DK177084B1 - Pharmaceutical composition containing brivudine for once-daily administration - Google Patents
Pharmaceutical composition containing brivudine for once-daily administration Download PDFInfo
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- DK177084B1 DK177084B1 DKPA200101019A DKPA200101019A DK177084B1 DK 177084 B1 DK177084 B1 DK 177084B1 DK PA200101019 A DKPA200101019 A DK PA200101019A DK PA200101019 A DKPA200101019 A DK PA200101019A DK 177084 B1 DK177084 B1 DK 177084B1
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Abstract
Der beskrives aktiviteten af brivudin indgivet én gang dagligt mod akutte herpes zoster-infektioner og post-herpes neuralgi samt sammensætningerne deraf.The activity of brivudine administered once daily against acute herpes zoster infections and post-herpes neuralgia as well as the compositions thereof is described.
Description
DK 177084 B1DK 177084 B1
Opfindelsens områdeFIELD OF THE INVENTION
Den foreliggende opfindelse angår farmaceutiske præparater indeholdende det 5 antivirale brivudin til indgivelse én gang dagligt til behandlingen af akutte herpes zoster-infektioner samt deres anvendelse til forebyggelse af forekomsten af post-herpes neuralgi.The present invention relates to pharmaceutical compositions containing the once daily antiviral brivudine for the treatment of acute herpes zoster infections and their use in preventing the occurrence of post-herpes neuralgia.
Teknikkens stade 10 I løbet af de seneste ti år er antallet af klinisk nyttige lægemidler, som er introduceret i kemoterapien af virale sygdomme, forøget betydeligt. Efter dets introduktion i 1982 er oralt acyclovir anvendt i stor udstrækning til behandlingen af akut herpes zoster hos immunokompetente patienter. En betydelig ulempe ved acyclovir-terapi 15 er, at grundet dets begrænsede biotilgængelighed, kræves hyppige og høje doser, hvilket ofte fører til ringe efterlevelse.State of the art 10 Over the past ten years, the number of clinically useful drugs that have been introduced in the chemotherapy of viral diseases has increased significantly. Following its introduction in 1982, oral acyclovir has been widely used for the treatment of acute herpes zoster in immunocompetent patients. A significant disadvantage of acyclovir therapy 15 is that due to its limited bioavailability, frequent and high doses are required, which often leads to poor compliance.
Dette har ført til udviklingen af nye antivirale (penciclovir) og til såkaldte pro-læge-midler (“pro-drugs”), såsom valaciclovir (prolægemidlet for acyclovir) og famciclovir 20 (prolægemidlet for penciclovir). Indtil nu tilbyder famciclovir den mest bekvemme behandling af akut herpes zoster hos ældre patienter med en dosis på tre tabletter eller kapsler dagligt, sammenlignet med fem tabletter dagligt for acyclovir og seks tabletter dagligt for valaciclovir. Famciclovir lindrer de akutte tegn og symptomer på herpes zoster, ligesom acyclovir gør, og tilvejebringer beskyttelse mod den 25 langvarige herpes zoster-forbundne smerte eller PHN. Hvis den tages mindre hyppigt, i lavere doser og uden en forøget risiko for ugunstige forløb sammenlignet med acyclovir, er en sådan behandling fordelagtig og mere bekvem, især for ældre patienter. Den anbefalede daglige dosis varierer mellem 750 mg og 1500 mg (De-greef et al., 1994, Int. J. Antimicrob. Agents 4, 241-246; Tyring et al., 1995, Ann.This has led to the development of new antivirals (penciclovir) and to so-called pro-drugs (such as pro-drugs) such as valaciclovir (the prodrug for acyclovir) and famciclovir 20 (the prodrug for penciclovir). To date, famciclovir offers the most convenient treatment for acute herpes zoster in elderly patients with a dose of three tablets or capsules daily, compared to five tablets daily for acyclovir and six tablets daily for valaciclovir. Famciclovir relieves the acute signs and symptoms of herpes zoster, just as acyclovir does, and provides protection against the 25 long-lasting herpes zoster-associated pain or PHN. If taken less frequently, at lower doses and without an increased risk of adverse events compared to acyclovir, such treatment is beneficial and more convenient, especially for elderly patients. The recommended daily dose ranges between 750 mg and 1500 mg (De-greef et al., 1994, Int. J. Antimicrob. Agents 4, 241-246; Tyring et al., 1995, Ann.
30 Intern. Med. 123, 89-96; Dworkin et al., 1995, Antiviral Res. 26, 344; Dworkin et al., 1996, Pain, 67, 241-251; Dworkin et al., 1998, Antiviral Research 33, 73-85).30 Intern. With. 123, 89-96; Dworkin et al., 1995, Antiviral Res. 26, 344; Dworkin et al., 1996, Pain, 67, 241-251; Dworkin et al., 1998, Antiviral Research 33, 73-85).
DK 177084 B1 2DK 177084 B1 2
Brivudin, en nukleosid-analog, er et stærkt virkende virostatisk middel med selektiv aktivitet over for varicella zoster-virus (VZV) og herpes simplex-virus type 1 (HSV-1) (De Clercq et al., 1979, Proc. Natl. Acad., Sci. USA, 76, 2947-2951; De Clercq et al, 1980, J. Infect. Dis. 141,563-574). Medens syntesen af viralt DNA inhiberes, 5 forbliver cellefunktionerne hovedsageligt upåvirkede. Den fortsatte udvikling af brivudin i løbet af de seneste år har været rettet mod behandlingen af VZV-infektioner hos immunokompetente patienter.Brivudine, a nucleoside analogue, is a potent virostatic agent with selective activity against varicella zoster virus (VZV) and herpes simplex virus type 1 (HSV-1) (De Clercq et al., 1979, Proc. Natl. Acad., Sci. USA, 76, 2947-2951; De Clercq et al., 1980, J. Infect. Dis. 141,563-574). While the synthesis of viral DNA is inhibited, cellular functions remain largely unaffected. The continued development of brivudine over recent years has been directed at the treatment of VZV infections in immunocompetent patients.
Baseret på resultaterne fra en række af ikke-kontrollerede og kontrollerede studier, 10 blev brivudin registreret i Tyskland i 1990 til behandlingen af HSV-1 og VZV-infektioner hos immunokompromitterede patienter ved en dosis på 125 mg tre eller fire gange dagligt (De Clercq et al., 1980, Br. Med. J, 281, 1178; Tricot et al., 1986, J. Med. Virology, 18, 11-20; Wutzler et al., 1995, J. Med. Virology, 46, 252-257; se også "Fachinformation" forenet med det farmaceutiske produkt Helpin®, 15 markedsført i tysk territorium i 1992).Based on the results of a series of uncontrolled and controlled studies, 10 brivudine was registered in Germany in 1990 for the treatment of HSV-1 and VZV infections in immunocompromised patients at a dose of 125 mg three or four times daily (De Clercq et al., 1980, Br. Med. J, 281, 1178; Tricot et al., 1986, J. Med. Virology, 18, 11-20; Wutzler et al., 1995, J. Med. Virology, 46, 252 -257; see also "Fachinformation" associated with the pharmaceutical product Helpin®, marketed in German territory in 1992).
Beskrivelse af opfindelsenDescription of the Invention
Opfindelsen angår et farmaceutisk præparat til oral indgivelse én gang dagligt in-20 deholdende brivudin som aktiv bestanddel sammen med farmaceutisk acceptable bærere og excipienser, hvor mængden af aktiv bestanddel er 125 mg, hvilket præparat er udvalgt fra gruppen bestående af: brivudin 125 mg, mikrokrystallinsk cellulose 74 mg, lactose-monohydrat 37 25 mg, povidon K-værdi 25 6,5 mg, magnesiumstearat 2,5 mg, rent vand indtil 245 mg samlet vægt, brivudin 125 mg, mikrokrystallinsk cellulose 74 mg, majsstivelse 37 mg, povidon K-værdi 25 6,5 mg, magnesiumstearat 2,5 mg, rent vand indtil 245 mg 30 samlet vægt, DK 177084 B1 3 brivudin 125 mg, mikrokrystallinsk cellulose 74 mg, lactose 37 mg, povidon K-værdi 25 6,5 mg, magnesiumstearat 2,5 mg, rent vand indtil 245 mg samlet vægt, 5 - brivudin 125 mg, mikrokrystallinsk cellulose 74 mg, majsstivelse 37 mg, copovidon VA 64 6,5 mg, magnesiumstearat 2,5 mg, rent vand indtil 245 mg samlet vægt, brivudin 125 mg, mikrokrystallinsk cellulose 74 mg, lactose 37 mg, 10 copovidon VA 64, 6,5 mg, collidone CL 5,0 mg, magnesiumstearat 2,5 mg, rent vand indtil 250 mg samlet vægt, brivudin 125 mg, mikrokrystallinsk cellulose/aerosil 122,5 mg, magnesiumstearat 2,5 mg, rent vand indtil 250 mg samlet vægt, 15The invention relates to a pharmaceutical composition for oral administration once daily containing brivudine as active ingredient together with pharmaceutically acceptable carriers and excipients, wherein the amount of active ingredient is 125 mg, which composition is selected from the group consisting of: brivudine 125 mg, microcrystalline cellulose 74 mg, lactose monohydrate 37 25 mg, povidone K value 25 6.5 mg, magnesium stearate 2.5 mg, pure water up to 245 mg total weight, brivudine 125 mg, microcrystalline cellulose 74 mg, corn starch 37 mg, povidone K -value 25 6.5 mg, magnesium stearate 2.5 mg, pure water up to 245 mg 30 total weight, DK 177084 B1 3 brivudine 125 mg, microcrystalline cellulose 74 mg, lactose 37 mg, povidone K value 25 6.5 mg, magnesium stearate 2.5 mg, pure water up to 245 mg total weight, 5 - brivudine 125 mg, microcrystalline cellulose 74 mg, corn starch 37 mg, copovidone VA 64 6.5 mg, magnesium stearate 2.5 mg, pure water up to 245 mg total weight , brivudine 125 mg, microcrystalline ce llulose 74 mg, lactose 37 mg, 10 copovidone VA 64, 6.5 mg, collidone CL 5.0 mg, magnesium stearate 2.5 mg, pure water up to 250 mg total weight, brivudine 125 mg, microcrystalline cellulose / aerosil 122.5 mg, magnesium stearate 2.5 mg, pure water up to 250 mg total weight, 15
brivudin 125 mg, mikrokrystallinsk cellulose/aerosil 100,5 mg, collidone CLbrivudine 125 mg, microcrystalline cellulose / aerosil 100.5 mg, collidone CL
22.0 mg, magnesiumstearat 2,5 mg, rent vand indtil 250 mg samlet vægt, brivudin 125 mg, mikrokrystallinsk cellulose 122,5 mg, magnesiumstearat 20 2,5 mg, rent vand indtil 250 mg samlet vægt (øjeblikkelig frigivelse), brivudin 125 mg, mikrokrystallinsk cellulose 74,0 mg, lactose-monohydrat 32.0 mg, aerosil 5,0 mg, copovidon VA 64 6,5 mg, magnesiumstearat 2,5 mg, macrogol 6000 1,5 mg, titandioxid 4,5 mg (coatet tablet med øjeblikkelig frigivel- 25 se).22.0 mg, magnesium stearate 2.5 mg, pure water up to 250 mg total weight, brivudine 125 mg, microcrystalline cellulose 122.5 mg, magnesium stearate 20 2.5 mg, pure water up to 250 mg total weight (immediate release), brivudine 125 mg , microcrystalline cellulose 74.0 mg, lactose monohydrate 32.0 mg, aerosil 5.0 mg, copovidone VA 64 6.5 mg, magnesium stearate 2.5 mg, macrogol 6000 1.5 mg, titanium dioxide 4.5 mg (coated tablet with immediate release).
Opfindelsen angår yderligere et farmaceutisk præparat til behandlingen af herpes zoster-infektioner eller post-herpes neuralgi.The invention further relates to a pharmaceutical composition for the treatment of herpes zoster infections or post-herpes neuralgia.
3030
Ved nylige, omfattende, multi-nationale studier af immunokompetente patienter med herpes zoster viste en daglig dosis-kur på 125 mg brivudin pr. dag i 7 dage DK 177084 B1 4 sig overraskende at være statistisk overlegen i forhold til standarden på fem gange daglig oral behandling med 800 mg acyclovir, med hensyn til dermatologiske endepunkter (5-Ho-b/0078BC). En post-studium-overvågning af patienter med alderen 50 år eller mere, som havde deltaget i disse studier, og som havde oplevet 5 PHN efter studiets afslutning, indikerede en betydelig lavere forekomst af PHN efter behandling med brivudin, sammenlignet med acyclovir (5-Ho[a+b+c]PHN/0078BC).In recent, comprehensive, multi-national studies of immunocompetent patients with herpes zoster, a daily dose regimen of 125 mg brivudine per day was shown. day to 7 days surprisingly, it is statistically superior to the standard of five times daily oral treatment with 800 mg acyclovir, with respect to dermatological endpoints (5-Ho-b / 0078BC). A post-study monitoring of patients aged 50 years or more who participated in these studies and who had experienced 5 PHNs at the end of the study indicated a significantly lower incidence of PHNs after treatment with brivudine, compared to acyclovir (5- Ho [a + b + c] PHN / 0078BC).
Brivudin frembyder derfor overraskende muligheden med behandling af herpes 10 zoster-patienter med en enkelt 125 mg-tablet pr. dag i stedet for den høje og hyppige dosis, som er planlagt for acyclovir, valaciclovir eller famciclovir. En enkelt 125 mg-tablet pr. dag er endnu mere overraskende, hvis den tages i betragtning i forhold til de tidligere planlagte 125 mg fire gange dagligt som registreret i Tyskland i 1990 til behandlingen af HSV-1 og VZV-infektioner hos immunokompromit-15 terede patienter. Med denne én-gang-dagligt-dosisplan opnåedes et yderligere overraskende resultat: at reducere hyppigheden af post-herpes neuralgi.Brivudine therefore offers surprisingly the possibility of treating herpes 10 zoster patients with a single 125 mg tablet per day. per day instead of the high and frequent dose scheduled for acyclovir, valaciclovir or famciclovir. One single 125 mg tablet per day. day is even more surprising when taken into consideration the previously planned 125 mg four times daily as registered in Germany in 1990 for the treatment of HSV-1 and VZV infections in immunocompromised patients. With this once-daily dosing schedule, a further surprising result was achieved: reducing the frequency of post-herpes neuralgia.
Eksperimentelt 20 Til fastsættelse af virkningsfuldheden og sikkerheden ved brivudin hos immuno-kompetente, voksne patienter med herpes zoster, blev tre omfattende, afgørende studier (studium 5-Ho-a, 5-Ho-b og 5-Ho-c) for nyligt gennemført i overensstemmelse med GCP-standard. Alle fire studier var prospektive, blev gennemført i flere centre, og var af et dobbeltblindt, tilfældigt parallelt design.Experimental 20 To determine the efficacy and safety of brivudine in immunocompetent adult patients with herpes zoster, three comprehensive, conclusive studies (studies 5-Ho-a, 5-Ho-b and 5-Ho-c) were recently conducted. in accordance with GCP standard. All four studies were prospective, conducted in multiple centers, and were of a double-blind, random parallel design.
2525
Patienterne blev observeret i op til 35 dage til vurdering af helbredelse af hududslæt og akut-fase smerte. Alle patienter var immunokompetente. Kun voksne patienter med alderen 18 år eller mere deltog.Patients were observed for up to 35 days to assess skin rash and acute-phase pain. All patients were immunocompetent. Only adult patients aged 18 years or older participated.
30 De primære parametre til fastsættelse af virkningsfuldhed var "tid fra påbegyndelse af behandlingen til sidste udbrud af nye blærer" i alle tre studier. Denne parameter forløber parallelt med virus-replikation i huden og beskriver derfor den viro- DK 177084 B1 5 statiske styrke af et lægemiddel. Den er accepteret i litteraturen og anses for at være det mest pålidelige kliniske tegn med hensyn til andre kutane fremtrædelsesformer. Yderligere parametre til fastsættelse af helbredelse af hududslæt var "tid fra påbegyndelse af behandling til påbegyndelse af skorpedannelse", "tid fra på-5 begyndelse af behandling til fuldstændig skorpedannelse" og "tid fra påbegyndelse af behandling til tab af skorper". Disseminering af hudlæsioner og forekomsten af andre komplikationer blev også fastsat.30 The primary parameters for determining efficacy were "time from onset of treatment to last onset of new blisters" in all three studies. This parameter runs parallel to viral replication in the skin and therefore describes the viral static strength of a drug. It is accepted in the literature and is considered to be the most reliable clinical sign with regard to other cutaneous forms of appearance. Additional parameters for determining skin rash were "time from initiation of treatment to onset of crust formation", "time from onset of treatment to complete crustal formation" and "time from commencement of treatment to crustal loss". Dissemination of skin lesions and the occurrence of other complications were also determined.
I litteraturen er de hyppigst anvendte mål til bedømmelse af fordelen ved antiviral 10 terapi for herpes zoster varigheden af hududslæt og forekomsten og intensiteten af smerte under den akutte fase af infektionen. På det seneste er imidlertid postterapeutisk neuralgi blevet af stigende vigtighed ved fastsættelsen af fordelen ved antivirale terapier. For at fastsætte den mulige virkning af brivudin til reduktion af forekomsten af post-herpes neuralgi på en foreløbig måde, blev retrospektive, 15 dobbelt-blinde post-studium-overvågningsstudier yderligere gennemført for patienter med alderen 50 år eller mere, som deltog i studierne.In the literature, the most frequently used targets for assessing the benefit of antiviral therapy for herpes zoster are the duration of skin rash and the incidence and intensity of pain during the acute phase of the infection. Recently, however, post-therapeutic neuralgia has become of increasing importance in determining the benefit of antiviral therapies. To determine the possible effect of brivudine on reducing the incidence of post-herpes neuralgia in a preliminary manner, retrospective, 15 double-blind post-study surveillance studies were further conducted for patients aged 50 years or more who participated in the studies.
I tabel 1 anføres testene, som gennemførtes med immunokompetente patienter med herpes zoster. Tidligere, ikke-kontrollerede studier gennemført med immuno-20 kompromiterede patienter, som tilvejebragte tidligt bevis for den potentielle nytte af brivudin, omtales ikke.Table 1 lists the tests performed with immunocompetent patients with herpes zoster. Previous, uncontrolled studies conducted with immuno-20 compromised patients that provided early evidence of the potential benefit of brivudine are not mentioned.
25 30 625 30 6
Tab®i 1: Oversigt omr kMmskø test liÉtte.......rteliéiiii...........................................................) ΐΜΜΜΜΜΜΜΜΜΜ&ά^^ ΜΜΜΜΜΜΜΜΜΜΜΜΜΜΜΜΜΜΜΜΜά^^ I S-Ho-i I DssJsteskdvefses- Brtvucln 12S mg x 1 || i studium (fase II) irlvudiin 82,5 mg n 1 ;jTab® 1: Overview of the test queue test ....... rteliéiiii ................................ ...........................) ΐΜΜΜΜΜΜΜΜΜΜ & ά ^^ ΜΜΜΜΜΜΜΜΜΜΜΜΜΜΜΜΜΜΜΜΜά ^^ I S-Ho-i I DssJsteskdvefses- Brtvucln 12S mg x 1 || in study (phase II) irlvudiin 82.5 mg n 1; j
Bdvudiri 31 :(25 mg x 1Bdvudiri 31: (25 mg x 1
Aoydlow SOO mg x 6 !j i S-Hchb i ISskræffsede virk» Brtvudln 125 mg x 1 i ml^gsfyfcfihede» Atyelovfy SOO mg x S !| i studium (fase III) ij i 5~Hqh3 i Bekræiteyde virk·» Brlvudim 12S mg x 1 I 3 dag© i nlygsfuldheds» Acyslavir 000 mg x i | i stadium (fase III) iS-Hs-l fb- i Pasf-efydlym-Q¥8F- Bdvudiri 125 mg x 1 i PHN i ligning med PHN Acyclovir SOO mg x: 6 ij | S“Hsh> | P^sesbidium-evep Brivudln 125 mg x 1 13 dags i PHN: ; vågmug med PHN Acyclovir 800 mg x S ij DK 177084 B1 7Aoydlow SOO mg x 6! J in S-Hchb in iScredited Effects »Brtvudln 125 mg x 1 in ml ^ gsfyfcfihede» Atyelovfy SOO mg x S! | in Study (Phase III) ij in 5 ~ Hqh3 in Confirmation Effect · »Brlvudim 12S mg x 1 For 3 days © in Cunning» Acyslavir 000 mg x i | in stage (phase III) iS-Hs-1 fb- in Pasf-efydlym-Q ¥ 8F- Bdvudiri 125 mg x 1 in PHN in equation with PHN Acyclovir SOO mg x: 6 ij | S “Hsh> | P ^ sesbidium-evep Brivudln 125 mg x 1 13 days in PHN :; dummy mold with PHN Acyclovir 800 mg x S ij DK 177084 B1 7
Disse kliniske test præsenteres nedenfor i en kronologisk rækkefølge.These clinical trials are presented below in a chronological order.
Studium 5-Ho-a 5 Eftersom brivudin-plasmakoncentrationer hos mennesket, som modtager 125 mg én gang dagligt er 10 til 50 gange IC50 af kliniske stammer af Varicella zoster-virus, og yderligere eftersom humane farmakokinetiske data viste, at brivudin-plasmakoncentrationer opretholdes over ICso-værdien i 24 timer efter en enkelt indgivelse af brivudin 125 mg, blev det fornuftigt antaget, at en én gang daglig ind-10 givelse af 125 mg brivudin ville være tilstrækkeligt til behandlingen af herpes zoster.Study 5-Ho-a 5 Since brivudine plasma concentrations in humans receiving 125 mg once daily are 10 to 50 times the IC50 of clinical strains of Varicella zoster virus, and further, since human pharmacokinetic data showed that brivudine plasma concentrations are maintained above The IC 50 value for 24 hours after a single administration of brivudine 125 mg, it was sensibly believed that a once daily administration of 125 mg brivudine would be sufficient for the treatment of herpes zoster.
Studium 5-Ho-a, et fase Il-studium, gennemført hos 642 patienter kunne derfor vurdere en én gang daglig indgivelse af brivudin 125 mg i syv dage sammenlignet 15 med 5 x 800 mg acyclovir i syv dage på orienterende vis. To studiegrene med én gang daglig brivudin-doser på 62,5 mg og 32,25 mg i syv dage blev tilføjet for også at fastsætte virkningsfuldheden af lavere doser.Therefore, study 5-Ho-a, a phase II trial, conducted in 642 patients could assess a once-daily administration of brivudine 125 mg for seven days compared to 15 with 5 x 800 mg for seven days in an oriental way. Two branches of once-daily brivudine doses of 62.5 mg and 32.25 mg for seven days were added to also determine the efficacy of lower doses.
Dette studium viste, at 1 x 125 mg brivudin i 7 dage hos patienter med akut herpes 20 zoster er lige så virkningsfuld som behandlingen med 5 x 800 mg acyclovir i 7 dage med hensyn til den primære parameter "tid fra påbegyndelse af behandling til sidste udbrud af nye blærer", såvel som med hensyn til alle sekundære parametre, herunder "tid fra påbegyndelse af behandling til ophør af smerte (intensitet ingen eller ringe)", som den klinisk mere relevante, sekundære parameter. Statistisk 25 analyse af den primære virkningsfuldhedsparameter og smerteparameteren demonstrerede ikke-mindreværd af 1 x 125 mg brivudin, sammenlignet med acyclovir. For parameteren "tid fra påbegyndelse af behandling til fuldstændig skorpedannelse" kunne overlegenhed opnås på eksplorativ vis. En grafisk præsentation af risikoforhold, beregnet ud fra Cox-proportional-faremodellen for 1 x 125 mg bri-30 vudin-gruppen, sammenlignet med 5 x 800 mg acyclovir-gruppen er præsenteret i fig. 1.This study showed that 1 x 125 mg brivudine for 7 days in patients with acute herpes 20 zoster is as effective as the treatment with 5 x 800 mg acyclovir for 7 days with respect to the primary parameter "time from start of treatment to last outbreak. of new blisters ", as well as with respect to all secondary parameters, including" time from commencement of treatment to cessation of pain (intensity none or little) ", as the clinically more relevant secondary parameter. Statistical analysis of the primary efficacy parameter and the pain parameter demonstrated non-inferiority of 1 x 125 mg brivudine, compared with acyclovir. For the parameter "time from start of treatment to complete crust formation" superiority could be achieved in explorative fashion. A graphical presentation of risk ratios, calculated from the Cox proportional hazards model of the 1 x 125 mg bri-30 vudine group, compared to the 5 x 800 mg acyclovir group is presented in Figs. First
DK 177084 B1 8DK 177084 B1 8
Brivudin har et lineært dosis-effekt-slægtsskab. Overlegenhed over for placebo blev demonstreret i en statistisk og klinisk signifikant grad hos immunokompetente patienter med akut herpes zoster-infektion. Brivudin-behandling med en dosis på 1 x 125 mg i syv dage er mindst så virkningsfuld som behandlingen med 5 x 800 mg 5 acyclovir i syv dage med hensyn til varigheden af blæreforekomst og akut smerte.Brivudine has a linear dose-effect relationship. Placebo superiority was demonstrated to a statistically and clinically significant degree in immunocompetent patients with acute herpes zoster infection. Brivudine treatment at a dose of 1 x 125 mg for seven days is at least as effective as the treatment with 5 x 800 mg 5 acyclovir for seven days for the duration of bladder incidence and acute pain.
Disse resultater, sammen med de tidligere farmakokinetiske overvejelser, førte til udvælgelsen af brivudin 125 mg én gang dagligt som den valgte behandling.These results, together with the previous pharmacokinetic considerations, led to the selection of brivudine 125 mg once daily as the treatment of choice.
Studium 5-Ho-b 10Study 5-Ho-b 10
Fase lll-studiet 5-Ho-b blev gennemført med 1227 patienter til tilvejebringelse af bekræftende statistik til sammenligningen af 1 x 125 mg brivudin i syv dage med 5 x 800 mg acyclovir i syv dage hos immunokompetente patienter med herpes zoster. En undergruppe af patienter med alderen 50 år eller mere, blev også vur-15 deret separat.The Phase II study 5-Ho-b was conducted with 1227 patients to provide confirmatory statistics for the comparison of seven x 125 mg brivudine for seven days with five x 800 mg acyclovir for seven days in immunocompetent patients with herpes zoster. A subgroup of patients aged 50 years or more was also evaluated separately.
En grafisk fremstilling af risikoforholdene beregnet ud fra Cox-proportional-faremo-dellen for 1 x 125 mg brivudin-gruppen sammenlignet med 5 x 800 mg acyclovir-gruppen er præsenteret i fig. 2.A graphical representation of the risk ratios calculated from the Cox proportional hazards fraction for the 1 x 125 mg brivudine group compared to the 5 x 800 mg acyclovir group is presented in FIG. 2nd
2020
Studium 5-Ho-c: Reduktion af behandlingsvarighedStudy 5-Ho-c: Reduction in treatment duration
For at fastsætte virkningsfuldheden af en tre-dages behandling med brivudin 125 mg én gang dagligt hos patienter med herpes zoster blev et andet omfattende stu-25 dium gennemført under anvendelse af præcist det samme studium-design som 5-Ho-b. Brivudin 125 mg én gang dagligt i tre dage (efterfulgt af fire dages placebo) blev sammenlignet med acyclovir 800 mg, 5 gange dagligt i 7 dage.To determine the efficacy of a three-day treatment with brivudine 125 mg once daily in patients with herpes zoster, another comprehensive study was conducted using exactly the same study design as 5-Ho-b. Brivudine 125 mg once daily for three days (followed by four days of placebo) was compared to acyclovir 800 mg, 5 times daily for 7 days.
I alt 1336 patienter deltog. Resultatet viser, at denne dosiskur med brivudin er ik-30 ke-mindreværdig i forhold til behandling med acyclovir ved standarddosen for de primære virkningsfuldhedsvariable. Overlegenhed kunne imidlertid ikke konstateres.A total of 1336 patients participated. The result shows that this dose regimen of brivudine is not inferior to treatment with acyclovir at the standard dose of the primary efficacy variables. However, superiority could not be ascertained.
DK 177084 B1 9DK 177084 B1 9
Disse data med reduceret behandlingsvarighed støtter derfor opfattelsen, at bri-vudin virkelig er en effektiv behandling, når den gives én gang dagligt mod herpes zoster hos immunokompetente voksne, og støtter gyldigheden af de opnåede resultater i de tidligere studier.Therefore, these data with reduced duration of treatment support the notion that bri-vudine is truly an effective treatment when given once daily against herpes zoster in immunocompetent adults, and supports the validity of the results obtained in previous studies.
55
Primær virkninasfuldhedsvariablePrimary efficacy variables
For den primære parameter kunne overlegenhed ved brivudin-gruppen sammenlignet med acyclovir, konstateres. Bekræftelsestestproceduren var statistisk signi-10 fikant på 5%-niveauet. Det estimerede risiko-forhold var 1,14 (for populationen per protokol), idet en 14% bedre effekt (slutpunkt blev nået hurtigere) for patienter behandlet med 1 x 125 mg brivudin, sammenlignet med patienter behandlet med acyclovir, indikeredes. Den tilsvarende deskriptive middelværdi for "tid fra påbegyndelse af behandling til sidste udbrud af herpes zoster-blærer" var 25% mindre 15 for brivudin (middel: 13,5 timer) end for acyclovir (middel: 18,0 timer).For the primary parameter, superiority of the brivudine group compared to acyclovir could be ascertained. The confirmation test procedure was statistically significant at the 5% level. The estimated risk ratio was 1.14 (for the population per protocol), indicating a 14% better effect (endpoint reached faster) for patients treated with 1 x 125 mg brivudine compared to patients treated with acyclovir. The corresponding descriptive mean for "time from onset of treatment to last outbreak of herpes zoster blisters" was 25% less 15 for brivudine (mean: 13.5 hours) than for acyclovir (mean: 18.0 hours).
For de primære virkingsfuldhedsvariable viste brivudin-behandling sig således bekræftende at være statistisk signifikant overlegen i forhold til acyclovir-behandling.Thus, for the primary efficacy variables, brivudine treatment was found to be statistically significantly superior to acyclovir treatment.
20 Sekundære virkninasfuldhedsvariable20 Secondary efficacy variables
De statistiske test for alle sekundære virkningsfuldhedsvariable, herunder de klinisk relevante smerte-parametre, viste ækvivalens mellem 1 x 125 mg brivudin, sammenlignet med 5 x 800 mg acyclovir.The statistical tests for all secondary efficacy variables, including the clinically relevant pain parameters, showed equivalence between 1 x 125 mg brivudine, compared to 5 x 800 mg acyclovir.
2525
Dissemination af hudlæsioner (brivudin: 1; acyclovir: 2) og andre komplikationer (brivudin: 0; acyclovir: 6) forekom hos mindre end 1% af patienterne i begge grupper.Dissemination of skin lesions (brivudine: 1; acyclovir: 2) and other complications (brivudine: 0; acyclovir: 6) occurred in less than 1% of patients in both groups.
DK 177084 B1 10DK 177084 B1 10
Undergruppe-analysen hos patienter i alderen 50 år eller mere gav resultater lignende disse, som blev opnået hos den samlede population, med en 18% bedre behandlingseffekt for de primære virkningsfuldhedsvariable hos patienter behandlet med brivudin, sammenlignet med disse, som var behandlet med acyclovir.The subgroup analysis in patients aged 50 years or more yielded similar results obtained in the overall population, with an 18% better treatment effect for the primary efficacy variables in patients treated with brivudine compared to those treated with acyclovir.
55
Overlegenhed af brivudin i forhold til acyclovir kunne demonstreres ved bekræftende statistikker for de primære virkningsfuldsvariable. Ikke-mindreværdighed kunne demonstreres ved 5%-signifikansniveauet for alle sekundære variable, herunder smerteparametre.Superiority of brivudine to acyclovir could be demonstrated by confirmatory statistics for the primary efficacy variables. Non-inferiority could be demonstrated at the 5% significance level for all secondary variables, including pain parameters.
1010
For underpopulationen af patienter med alderen 50 år eller mere viste der sig en endnu større fordel med brivudin, hvad angår den primære virkningsfuldhedspa-rameter, sammenlignet med acyclovir.For the subpopulation of patients aged 50 years or more, brivudine showed an even greater benefit in terms of its primary efficacy parameter compared to acyclovir.
15 Post-studium-overvåanina af post-herpes neuralai15 Post-study surveillance of post-herpes neuralai
To retrospektive post-studium-overvågninger blev gennemført under dobbeltblinde betingelser med GCP-standard til undersøgelse af forekomsten af post-herpes neuralgi (PHN) hos patienter med alderen 50 år eller mere: 20 1) udvalgt fra studierne 5-Ho-a og 5-Ho-b (7-dages brivudin mod 7-dages acyclovir-behandling) 2) udvalgt fra studiet 5-Ho-c (3-dages brivudin mod 7-dages acyclovir-25 behandling).Two retrospective post-study surveys were conducted under double-blind conditions with GCP standard to investigate the incidence of post-herpes neuralgia (PHN) in patients aged 50 years or more: 20 1) selected from studies 5-Ho-a and 5 -Ho-b (7-day brivudine versus 7-day acyclovir treatment) 2) selected from the study 5-Ho-c (3-day brivudine versus 7-day acyclovir treatment).
Patienter som efter telefonisk kontakt, rapporterede zoster-relateret smerte efter afslutningen af studiet blev inviteret til centreret og undersøgt af undersøgeren for at bekræfte forekomsten af PHN og for at besvare spørgsmål angående karakteri-30 stikken af smerte. PHN blev defineret som smerte i herpes zoster-påvirkede der-matomer efter den enkelte afslutning af studiet (patienter skulle have afsluttet stu- DK 177084 B1 11 dierne 5-Ho-a, 5-Ho-b og 5-Ho-c, når al skorpe er faldet af, eller på dag 35 efter påbegyndelse af behandling, alt efter hvad, der forekom først).Patients who, after telephone contact, reported zoster-related pain after completing the study were invited to the center and examined by the investigator to confirm the presence of PHN and to answer questions regarding the characteristics of the pain. PHN was defined as pain in herpes zoster-affected dermatomas after the individual completion of the study (patients should have completed studies 5-Ho-a, 5-Ho-b and 5-Ho-c when all crust has dropped off, or on day 35 after treatment begins, whichever occurred first).
Studierne blev gennemført som dobbeltblinde forsøg (både patienterne og under-5 søgerne kendte stadig ikke til behandlingen, som var indgivet under studierne 5-Ho-a, 5-Ho-b og 5-Ho-c), hvilket stærkt underbygger resultaterne af disse studier.The studies were conducted as double-blind trials (both patients and under-5 applicants still did not know the treatment administered under studies 5-Ho-a, 5-Ho-b and 5-Ho-c), which strongly supports the results of these studies. studies.
1. Post-studium-overvåanina af PHN efter en svv-daaes brivudin-behandlina 10 Et stort udvalg af 608 mandlige og kvindlige patienter med alderen 50 år eller mere fra studierne 5-Ho-a og 5-Ho-b blev genundersøgt retrospektivt (mellem 8 og 17 måneder efter behandling) til fastsættelse af fordelene ved brivudin til forebyggelse af forekomsten af post-herpes neuralgi. Hos patientgruppen, som tidligere var behandlet med 125 mg brivudin i syv dage, rapporterede 32,7% post-herpes neu-15 ralgi-lidelser efter studiets afslutning, hvorimod andelen i acyclovir-behandlingsgruppen var 43,5%. Således var den relative risiko for forekomst af post-herpes neuralgi 25% lavere i 125 mg brivudin-gruppen sammenlignet med acyclovir-gruppen. Dette var en statistisk signifikant reduktion og kan ses som en klinisk relevant fordel ved brivudin.1. Post-Study Surveillance of PHN Following an SVR-Day Brivudine Treatment Line 10 A large selection of 608 male and female patients aged 50 years or older from Studies 5-Ho-a and 5-Ho-b were retrospectively reviewed ( between 8 and 17 months after treatment) to determine the benefits of brivudine in preventing the occurrence of post-herpes neuralgia. In the patient group, previously treated with 125 mg brivudine for seven days, 32.7% reported post-herpes neuralgia after the end of the study, whereas the proportion in the acyclovir treatment group was 43.5%. Thus, the relative risk of occurrence of post-herpes neuralgia was 25% lower in the 125 mg brivudine group compared to the acyclovir group. This was a statistically significant reduction and can be seen as a clinically relevant benefit of brivudine.
20 2. Post-studium-overvåanina af PHN efter en tre-daaes brivudin-behandlina2. Post-study monitoring of PHN after a three-day brivudine treatment
Dette studium indbefattede patienter i alderen 50 år eller ældre, som havde modtaget tre-dages-forløbet af brivudin 125 mg eller standard syv-dages-dosisplanen 25 med acyclovir i studium 5-Ho-c. Patienter blev udspurgt mellem 3 og 8 måneder efter behandling.This study included patients aged 50 years or older who had received the three-day course of brivudine 125 mg or the standard seven-day dosing schedule 25 with acyclovir in Study 5-Ho-c. Patients were questioned between 3 and 8 months after treatment.
Resultaterne viser, at forekomsten af post-herpes neuralgi hos patienter, som modtog et tre-dages-forløb af brivudin 125 mg, én gang dagligt, er sammenlignelig 30 med den hos patienter, som modtog acyclovir i standard-dosen i syv dage (henholdsvis 41,6% mod 39,7%).The results show that the incidence of post-herpes neuralgia in patients who received a three-day course of brivudine 125 mg once daily is comparable to that in patients who received acyclovir at the standard dose for seven days (respectively). 41.6% versus 39.7%).
DK 177084 B1 12DK 177084 B1 12
Disse yderligere data understøtter beviset, at brivudin 125 mg indgivet én gang dagligt i kun tre dage, er ikke-mindreværdig i forhold til acyclovir ved behandlingen af herpes zoster.These additional data support the evidence that brivudine 125 mg administered once daily for only three days is non-inferior to acyclovir in the treatment of herpes zoster.
5 Eksempler5 Examples
Eksempel 1: 1 brivudin 125 mg tablet - tabletter med øjeblikkelig frigivelseExample 1: 1 brivudine 125 mg tablet - immediate release tablets
Nr. Råmateriale mg/tablet 1 brivudin 125,0 2 mikrokrystallinsk cellulose 74,0 3 lactose-monohydrat 37,0 4 povidon. K-værdi 25 6,5 5 magnesiumstearat 2,5 6 rent vand 245.0No. Raw material mg / tablet 1 brivudine 125.0 2 microcrystalline cellulose 74.0 3 lactose monohydrate 37.0 4 povidone. K value 25 6.5 5 magnesium stearate 2.5 6 pure water 245.0
Eksempel 2: 10Example 2: 10
Nr. Råmateriale mg/tablet 1 brivudin 125,0 2 mikrokrystallinsk cellulose 74,0 3 majsstivelse 37,0 4 povidon. K-værdi 25 6,5 5 magnesiumstearat 2,5 6 rent vand 245.0 13 DK 177084 B1No. Raw material mg / tablet 1 brivudine 125.0 2 microcrystalline cellulose 74.0 3 corn starch 37.0 4 povidone. K value 25 6.5 5 magnesium stearate 2.5 6 pure water 245.0 13 DK 177084 B1
Eksempel 3:Example 3:
Nr. Råmateriale mg/tablet 1 brivudin 125,0 2 cellulosepulver 74,0 3 lactose 37,0 4 povidon. K-værdi 25 6,5 5 magnesiumstearat 2,5 6 rent vand 245.0No. Raw material mg / tablet 1 brivudine 125.0 2 cellulose powder 74.0 3 lactose 37.0 4 povidone. K value 25 6.5 5 magnesium stearate 2.5 6 pure water 245.0
Eksempel 4: 5Example 4: 5
Nr. Råmateriale mg/tablet 1 brivudin 125,0 2 mikrokrystallinsk cellulose 74,0 3 majsstivelse 37,0 4 copovidon VA 64 6,5 5 magnesiumstearat 2,5 6 rent vand 245.0 10 14 DK 177084 B1No. Raw material mg / tablet 1 brivudine 125.0 2 microcrystalline cellulose 74.0 3 corn starch 37.0 4 copovidone VA 64 6.5 5 magnesium stearate 2.5 6 pure water 245.0 10 14 DK 177084 B1
Eksempel 5:Example 5:
Nr. Råmateriale mg/tablet 1 brivudin 125,0 2 mikrokrystallinsk cellulose 74,0 3 lactose 37,0 4 copovidon VA 64 6,5 5 collidone CL 5,0 6 magnesiumstearat 2,5 7 rent vand 250.0No. Raw material mg / tablet 1 brivudine 125.0 2 microcrystalline cellulose 74.0 3 lactose 37.0 4 copovidone VA 64 6.5 5 collidone CL 5.0 6 magnesium stearate 2.5 7 pure water 250.0
Eksempel 6:Example 6:
Nr. Råmateriale mg/tablet 1 brivudin 125,0 2 mikrokrystallinsk cellulose/aerosil 98/2 122,5 3 magnesiumstearat 2,5 4 rent vand 250.0 5 10No. Raw material mg / tablet 1 brivudine 125.0 2 microcrystalline cellulose / aerosil 98/2 122.5 3 magnesium stearate 2.5 4 pure water 250.0 5 10
Eksempel 7:Example 7:
Nr. Råmateriale mg/tablet 15 DK 177084 B1 1 brivudin 125,0 2 mikrokrystallinsk cellulose/aerosil 98/2 100,5 3 collidone CL 22,0 4 magnesiumstearat 2,5 5 rent vand 250,0 5No. Raw material mg / tablet 15 DK 177084 B1 1 brivudine 125.0 2 microcrystalline cellulose / aerosil 98/2 100.5 3 collidone CL 22.0 4 magnesium stearate 2.5 5 pure water 250.0 5
Eksempel 8 - kapsel med øjeblikkelig frigivelseExample 8 - Instant Release Capsule
Nr. Råmateriale mg pulver/kapsel 1 brivudin 125,0 2 mikrekrystallinsk cellulose 122,5 3 magnesiumstearat 2,5 4 rent vand 250,0 10No. Raw material mg powder / capsule 1 brivudine 125.0 2 microcrystalline cellulose 122.5 3 magnesium stearate 2.5 4 pure water 250.0 10
Eksempel 9 - coatet tablet med øjeblikkelig frigivelse 16 DK 177084 B1Example 9 - Immediate Release Coated Tablet 16
Nr. Råmateriale mg/tablet 1 brivudin 125,0 2 mikrokrystallinsk cellulose 74,0 3 lactose-monohydrat 32,0 4 Aerosil 5,0 5 copovidon. VA 64 6,5 6 magnesiumstearat 2,5 7 hydroxypropyl-methylcellulose 5,0 8 macrogol 6000 1,5 9 Titandioxid 4,5 256,0No. Raw material mg / tablet 1 brivudine 125.0 2 microcrystalline cellulose 74.0 3 lactose monohydrate 32.0 4 Aerosil 5.0 5 copovidone. VA 64 6.5 6 magnesium stearate 2.5 7 hydroxypropyl methyl cellulose 5.0 8 macrogol 6000 1.5 9 Titanium dioxide 4.5 256.0
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| ITMI20010009 | 2001-01-03 | ||
| IT2001MI000009A ITMI20010009A1 (en) | 2001-01-03 | 2001-01-03 | PHARMACEUTICAL COMPOSITIONS CONTAINING BRIVUDINA FOR SINGLE DAILY ADMINISTRATION |
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| BE1014522A5 (en) | 2003-12-02 |
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| CZ20012464A3 (en) | 2002-08-14 |
| DK200101019A (en) | 2002-07-04 |
| SK287043B6 (en) | 2009-10-07 |
| GR20010100322A (en) | 2002-10-08 |
| PT102642A (en) | 2002-07-31 |
| IE20010413A1 (en) | 2003-04-16 |
| SK9572001A3 (en) | 2003-03-04 |
| HUP0102816A3 (en) | 2005-01-28 |
| PT102642B (en) | 2003-06-30 |
| NL1018431C2 (en) | 2002-07-05 |
| ES2192456B1 (en) | 2005-02-01 |
| GR1004012B (en) | 2002-11-01 |
| ES2192456A1 (en) | 2003-10-01 |
| GB2370771A (en) | 2002-07-10 |
| AT6141U1 (en) | 2003-05-26 |
| PL348480A1 (en) | 2002-07-15 |
| HU0102816D0 (en) | 2001-09-28 |
| FI20011446A (en) | 2002-07-04 |
| HRP20010345A2 (en) | 2003-08-31 |
| CH695662A5 (en) | 2006-07-31 |
| ITMI20010009A1 (en) | 2002-07-03 |
| FI20011446A0 (en) | 2001-07-03 |
| UA76402C2 (en) | 2006-08-15 |
| SE0102309D0 (en) | 2001-06-28 |
| SE0102309L (en) | 2002-07-04 |
| HUP0102816A2 (en) | 2002-10-28 |
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| Date | Code | Title | Description |
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| PUP | Patent expired |
Expiry date: 20210629 |