WHO Drug Information Vol. 20, No. 1, 2006 - World Health ...

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WHO Drug Information Vol 20, No. 1, 2006Safety and Efficacy Issuesvery rare postmarketing reports of new onset andworsening diabetic macular oedema. In themajority of these cases, the patients also reportedconcurrent peripheral oedema. In some cases,the macular oedema resolved or improvedfollowing discontinuation of therapy and in onecase resolved after dose reduction.Macular oedema typically occurs in associationwith diabetic retinopathy, although it is morelikely to occur as retinopathy progresses. Riskfactors for macular oedema include duration ofdiabetes, presence of retinopathy, hypertension,and poor glycaemic control. Symptomssuggestive of macular oedema include blurred ordistorted vision, decreased colour sensitivity,and decreased dark adaptation.Reference: Communication from GlaxoSmithKlineavailable at: http://www.fda.gov/medwatch. December2005.Topical immunomodulators :carcinogenic potential?Singapore — Pimecrolimus cream (Elidel®) andtacrolimus ointment (Protopic®) are topicalimmunomodulators granted local marketingapproval in January 2003 and March 2004respectively.Elidel® (1%) is licensed for short-term andintermittent long-term treatment of mild to moderateatopic dermatitis in non-immunocompromisedpatients who are 2 years and older in whom theuse of alternative, conventional therapies isdeemed inadvisable because of potential risks, orin the treatment of patients who are not adequatelyresponsive to or intolerant of conventionaltherapies.Protopic® (0.1%; 0.03%) is licensed for thetreatment of moderate to severe atopic dermatitisin adults (0.1%) and children aged 2 years andabove (0.03%) who are not adequately responsiveto or are intolerant of conventional therapies.Topical immunomodulators are increasingly beingused in the US as first-line therapy in atopicdermatitis because they are perceived to be saferthan steroid preparations. This perception byphysicians and patients has been attributed toaggressive promotion of the drugs in the USmarket.Prompted by concern over the increasing use ofthese products especially in very young childrenand findings of carcinogenicity in some of theanimal studies as well as postmarketing reports ofmalignancies, the US Food and Drug Administration(FDA) issued a public advisory in March2005.HSA’s assessmentThe HSA Pharmacovigilance Advisory Committee(PVAC) have reviewed the following safetyinformation.(i) Animal studiesCarcinogenicity findings were not uniformlydetected in all animal studies. Although someanimal studies revealed no carcinogenic potential,others demonstrated some signals. For studieswith positive findings, the data showed that therisk of cancer increased with increasing dose andduration of treatment. It was noted that in generalthe doses used in these animal studies werehigher than the maximum recommended humandose (MRHD). For example, lymphoma formationin mice was reported with dermal application oftacrolimus and pimecrolimus dissolved in ethanol,at 26 times and 47 times MRHD, respectively.(ii) Postmarketing reportsAs of December 2004, the US FDA reported thatit received 10 and 20 cases of postmarketingreports of malignancy-related events (e.g.lymphoma) with pimecrolimus and tacrolimus,respectively. For many of these cases, thecausality could not be established due to thepresence of other confounding factors. To-date,HSA has not received any reports of malignancyassociated with pimecrolimus or tacrolimus.RecommendationsHSA and its PVAC advise physicians to weigh therisks and benefits of the drugs for individualpatients and to take into consideration thefollowing:• Pimecrolimus and tacrolimus are approved forshort-term and intermittent treatment of atopicdermatitis in patients unresponsive to, orintolerant of other treatments• They are not approved for use in childrenyounger than 2 years old. The long term effectof these drugs on the developing immunesystem is not known• They should not be used continuously for aprolonged period of time as their long-termsafety has yet to be determined.13
Safety and Efficacy IssuesWHO Drug Information Vol 20, No. 1, 2006• Patients who are immunocompromised shouldnot be prescribed pimecrolimus or tacrolimus.References1. FDA Paediatric Advisory Committee Meeting. http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4089b2.htm2. FDA Talk Paper on Elidel® and Protopic®. http://www.fda.gov/bbs/topics/ANSWERS/2005/ANS01343.html3. HSA Product Safety Alert. 12 December 2005.http://www.hsa.gov.sg/cda/safetyalertsTelithromycin: serious liver toxicityUnited States of America — An article reportingthree patients who experienced serious livertoxicity following administration of telithromycin(Ketek®) has recently been published. The caseshave also been reported to the Food and DrugAdministration (FDA).FDA is continuing its investigation of this issue,and is providing the following recommendations tohealthcare providers and patients:• Healthcare providers should monitor patientstaking telithromycin for signs or symptoms ofliver problems. Telithromycin should be stoppedin patients who develop signs or symptoms ofliver problems.• Patients who have been prescribed telithromycinand are not experiencing side effects such asjaundice should continue taking their medicineas prescribed unless otherwise directed by theirhealthcare provider.• Patients who notice any yellowing of their eyesor skin or other problems like blurry visionshould contact their healthcare provider immediately.• As with all antibiotics, telithromycin should onlybe used for infections caused by a susceptiblemicroorganism. Telithromycin is not effective intreating viral infections, so a patient with a viralinfection should not receive telithromycin sincethey would be exposed to the risk of side effectswithout any benefit.A case review of the reports shows seriousadverse events following administration oftelithromycin. All three patients developedjaundice and abnormal liver function. One patientrecovered, one required a transplant, and onedied. When the livers of the latter two patientswere examined in the laboratory, they showedmassive tissue death. These two patients hadreported some alcohol use. All three patients hadpreviously been healthy and were not using otherprescription drugs. The FDA is also aware thatthese patients were all treated by physicians inthe same geographic area. The significance ofthis observation is not clear at the present time.In pre-marketing clinical studies, including a largesafety trial and data from other countries, theoccurrence of liver problems was infrequent andusually reversible. Based on the pre-marketingclinical data, it appeared that the risk of liver injurywith telithromycin was similar to that of othermarketed antibiotics. Nonetheless, the productlabel advises doctors about the potential for liverrelatedadverse events associated with the use oftelithromycin.Telithromycin is an antibiotic of the ketolide class.It was the first antibiotic of this class to be approvedby the FDA in April, 2004 for the treatmentof respiratory infections in adults caused byseveral types of susceptible microorganismsincluding Streptococcus pneumoniae andHaemophilus influenzae.Reference.1. FDA Public Health Advisory. 20 January 2006. http://www.fda.gov/medwatch/2. Clay, K.D., Hanson, J.S., Pope, S.D. Brief communication:severe hepatotoxicity of telithromycim: threecase reports and literature review. Annals of InternalMedicine (on-line edition), January 20, 2006, http://www.acponline.orgDeaths with galantamine in mildcognitive impairment studiesAustralia — Galantamine (Reminyl®), donepezil(Aricept®) and rivastigmine (Exelon®) areapproved for the treatment of mild to moderatelysevere Alzheimer dementia. Cardiac arrhythmiaswith these cholinesterase inhibitors have beenreported (1).Galantamine has also been investigated inpatients with mild cognitive impairment, anindication which is not approved in Australia. Intwo placebo controlled trials, there was a highermortality with galantamine than placebo, andgalantamine was not effective (2). The deaths14
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