Safety Remicade (Infliximab) (fda.gov)

Postmarketing Reviews (fda.gov 2008;1(2))

Humira - ny sikkerhetsinformasjon (legemiddelverket.no 31.7.2008)

FDA kräver skärpt varningstext på TNF-blockerare (lakemedelsvarlden.se 5.9.2008)

Pakningsvedlegg (fda.gov):

- Remicade (infliximab/infliksimab)

- Humira (adalimumab)

- Enbrel (etanercept) etc.)

- Gennemgang af bivirkningsindberetninger relateret til udvalgte biologiske lægemidler samt forbruget af disse i 3. Kvartal

Gennemgang af bivirkningsindberetninger relateret til udvalgte biologiske lægemidler samt forbruget af disse i 3. kvartal
laegemiddelstyrelsen.dk (Nyt Om Bivirkninger NR. 10 • ÅRGANG 7 • NOVEMBER 2016)
Lægemiddelstyrelsen modtog i 3. kvartal 2016 42 bivirkningsindberetninger* relateret til biologiske/biosimilære lægemidler, der fremgår af Liste over udvalgte biologiske lægemidler1. Lidt over halvdelen blev klassificeret som alvorlige (tabel 1). (...)

Indberetninger om infliximab
Den største andel af indberetningerne omhandler lægemidler med infliximab – i alt 23 af de 42 indberetninger. Heraf omhandler ni referencelægemidlet Remicade og ti det biosimilære Remsima. I de sidste seks indberetninger er lægemiddelnavnet ikke opgivet (tabel 1). I to af de alvorlige indberetninger er både Remsima og Remicade mistænkt. 

I de alvorlige indberetninger om Remicade er bl.a. beskrevet tilfælde af infektioner (laryngitis og abscesser) samt udvikling af maligniteter (Hodgkins sygdom og basalcellekarcinom). Det er overvejende kendte bivirkninger, som er beskrevet i produktresuméerne. Med den nuværende viden kan en mulig risiko for udvikling af lymfomer eller andre maligne sygdomme hos patienter behandlet med et TNF-blokerende middel ikke udelukkes. Når TNF-blokerende behandling overvejes bør forsigtighed udvises hos patienter med en fortid med maligne sygdomme, eller når fortsat behandling overvejes hos patienter, der udvikler maligne sygdomme3. 

Blandt de alvorlige indberetninger vedrørende Remsima er beskrevet forskellige former for allergiske reaktioner, bl.a. urticaria og hævelse og kløe i munden. Allergiske reaktioner er kendte bivirkninger.

Indberetninger om infliximab Den største andel af indberetningerne omhandler lægemidler med infliximab – i alt 23 af de 42 indberetninger. Heraf omhandler ni referencelægemidlet Remicade og ti det biosimilære Remsima. I de sidste seks indberetninger er lægemiddelnavnet ikke opgivet (tabel 1). I to af de alvorlige indberetninger er både Remsima og Remicade mistænkt. 

I de alvorlige indberetninger om Remicade er bl.a. beskrevet tilfælde af infektioner (laryngitis og abscesser) samt udvikling af maligniteter (Hodgkins sygdom og basalcellekarcinom). Det er overvejende kendte bivirkninger, som er beskrevet i produktresuméerne. Med den nuværende viden kan en mulig risiko for udvikling af lymfomer eller andre maligne sygdomme hos patienter behandlet med et TNF-blokerende middel ikke udelukkes. Når TNF-blokerende behandling overvejes bør forsigtighed udvises hos patienter med en fortid med maligne sygdomme, eller når fortsat behandling overvejes hos patienter, der udvikler maligne sygdomme3. 
Blandt de alvorlige indberetninger vedrørende Remsima er beskrevet forskellige former for allergiske reaktioner, bl.a. urticaria og hævelse og kløe i munden. Allergiske reaktioner er kendte bivirkninger

I de ikke-alvorlige indberetninger relateret til infliximab er der ligeledes beskrevet primært kendte bivirkninger, som fx infektioner og kortvarigt synstab. Kortvarigt synstab under infusionen eller inden for to timer efter infusionen er beskrevet i produktresuméet.     

Eksponering af fostre
I fem tilfælde har fostre været eksponeret for Remicade. Fire af tilfældene er beskrevet i litteraturen. I to af indberetningerne er beskrevet formodede bivirkninger hos barnet: et nyfødt barn blev diagnosticeret med en dobbeltnyre, et andet med en karanomali. 

I produktresuméer for infliximab er beskrevet, at fertile kvinder skal anvende sikker antikonception for at undgå graviditet og fortsætte med anvendelse i mindst seks måneder efter den sidste behandling med lægemidlet. Infliximab passerer placenta og er fundet i serum hos spædbørn op til seks måneder efter fødslen. Spædbørn, der har været eksponeret for infliximab in utero, kan have en øget risiko for infektion. 

Den eksisterende kliniske erfaring er for begrænset til at udelukke en risiko, og indgift af infliximab anbefales derfor ikke under graviditet. 

Indberetninger i forbindelse med skift fra Remicade til Remsima
Der er ikke indberettet nogen bivirkninger i forbindelse med skift fra Remicade til Remsima i 3. kvartal 2016. Næsten alle patienter, der får infliximab i Danmark, er siden sommeren 2015 blevet behandlet med Remsima (figur 1). Man må derfor forvente, at der fremover kun bliver indberettet meget få formodede bivirkninger relateret til skift.  Indberetninger om etanercept 15 ud af de i alt.

Indberetninger i 3. kvartal omhandler etanercept.
Tre af disse beskriver formodede bivirkninger ved referencelægemidlet Enbrel, og 11 indberetninger beskriver formodede bivirkninger ved det biosimilære lægemiddel Benepali. I en indberetning er lægemiddelnavnet ikke opgivet.  

I de alvorlige indberetninger (6 ud af 15) er beskrevet formodede bivirkninger som angioødem, multipel sklerose og systemisk lupus erythematosus – alle sammen kendte formodede bivirkninger. Dissemineret sklerose-lignende sygdom er i produktresuméet beskrevet som en sjælden bivirkning, mens lupus-lignende syndrom er beskrevet som en ikkealmindeligt forekommende bivirkning.    

De ikke-alvorlige indberetninger beskriver især forskellige former for hovedpine samt kvalme og opkast. Disse bivirkninger er ikke beskrevet i produktresuméet.

Indberetninger i forbindelse med skift fra Enbrel til Benepali 
Vi modtog fire indberetninger om bivirkninger ved skift fra Enbrel til Benepali i 3. kvartal.

En indberetning beskriver en patient, der to uger efter skift til det biosimilære lægemiddel Benepali fik tiltagende gigtaktivitet med ledsmerte og hævelser. Patienten blev skiftet tilbage til Enbrel, og symptomerne fortog sig igen.

En anden indberetning beskriver en patient, der blev skiftet fra Enbrel til Benepali. Umiddelbart efter første indsprøjtning udviklede patienten kvalme og almen utilpashed, som varede omkring en uge. Halveringstiden er 70 timer for etanercept, hvilket svarer til, at eventuelle bivirkningssymptomer vil forsvinde i løbet af en uge. Det kan derfor ikke udelukkes, at symptomerne har sammenhæng med lægemidlet.
Den tredje indberetning beskriver en patient, der fik forhøjet blodtryk, svimmelhed, rødme i hovedet og varme ører i forbindelse med skiftet til Benepali. Behandlingen blev stoppet pga. bivirkninger, og patienten blev skiftet tilbage til Enbrel. Det er oplyst, at de formodede bivirkninger ikke forsvandt efter skiftet til Enbrel.

Hypertension er ikke beskrevet i produktresuméet, men der er tidsmæssig sammenhæng mellem administration af lægemidlet og symptomerne, hvorfor det ikke kan udelukkes, at symptomerne har sammenhæng med lægemidlet. Den sidste indberetning beskriver en gigtpatient, der var symptomfri i kortere tid ved behandling med Benepali end ved behandling med Enbrel. Der er ingen oplysninger om aktiviteten i gigtsygdommen, og det er derfor ikke muligt at afgøre, om det skyldes nedsat effekt af Benepali i forhold til Enbrel. (…)

(Anm: Early Symptoms of Rheumatoid Arthritis (medicinenet.com 17.8.2016).)

(Anm: Warning Signs of Rheumatoid Arthritis. What Is Rheumatoid Arthritis (RA)? (webmd.com 23.8.2016).)

(Anm: Risk of serious infections associated with use of immunosuppressive agents in pregnant women with autoimmune inflammatory conditions: cohort study. Objective To compare the risk of serious infections associated with use of systemic steroids, non-biologic agents, or tumor necrosis factor α (TNF) inhibitors in pregnancy. (…) Conclusions Risk of serious infections is similar among pregnant women with systemic inflammatory conditions using steroids, non-biologics, and TNF inhibitors. However, high dose steroid use is an independent risk factor of serious infections in pregnancy. BMJ 2017;356:j895. (Published 06 March 2017).)

- Forskere ved Diakonhjemmet sykehus i Oslo har utviklet en ny behandlingsstrategi for pasienter med leddgikt. Nesten 240 pasienter deltok i en studie som viste at to av tre oppnådde remisjon - altså at de ble tilnærmet symptomfrie.)

Norske pasienter med leddgikt symptomfri av ny behandling
nhi.no 9.1.2017
To av tre pasienter med leddgikt som deltok i en norsk studie, var symptomfrie etter to år. Nå skal den nye behandlingsmåten inn i nye, norske behandlingsanbefalinger for leddgikt.
Forskere ved Diakonhjemmet sykehus i Oslo har utviklet en ny behandlingsstrategi for pasienter med leddgikt. Nesten 240 pasienter deltok i en studie som viste at to av tre oppnådde remisjon - altså at de ble tilnærmet symptomfrie.

Resultatene av studien er nylig publisert i tidsskiftet the BMJ, og behandlingen skal implementeres i norske behandlingsanbefalinger.

- Dette er en gladsak. Før var man fornøyd med at pasienten med leddgikt ble bedre, nå vil vi at de skal bli bra, sier Anna-Birgitte Aga (bildet under), når NHI.no møter henne på Diakonhjemmet sykehus. (…)

Spørsmålet forskerne stilte innledningsvis, var om behandlingsresultatene blir bedre hos pasienter med nyoppstått leddgikt hvis de følges opp tett med systematiske ultralydundersøkelser, og behandlingen intensiveres dersom det foreligger betennelse ved ultralyd.

Pasientene ble randomisert til to forskjellige grupper hvor alle ble fulgt med tette kontroller i to år. Den ene gruppen ble i tillegg jevnlig undersøkt med ultralyd. (…)

I behandlingen av pasientene ble det brukt allerede kjente medisiner - det var behandlingsstrategien som var ny.

- Behandlingsstrategi er veldig viktig – hvor ofte pasienten kommer til kontroll og hvordan medisinene blir justert til rett nivå, sier Aga. (…)

(Anm: Ultrasound in management of rheumatoid arthritis: ARCTIC randomised controlled strategy trial. (…) Conclusions The systematic use of ultrasound in the follow-up of patients with early rheumatoid arthritis treated according to current recommendations is not justified on the basis of the ARCTIC results. The findings highlight the need for randomised trials assessing the clinical application of medical technology. BMJ 2016;354:i4205. (Published 16 August 2016).)

- Reumatoid artritt kan behandles med en ny hydrogel.

(Anm: Rheumatoid arthritis could be treated with a novel hydrogel. Researchers have developed a hydrogel that they believe could help to treat rheumatoid arthritis. A simple yet effective new treatment for rheumatoid arthritis may be in sight; researchers have now created a hydrogel that could absorb the excess joint fluid that arises with disease, as well as deliver medications to affected joints. Created by researchers from the Institute for Basic Science (IBS) in the Republic of Korea, the gel works by responding to nitric oxide, which is a gas that has been linked to the development of rheumatoid arthritis. The team recently reported the details of their novel hydrogel in the journal Advanced Materials. (medicalnewstoday.com 13.10.2017).)

- Dette skjoldet av patenter beskytter verdens bestselgende legemiddel.

(Anm: Dette skjoldet av patenter beskytter verdens bestselgende legemiddel. (- Produktet med 16 milliarder dollar i årsomsetning. (...) - Det har dessuten vært tilgjengelig i nærmere 15 år. (…) Den virkelige utfordringen var den tilsynelatende ugjennomtrengelige festningen av patenter som AbbVie metodisk har bygget rundt sin verdsatte pengemaskin. (…) Humira, som står for mer enn 60 prosent av AbbVies inntekter har en listepris på mer enn 50 000 dollar per pasient. (bloomberg.com 7.9.2017).)

Diverse artikler

(Anm: FDA delays decision on Lilly RA hopeful. US regulators are to delay a decision on Eli Lilly’s potential rheumatoid arthritis blockbuster, baricitinib, by three months in order to consider further information submitted by the manufacturer. (…) New CEO David Ricks hopes that baricitinib, which will likely be marketed in the EU as Olumiant, will lift sales and spirits in the company after a disastrous end to 2016, which saw Alzheimer’s drug solanezumab fail in a late-stage trial. (…) Trial data shows that baricitinib, developed in partnership with Incyte, could be more effective than Humira. Lilly’s drug is administered in a pill, which patients will likely find more convenient than injections of Humira. (pharmaphorum.com 16.1.2017).)

(Anm: Flesh-eating infections in rheumatoid arthritis patients spur new discovery. Rheumatoid arthritis patients taking medications that inhibit interleukin-1beta (IL-1beta), a molecule that stimulates the immune system, are 300 times more likely to experience invasive Group A Streptococcal infections than patients not on the drug, according to University of California San Diego School of Medicine researchers. Their study, published in Science Immunology, also uncovers a critical new role for IL-1beta as the body's independent early warning system for bacterial infections. (medicalnewstoday.com 23.8.2016).)

(Anm: IL-1β is an innate immune sensor of microbial proteolysis. (…) Review of postmarketing surveillance of patients receiving IL-1β inhibitors found a disproportionate reporting of invasive infections by group A Streptococcus (GAS). IL-1β inhibition increased mouse susceptibility to GAS infection, but IL-1β was produced independent of canonical inflammasomes.Science Immunology 2016;1(2):19:eaah3539 (Aug 2016).)

(Anm: Common Drugs Boost Diabetes Risk in RA Patients. (…) Patients treated for rheumatoid arthritis (RA) should be monitored over the long term for diabetes mellitus, according to a large longitudinal databank study in Annals of the Rheumatic Diseases. Confirming previously observed elevated diabetes risk with glucocorticoids, the study found a more than 30% increase in risk with these anti-inflammatories and also found a rise in diabetes risk of almost 60% with statin treatment. (medpagetoday.com 25.11.2016).)

Are patients with rheumatoid arthritis still at an increased risk of tuberculosis and what is the role of biological treatments?
Ann Rheum Dis. 2014 Mar 7. [Epub ahead of print]
OBJECTIVE: To estimate the risk of tuberculosis (TB) in patients with rheumatoid arthritis (RA) both with and without exposure to biological therapy and to directly compare the risks between therapies. (...)

CONCLUSIONS: In the past decade, the risk of TB has decreased among biological-exposed RA patients but remains higher than in biological-naïve RA patients. Most cases of TB in RA occur in biological-naïve RA patients, underscoring the elevated risk also in these patients. (...)

(Anm: Safety Of Adalimumab In RA Confirmed —No new concerns revealed in large study. Despite some limitations, "the data are reassuring in that in this very large patient population, no new safety signals were evident with regard to infections and laboratory parameters," Burmester told MedPage Today. (...) The most frequently reported serious adverse events involved infections, including pneumonia, cellulitis, bacterial arthritis, and sepsis. Serious infections occurred at a rate of 4.7 events/100 patient-years. The incidence rate for tuberculosis (TB), usually after screening for latent TB and, when appropriate, preventive treatment, was 0.3 events/100 patient-years. advertisement Opportunistic infections, including esophageal candidiasis, coccidioidomycosis, cytomegalovirus infection, and Mycobacterium avium complex infection, occurred at a rate below 0.1 events/100 patient-years. (medpagetoday.com 4.7.2016).)

(Anm: Forskere finder sammenhæng mellem kroppens bakterier og leddegigt. Mennesker med leddegigt har en anderledes bakteriesammensætning i tarmen og munden end raske personer. Opdagelsen kan bruges til nemt at diagnosticere sygdommen. (videnskab.dk 14.8.2015).)

(Anm: Reactions to Remicade Are Rare. —Canadian real-world study confirms infliximab safety. (…) The incidence of infusion reactions in the registry, known as RemiTRAC, was 1.3%, compared with a rate of 2.5% to 6.1% in other cohort studies, the investigators reported in The Journal of Rheumatology. (medpagetoday.com 16.7.2015).)

(Anm: The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. (...) In particular, Haemophilus spp. were depleted in individuals with RA at all three sites and negatively correlated with levels of serum autoantibodies, whereas Lactobacillus salivarius was over-represented in individuals with RA at all three sites and was present in increased amounts in cases of very active RA. (...) Functionally, the redox environment, transport and metabolism of iron, sulfur, zinc and arginine were altered in the microbiota of individuals with RA. Nat Med. 2015 Aug;21(8):895-905. Epub 2015 Jul 27.)

(Anm: High-zinc diet may raise risk of C. difficile infection. Published in the journal Nature Medicine, the study reveals how mice fed a high-zinc diet experienced changes to gut microbiota - the population of microbes in the intestine - and increased susceptibility to C. difficile infection. (medicalnewstoday.com 26.9.2016).)

(Anm: Gut bacteria can cause, predict and prevent rheumatoid arthritis. The bacteria in your gut do more than break down your food. They also can predict susceptibility to rheumatoid arthritis, suggests Veena Taneja, Ph.D., an immunologist at Mayo Clinic's Center for Individualized Medicine. Dr. Taneja recently published two studies—one in Genome Medicine and one in Arthritis and Rheumatology—connecting the dots between gut microbiota and rheumatoid arthritis. (…) "Using genomic sequencing technology, we were able to pin down some gut microbes that were normally rare and of low abundance in healthy individuals, but expanded in patients with rheumatoid arthritis," Dr. Taneja says. (medicalxpress.com 16.7.2016).)

(Anm: Choice of Biologic Therapy for Patients with Rheumatoid Arthritis: The Infection Perspective. Curr Rheumatol Rev. Feb 2011; 7(1): 77–87.)

(Anm: Risk of serious infection in biological treatment of patients with rheumatoid arthritis: a systematic review and meta-analysis. (…) INTERPRETATION: Standard-dose and high-dose biological drugs (with or without traditional DMARDs) are associated with an increase in serious infections in rheumatoid arthritis compared with traditional DMARDs, although low-dose biological drugs are not. Clinicians should discuss the balance between benefit and harm with the individual patient before starting biological treatment for rheumatoid arthritis.Lancet. 2015 May 11. pii: S0140-6736(14)61704-9. [Epub ahead of print].)

(Anm: Nya trenden: Läkemedel som är svåra att tillverka – men otroligt lönsamma. Biologiska läkemedel toppar listan över läkemedel som drar in mest pengar i världen. Cobra Biologics är en av få svenska tillverkare i branschen. (nyteknik 28.5.2015).)

(Anm: Abbvie får böta för marknadsföring. Läkemedelsföretaget Abbvie kritiseras för marknadsföring av TNF-alftahämmaren Humira, adalimumab. Det gäller bland annat en förminskning av redovisade biverkningar. (…) Granskningsmannen anser att man genom att skriva att biverkningar är jämförbara med placebo, förringar både uppgifter om varningar samt möjliga biverkningar. (lakemedelsvarlden.se 14.12.2015).)

(Anm: AbbVie Inc: New Drugs May Overcome Humira Loss. (…) Why HumiraIs In Trouble. Humira, which makes up more than 60% of the company’s topline, is approved to treat as many as 10 different conditions, including rheumatoid arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, polyarticular juvenile idiopathic arthritis, Crohn's disease (CD), hidradenitis suppurativa, ulcerative colitis, moderate-to-severe CD in children aged six or above and non-infectious intermediate and posterior panuveitis in adults. (…) Morgan Stanley’s David Risinger raised additional Humira-related issues in a June research report, saying: “Humira not only faces challenges from several biosimilar players (including Amgen (AMGN), Novartis’ (NVS) Sandoz, and Pfizer (PFE)), but also from novel branded injectables and orals.” These include drugs like Novartis’ Cosentyx and Eli Lilly’s Taltz and baricitinib. (bidnessetc.com 1.8.2016).)

Rheumatoid arthritis, anti-tumour necrosis factor therapy, and risk of malignant melanoma: nationwide population based prospective cohort study from Sweden
BMJ 2013;346:f1939 (8 April 2013)
(...) Objectives To investigate the potential association between tumour necrosis factor (TNF) inhibitor treatment and malignant melanomas in rheumatoid arthritis, melanoma risks in rheumatoid arthritis patients not treated with biological drugs, and risk of all site cancer with TNF inhibitors as used in rheumatoid arthritis. (...)

Conclusion Overall, patients with rheumatoid arthritis who have not been treated with biological drugs are not at increased risk of invasive melanoma compared with the general population. Rheumatoid arthritis patients selected for TNF inhibitor treatment are not at increased overall risk for cancer but have a 50% increased relative risk of invasive melanoma. Given the small increase in absolute risk, these finding may not markedly shift the overall risk-benefit balance of TNF inhibitors as used in clinical practice but might do so in patients at high risk of melanoma for other reasons. (...)

(Anm: Industry and drug regulators disagree on which data should remain confidential (Industrien og legemiddelkontroller uenige om hvilke data som skal forbli konfidensielle (forretningshemmeligheter)) BMJ 2013;347:f5390 (3 September 2013).)

(Anm: Drug-Induced Lupus Rate Low With Anti-TNF. —Most cases consisted solely of skin involvement. (…) Drug-induced lupus is a rare but well-recognized phenomenon, and is generally considered to be milder than systemic lupus erythematosus (SLE). (medpagetoday.com 5.5.2015).)

Lika bra med halva dosen
lakemedelsvarlden.se 22.3.2013
Patienter med ledgångsreumatism som blivit bättre efter behandling med TNF-hämmaren etanercept kan halvera dosen och ändå behålla effekten. Det visar en ny studie.

Kostnaden för TNF-hämmare och andra biologiska läkemedel är hög och många landsting har försökt att få ned kostnaden genom olika rabattavtal. Nu visar en dubbelblind studie som publicerats i Lancet att även en mindre dos av TNF-hämmaren Enbrel (etanercept) kan ge en bra effekt. (...)

Forskarna tolkar resultaten som att etanercept tillsammans med metotextrat både i normal och låg dos hjälper patienter med medelsvår ledgångsreumatism att bibehålla låg sjukdomsaktivitet. (...)

Abbvie stämmer EMA
lakemedelsvarlden.se 14.3.2013
Företaget Abbvie vill hindra den europeiska läkemedelsmyndigheten från att släppa data om deras läkemedel Humira.

Mitt under diskussionerna om krav på läkemedelsföretagens öppenhet vill företaget Abbvie stoppa EMA från att släppa data om Humira. Humira (adalimumab) används för att behandla bland annat reumatiod artrit och de uppgifter som Abbvie vill skydda är rådata om preparatets effekt och säkerhet.

Enligt Financial Times är det ett annat läkemedelsföretag, UCB, som har vänt sig till EMA för att få ut informationen, något som Abbvie sätter sig emot. Företaget menar att det rör sig om konfidentiella uppgifter och kommersiellt känslig information och bekräftar att man lämnat in en ansökan till EU-domstolen för att hindra EMA att dela med sig av informationen.

Martin Harvey-Allchurch, kommunikationschef på EMA säger till Pharma Times att tre liknande fall väntar på svar i domstolen, ytterligare ett från Abbvie och ett från företaget Intermune.

- Vi kommer att fortsätta att svara på och behandla alla förfrågningar om data tills des att domstolen säger annat, säger Martin Harvey-Allchurch.

Abbvie bildades vid årsskiftet när företaget Abbott delades upp i två. (...)

(Anm: Pasientsikkerhet (rettssikkerhet) (mintankesmie.no).)

(Anm: Fri tilgang til forskningsresultater? (forskningsdata) (mintankesmie.no).)

(Anm: The hidden side of clinical trials | Sile Lane | TEDxMadrid (youtube.com).)

(Anm: Forvaltningsmakt og kunnskapspolitikk. Sammendrag. Helse- og omsorgsdepartementet benekter at de ønsker å styre forskninga i underliggende etater, og ser ingen problemer med at forskninga ligger under forvaltninga. Rus & Samfunn 05 / 2016 (Volum 9) Side: 33-35.)

(Anm: Frie forskere eller maktens lakeier? Abstrakt. Det går et skisma gjennom den samfunnsvitenskapelige rusforskningen. Ved første øyekast er det vanskelig å forstå hvorfor. Rus & Samfunn 05 / 2016 (Volum 9) Side: 36-40.)

(Anm: Nesten halvparten av alle studier som er gjennomført av store sponsorer i det siste tiåret er upublisert (Nearly half of all trials run by major sponsors in past decade are unpublished.) BMJ 2016;355:i5955 (Published 04 November 2016).)

(Anm: Who's not sharing their trial results? (trialstracker.ebmdatalab.net).)

(Anm: Transparency for patients: How much is too much? (pharmafile.com 11.10.2016).)

(Anm: Parlamentsmedlemmer hører at kliniske forsøk er byråkratiske, uklare, og forvirrende for forskere og pasienter. (…) "Det har vært en rekke kjente tilfeller hvor godkjente legemidler er basert på ufullstendig informasjon — og hvor den informasjonen som senere er stilt til rådighet har vist at legemidlet er ineffektivt eller faktisk skadelig.  (Clinical trials are bureaucratic, opaque, and offputting to researchers and patients, MPs hear.) BMJ 2013;346:f1711 (14 March 2013).)

Grönt för nytt RA-medel
lakemedelsvarlden.se 7.11.2012
FDA har nu godkänt Pfizers nya läkemedel för behandling av reumatism. Men bara den lägre doseringen.

Pfizers nya behandling för reumatoid artrit, ledgångsreumatism har nu godkänts av den amerikanska läkemedelsmyndigheten, FDA. En ansökan ligger också hos den europeiska myndigheten.

Xeljanz, tofacitinib är ett traditionellt kemiskt läkemedel som tas oralt och bland annat därför tros kunna bli en konkurrent till biologiska medel som behöver injiceras.

Tofacitinib har godkänts för behandling av patienter som inte tål eller svarar på traditionell behandling med metotrexat. Det nya läkemedlet har en mängd allvarliga biverkningar som FDA varnar för, som allvarliga infektioner, tuberkulos, och cancersjukdomar, biverkningar som också de konkurrerande behandlingarna har.

Förutom varningstexter om de allvarliga biverkningarna ska Pfizer lämna in en säkerhetsstudie för att följa upp riskerna.

Pfizer hade ansökt om att få det nya läkemedlet godkänt i två doseringar, men i första vändan fick man bara den lägre doseringen godkänd.

Trots detta är godkännandet viktigt för Pfizer enligt amerikanska bedömare som tror att medlet kommer att kunna sälja för runt tre miljarder dollar. Det är förstås betydligt mindre än Lipitor som under sina storhetsdagar sålde för 12 miljarder dollar, (2010), men i klass med Pfizers andra storsäljare Lyrica som drar in runt 3,7 miljarder dollar om året. (...)

For mange gigtpatienter er syge trods biologisk behandling
dagenspharma.dk 20.9.2012
Gigtlæger har nedbragt antallet af patienter, der har moderat eller svær sygdomsaktivitet trods biologisk behandlingen, men en tredjedel opnår fortsat ikke den ønskede effekt. (...)

2-Deaths in Pfizer arthritis trial hurt shares
reuters.com 21.4.2011
* 4 patient deaths reported in Pfizer drug study
* Pfizer shares close down 3 percent
* Pfizer says one of four deaths found drug study-related (Adds Pfizer comment)

NEW YORK, April 21 (Reuters) - New data raising safety concerns for Pfizer Inc's (PFE.N) experimental arthritis drug sent its shares down 3 percent, while lifting shares of rival drugmaker Abbott Laboratories (ABT.N), analysts said.

Wells Fargo analyst Larry Biegelsen in a research report on Thursday said four deaths were seen in one late-stage study of tofacitinib, Pfizer's oral drug for rheumatoid arthritis, which has been considered a potential rival to Abbott's big-selling Humira.

It was not clear from a brief description of the study, called an abstract, that the drug caused the deaths, Biegelsen said. But the report of the fatalities spooked investors.

The abstract from a 792-patient study to be presented at a meeting of the European League against Rheumatism said four patients who had been taking the 10-milligram dose of the Pfizer drug had died, including one from heart failure.

Pfizer said in a statement late on Thursday that the investigator reported only one of the four deaths -- the case of respiratory failure -- as study-drug related.

The drugmaker also said that the mortality rate from all causes across its drug development program, including this study, is within the range of rates reported for all biologic therapies for rheumatoid arthritis. (...)

Clues to Why Rheumatoid Arthritis Drug Humira Fails Some Patients
health.yahoo.net 12.4.2011
TUESDAY, April 12 (HealthDay News) -- In a new study, close to a third of patients taking the arthritis drug Humira developed an immune system reaction to it that rendered it ineffective.

Researchers say the finding helps to explain why some people get relief from their rheumatoid arthritis symptoms while on Humira (adalimumab), which is made by Abbott Laboratories, while others gain little or no benefit. Humira belongs to a class of drugs known as biologics. (...)

Humira (adalimumab) injection
fda.gov/Safety/MedWatch 15.12.2009
BOXED WARNING
Malignancy
Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which HUMIRA is a member. (...)

Enbrel (etanercept)
fda.gov/Safety/MedWatch 15.12.2009
BOXED WARNING
Malignancy
Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers including Enbrel. (...)

Remicade (infliximab) for IV injection
BOXED WARNING
Malignancy
Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including Remicade. (...)

Tumor Necrosis Factor (TNF) Blockers (marketed as Remicade, Enbrel, Humira, Cimzia, and Simponi)
fda.gov/Safety/MedWatch 2009 (August 31)
FDA notified healthcare professionals that it has completed its analysis of tumor necrosis factor (TNF) blockers and has concluded that there is an increased risk of lymphoma and other cancers associated with the use of these drugs in children and adolescents. This new safety information is now being added to the Boxed Warning for these products. (...)

FDA: Arthritis Drugs Pose Cancer Risk to Children (FDA: Artritt-legemidler utgjør kreftrisiko for barn)
online.wsj.com 5.8.2009
WASHINGTON -- The Food and Drug Administration said Tuesday there's an increased risk of lymphoma and other cancers associated with the use of drugs like Remicade and Humira for children and adolescents.

The agency said a new cancer-related warning will be added to the boxed-warning that's already on the drugs, which are known as tumor necrosis factor, or TNF blockers.

The drugs, which also include Enbrel, Cimzia and Simponi, are approved to treat various immune system diseases including juvenile idiopathic arthritis, rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, Crohn's disease and ankylosing spondylitis. (...)

Study Clears Gene Therapy in Death of Arthritis Patient
medpagetoday.com 8.7.2009
PRINCETON, N.J., July 8 -- The death of a young patient participating in a gene-therapy trial for a rheumatoid arthritis drug was most likely the result of another arthritis drug, adalimumab (Humira), and not the novel gene therapy agent, a new study found.

"The death of this young patient who was receiving multiple forms of TNF inhibitors highlights the risk of opportunistic infections in patients receiving such agents, and the importance of having a well-designed monitoring plan when a patient in a study becomes ill," Karen M. Frank, MD, of the University of Chicago Medical Center, and colleagues wrote in the July 9 issue of New England Journal of Medicine. (...)

(Anm: Investigation of the Cause of Death in a Gene-Therapy Trial. NEJM 2009;61:161-169 (July 9).)

Rheumatoid Arthritis Drugs Raise Shingles Risk (Legemidler mot revmatisk artritt øker risiko for helvetesild)
healthfinder.gov 18.2.2009
Older people and those also taking steroids are most vulnerable, study finds.

(SOURCES: Guy Fiocco, M.D., assistant professor, internal medicine, Texas A&M Health Science Center College of Medicine, and director, rheumatology, Scott & White, Temple, Texas; Anja Strangfeld, M.D., epidemiology unit, German Rheumatism Research Centre, Berlin; Feb. 18, 2009, Journal of the American Medical Association)

TUESDAY, Feb. 17 (HealthDay News) -- A class of medications used widely to treat rheumatoid arthritis and other autoimmune diseases might increase the risk of shingles, especially among older people and those who are also taking steroids.

But while the findings, appearing in the Feb. 18 issue of the Journal of the American Medical Association, might raise awareness of the potential complication among physicians and patients, some experts say it's unlikely to change how the drugs are used. (...)

FDA says ad for Abbott's Humira downplays risks
reuters.com 23.12.2008
WASHINGTON (Reuters) - An advertisement for Abbott Laboratories' Humira minimizes the arthritis drug's risks while suggesting it can treat a wider range of patients than it is approved to treat, the U.S. Food and Drug Administration said in a letter released on Tuesday.

The drug is cleared to treat certain patients with arthritis, psoriasis, Crohn's Disease or a form of arthritis called ankylosing spondylitis. (...)

Svårt hitta säkra testmodeller för biologiska läkemedel
lakemedelsvarlden.se 13.11.2008
De biologiska läkemedlen blir allt fler och utvecklingen går snabbt. Men det är svårt att hitta pålitliga metoder för att undersöka säkerheten med de nya preparaten. (...)

Som biologiska läkemedel räknas sådana vars aktiva substans har biologiskt ursprung. Många av dessa ingår i vanliga läkemedel som till exempel antikroppar, enzymer, interferoner och hormoner. Omkring 25 procent av alla läkemedel som 2006 godkändes av FDA och EMEA var biologiska.

Denna relativt nya läkemedelsgrupp har haft en enorm betydelse för flera behandlingar av bland annat autoimmuna sjukdomar och cancer. Monoklonala antikroppar registreras till exempel ett stort antal varje år. En utmaning med dessa är att det krävs andra metoder för att mäta renhet och mängd aktiv substans preparat.

- Vissa problem är förväntade, till exempel när man använder djurantikroppar i människa. Men även med adalimumab (Humira) som är en human antikropp drabbas upp till 16 procent av allergiska reaktioner, sade Nina Brenden från Astrazeneca. (...)

FDA kräver skärpt varningstext på TNF-blockerare
lakemedelsvarlden.se 5.9.2008
Det amerikanska Läkemedelsverket, FDA, gick på torsdagen ut med nya riktlinjer för fyra stycken läkemedel innehållande TNF-alfa-blockerare. Det är risken för allvarliga infektioner som nu måste finnas med i varningstext på produkterna.

Varning Produkterna det handlar om är Johnson & Johnson:s Remicade (infliximab), Wyeth:s Enbrel (etanercept), Abott:s Humira (adalimumab) och UCB:s Cimzia (cerolizumab). Alla fyra är så kallade TNF-alfa-blockerare som hämmar immunsystemet och används för behandling av bland annat reumatism, psoriasis och Crohn´s sjukdom. (...)

Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate
Ann Rheum Dis. 2008 Aug;67(8):1096-103. Epub 2007 Nov 29.
(...) CONCLUSIONS: In this study, abatacept and infliximab (3 mg/kg every 8 weeks) demonstrated similar efficacy. Overall, abatacept had a relatively more acceptable safety and tolerability profile, with fewer SAEs, serious infections, acute infusional events and discontinuations due to AEs than the infliximab group. Trial registration number: NCT00095147. (...)

Humira - ny sikkerhetsinformasjon
legemiddelverket.no 31.7.2008
Viktig informasjon til helsepersonell angående rapporter om hepatosplenisk T-cellelymfom (HSTCL) hos pasienter behandlet med Humira (adalimumab)

Legemiddelet Humira (adalimumab) er en TNF-alfa-hemmer godkjent til behandling av voksne pasienter med revmatoid artritt, psoriasisartritt, ankyloserende spondylitt, Crohns sykdom og psoriasis. Siden lanseringen i 2002, er det hos pasienter behandlet med Humira rapportert om tre tilfeller av hepatosplenisk T-cellelymfom (HSTCL). Dette er en sjelden form av non-Hodgkins lymfom med dårlig prognose. Produsenten Abbott sender nå ut brev med den nye informasjonen. Les den nye sikkerhetsinformasjonen her. (...)

Early Communication About an Ongoing Safety Review of
Tumor Necrosis Factor (TNF) Blockers
(marketed as Remicade, Enbrel, Humira, and Cimzia)

fda.gov 4.6.2008
FDA is investigating the possible association between the use of medicines known as tumor necrosis factor (TNF) blockers and the development of lymphoma and other cancers in children and young adults. These individuals were treated with TNF blockers for Juvenile Idiopathic Arthritis (JIA), Crohn’s disease or other diseases. JIA is the new name for what was called Juvenile Rheumatoid Arthritis (JRA). (...)

RA Drugs Linked to Slight Skin Cancer Risk
washingtonpost.com 29.8.2007
WEDNESDAY, Aug. 29 (HealthDay News) -- People taking rheumatoid arthritis drugs such as etanercept (Enbrel) or infliximab (Remicade) may be at a slightly increased risk for skin cancer, researchers report.

However, the risk is probably not significant enough to outweigh the benefits of these drugs, the researchers said.

These so-called biologic treatments work by blocking tumor necrosis factor alpha (TNF-alpha), which previous studies had found to be linked with increased risk of skin, lung and blood cancers.

"The risk of skin cancer is marginally increased among people with rheumatoid arthritis," said lead researcher Dr. Frederick Wolfe, a clinical professor of internal medicine at the University of Kansas School of Medicine. "But it's nothing that anybody should be worried about," he added. (...)

CORRECTED: Cancer risk from arthritis drugs overstated
reutershealth.com 11.8.2006
- Two biotech drugs used to treat rheumatoid arthritis -- Abbott Laboratories Inc.'s Humira and Johnson & Johnson's Remicade -- may raise the risk of cancer and infections but not as much as was feared, researchers said on Tuesday. (...)

Dr. Eric Matteson and colleagues at the Mayo Clinic in Rochester, Minnesota, who did the study published in May re-analyzed the data and added more data from other studies they had not considered before.

"We re-did the analysis completely," Matteson said in a telephone interview. The new analysis showed the cancer risk was 2.4 times greater among patients who used the drugs, and the risk of infectious disease was 1.8 times greater. (...)

Rheumatoid Arthritis Drug Linked to Cancers
ivanhoe.com 17.5.2006
-- A new analysis of previous studies shows rheumatoid arthritis drugs known as TNF- (tumor necrosis factor) blocking antibodies may increase the risk of cancer and infectious diseases.

"This study shows a strong association between treatment with TNF-blocking antibodies and the development of serious infections, such as pneumonia, and cancers," says Eric Matteson, M.D., from the Mayo Clinic in Rochester, Minn. "It's a very serious issue. TNF-blocking antibodies are effective for treatment for rheumatoid arthritis and related conditions, but patients and health care providers must know that there is an increased risk for these complications and be alert for them."

Investigators studied 3,493 patients who received TNF-blocking antibodies and 1,512 patients who received placebos. Researchers found those treated with TNF-blocking antibodies had about three-times the risk of developing cancer than those given a placebo and about two-times the risk of serious infection. Cancers were much more common in those patients treated with high doses of TNF-blocking antibodies. (...)

(Anm: Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA. 2006;295(19):2275-85 (May 17).)

Rare Risks Tied to Anti-TNF Agents for RA
medpagetoday.com 16.5.2006
— Anti-tumor necrosis antibody factor therapy has been linked to a rare but increased risk of malignancy and serious infections in rheumatoid arthritis patients.

Seeking out the sparse harmful effects of anti-TNF antibody therapy, researchers at the Mayo Clinic here undertook a review and meta-analysis of nine "high-quality" controlled clinical trials, according to a report in the May 17 issue of the Journal of the American Medical Association.

Although meta-analysis is used as a powerful tool to assess drug efficacy, it is rarely used to assess harmful drug effects, wrote Tim Bongartz, M.D., of the Mayo Clinic, and colleagues.

The study database from EMBASE, MEDLINE, Cochrane Library, and electronic abstracts from major medical meetings, produced 3,493 RA patients treated with Remicade (infliximab) and Humira (adalimumab) for 12 weeks or more compared with 1,512 patients given a placebo.

Remicade is a partially humanized and Humira a fully humanized monoclonal antibody specific for TNF. The drugs neutralize both extracellular and membrane forms of TNF, a cytokine considered of major importance in the pathophysiology of rheumatoid arthritis, the researchers said.

The researchers used statistical methods designed for sparse data to calculate a pooled odds ratio (OR) for malignancies and for infections requiring antimicrobial therapy or hospitalization, or both, in the two groups of patients.

Effects for high and low drug doses were calculated separately, while published information was supplemented by direct contact with principal investigators and industry sponsors, Abbot and Centocor. The drug firms had no role in the study, the researchers said.

Combining the individual ORs of studies with at least one event in any group, the researchers found that the pooled OR for malignancy compared with placebo patients was 3.3 (95% confidence interval 1.2-9.1).

Malignancies were significantly more common in patients treated with higher doses compared with patients given lower doses of anti-TNF antibodies, the researchers said.

Subgroup analysis of malignancy in trials that used low- and high-dose treatment revealed a consistent and significant difference between the dose groups. (...)

(Anm: Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA. 2006;295(19):2275-85 (May 17).)

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