk of acquiring HIV. Conversely, in individuals who are dually infected with HSV2 and HIV reducing the severity and duration of the person’s herpes outbreaks would reduce the risk of transmitting HIV. Finally, irrespective of HIV status, antiviral therapy would reduce the risk of transmission of HSV2 itself among sexual partners. Compliance for suppressive therapy may be affected by dosing convenience, understanding asymptomatic transmission and understanding the relationship between HSV and HIV and concern for partner’s health. WHO Treatment Guidelines for the management of Sexually Transmitted infections 2002 15 In the updated WHO treatment guidelines due to be published in 2002, a number of new recommendations were made for the management of various STI. The choice of antimicrobials for WHO guidelines is guided by criteria which include: Only drugs that have efficacy of 95% or more. Regimens yielding cure rates between 85% may be used with caution but lower cure rates are unacceptable Organism resistance is unlikely to develop or likely to be delayed Have acceptable toxicity and tolerance. Drugs that have oral administration are favoured over parental drugs; this however depends on the above criteria being satisfied. Single doses are favoured over multiple dose regimens since this has been shown to improve client compliance and acceptability. Drugs that can also be administered during pregnancy and lactation are preferred In these guidelines valaciclovir is included in the recommendations for the management of the following: First Clinical episode of genital herpes episode In first clinical episodes management regimens are follows: Aciclovir, 200 mg 5 times daily for 7 days Or Aciclovir, 400 mg 3 times daily for 7 days Or Valaciclovir, 1g 2 times daily for 7 days Or Famciclovir 250 mg 3 times daily for 7 days Recurrent infections For recurrent infections regimens are as follows: Aciclovir, 200mg orally 5 times daily for 5 days Or Aciclovir 400mg 3 times daily for 5 days 4 Or Or Or Or Aciclovir 800 mg orally twice daily for 5 days Famciclovir 125 mg orally twice daily for 5 days Valaciclovir 500 mg orally twice daily for 5 days Valaciclovir 1000 mg orally once daily for 5 days Suppressive therapy For suppressive treatment regimens are as follows: Aciclovir, 400mg orally, 2 times daily, continuously Or Famciclovir 250 mg orally twice daily Or Valaciclovir 500mg orally once daily Or Valaciclovir 1000mg orally daily European Sexually Transmitted Diseases Guidelines 16 In the European guidelines antiviral therapy is recommended for patients presenting within 5 days of onset of lesions or while lesions are still forming. Aciclovir, famciclovir and valaciclovir are recommended as follows: For first clinical episodes Aciclovir 200mg five times a day, Or Famciclovir 250mg 3 times a day Or Valaciclovir 500mg 2 times day Choice should be made by individual clinicians taking cost of therapy and likely compliance into account. For recurrent episodes Aciclovir 200mg five times daily Or Valaciclovir 500mg twice daily Or Famciclovir 125ng twice daily, plus supportive measures For suppressive therapy The optimal regimens are as follows: Aciclovir 800mg daily Or Famciclovir 250mg twice daily Or Valaciclovir 500 mg daily (for patients with less than 10 recurrences per annum) Or Valaciclovir 1000mg daily (for patients with more than 10 recurrences per annum) 5 Therapy should be discontinued after a maximum one year of continuous antiviral therapy. Centers for Diseases Control and Prevention’s Sexually Transmitted Diseases Treatment Guidelines 2002 17 In these treatment guidelines treatment recommendations are as follows: For the first clinical episode of genital herpes: Aciclovir 400mg orally three times a day for 7-10 days Or Aciclovir 200mg orally five times a day for 7-10 days Or Famciclovir 250mg orally three times a day for 7-10 days Or Valaciclovir 1g twice a day for 7-10 days Treatment may be extended if healing is incomplete after 10 days of therapy. For Episodic treatment for recurrent episodes: Aciclovir 400mg orally three times a day for 5 days, Or Aciclovir five times a day for 5 days Or Aciclovir 800mg twice a day for 5 days Or Famciclovir 125mg orally twice a day for 5 days Or Valaciclovir 500mg orally twice a day for 3-5 days Or Valaciclovir 1.0g orally once a day for 5 days Suppressive Therapy for recurrent genital herpes Aciclovir 400mg orally twice a day Or Famciclovir 250mg orally twice a day Or Valaciclovir 500mg orally once a day Or Valaciclovir 1.0 g orally once a day Recommended regimen for episodic infection in persons infected with HIV: Aciclovir 400mg orally three times a day for 5-10 days Or Aciclovir 200mg orally five times a day for 5-10 days Or Famciclovir 500mg orally twice a day for 5-10 days Or Valaciclovir 1.0g orally twice a day for 5-10 days 6 Suppressive Therapy for recurrent genital herpes in persons infected with HIV: Aciclovir 400-800mg orally twice to three times a day Or Famciclovir 500mg orally twice a day Or Valaciclovir 500mg orally twice a day 8. Summary of comparative effectiveness in a variety of clinical settings: Identification of clinical evidence (search strategy, systematic reviews identified, reasons for selection/exclusion of particular data) Details of literature searches conducted: The principal data-bases maintained by WHO that were searched were: The Cochrane Data-base of systematic reviews The ACP Journal Club reviews published trials The data-base of reviews of abstracts of reviews of effectiveness (DARE) The Cochrane controlled trials register (CCTR) Medline Clinical Evidence Searched terms included: Valaciclovir Herpes simplex Randomised controlled trials Cost effectiveness tolerability safety Study selection: Meta-analysis Systematic reviews Randomised controlled trials compared with either placebo or aciclovir Exclusion criteria: Trials which are not randomised. Trials with no controls. Summary of available estimates of comparative effectiveness First Episode of genital herpes The management of the first episode of genital herpes plays an important role in the management of the infection. A meta-analysis has shown that there is a significant difference in the time or frequency of recurrences between people given oral aciclovir and those given placebo.18 (Table 1) A systematic review of treatment comparison showed that in a randomised controlled trial of 643 healthy adults with first episode genital herpes there was no significant 7 difference between 1000 mg valaciclovir twice daily and 200 mg of aciclovir 5 times a day for 10 days.19, 20(Table 1) Episodic treatment Studies on episodic treatment revealed that valaciclovir is effective in the management of herpes simplex episodes. In a randomised controlled trial 987 healthy volunteers, who had four or more recurrences per year, were managed on valaciclovir 1000mg twice daily for 5 days (n=368), valaciclovir 500mg twice daily for 5 days (n= 360) or placebo twice daily for 5 days by self initiated treatment (n=259). The results showed a decrease in the median episode length in the treatment arm compared to placebo arm. Healing time was shortened and both valaciclovir dosages reduced the percentage of people with disease episodes (p=0.005). Valaciclovir accelerated the cessation of pain and viral shedding. Adverse effects were similar in all groups. The study concluded that administration of valaciclovir within 24 hours after onset of an episode of herpes genitalis accelerated the time of resolution of the episode and time of lesion healing.21 A multi-centre, double–blind, placebo-controlled, randomised parallel-design study of 1200 patients on either 1000 mg valaciclovir twice daily or 200 mg of aciclovir 5 times daily or placebo for 5 days revealed that both drugs were significantly more effective than placebo in speeding resolution of herpes episodes and aborting episodes. The nature, severity and frequency of adverse events did not differ among the 3 treatment groups. Valaciclovir was deemed to be a useful alternative to aciclovir when convenience of dosing and compliance issues are the prime consideration in treatment.22 A systematic review in HIV infected individuals found no significant difference between aciclovir and valaciclovir.23 (Table 1) Suppressive treatment Three randomised controlled trials (RCT) and 1 open label study demonstrated the efficacy and long-term safety of oral valaciclovir for the suppression of recurrent genital HSV infection. Three thousand and fifty patients (1062 immunocompromised) were enrolled in the studies and 2206 received valaciclovir 250-1000mg/day for up to 1 year. In immunocompetent patients a dose of 500mg or more of valaciclovir in once or twice daily regimens significantly prevented or delayed recurrences compared with placebo and was comparable in efficacy to 400mg aciclovir twice a day.24 In a RCT to determine the effect of suppressive therapy in HIV infected individuals 1062 individuals were enrolled and received valaciclovir 500mg twice daily or valaciclovir 1000mg once daily or aciclovir. Valaciclovir was found to be as effective as acyclovir in preventing recurrences. The dosages of 500mg twice daily was found to be more effective than 1000mg daily in preventing recurrences, resulting in 82% versus 71% being recurrence-free at 48 weeks (p<0.05).23 8 TABLE 1. Summary of available data (appraisal of quality, outcome measures, summary of results) Reference Setting Design Tyring SK, Douglas JM Jr, Corey L, Spruance SL, Esman J. Archives of Dermatology. 134(2):185-1919,1998 1200 patients with recurrent genital herpes A randomised, placebocontrolled comparison of oral valaciclovir and aciclovir in immunocompetent patients with recurrent genital herpes infections Tyring SK, Baker D, Snowden W. The Journal of Infectious Diseases 2002;186 (suppl) : s40-6 Postmarketing experience. Systematic review of patients over 10 years. Valaciclovir for herpes simplex virus infection: Long-term safety and sustained efficacy after 20 years’ experience with aciclovir. A prospective study of 1175 randomised and double blind in parts aciclovir 3050 valaciclovir Drug Dosages Valaciclovir 100mg twice daily x 5 Aciclovir 200 mg 5 times a day x 5 days Outcome measures Adverse event Resolution of symptoms: Valaciclovir - 4.8days Aciclovir - 4.8 days Placebo - 5.9 days Hazard ratios: Valaciclovir - 1.66 Aciclovir -1.71 (P=0.001) Duration of pain: Valaciclovir - 2 days Aciclovir - 3 days Viral shedding: Valaciclovir - 2.55 faster than placebo Aciclovir - 2.24 faster than placebo Aborted episodes Valaciclovir- 25.9% Aciclovir- 24.8% Placebo – 19.8% 111 women exposed to valaciclovir (the aciclovir pregnancy registry) no increase in birth defects: aciclovir – 3.3% risk of birth defect birth defects in general population 3% -5% No difference for three groups Similar side effects in nature and incidence: 0.2% valaciclovir 0.7% aciclovir 9 Table 1 contd. Summary of available data (appraisal of quality, outcome measures, summary of results) Reference Weller S, Blum MR, Doucette M, BurnetteT, Cederberg DM, de Miranda P, Smiley ML. Clin Pharmacol Ther 1993 Dec; 54(6): 595605 Spruance SL, Tyring SK DeGregorio B, Miller C, Beutner K and the Valaciclovir HSV study group. Arch Intern Med. 1996 Aug 12/26; 156: 1729-35 Setting 987 healthy volunteers with one episode of recurrent herpes Design Pharmacokinetics of the aciclovir pro-drug valaciclovir after escalating single- and multiple-dose administration to normal volunteers. Phase 1 trial A large scale placebo controlled dose-ranging trial of per oral valaciclovir for episodic treatment of recurrent herpes genitalis Drug Dosages 739 patients with history of recurrent genital herpes 1000 mg valaciclovir twice daily x 5 days 500 mg valaciclovir twice daily x 5 days Valaciclovir versus aciclovir in patient initiated treatment of recurrent genital herpes: a randomised, double blind clinical trial Adverse event Bioavailability of valaciclovir Three to five fold of bioavailability of aciclovir placebo twice daily x 5 days Bodsworth N.J, Crooks RJ, Borelli S, Veilsgaard et al. Geniturin Med. 1997; 73: 110-116 Outcome measures Valaciclovir 500 mg twice daily Aciclovir 200 mg five times daily Median episodes length Lower doses- 4.0 days Placebo - 5.0 days Hazard ratio 1.94 (p=0.001) Healing time Lower dose 4.1days Placebo- 6.0 days Percentage of episodes Lower dose - 69% Placebo - 79% p=0.005 Valaciclovir accelerated cessation of pain. Hazard ratio 1.8% Viral shedding HR 2.8% No significant difference between valaciclovir and aciclovir hazard ratio 0.93 ( 95% CI 0.79, 1.08) p = 0.34 Duration of episode 4.7 and 4.6 days Lesion healing valaciclovir 4.4 and 4.5 days (Hazard ratio 0.96) No significant difference in prevention of ulceration No significant difference in virus shedding Similar in all groups Similar in both groups Valaciclovir 9% Aciclovir 8.6% 10 TABLE 1 contd. Summary of available data (appraisal of quality, outcome measures, summary of results) Reference Patel R, Bodsworth NJ, Woolley P, Peters B et al. Genitourin. Med. 1997: 73: 105-109 Wald A Clinical Evidence Issue 7, 2002 Wald A Clinical Evidence Issue 7, 2002 Kimberlin DF, Weller S, Whitley RJ, et al. Am J Obstet Gynecol October 1998, volume 179, Number (4)846-851 Setting 382 healthy volunteers with a history of recurrent herpes (eight recurrences per year) Systematic review of randomised control trials (RCT) 643 volunteers Systematic review of randomised control trials 2 RCT Design Valaciclovir for the suppression of recurrent genital HSV infection: a placebo controlled study of once daily therapy Drug Dosages Valaciclovir 500mg once daily Placebo Outcome measures Median time for first recurrence Placebo - 20 days Valaciclovir - 112 days Adverse event Systematic review: What are the effects of antiviral treatment in people with a first episode of genital herpes? Valaciclovir 1000 mg twice daily for 10 days Aciclovir 200mg 5 times daily for 10 days Aciclovir 200mg 5 times daily x 5 days Valaciclovir 1g twice daily for 5 days Valaciclovir 1000mg once daily No significant difference Similar to acyclovir: Headaches and nausea No significant difference between the two drugs in recurrence rates Recurrences less likely with valaciclovir 500mg twice daily Similar to acyclovir: Headache and nausea Systematic review What are the effects of treatments in people with genital herpes and HIV infection? Pharmacokinetics of oral valaciclovir and aciclovir in late pregnancy. Safe in pregnancy 11 A randomised controlled trial comparing patients on antiviral suppressive therapy (valaciclovir 1000 mg daily, valaciclovir 500 mg daily, valaciclovir 250 mg twice daily and aciclovir 400 mg twice daily) to placebo revealed that the herpes specific quality of life was improved in the treatment arms.25 It was concluded that suppressive therapy was an effective strategy for the improvement of quality of life of patients with recurrent herpes. This was sustained over time and thus indicating the value of long-term management of the diseases. 9. Summary of comparative evidence on safety: Estimate of total patient exposure to date It is estimated that aciclovir and valaciclovir have been prescribed for more than 80 million persons for a different range of indications. The clinical development programme for valaciclovir has involved over 10,000 patients in clinical trials of up to 1-year duration.24 Use in pregnancy The risk of transmission of HSV2 from an infected mother to a neonate is between 30% and 50% in women who acquire herpes around the time of delivery, but the risk is low (<1%) in women with recurrent genital herpes. Management of genital herpes in pregnancy includes antiviral therapy, caesarean section or both. Aciclovir has been used for the management of HSV2 in pregnancy. The Aciclovir Registry established in 1984 reported that 1207 pregnancies were exposed to aciclovir during pregnancy. The observed risk of birth defects was 3.3%. This did not exceed that expected in the general population and the type of defects did not differ from those in untreated women. 24 In a phase 1 trial, maternal valaciclovir therapy resulted in higher plasma aciclovir levels with significantly higher peak concentrations, than did aciclovir therapy. Aciclovir and valaciclovir were found to be effective in reducing recurrences. Both aciclovir and valaciclovir were well tolerated by patients with no evidence of significant drug toxicity to mother or foetus.26 There is no evidence that aciclovir is carcinogenic in humans and no embryonic or fetotoxic effects were demonstrated in animal studies.27 The Aciclovir Pregnancy Registry has documented pregnancy outcomes in 111 women exposed to valaciclovir. There was no increase in the number of birth defects compared with the general population and no consistent pattern or uniqueness that would suggest a common cause.24 Aciclovir has been found in breast milk after systemic administration. The amount of aciclovir in the breast milk after valaciclovir administration is considerably less (2%) than that used in therapeutic dosing of neonates and should, therefore, be compatible with breast-feeding.28 Manufacturers suggest that physicians use it with caution.29 12 Summary of comparative safety against comparators Description of adverse effects/reactions Most studies reviewed reported similar adverse events in nature and incidence, for valaciclovir, aciclovir and placebo. 19, 23, 24,26 There was no apparent relationship between the total daily exposure to valaciclovir and the nature, severity or frequency of the common adverse events. The most common side effect for immunocompetent patients receiving aciclovir and valaciclovir were headache and nausea. For HIV infected individuals the most common adverse events were diarrhoea, nausea and the onset of some infectious illnesses. Long-term valaciclovir therapy did not result in haemotologic or clinical chemistry abnormalities.24 Severe adverse events attributable to valaciclovir occurred in 0.2% compared to 0.7% in immunocompetent individuals taking aciclovir. In HIV infected individuals 1.1% of patients on valaciclovir experienced severe adverse effects compared to 0.7% of aciclovir recipients. In three randomised controlled trials valaciclovir was discontinued due to adverse effects in only 0.3% of patients in immunocompetent individuals and 0.4% in HIV infected individuals.24 Manifestations resembling thrombotic microangiopathy have been reported in clinical trials with high doses of valaciclovir (8000mg/day) administered over long periods. 30 However, there were no such reports in 4 trials evaluating 3050 patients for suppression of recurrent genital herpes using standard doses. It has been concluded that the occurrence of thrombotic microangiopathy is restricted to severely immunocompromised persons receiving higher valaciclovir dosages (e.g. prophylaxis for CMV) than the standard doses required to control HSV infections.24 Drug interactions Although some interactions which affect the extent of conversion of valaciclovir to aciclovir and reduce the renal tubular secretion of aciclovir have been noted with cimetidine and probenecid, these interactions are not expected to have clinical consequences regarding the safety of valaciclovir.31 There is no clinically significant interaction when valaciclovir and digoxin are co-prescribed.32 Bioavailability and compliance Aciclovir was the first specific effective orally bioavailable antiherpes agent. However, its limited oral bioavailability of 10%-20% requires dosing regimens of up to 5 times a day to achieve efficacy in a range of indications. In a phase 1 placebo–controlled trial in normal volunteers, which included a single dose study with doses from 100 to 1000 mg (single cohort) and a multiple–dose investigation with doses from 250 to 2000 mg (for separate cohorts), valaciclovir was rapidly and extensively converted to aciclovir. This resulted in significantly greater bioavailability approximately threefold to fivefold (i.e. bioavailability is greater than or equal to 50% in adults) compared to that historically observed with high-dose (800 mg) oral aciclovir.33 In one study the plasma aciclovir exposure obtained following oral administration of valaciclovir was similar to that achieved with doses of intravenous aciclovir and was effective in the treatment and suppression of the less susceptible herpes viral diseases.34 Compliance in STI management has been one factor that affects the cure rate of patients receiving management for STI. Non-compliance in STI patients for short course treatments has been shown to be as low as 24%. In one study 44% of patients attending 13 an STI clinic on a twice daily dose of treatment for five days interrupted their treatment on at least 2 occasions for intervals of more than 24 hours.35, 36 In long-term treatment this tends to be even worse. 10. Summary of available data on comparative cost1 and costeffectiveness within the pharmacological class or therapeutic group: TABLE 2. Range of costs of the proposed medicine Drug Unit cost Cost per course of 5 days in local currency $1.46 Cost per course of 5 days in USD Source Aciclovir 500 Tab package price 29.19 unit price 0.0584/Tablet $1.46 (International Dispensary Association) IDA $3.15 $3.15 Tender price 100 Tab 10.48 Unit price 0.1048 /Tablet $4.10 $4.10 Tablets, aciclovir 200 mg, net price 25-tab pack = £4.23 £4.23 $6.60 British National Formulary BNF29 200 mg, net price 25-tab pack = £6.03; 400 mg, 56-tab pack = £22.19; 800 mg, 35-tab pack = £22.29. 200 mg, 25-tab pack = £20.22; 400 mg, 56-tab pack = £74.17; £6.03; $9.42 BNF29 £20.22 $31.69 BNF29 500 mg, net price 10-tab pack = £23.50, 42-tab pack = £98.50. £23.50 $36.72 BNF29 Famciclovir 125 mg, net price 10-tab pack = £28.12; 250 mg, 15-tab pack = £84.35, 21-tab pack = £118.08; 56-tab pack = £314.90; 500 mg, 14-tab pack = £157.47, 30-tab pack = £337.34, 56-tab pack = £629.89; 750 mg, 7-tab pack = £112.72. £28.12 $43.94 BNF29 30 Tab package price (30) 2.4200 Unit price 0.0807/Tablet Aciclovir (Nonproprietary) Aciclovir Zovirax ® (GSK) aciclovir Valtrex ® (GSK) Tablets, f/c, valaciclovir Famvir ® (Novartis) ECHO (International Health Services Limited) BDS ( Barbados drug service) International Drug Price Indicator Guide 14 Comparative cost-effectiveness presented as range of cost per routine outcome (e.g. cost per case, cost per cure, cost per month of treatment, cost per case prevented, cost per clinical event prevented, or, if possible and relevant, cost per quality-adjusted life year gained) The cost per five-day course of patented valaciclovir (Valtrex) is US$36.72 and the cost per course of aciclovir ranged from US$1.42 to US$31.69. Thus, for a five-day course of treatment, valaciclovir is between 5 to 25 fold more expensive than aciclovir (Table 2). No cost-effectiveness studies were found to evaluate valaciclovir in the management of HSV2. However cost-effectiveness studies of valaciclovir for the management of varicella zoster and cytomegalovirus infections, which require long-term treatment, have use of valacyclovir to be cost-effective.37 This latter situation differs from genital herpes as there are usually no chronic hospitalisation requirements with it. 11. Summary of regulatory status of the medicine (in country of origin, and preferably in other countries as well) Valaciclovir is licensed in the United Kingdom of Britain for herpes zoster and herpes simplex infection (initial and recurrent treatment) as Valtrex. It has also been licensed in United States of America, Spain and Canada. 12. Availability of pharmacopoieal standards (British Pharmacopoeia, International Pharmacopoiea, United States Pharmacopoeia) Not found in British, European, International or United States Pharmacopoeias. 13. Proposed (new/adapted) text for the WHO Model Formulary General Information Valaciclovir is an antiherpes drug used in the management of human herpes viruses including HSV1 and HSV 2. It is the L-valyl ester pro-drug of acyclovir. After oral administration it provides a bioavailability of aciclovir three to five times compared to oral aciclovir. In HSV- and varicella–zoster virus infected cells aciclovir is selectively activated by viral thymidine kinase enzyme. In the active form aciclovir acts specifically to inhibit viral replication by acting as a competitive substrate for viral DNA polymerase and as an obligate chain terminator, effectively preventing any further elongation of the viral DNA chain. Indications for use: Treatment of first episode and suppression of recurrent herpes simplex infections of the genitals, skin and mucous membranes 15 Dosage and administration: First Clinical episode of genital herpes episode In first clinical episodes management regimens are as follows: Oral valaciclovir, 1g twice daily for 7 days Recurrent infections For recurrent infections regimens are as follows: Oral valaciclovir 500 mg orally twice daily for 5 days Or Oral valaciclovir 1000 mg orally once daily for 5 days Suppressive therapy For suppressive treatment regimens are as follows: Oral valaciclovir 500mg orally once daily Or Oral Valaciclovir 1000mg orally daily The benefits of episodic treatment of recurrent infections are minimal in immunocompetent persons. Decisions to treat should be made on individual cases taking into account cost and compliance issues. Contraindications Valaciclovir is contraindicated in patients with known hypersensitivity or intolerance to valaciclovir, aciclovir and or any component of its formulation. Caution Thrombocytopenic purpura or haemolytic anaemia have been observed in patients with advanced HIV disease and recipients of allogenic transplants receiving high dose valaciclovir of 8g/day. Use in Pregnancy and lactation Valaciclovir should be used in pregnancy only if the potential benefits justify the risk to the foetus. Adverse Effects The adverse effects are nausea, vomiting, abdominal pain and diarrhoea. Precautions Patients should be adequately hydrated during the course of treatment. Drug interactions No clinical drug interactions have been found at the doses used in the management of herpes simplex infections. 16 References 1 Fleming DT, McQuillan GM, Johnson RE, et al. Herpes Simplex virus type 2 in the United States, 1976 to 1994. N Engl J Med 1997; 337 (16): 1105 – 11. 2 Krone Mr, Wald A Tabet SR, Paradise M, Corey L, Celum CL. Herpes simplex virus type2 shedding in human immuno-deficiency virus-negative men who have sex with men: frequency, patterns and risk factors. Clin Infect Dis 2000; 30 (2): 261-7. 3 Weiss HA, Buve A, Robinson NJ, et al Study Group on Heterogeneity of HIV Epidemics in African Cities. The epidemiology of HSV2 Infection and its association with HIV infection in four urban African populations. AIDS 2001: 165 ( supp 4) :S97S108) 4 Smith J, Robinson J. Age-specific Prevalence of Infection with Herpes Simplex Virus types 2 and 1: A Global Review. The Journal of Infectious Diseases 2002; 186 ( Suppl 1) : S3-S8 5 Austin H, Macalusco M, Nahmias A et al. Correlates of herpes simplex virus seroprevalence among women attending a sexually transmitted disease clinic. Sex Transm Dis 1999; 26 (6): 329-34. 6 Cowan FM, Johnson AM, Ashley R Corey L, Mindel A. Antibody to herpes simplex virus type 2 as serological marker of sexual lifestyle in populations. BMJ 1994; 309 (6965): 1325 – 9. 7 Kamali A, Nunn AJ, Mulder DW, Van Dyke E, Dobbins JG, Whitworth JA. Seroprevalence and incidence of genital ulcer infection in a rural Uganda population. Sex Transm Inf 1999;75: 98 –102. Davis G, Corey L. Herpes and HIV : New advice from the CDC, Medscape Infectious Diseases 4 (2), 2002 8 9 Prober CG, Hensleigh PA, Boucher FD, Yasukawa, LL,Au DS, Arvin AM. Use of routine cultures at delivery to identify neonates exposed to herpes simplex virus. N Engl J Med 1988;318:887-91 10 Wald et al., Reactivation of Genital Herpes Simplex Virus Type 2 Infection in asymptomatic seropositive persons, N Engl J Med 2000; 342: 844 – 850. Mar 23, 2000 11 Benedetti JK, Corey L Ashley R et al. Recurrence rates in genital Herpes after symptomatic first episode infection. Ann Intern Med 1994; 121 (11):847 – 54. 12 Benedetti JK, Zeh J, Corey L. Clinical reactivation of genital herpes simplex virus infection decreases in frequency over time. Ann Intern Med 1999; 131(1): 14-20 13 Wald A, Zeh J, Selke S, Ashley RL, Corey L. Virologic characteristics of subclinical and symptomatic genital herpes infections. N Engl J Med 1995; 333: 770-775 17 14 Wald A, Corey L, Cone R, Hobson A, Davis G, Zeh J. Frequent genital herpes simplex virus 2 shedding in immunocompetent women. Effect of acyclovir treatment. J Clin Invest. 1997 Mar 1; 99(5): 1092-7. 15 World Health Organisation .Guidelines for the management of sexually transmitted infections, WHO/RHR/2002 (in press) 16 European guideline for the management of genital herpes. International Journal of STD& AIDS 2001; 12 (Suppl. 3): 34-39. 17 Centers for Disease Control and Prevention, Guidelines for Sexually Transmitted Diseases. MMWR Morb Mortal Wkly Rep 2002; 51: RR-6. 18 Corey L, Mindel A, Fife KH, et al. 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