CONTENTS

ISSN: 0219 - 2152

July 2008Vol.10 No.2

Published by the Centre for Drug Administration, HSA and the HSA Pharmacovigilance Advisory Committee

1 Adulterated illegal sexualenhancement products

2 Tumor necrosis factor alpha antagonists& serious skin reactions

3 Update on aprotinin (Trasylol®)

4 Withdrawal of indication of primarynocturnal enuresis for desmopressinnasal preparations

Letter from EditorLetter from EditorLetter from EditorLetter from EditorLetter from Editor

Adulterated illegal sexual enhancement products

T he Health Sciences Authority’s recent investigationsinvolving Power 1 Walnut and several other illegal sexualenhancement products found adulterated with toxic

doses of glibenclamide is the most serious case of adverse dugreactions to illegal health products that we have encountered.If not for our astute healthcare professionals who promptly

reported theirsuspicions aboutthese products tous, potentially manymore of ourconsumers couldhave been harmedby the serious healthhazards posed bythese products.

We would like to take this opportunity to express our sincereappreciation to our doctors, pharmacists, nurses and healthcareadministrators who have contributed to this investigation inmany ways. These include reporting of adverse drug reactionsreports to us, retrieving suspected samples of products frompatients or their relatives for analytical testing and interviewingpatients on the source of the products.

We feel that it is also opportune to provide an update on ourinvestigations to keep our healthcare professionals informed.

Adulterated productsIn addition to Power 1 Walnut, the other three illegal healthproducts found to contain glibenclamide are counterfeit Cialis,Santi Bovine Penis Erecting Capsule and (Zhong HuaNiu Bian). The amount of glibenclamide was found to varyamong the different products and among different batches.The amount of glibenclamide detected from the samplesobtained from patients were between the range of 14-100mgper tablet. The other adulterants detected in these productsinclude varying concentrations of sildenafil, tadalafil andsibutramine.

Summary of adverse drug reactions casesAs of 16 June 2008, we have 47 confirmed cases of adversereact ions to adulterated i l legal products and another98 suspected cases where it is highly probable that the patient

also consumed health products adulterated with glibenclamideas they exhibited s imi lar symptoms of hypoglycaemia(e.g. giddiness, seizures, unconsciousness). These patients alsohave positive laboratory findings of glibenclamide (or itsmetabolites) in either their blood or urine. Ten of the patientspresented in a coma state of which six have since passed awayand the remaining four have permanent neurological damage.

All the patients were males except for one female. Their agesrange between 21-97 years, comprising 69% residents and 31%foreigners; 57% were Chinese, 17% Malay, 13% Indian and 13%of other races. Hypocounts of these patients upon presentationwere reported to be as low as 0.7mmol/L. Clinical investigationsrevealed findings of positive urine/blood test for glibenclamide,high insulin and C-peptide levels.

HSA’s assessment and actionsWe have assessed that the adulteration with glibenclamide isnot limited to these four products and potentially can affect awider range of illegal sexual enhancement products. It is likelythat there could have been a mix-up at the source ofmanufactur ing as we found that in products whereglibenclamide was detected, the sildenafil concentration waspresent in very low levels. For instance, one particular batch ofPower 1 Walnut from a patient contained 98mg glibenclamideand only 1mg of sildenafil.

HSA officers have intensified our surveillance and enforcementactivities in this area. To date, more than 100,000 units of illegalhealth products have been seized and eight peddlers caughtdealing in such products have been charged in court.

As part of our educational efforts to reduce demand of theseproducts, we have also produced posters in foreign languagesand depiction in cartoons to reach out to a wider audience.

ConclusionWe look forward to your continuedsupport of reporting adverse drugreactions to the PharmacovigilanceUnit, HSA. A high level of vigilance byour healthcare professionals is essentialin ensuring safer drugs on the market.

Editor-in-ChiefChan Cheng Leng

4 Clozapine-induced gastrointestinalhypomotility

5 PDE5 inhibitors associated sensorineuralhearing loss

6 Updates on mycophenolate group of drugs

7 Package insert amendments reflectingsafety issues

8 Varenicline (Champix®) & neuropsychiatricadverse events

2 Adverse Drug Reaction News July 2008 Vol.10 No.2

T umor necrosis factor-alpha (TNF-α)is a cytokine produced by monocytesand macrophages and has a role in

promoting an inflammatory responsewhich may lead to the development ofcertain autoimmune disorders such asrheumatoid arthritis or Crohn’s disease.TNF-α antagonists are biological proteinmolecules designed to block the TNF-α’sinflammatory responses. Since 2002, HSAhas registered three TNF-α antagonists:

Adalimumab (Humira® 40mg/0.8mL,Abbott)

Etanercept (Enbrel® 25mg, Wyeth)

Infliximab (Remicade® 100mg,Centocor BV)

TNF-α antagonists are currently locallyapproved for the management of severearthritic conditions and Crohn’s’ disease(infliximab only). As TNF-α antagonists areprotein molecules, they have the capabilityto elicit an immune response possiblyleading to hypersensitivity reactions.

Serious dermatological adversereactionsSince August 1998, following the firstmarketing authorization of infliximab, theUS Food and Drug Administration(FDA) has been receiving adverse drugreports (ADR) of serious cutaneousadverse reactions associated with theuse of adalimumab, etanercept andinfliximab. The adverse reactions, fromboth domestic and overseas reportsinclude erythema multiforme (EM),Stevens Johnson syndrome (SJS) andtoxic epidermal necrolysis (TEN) (refer toTable 1 for details). To date, there are:

7 reports associated with adalimumab

22 reports associated with etanercept

21 reports associated with infliximab

The evaluation of the potential of TNF-αantagonists’ capability to elicit seriousdermatological reactions are difficult asother confounding factors were present.A significant number of these patientswere co-administered with one or moremedications such as carbamazepine,amoxicillin, ciprofloxacin, methotrexateand celecoxib, which are also knownto be associated with EM, SJS and TEN.However, a certain number of thesecases yielded positive rechallenge anddechallenge outcomes, supporting theassociation of serious skin reactions withthe use of adalimumab, etanercept andinfliximab. Despite the lack of information,

Tumor necrosis factor-alpha antagonists& serious skin reactions

Time to onset since first dose (days)

Skin reactions

Age

FDA reported that there was a time related relationship between the first dose orthe most recent dose of TNF-α antagonists and the time to onset of theskin reaction.

Table 1: Summary of demographics and characteristics of the seriousdermatological cases reported by US FDA

Infliximab Etanercept Adalimumab

Male 5 7 1

Female 16 14 6

Unknown - 1 -

Median 54 53 51

Range 27-70 (data provided 16-84 23-61for 20 patients)

Erythema15 13 4

multiforme (EM)

Stevens Johnson5 4 2

syndrome (SJS)

Toxic epidermal1 4 -

necrolysis (TEN)

SJS/TEN - 1 -

EM/SJS - - 1

Median 28 50 60

Range 4 days - 18 months 5 days - 52 months 6 days - 3 years(Data provided for11 patients)

Other 15 (71%) were on 15 (68%) were on 2 (29%) onmedications concomitant medications concomitant medications methotrexate

e.g. carbamazepine, e.g. aspirin, amoxicillin,diltiazem, frusemide/ celecoxib, ciprofloxacin,hydrochlorothiazide, diclofenac, etoricoxib,leflunomide, methotrexate, ethinyl estradiol/mercaptopurine, levonorgestrol, flurbiprofen,meloxicam, naproxen, hydroxychloroquine,rofecoxib, sulfasalazine, methotrexate, indapamide,sertraline isoniazid, lamotrigine,

meloxicam, naproxen,rofecoxib, sulfasalazine,terbinafine, venlafaxine,warfarin

Actions taken in the USThe US product label for infliximab has been updated to include these post-marketingfindings of serious skin adverse drug reactions. The FDA is currently reviewing whetherthere is a need to revise the product labels for etanercept and adalimumab and will continueto monitor the situation through their MedWatch program. Healthcare professionals andpatients have been advised to maintain vigilance for such skin reactions associated withthe use of adalimumab, etanercept and infliximab.

Local findings and regulatory actionsIn Singapore, the local package insert of infliximab has been updated to reflect these recentpost-marketing findings of serious skin reactions. HSA is currently reviewing the packageinserts of the other two TNF-α antagonists.

HSA has not received any local reports of serious skin-related adverse drug reactionsassociated with the use of TNF-α antagonists. Healthcare professionals are encouragedto report any suspected adverse drug reactions associated with TNF-α antagonists to HSA.

Reference1. FDA Drug Safety Newsletter. Winter 2008.

3July 2008 Vol.10 No.2 Adverse Drug Reaction News

T he findings of theBlood ConservationUsing Antifibrinolytics

Randomized Trial (BART)that compared the use ofaprotinin against lysineanalogues, tranexamic acidand aminocaproic acid,conducted by the OttawaHealth Institute in Canadaon 2,331 high risk cardiacsurgery patients fromAugust 2002 to October2007 was recently publishedin the New England Journalof Medicine.1 In this study, 781 patients were administeredaprotinin, 770 were given tranexamic acid and 780 patientswere given aminocaproic acid. The study was terminated earlyupon the recommendation of the independent data and safetymonitoring committee in October 2007 due to the interimdata suggesting a strong trend toward higher mortality in theaprotinin group compared with the tranexamic acid and theaminocaproic acid groups.

Results of the BART trialThe findings of the BART trial revealed that high-risk cardiacsurgery patients using aprotinin had fewer incidents of massivebleeding as defined by the investigators but had a higher 30-daymortality when compared with the other patients given tranexamicacid or aminocaproic acid. These trends were not statisticallysignificant (see Table 1). In the aprotinin group, 74 (9.5%) patientsexperienced massive bleeding, as compared to 93 (12.1%) patientsin the tranexamic acid group and 94 (12.1%) in the aminocaproicacid group (relative risk of aprotinin for both comparisons was 0.79;95% CI, 0.59 to 1.05). The 30-day mortality rate from any cause forpatients on aprotinin was 6%, which were 2% points higher thanthe 3.9% among the patients on tranexamic acid (relative risk, 1.55;95% CI, 0.99 to 2.42) or 4% among patients on aminocaproic acid(relative risk, 1.52; 95% CI, 0.98 to 2.36). In a post hoc analysisthat combined the groups receiving tranexamic acid andaminocaproic acid, the relative increase in the percent of deaths inthe aprotinin group was 53% compared with the other groupscombined (relative risk, 1.53; 95% CI, 1.06 to 2.22). The use ofaprotinin was associated with a higher risk of death from acardiac cause when compared to both tranexamic acid andaminocaproic acid groups combined (relative risk, 2.19; 95% CI,1.25 to 3.84). The number of deaths due to a cardiac causetotaled 25 (3.2%) in the aprotinin group as compared to 10(1.3%) cases recorded in the tranexamic acid (relative risk, 2.47;95% CI, 1.19 to 5.10) and 13 (1.7%) cases in the aminocaproicacid (relative risk, 1.93; 95% CI 0.99 to 3.74) groups respectively.

Table1: Risks of bleeding and deaths in BART

Study Aprotinin vs. Aprotinin vs.outcomes tranexamic acid aminocaproic acid

30 day 1.55 1.52mortality (95% CI, 0.99 - 2.42) (95% CI, 0.98 - 2.36)

Massive 0.79 0.79bleeding (95% CI, 0.59 - 1.05) (95% CI, 0.59 - 1.05)

Death due to 2.47 1.93cardiac causes (95% CI, 1.19 - 5.10) (95% CI, 0.99 - 3.74)

Update on aprotinin (Trasylol®)

The study, however, noted that the use ofaprotinin did not significantly increasethe risk of renal failure or the need forpostoperative renal replacements despitean increase in the proportion of patientswho were experiencing a doubling of theirserum creatinine levels.

The invest igators of the BART tr ia lconcluded that, although aprotinin ispotentially more effective in controllinghaemostasis than other agents, their resultsfrom this trial only noted a possible trendsuggesting aprotinin may decrease massivebleeding. The authors also noted that onlyrepeat surgeries and important blood losses

through chest tubes, one of the main indications for surgery,were potentially improved with the use of aprotinin. Aprotinindid not appear to prevent massive bleeding or save the lives ofpatients who had massive bleeding.

International regulatory actionsThe UK Medicines and Healthcare products RegulatoryAgency has suspended the marketing authorization of aprotininin the UK on 7 December 2007, pending the outcome of afull Europe-wide review of the balance of the risks and benefitsof aprotinin.

Currently, a limited access route has been established in Australia,Canada and the US, as well as several other countries, for patientsundergoing coronary artery bypass graft (CABG) surgeryrequiring cardiopulmonary bypass who are at increased risk ofblood loss and transfusion and who may still require aprotinin.In such cases, when the benefits of aprotinin use outweigh therisks, the patients are able to obtain aprotinin through limitedaccess e.g. Australia’s Special Access Scheme or Canada’s limitedaccess program. In the US, a limited access protocol has beenagreed to with the US Food and Drug Administration (FDA),in which aprotinin treatment is limited to patients undergoingCABG surgery requiring cardiopulmonary bypass who are atincreased risk of blood loss and transfusion and who do nothave any acceptable alternative therapies.2 In the meantime,the Australian Therapeutic Goods Administration, FDA and HealthCanada are conducting their safety reviews on aprotinin beforetaking any further regulatory actions.

Local regulatory actionsHSA temporarily suspended the sales of aprotinin in Singaporein November 2007 following the earlier findings of BART. As aninterim measure, the supply of aprotinin is made available locallythrough a restricted access programme. Aprotinin is available toa small group of patients, for whom their physicians havedetermined that the benefits of aprotinin may outweigh the risksassociated with its use. Physicians are reminded that they arerequired to discuss the risks associated with the use of aprotininand obtain written consent from the patient or the next of kinshould the patient be incapable or incompetent of doing sobefore prescribing aprotinin.

In the meanwhile, HSA is reviewing the recent findings of theBART trial and will be monitoring the situation closely both locallyand internationally to decide whether further regulatory actionsare needed to safeguard the use of this product locally.

References1. N Engl J Med. 2008 May 14;358(22):2319-2331.2. http://www.fda.gov/bbs/topics/NEWS/2008/NEW01834.html

4 Adverse Drug Reaction News July 2008 Vol.10 No.2

HSA would like to bring the attention of healthcareprofessionals to a study recently published (online aheadof print) in the Journal of Clinical Psychiatry1 to raise

awareness of rare but potentially lethal clozapine-inducedgastrointestinal hypomotility (CIGH).

Although the adverse reaction of constipation with clozapine isnot a new safety signal and there have been publications aboutthis since the 1990s, CIGH is not readily distinguishable leading toits under-recognition.

Details of studyThe electronic adverse drug reactions database of the TherapeuticGoods Administration, Australia and the New Zealand IntensiveMedicines Monitoring Program (IMMP), which cited clozapine-related gastrointestinal side effects were analysed. In addition,databases like PsycINFO, MEDLINE and EMBASE were searchedusing relevant key words.

A total of 102 cases were identified for analysis; 66.7% of thepatients were male and the age reported for 96 of the patientsranged from 17 to 73 years, with a median of 42 years. Of these102 patients, 28 patients died, 42 recovered and the outcome was

Clozapine-induced gastrointestinal hypomotility

T he UK Medicines and Healthcare products Regulatory Agencyand the US Food and Drug Administration (FDA) have recentlyrequested the companies marketing desmopressin products

in their respective countries to remove the indication for thetreatment of primary noctural enuresis (PNE) from all their nasalpreparations. This was due to concerns of a higher incidence ofhyponatraemia reported with desmopressin nasal preparationscompared to oral preparations when used for the treatment ofprimary nocturnal enuresis.

BackgroundDesmopressin is a synthetic analogue of 8-arginine vasopressin(ADH), a natural pituitary hormone that prevents excessive waterloss in the urine. It is indicated for the treatment of central diabetesinsipidus; polyuria and polydipsia following hypophysectomy orsurgery in the hypophyseal area; primary nocturnal enuresis (PNE)from the age of 5 years; and for the diagnosis of diabetes insipidus.

Desmopressin has increased antidiuretic activity and prolongedduration of action compared with the natural peptide. In thepresence of an inappropriate fluid intake, the sustained decreasein urine output and decrease in urine osmolality can causehyponatraemia, water intoxication and convulsions.

Withdrawal of indication of primary nocturnalenuresis for desmopressin nasal preparations

Post-marketing adverse reportsFDA reviewed 61 post-marketing cases of hyponatraemic-relatedseizures associated with the use of desmopressin. Fifty-five casesreported sodium levels ranging from 104 to 130mEq/L during theseizure event. Of these cases, two died. Both patients experiencedhyponatraemia and seizures but the direct contribution ofdesmopressin to the deaths was unclear. Thirty-six cases wereassociated with intranasal formulations, of which 25 cases occurredin paediatric patients (<17 years old). The most commonly reportedindication of use in these 25 paediatric cases was nocturnalenuresis. Thirty-nine of the 61 cases were associated with at leastone concomitant drug or disease that was also associated withhyponatraemia and/or seizures.

In addition to the removal of the indication of PNE for nasaldesmopressin preparations, FDA also requested that themanufacturers update the prescribing information of desmopressinproducts to include important new safety information about severehyponatraemia and seizures. Recommendations included thatdesmopressin nasal preparations should not be used inhyponatraemic patients or patients with a history of hyponatraemia;treatment with desmopressin tablets should be interrupted duringepisodes of fluid and/or electrolyte imbalance, such as fever,recurrent vomiting or diarrhoea, vigorous exercise or otherconditions associated with increased water consumption; fluidintake should be restricted one hour before to eight hours afteradministration of desmopressin tablets. FDA also recommendedthat all desmopressin preparations should be used cautiously inpatients at risk for water intoxication with hyponatraemia.

Local actionsTo date, HSA has not received any local adverse drug reactions ofhyponatraemia associated with desmopressin nasal preparations.

In line with the regulatory actions taken internationally, United ItalianTrading which markets Minirin® has also sought approval from HSAto remove the approved licensed indication of PNE from its nasalpreparation in Singapore. HSA will also be working with themanufacturers of the other brands of desmopressin (namelyOctostim® and Presinex®) to ensure the prescribing information isupdated to highlight this safety information.

unknown in 32 cases. From the review, the dose of clozapine wasknown for 92 patients, with a range of 12 to 1000mg/day (meanof 428mg/day). The doses were noted to be higher among thefatal cases at 250 – 900mg/day (mean of 535mg/day).

The treatment duration with clozapine prior to onset of symptomsranged from 3 days to 15 years with 20% of patients developingserious CIGH within the first month of treatment, 36.3% within thefirst 4 months, and just over 50% occurred within the first year oftreatment. The mortality rate was found to be at 27.5% withconsiderable morbidity mainly due to bowel resection. Probablerisk factors for CIGH were identified as new to clozapine therapy,higher doses of clozapine, co-prescription with other anticholinergicmedication, concomitant medical illness, fever, and medicationssuch as cytochrome P450 enzyme inhibitors which may inhibitmetabolism of clozapine, thus increasing its serum concentration.History of bowel surgery, constipation or gastrointestinal pathologymay also contribute to the risk of developing CIGH.

PathophysiologyThe paper postulated three main mechanisms whereby CIGH canhave a fatal outcome:

continued on Page 5

5July 2008 Vol.10 No.2 Adverse Drug Reaction News

T hree phosphodiesterase type 5 (PDE5) inhibitors are currently registered inSingapore - sildenafil (Viagra® and Revatio®, Pfizer), tadalafil (Cialis®, Eli Lilly)and vardenafil (Levitra®, Bayer). Viagra®, Cialis® and Levitra® are all indicated

for the treatment of erectile dysfunction (ED) while Revatio® is indicated for thetreatment of pulmonary arterial hypertension (PAH).

PDE5 inhibitors work to block the type 5-mediated catabolism of cyclic guanosinemonophosphate (cGMP), allowing the build up of cGMP, which causes smooth musclerelaxation. Smooth muscle relaxation in the penile vasculature and pulmonary arteriesis responsible for the PDE5 inhibitor effects seen in ED and PAH, respectively.

Post-marketing reportsRecently, the US Food and Drug Administration (FDA) warned of a reasonably plausibletemporal relationship of sudden sensorineural hearing loss (SSHL) with the use ofsildenafil, tadalafil and vardenafil. This warning was based on 29 post-marketing casesthat occurred with patients on sildenafil, tadalafil and vardenafil. Of these 29 reports,sildenafil accounted for 19 of these cases, while vardenafil and tadalafil each accountedfor five of them. In approximately one-third of the cases, the hearing loss was temporary,with majority of the cases reporting onset of SSHL within 24 hours of PDE5 inhibitorsuse. In some reports, the sudden loss or decrease in hearing was accompanied byvestibular symptoms such as tinnitus, vertigo, and dizziness.

Mechanism of SSHLAccording to the National Institute on Deafness and Other Communication Disorders(NIDCD), SSHL, more commonly known as “sudden deafness”, is a rapid loss of hearing

that can occur all at once or over a periodof up to three days. The mechanismbehind how PDE5 inhibitors may beassociated with SSHL remains unclear.There is not enough information todetermine whether any specific type ofpatient is at increased risk for this possibleadverse effect. In addition, it is uncertainwhether these events are caused bymedication use, underlying medicalconditions, or a combination of both orother factors.

Regulatory actions by FDAFollowing FDA’s warning, the productlabel for this class of drugs was revised toreflect this information and guidance wasalso provided in the label for patients whoexperience sudden hearing loss.

Local situationHSA has not received any adverse drugreaction reports pertaining to hearing lossassociated with the use of PDE5 inhibitors.However, physic ians who prescr ibeViagra®, Levitra® or Cialis® for ED areencouraged to advise their patients toimmediately stop taking the drug if theyexperience any sudden decrease inhearing and to seek prompt medicalattention.

Physic ians should also advise theirpatients with PAH, who experience asudden decrease or loss of hearing whiletaking Revatio® to seek prompt medicalattention. In addition, these patientsshould be told not to discontinue themedication without consult ing theirphysic ian about other treatmentoptions as PAH can be a life-threateningcondition.

Both the local package inserts of Viagra®and Revatio® have recently been updatedto reflect the warning on hearing loss. Thepackage insert of Levitra® is in the processof being updated with this safety warning.Healthcare professionals are encouragedto report suspected PDE5 inhibitors relatedadverse events to the PharmacovigilanceUnit of HSA.

References1. FDA Drug Safety Newsletter,

Vol.1 No.2, 2008.http://www.fda.gov/cder/dsn/default.htm

2. National Institute on Deafness andOther Communication disorders:Sudden Deafness.http://www.nidcd.nih.gov/health/hearing/sudden.htm

3. Information for Healthcare Professionals:Sildenafil, vardenafil & tadalafil.http://www.fda.gov/cder/drug/InfoSheets/HCP/ED_HCP.htm

PDE5 inhibitorsassociated sensorineural hearing loss

i) Untreated bowel obstruction/pseudo-obstruction leading to distension,necrosis, perforation, or sepsis.

ii) Aspiration from inhalation of feculentvomitus or dysphagia.

iii) Faecal stasis leading to infection.

Conclusion of studyEven though it is known that clozapine canaffect the entire digestive system causingoesophageal to rectal hypomotility, theauthors emphasized the need to preventand manage CIGH-related constipation asit can result in bowel obstruction, ischaemiaand necrosis, perforation, and aspirationpneumonia.

Suggestions for prevention include:

Take gastrointestinal history and performabdominal examination

Treat pre-existing constipation beforestarting clozapine treatment

Inform patients about the risks ofconstipation and provide them withinformation regarding diet, fluid intake,and exercise

Avoid prescribing concomitant medicineswhich may cause constipationRegular screening for change in bowelhabit during the first four months oftreatment which is thought to be thehigher-risk period

Local situationThere are three brands of clozapineregistered in Singapore – Clozaril®(Novartis), Clozapine® (Delfi), ClozapinHexal® (Novem Healthcare), and theyare indicated for the managementof treatment-resistant schizophrenia.The package inserts of all three productscarry precautionary warnings ofconstipation and paralytic ileus, withClozaril® and Clozapin Hexal® mentioningthe association of clozapine with intestinalobstruction and faecal impaction, whichon rare occasions have proven fatal.

HSA has not received any local reportpertaining to clozapine and impairment ofintestinal peristalsis.

Reference1. J Clin Psychiatry. 2008 April 29;e1-e10

continued from Page 4 Clozapine-induced gastrointestinal hypomotility

6 Adverse Drug Reaction News July 2008 Vol.10 No.2

T here are currently two types of mycophenolatepreparations available in Singapore ⎯mycophenolate mofetil (MMF) (Cellcept®,

Roche) and mycophenolic acid (MPA) as sodium salt(Myfortic®, Novartis). MMF is approved for use incombination with ciclosporin and corticosteroids forthe prophylaxis of acute transplant rejection in adultsreceiving allogenic renal, cardiac or hepatic transplantswhile MPA is approved for use in combination withciclosporin microemulsion and corticosteroids for theprophylaxis of acute transplant rejection in patientsreceiving allogenic renal transplants.

A) Teratogenic risks associated withmycophenolate group of drugsBased on the publication by Sifontis et al1, post-marketingdata from the US National Transplant Pregnancy Registry(NTPR), and MMF worldwide adverse event reporting,use of MMF during pregnancy is associated with an increased riskof first trimester pregnancy loss and an increased risk of congenitalmalformations. External ear and other facial abnormalities includingcleft lip and palate, and anomalies of the distal limbs, heart,oesophagus, and kidney were the main congenital malformationsobserved.

In December 2006, the NTPR published data about the pregnancyoutcomes of 24 female transplant patients exposed to MMF-containing regimens. A total of 33 pregnancies were reported bythese patients to the registry, of which there were 15 spontaneousabortions (45%). Of the 18 live-born infants, four had structuralmalformations (22%). Three of the four of these structuralmalformations include microtia.2

In post-marketing data collected worldwide from 1995 to 2007,of the 77 women exposed to systemic MMF during pregnancy,25 had spontaneous abortions and 14 had a malformed infant orfoetus. Six of these 14 malformed offsprings had ear abnormalities.As these post-marketing data were reported voluntarily, it was notalways possible to reliably estimate the frequency of any particularadverse outcomes.

Similar structural malformations have been observed in preclinicalanimal reproductive toxicology studies.

B) Post-marketing reports of progressive multifocalleukoencephalopathyThe US Food and Drug Administration recently issued aclass-label request to all US manufacturers of marketedmycophenolate group of drugs with respect to the risk ofprogressive multifocal leukoencephalopathy (PML).

Background information on PMLPML is a rare, progressive, demyelinating disease of the centralnervous system (CNS) that usually leads to death or severe disability.3

PML is caused by the reactivation of the JC virus, a polyomavirusthat resides in latent form in 70%-90% of the adult populationworldwide. JC virus usually remains latent, typically only causingPML in immunocompromised patients. The factors leading toactivation of the latent infection are not fully understood althoughabnormalities in T-cells have been described as important forreactivation of JC virus and PML. Patients usually present with focalCNS abnormalities and radiographic evidence of white matterdisease without mass effect.

Updates on the mycophenolate group of drugs

PML cases reported with mycophenolate groupof drugsPML has been described in transplant patients involving differentimmunosuppressant medicines. Seventy-five percent of all the PMLcases reported in transplant recipients presented subacutely:haemiparesis, apathy, confusion, cognitive deficiencies, and ataxiawere the most frequently presented features. Roche has confirmedthat in the Roche worldwide adverse event reporting system, thereare currently 17 cases of PML that are potentially associated withMMF. To date, Novartis’ global safety database for MPA has no casesof PML.

ConclusionIn view that MMF is converted to MPA following oral or intravenousadministration, both drugs would be deemed to carry the samepotential risks for teratogenicity and PML.

The local package inserts of Cellcept® and Myfortic® have beenamended to include the updated safety information onteratogenic risks and PML associated with the use of theseproducts. Roche and Norvartis have separately issued DearHealthcare Professional Letters to alert healthcare professionalsabout the labelling update regarding the teratogenic risks withCellcept®. The letters also reiterated that these drugs are notrecommended in pregnancy unless the benefit outweighs thepotential risk to the foetus.

Roche has updated the local Cellcept® package inserts withinformation on PML and issued a Dear Healthcare ProfessionalLetter to provide more information about this matter.The product insert of Myfortic® is in the process of beingupdated with safety information on PML. Healthcareprofessionals are advised to consider PML in the differentialdiagnosis of any transplant recipient who develops neurologicalsymptoms. Consideration should also be given to reducing theamount of immunosuppression if a patient develops PMLwhilst balancing against the possible risk of graft rejection.

References1. Transplantation Dec 2006;82:1698-17022. FDA Information for Healthcare Professionals.

http://www.fda.gov/cder/drug/InfoSheets/HCP/mycophelolateHCP.htm

3. Communication About an Ongoing Safety Review ofCellCept and Myfortic.http://www.fda.gov/cder/drug/early_comm/mycophenolate.htm

7July 2008 Vol.10 No.2 Adverse Drug Reaction News

Abacavir (Ziagen®, GSK) Special warning: Carriage ofHLA-B*5701 allele is associated with increased risk ofhypersensitivity to abacavir. Screening for allele carriershould be performed in all HIV-infected patients beforeinitiating treatment. Not to be used in patients carryingHLA-B*5701 allele. Non-carriers can still develop a severeor fatal hypersensitivity reaction.

Activated charcoal (Charcodote®, IDS) Interaction: Notfor diabetics unless recommended by a physician.

Atovaquone, proguanil (Malarone®, GSK) Interaction:Proguanil may potentiate the anticoagulant effect ofall coumarin based anticoagulants. ADRs: Vasculitis& cholestasis.

Budesonide (Pulmicort®, AstraZeneca) Specialwarnings: Caution in patients with risk of impaired adrenalfunction, severely compromised liver function, requiringhigh dose emergency corticosteroid therapy, on prolongedtreatment at the highest recommended dose orpatients on concomitant CYP3A-metabolised medication.Consider additional systemic glucocorticosteroid coverfor these patients during stress, severe asthma attack orelective surgery. Patients may suffer from lassitude &depression when switching from oral corticosteroid toPulmicort®. Interaction: Itraconazole increases systemicexposure to budesonide. ADRs: Cataracts & glaucoma.

Cefoperazone (Cefobid®, Pfizer) Special warnings:Monitor for organ system dysfunction (renal, hepatic &haematopoietic) during extended therapy with Cefobid®particularly in neonates & infants. Clostridium difficileassociated diarrhea (CDAD) reported, occurring overtwo months after administration & ranging from milddiarrhoea to fatal colitis.

Darunavir (Prezista®, J&J) Special warnings: A historyof sulphonamide allergy was not shown (in clinical studies)to be related to incidence and severity of rash. Caution insevere hepatic impairment. Interactions: 1) Medicinalproducts that affect CYP3A activity may affect the clearance& plasma concentrations of darunavir. 2) Digoxin& pravastatin - titrate digoxin & pravastatin from thelowest dose upwards; 3) Carbamazepine (CBZ) - reduceCBZ 25% to 50% & observe for CBZ-related side effects;4) Methadone - monitor patient during maintenancetherapy; 5) Ethinylestradiol & norethindrone - considernon-hormonal contraceptives when using hormonalcontraceptive; 6) Rifabutin - reduce dose of rifabutinby 75% of usual dose of 300mg/day & increasemonitoring for rifabutin-related adverse events.

Deferasirox (Exjade®, Novartis) Special warnings:1) Elevations of transaminases (>10x ULN) is suggestive ofhepatitis. Reports of hepatic failure mostly involved thosewith significant co-morbidities including liver cirrhosis &multi-organ failure; some with fatal outcomes; 2) Upper GIulceration & haemorrhage (also in children & adolescents).Caution when in combination with anticoagulants;3) Inappropriately high doses given in patients with a lowiron burden or with slightly elevated serum ferritin levelsmay increase toxicity of Exjade®. Interactions: CYP3A4substrates e.g. ciclosporin, simvastatin, hormonalcontraceptive agents. A decrease of midazolam exposureby 17% observed. Increased risk of GI irritation withNSAIDs & corticosteroids. ADRs: Optic neuritis, oesophagitis,renal tubulopathy (Fanconi’s syndrome), hepatic failure.

Desferrioxamine (Desferal®, Novartis) Specialwarning: Rare cases (some fatal) of mucormycosisreported. ADR: Lung infiltration.

Diclofenac (Voltaren® emulgel, Novartis)Contraindications: Hypersensitivity to diclofenac usuallymanifests as asthma, respiratory problems, rashes,urticaria, swelling of the face & tongue, runny nose.Special precautions: Avoid application of gel for longperiods of time over large areas of skin. ADRs: Serious skinrash with blisters, urticaria, wheezing, shortness ofbreath, asthma, swelling of the face, lips, tongue & throat.

Domperidone (Motilium®, J&J) ADRs: Anaphylacticshock, angioneurotic oedema, agitation, nervousness,convulsion, somnolence, headache, pruritus, rash,abnormal liver function test. Very rare: Convulsion, agitation,somnolence (primarily reported in infants & children).

Epoprostenol (Flolan®, GSK) Warning: Increased riskfor haemorrhagic complications particularly for patientswith other risk factors for bleeding. Interaction: Patients ondigoxin may show transient elevations of digoxinconcentrations after initiation of therapy with Flolan®,may be clinically significant in patients prone to digoxintoxicity. ADR: Bleeding at various sites.

Estradiol (Estrofem®, Novo Nordisk) Special warning:Safety of added progestagens have not been studied forestradiol doses >2mg. ADRs: Venous thromboembolism,oestrogen-dependent neoplasms.

Estradiol, cyproterone (Climen®, Schering) Specialwarning: In women with hereditary angioedema,exogenous estrogens may induce or exacerbatesymptoms of angioedema. ADRs: Erythema nodosum,urticaria, hirsutism, acne.

Estradiol, dydrogesterone (Femoston®, SolvayPharma) Contraindications: Known or suspectedestrogen-dependent malignant tumours (e.g. endometrialcancer), undiagnosed genital bleeding, untreatedendometrial hyperplasia, angina, myocardial infarction,porphyria, known or suspected pregnancy innon-postmenopausal women.

Warnings & special precautions in patients with: 1) risk factorsfor estrogen dependent tumours, cholelithiasis or a historyof endometrial hyperplasia; 2) deterioration in liver function;3) fluid retention & cardiac/renal dysfunction; 4) terminalrenal insufficiency; 5) pre-existing hypertriglyceridemiain women; 6) rare hereditary problems of galactoseintolerance, the Lapp lactase deficiency or glucose-galactose malabsorption; 7) perimenopausal phase.Circulating total thyroid hormone also increased.

Interactions: Phenobarbital, rifabutin, ritonavir, nelfinavir,St. John’s Wort. ADRs: Breast pain, pelvic pain, estrogendependent neoplasms e.g. endometrial cancer,nervousness, venous thromboembolism, gall bladderdisease, back pain, alterations in liver function,haemolytic anaemia, myocardial infarction, stroke,vascular purpura, angioedema, probable dementia.

Gestodene, ethinyl estradiol (Minulet®, Wyeth)Contraindications: Hereditary or acquired thrombophilias,headache with focal neurological symptoms such as aura,undiagnosed vaginal bleeding. Special warnings:Discontinue four weeks prior to & for two weeks afterelective surgery with increased risk of thrombosis. Mayincrease the risk of transient ischaemic attack. Precaution:Minority of women will have adverse lipid changes whiletaking OCs. Consider nonhormonal contraception inwomen with uncontrolled dyslipidaemias. Elevations ofplasma triglycerides may lead to other complicationsbesides pancreatitis. Interaction: Ethinyl estradiol mayinduce hepatic drug conjugation & plasma/tissueconcentrations of lamotrigine may be decreased.ADRs: Hepatic adenomas, hepatocellular carcinomas.

Heparin (DBL Heparin®, Hospira) Precaution: Heparin-induced thrombocytopenia (HIT) & heparin-inducedthrombocytopenia & thrombosis (HITT) can occur up toseveral weeks after discontinuation of heparin therapy.Patients presenting with thrombocytopenia orthrombosis after discontinuation of heparin should beevaluated for HIT & HITT.

Iodixanol (Visipaque®, GE healthcare) & Iohexol(Omnipaque®, GE healthcare) Special warning:No evidence that haemodialysis protects patients withimpaired renal function from contrast media inducednephropathy. Patients on haemodialysis may receiveVisipaque® for radiological procedures. ADRs: Dyspnoea,non-cardiogenic pulmonary oedema, cough.

Itraconazole (Sporanox®, J&J) Contraindication:Concurrent use with quinidine. Special warning: Transientor permanent hearing loss reported. Hearing loss usuallyresolves when treatment is stopped, but can persist insome. Interaction: Fluticasone - monitor side effect & reducedose if necessary.

Lamotrigine (Lamictal®, GSK) Warnings & precautions:Patients with epilepsy have an elevated risk for suicidality.Patients with a history of suicidal behaviour or thoughts,young adults, & those patients exhibiting a significantdegree of suicidal ideation prior to commencement oftreatment, may be at a greater risk of suicidal thoughtsor suicide attempts, & should receive careful monitoringduring treatment. Interactions: Lopinavir/ritonavir.

Lapatinib (Tykerb®, GSK) Precaution: Hepatotoxicityhas occurred (rarely severe). Monitor liver functionbefore initiation of treatment & monthly thereafter.Discontinue therapy if changes in liver function aresevere & patients should not be retreated.

Lidocaine (Xylocaine® inj, AstraZeneca) Precautions:Treat hypotension due to epidural anaesthesia promptlywith IV sympathomimetic & repeated as necessary.Xylocaine® injection is probably porphyrinogenic.ADRs: CV toxicity is generally preceded by signs ofCNS toxicity, unless the patient is receiving generalanaesthetics or is heavily sedated with drugs such as abenzodiazepine or barbiturate. In children, early signs oflocal anaesthetic toxicity may be difficult to detect in caseswhere the block is given during general anaesthesia.

Meropenem (Meronem®, AstraZeneca) Specialwarning: May reduce serum valproic acid levels leadingto subtherapeutic levels. ADR: Haemolytic anaemia.

Mycophenolate mofetil (Cellcept®, Roche) Warnings& precautions: Progressive multifocal leukoencephalopathy(sometimes fatal) reported. Interaction: Ciclosporin,rifampicin, combination of norfloxacin & metronidazole,sevelamer. ADRs: Decrease in renal function, elevated serumcreatinine, metabolic or respiratory acidosis, elevated LFTs,actinic keratosis, elevated PTH, congenital ear malformations.

Olanzapine (Zyprexa®, Eli Lilly) Special warnings:Undesirable alterations in lipids, hepatitis, cholestatic ormixed liver injury have been observed. ADRs: Fastingborderline to high total cholesterol/triglycerides/glucose,glycosuria, pulmonary embolism, deep vein thrombosis,hyperglycaemia, jaundice, alopecia, increased alkalinephosphatase, increased total bilirubin.

Phenytoin (Phenytoin® inj, Hospira) Interaction:Capecitabine or metabolite fluorouracil reported toincrease phenytoin plasma concentrations. Serum levelsof phenytoin above optimal range may produceencephalopathy, confusional states (delirium psychosis),or rarely irreversible cerebellar dysfunction.

Ropivacaine (Naropin®, AstraZeneca) Precautions:Naropin® is possibly porphyrinogenic. ADRs: Anaphylactoidreactions, angioneurotic oedema & urticaria. Total spinalblock may occur if an epidural dose is inadvertentlyadministered intrathecally, or if a too large intrathecaldose is administered. Bradycardia, headache, vomiting,urinary retention, hypoaesthesia, syncope, dyspnoea,hypothermia are more frequent after spinal anaesthesia.

Sodium polystyrene sulfonate (pms-Sodiumpolystyrene sulfonate®, IDS) Interactions: May bindwith magnesium or calcium found in nonsystemicantacids & laxatives, preventing neutralization ofbicarbonate ions & leading to systemic alkalosis thatmay be severe. Concurrent use not recommended.Risk may be less with rectal administration. May reducepotassium concentrations by replacing potassiumwith sodium & fluid retention may occur.

Sotalol (pms-Sotalol®, IDS) Precaution: If vagaldominance occurs during use of pms-Sotalol® withanaesthetic agents that depress the myocardium,it may be corrected with atropine. Interaction: Concomitantuse with calcium blocking drugs may lead to hypotension.ADRs: Colon problem, extremity/back/localized pain,perspiration, altered consciousness, appetite disorder,stroke, genitourinary disorder, infection, pulmonary/upper respiratory tract problem, asthma, weight change.

Sultamicillin (Unasyn®, Pfizer) Special warning:Clostridium difficile associated diarrhoea reported,ranging from mild diarrhea to fatal colitis, & may occur overtwo months after administration.

Sumatriptan (Imigran®, GSK) Warnings & precautions:Rare cases of patients with serotonin syndrome reportedfollowing use of selective serotonin reuptake inhibitors (SSRIs)& sumatriptan. Serotonin syndrome has also been reportedfollowing concomitant treatment with triptans & serotoninnoradrenaline reuptake inhibitors (SNRIs). Concomitantadministration of any triptan/5-HT1 agonist with sumatriptanis not recommended. Overuse of acute migraine treatmentshas been associated with the exacerbation of headache insusceptible patients & withdrawal of treatment may benecessary. ADRs: Sensory disturbance including paraesthesia& hypoaesthesia, dyspnoea, sensations of cold, angina.

Telbivudine (Sebivo®, Novartis) Special warning:Increased risk of developing peripheral neuropathyobserved with combination use of telbivudine & pegylatedinterferon alfa-2a. ADR: Peripheral neuropathy.

Zoledronic acid (Zometa®, Novartis) Do not mixwith calcium or other divalent cation-containinginfusion solutions, e.g. Lactated Ringer’s solution.ADRs: Anaphylactic reaction/shock, urticaria.

HSA has approved the followingpackage insert changes due tosafety updates from January 2008 to

May 2008. Please note that due to spaceconstraints, the list published is not exhaustiveand you are encouraged to refer to thefollowing website for the complete listingwith details: http://www.hsa.gov.sg/safetyinfo_and_recalls. Please also notethat there might be some lag time in theavailability of the package insert whichreflects the latest change(s).

14

15

16

17

18

20

21

221

23

4

5

6

7

89

10

11

12

13

Package insert amendments reflecting safety issues

19

23

24

25

26

27

28

29

30

31

32

8 Adverse Drug Reaction News July 2008 Vol.10 No.2

Editor-in-ChiefMs Chan Cheng Leng, BSc (Pharm) Hons

Executive EditorMs Ang Pei San, BSc (Pharm)

Editorial BoardClinical Prof. Goh Chee Leok

Prof. Edmund Lee Joo Deoon

Clinical Prof. Chng Hiok Hee

Clinical A/Prof. Gilbert Lau Kwang Fatt

Dr Lee Kheng Hock

Enquiries, comments andsuggestions to:Pharmacovigilance UnitCentre for Drug AdministrationHealth Products Regulation GroupHealth Sciences Authority

11 Biopolis Way, #11-03,Helios, Singapore 138667

Tel: (65) 6866 3538Fax: (65) 6478 9069Website: http://www.hsa.gov.sgEmail: HSA_drugsafety@hsa.gov.sg

The contents are not to be reproduced in partor in whole, without prior written approval fromthe editor. Whilst every effort is made incompiling the content of this publication, thepublishers, editors and authors accept no liabilitywhatsoever for the consequences of anyinaccurate or misleading data, opinions orstatements. The mention of any product by theauthors does not imply any official endorsementof the product by the Health Sciences Authority.

Copyright © 2008 Health Sciences Authority ofSingapore. All Rights Reserved.

Staff Editors

Mr Choong Chih Tzer, BPharm

Ms Christine Ho, BSc (Pharm) Hons

Dr Yvonne Koh, BSc (Pharm) Hons, PhD

Ms Adena Lim, BSc (Pharm) Hons, MPharm

Ms Belinda Tan, BSc (Pharm)

Ms Liesbet Tan, BSc (Pharm) Hons

Ms Tan Wei Chuen, BSc (Pharm)

V arenicline (Champix®, Pfizer), a partial nicotinicacetylcholine receptor agonist, is licensed as an aid tosmoking cessation treatment and was registered in

Singapore in August 2007.

Post-marketing neuropsychiatric adverse eventsSince the drug was approved in May 2006 in the United States,the US Food and Drug Administration (FDA) had received post-marketing adverse event reports describing serious neuropsychiatricsymptoms, which include changes in behaviour, agitation,depressed mood, suicidal ideation, and cases of attempted andcompleted suicide associated with the use of varenicline. FDA’spreliminary assessment of these adverse drug reaction reports (ADRs)revealed that in many of the cases, the neuropsychiatric symptomsoccurred within days to weeks after the initiation of vareniclinetherapy. However, the causal role of varenicline in these casesremained unclear as smoking cessation (with or without treatment)is associated with nicotine withdrawal symptoms and has beenlinked with the exacerbation of underlying psychiatric illness.Nevertheless, not all patients described in FDA’s cases had pre-existing psychiatric illness and not all had discontinued smoking.

Since the introduction of Champix® in Canada, Health Canadahas received a total of 226 cases of neuropsychiatric adverseevents over the period between April 2007 and April 2008.The types of reports include events of depressed mood,agitation, hostility, changes in behaviour, suicidal ideation andsuicide, as well as worsening of pre-existing psychiatric illnessregardless of whether it was previously diagnosed.

International regulatory actionsThe US FDA has recently included these serious post-marketingneuropsychiatric symptoms in the warnings and precautions sectionof varenicline’s prescribing information. Additionally, the FDA has

recently approved a patient medication guidedesigned to highlight important safety information topatients who are prescribed varenicline. Similarly,Health Canada has recently revised the CanadianProduct Monograph of varenicline to include thesepost-marketing neuropsychiatric adverse events.

In Europe, the European Medicines Agency hasreviewed the case reports of suicidal ideation orattempted suicide while taking varenicline and haverequested that the product information of Champix®to include warnings of behavioural changes noted inpost-marketing reports.

HSA’s advisoryChampix® was recently launched locally in April 2008and HSA has not received any local adversereaction reports. In view of the nature of adverse

events observed overseas, prescribers are advised to carefullyassess patients’ suitability (e.g. medical history, lifestyle, occupation)for treatment with Champix® before prescribing this medicationto them.

As a risk management strategy to enhance the safe use ofChampix®, HSA is working with Pfizer (Singapore) to develop apatient medication guide for patients taking the medicationwith the aim of providing information on possible adverse reactionsassociated its use so that patients can identify these reactions andseek medical help if they experience these effects. In line with thisrisk management strategy, prescribers are strongly encouraged todiscuss the potential neuropsychiatric adverse effects associated withChampix® or smoking cessation with their patients.

HSA continues to monitor the overseas and local situation closelyand requests that healthcare professionals report any adversereactions suspected to be associated with Champix® to thePharmacovigilance Unit.

References1. JAMA 2006 Jul;296(1):56-63.

(varenicline tartrate), 3 June 2008. http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2008/champix_hpc-cps eng.php

3. FDA Press Release: Early Communication About an Ongoing SafetyReview: Varenicline (marketed as Chantix), 20 November 2007.

4. FDA News: Early Communication About an Ongoing Safety ReviewVarenicline (marketed as Chantix), 1 February 2008.http://www.fda.gov/cder/drug/early_comm/varenicline.htm

5. FDA Public Health Advisory: Important Information onChantix (varenicline), 1 February 2008.http://www.fda.gov/cder/drug/advisory/varenicline.htm

6. FDA Alert: Information for Healthcare Professionals Varenicline(marketed as Chantix), 1 February 2008.http://www.fda.gov/cder/drug/infopage/varenicline/default.htm

Varenicline (Champix®) &neuropsychiatric adverse events

2. Health Canada’s Advisory to Healthcare Professionals on Champix®