ADR News Dec2008 Vol10 No3

These differences form the basis for c lass i f icat ion ofsulphonamide drugs (see Table 1 for details).

Fig 1. This shows the basic form of a sulphonamide antimicrobial. Besidesthe SO2–NH2 moiety, other important structures unique to thesulphonamide antibiotics and not found in non-antimicrobialsulphonamides are shown.

Fig 2. This is a selection of non-antimicrobial sulphonamides with theSO2–NH2 moiety labelled. It is clear that, besides the SO2–NH2 moiety,there is no resemblance with sulphonamide antimicrobials.

CONTENTS

ISSN: 0219 - 2152

December 2008Vol.10 No.3

Published by the Health Products Regulation Group, HSA and the HSA Pharmacovigilance Advisory Committee

1 Sulphur allergy – A common misnomerin ADR reporting

2 CPE accreditation of ADR NewsBulletin

3 Abacavir hypersensitivity reactionsassociated with HLA-B*5701 allele

4 Slimming health products (Relacore &Lami) adulterated with sibutramine

Sulphur Allergy – A common misnomer in ADR reporting

5 Fentanyl transdermal patch & overseasreports of fatality

6 Haemorrhagic or necrotizing pancreatitisassociated with Byetta®

6 Summary of advisories issued by HSA &pharmaceutical companies

7 Package insert amendments reflectingsafety issues

8 Biosimilar products

continued on Page 2

T he Pharmacovigilance Branch, HSA has received six seriousadverse drug reactions (ADR) reports and 246 non-seriousreports of patients who were labelled as being allergic

to sulphur over the period July 2007 to July 2008. Somepatients who have suffered hypersensitivity to sulphonamideantimicromials such as co-tr imoxazole may have beenlabelled as hypersensitive to sulphur. As there are importantdist inct ions between sulphonamide antimicrobials,sulphonamide non-antimicrobials, sulphites, sulphates andsulphur allergy, this article is intended to clarify this misnomerand to discourage the use of the term as it may be impreciseand misleading.

Differentiating sulphur compounds

I. Elemental sulphurSulphur is a natural element and exists in a yellow crystallineform. Elemental sulphur is usually not the allergenic agent andis mainly used as a precursor to other chemicals. In traditionalmedicine, sulphur has been used mainly as part of creams toalleviate various conditions such as psoriasis, eczema and acne.

II. Sulphur compoundsSulphates are commonly found in drugs, soaps and cosmetics.Examples of common sulphates include glucosamine sulphate,ferrous sulphate, heparin sulphate and sodium lauryl sulphate.

Sulphites are present as preservatives in food, beverages andpharmaceuticals. Examples of common sulphite preservativesare sodium sulphite (Na2SO3), sodium bisulphite (NaHSO3),and sodium metabisulphite (Na2S2O3).

Patients sensitive to sulphites frequently have underlyingallergic or asthmatic conditions. In rare cases, sulphites cancause anaphylaxis. However, these responses are mediated bydifferent mechanisms and different antigenic sites as thoseof sulphonamide antimicrobials making cross reactivity highlyunlikely.

III. SulphonamidesA sulphonamide is any compound with a SO2–NH2 moiety.Sulphonamide antimicrobials contain an aromatic amine(arylamine) at the N4 position and a five or six member heterocyclicring with one or more nitrogen at the sulphonamide N1 position.(see Fig. 1). Sulphonamide non-antimicrobials do not have bothcomponents.

8pp_ADR_News_Dec2008_Vol10_No3.p65 11/18/2008, 3:22 PM1

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

continued from Page 1 Sulphur allergy – A common misnomer in ADR reporting

References1. Medical Digest. Tan Tock Seng Hospital,

Oct-Dec 2001; 14-16.2. Ann Allergy Asthma Immunol 2008 Feb;

100(2):91-100; quiz 100-3, 111.3. Australian Prescriber Vol 31 No: 1 Feb 2008

http://www.australianprescriber.com/upload/pdf/articles/933.pdf

4. Pharmacotherapy 2004;24(7):857-70.5. Ann Pharmacother 2006 Jun;40(6):1040-6.6. Drug Safety 2001;24(4):239-47.7. N Eng J Med 2003; 349:1628-35.

Fig 3. Two sulphonamide antimicrobials and thecommon site that interacts with IgE antibodies.

All illustrations (Figs 1-3) are abstracted withpermission from Dr Leong KP’s article publishedin the Medical Digest: The Truth about SulphaDrug Allergy.1

Allergic mechanism and cross-reactivitybetween sulphonamide drugs

Sulphonamide antimicrobials are second onlyto the ß-lactams as the most common causeof drug allergy.2 Cross-allergenicity betweensulphonamide antimicrobials is possiblebased on their structural similarities.

Type I hypersensitivity reactions (immediate-type hypersensitivity) are IgE-mediated andcan manifest as urticaria, angioedema,bronchospasm and anaphylaxis. The N1heterocyclic ring moiety has been found tobe the epitope for these IgE antibodies.

Nearly all hypersensitivity responses tosulphonamide antimicrobials are not type Iand appear to be mediated by cytotoxicor immunogenic hydroxylamine andnitrosoamine metabolites involving the N4arylamine rather than by the sulphonamidemoiety itself. Examples of non-type 1hypersensitivity reactions are maculopapularrash, Stevens-Johnson Syndrome and

toxic epidermal necrolysis (TEN). The oxidative formation of these metabolites occursby means of the cytochrome P450 system. These reactive metabolites act by formingimmunogenic structures for antibodies or T cells and also by direct cytotoxicity tolymphocytes and other immune cells.3

Although non-antimicrobial sulphonamides have the potential to cause allergicreactions, the predominance of scientific evidence suggests that cross-reactivity withantimicrobial sulphonamides is unlikely. However, patients with sulphonamideantimicrobial allergies may develop subsequent allergies to a sulphonamide non-antimicrobial. This association appears to be due to a predisposition of such patientsto allergic reactions rather than to cross- reactivity with sulphonamide antimicrobial.7

Conclusion

Accurate reporting of ADRs is crucial in themanagement of allergies. Being labelled asallergic to sulphur often creates confusionfor both the patient and the attendinghealthcare professional. The term ‘sulphurallergy’ should thus be avoided. Instead,the specific drug name should beidentified.

T he editorial team of the HSAAdverse Drug Reactions (ADR)News Bulletin is pleased to

announce that the S ingaporePharmacy Council has approved theinclusion of the news bulletin tothe l i s t o f pub l i ca t ions whichpharmacists can read to obtain theirContinuing Professional Education(CPE) points.

Pharmac i s t s can app ly fo r onepat ient -care CPE po in t undercategory 3A for reading each issueof the news bulletin. The CPE pointscan be logged in via the SingaporePharmacy Counc i l webs i te a thttp://www.spc.gov.sg

Continuing Professional Education (CPE) accreditationof the HSA ADR News Bulletin for pharmacists

More about the bulletinThe HSA ADR News Bulletin, producedthree times a year, was first publishedin 1999 and is now in its tenth year ofpublication. The main objectives of thebulletin are to increase awareness ofadverse drug reactions (ADRs) amonghealthcare profess ionals and topromote ADR reporting. Additionally,the bul let in also covers currenttopics of relevance to healthcareprofessionals such as safety concernsthat have significant impact on clinicalpractice, new safety information,emerging safety concerns, productwithdrawals and suspensions,and safety-related package insertamendments.

Table 1Drug groups Cross-reactivity with

(and examples of drugs in these groups) sulphonamide antimicrobial

1. Aromatic amidesa. Sulphonamide antimicrobials: Cross-reactivity within this group is

sulphadiazine, sulphamethoxazole, likely based on structural similaritiessulphisoxazole

b. Sulphonamide antivirals: amprenavir,fosamprenavir

2. Nonaromatic amidesa. Diuretics: hydrochlorothiazide, Based on current information, there is

chlorthiazide, furosemide, bumetanide lack of documentation for cross-reactivityb. Sulphonylureas: chlorpropamide, between the two drug groups,

tolbutamide, glibenclamide, glipizide i.e. aromatic amides and nonaromatic

c. Carbonic anhydrase inhibitors : amides. Allergies when they do occur

acetazolamide appears to be due to a predisposition

d. COX-2 selective inhibitors: celecoxib of the patient to allergic reactions ratherthan cross-reactivity between thesetwo groups of drugs


3December 2008 Vol.10 No.3 Adverse Drug Reaction News

Abacavir hypersensitivity reactions associatedwith HLA-B*5701 allele

Abacavir is a nucleoside reverse

transcriptase inhibitor (NRTI)

used in the treatment of

infect ion caused by the human

immunodeficiency virus (HIV). There are

two licensed products carrying abacavir

namely Ziagen® (GlaxoSmithKl ine),

which contains abacavir only and

Kivexa® (GlaxoSmithKl ine) which

contains a combination of abacavir

and lamivudine.

HLA-B*5701 associated AbacavirHypersensitivity Reactions (HSR)

Recently, the US Food and Drug

Administration (FDA) issued an alert

informing healthcare profess ionals

that ser ious and sometimes fatal

hypersensit ivity reactions caused by

abacavir therapy are s ignif icant ly

more common in pat ients with the

human leukocyte antigen (HLA) allele,

HLA-B*5701. This alert was based on

the review of two studies, PREDICT-1

and SHAPE, which supported the

recommendation for pre-therapy

screening for the presence of

HLA-B*5701 allele and the selection of

alternative therapies in positive subjects.

Abacavir Hypersensitivity Reactions

Abacavir HSR is a multi-organ syndrome

characterized by two or more clinical signs

and symptoms that include fever, rash,

gastrointestinal symptoms, respiratory

symptoms and constitutional symptoms.

Symptoms can occur any time during

treatment with abacavir but usually

appear within the first six weeks (median,

11 days).

Details of the studies

PREDICT-1 is a prospective, randomized,

double-blind study that evaluates the

clinical utility of pre-therapy HLA-B*5701

screening compared to no screening on

the incidence of abacavir HSR in

abacavir-naïve patients infected with

HIV type 1. Data from PREDICT-1 estimates

that 61% of HLA-B*5701 posit ive

subjects wi l l develop abacavir HSR

during treatment with abacavir compared

with 4.5% of HLA-B*5701 negative

subjects. Screening of HIV-1 infected

subjects for the presence of

HLA-B*5701 resulted

in a reduct ion in

the incidence of

clinically-suspected

HSR of approximately

60% compared with

no screening.

The SHAPE study

is a retrospect ive,

case-control study

designed to evaluate

the sensit iv i ty of

HLA-B*5701 allele with respect to abacavir HSR in black and white subjects in the

United States. In this study, the data supports the strong association between

HLA-B*5701 and clinically-suspected abacavir HSR in both black and white patients as

well as the pre-screening for the HLA-B*5701 allele in the broader United States

population to improve the safety profile of abacavir.

International regulatory actions

Following the safety alert by FDA, the US package inserts of abacavir and abacavir-

containing medications were updated to include recommendation to test patients

for HLA-B*5701 allele before starting or restarting these medications. The US

abacavir medication guide for patients was also updated to highlight the safety

information on the increase risk of abacavir HSR in patients with the HLA-B*5701

allele carriage. Similar warnings on strong association between HLA-B*5701

allele carriage and abacavir HSR and the recommendation to do pre-therapy

HLA-B*5701 screening have also been updated in the European package inserts for

abacavir containing medications.

Local situation

HSA has not received any local reports pertaining to abacavir HSR. However,

physicians who prescribe abacavir-containing medications are encouraged to

advise their patients to look out for signs and symptoms of abacavir hypersensitivity

reactions. If they develop signs and symptoms suggestive of hypersensitivity

reactions, they should be advised to stop their medication and seek prompt medical

attention. Although our Asian population has a low prevalence of the HLA-B*5701

allele, it is important to bear in mind the potential risk of abacavir HSR associated

with this allele.

The local package insert for Ziagen® has recently been updated to reflect the safety

information on HLA-B*5701 allele associated abacavir HSR and the recommendation

to do pre-therapy screening for this allele. The package insert of Kivexa® is in the

process of being updated with this safety information. Healthcare professionals are

encouraged to report suspected adverse drug reactions associated with abacavir to

the Pharmacovigilance Branch of HSA.

References

1. FDA alert. Information for Healthcare Professionals Abacavir (marketed as Ziagen) and

Abacavir-containing Medications.

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

2. European Public Assessment Report for Abacavir (Ziagen®)

http://www.emea.europa.eu/humandocs/PDFs/EPAR/Ziagen/101999en8b.pdf.

3. N Eng J Med 2008 Feb 7;358:568-79

4. CID 2008 Apr 1; 46: 1111-8

Prospective screening for relevant alleles



In recent months, thePharmacovig i lanceBranch, HSA has

received three reportso f adverse drugreac t ions (ADR)assoc ia ted wi th twos l imming hea l thproducts . On fur therinves t iga t ion, theproducts namely,‘Relacore’ and ‘Lami ’ ,were found tocontain sibutramine, anundec la red wes terndrug ingredient used as an appetitesuppressant in the management o fobesity.

A) Relacore

In June 2008, HSA i s sued a pressstatement to a lert the publ ic of theadu l te ra ted product labe l led as‘Relacore’. This was prompted by twoADR reports involving two adult patients(a male and female) in their early 20s,that were brought to HSA’ s attentionby doctors at a hospital. Noteworthy wasthat both patients admitted to purchasingthe slimming product over the Internet. One of the patientprovided samples of ‘Relacore’, which was ordered from aChinese website. The product was subsequently tested byHSA’ s ana ly t i ca l l abora tor y to conta in 12.22 mg o fsibutramine in each capsule.

The adulterated product labelled as ‘Relacore’ (could be acounterfeit of the product sold in the US) was promoted as adietary supplement and claimed to contain “stress mitigatingcompound” for “belly fat and stress control”.

Details of one case report

The male patient mentioned above, presented with symptomsof psychosis, including hallucination and palpitation at theemergency department. On further probing by the doctor,he admitted to taking ‘Relacore’ for three months at a doseof 3–4 capsules daily, which was beyond the dose of twocapsules recommended on the product’s label. Based on theamount of sibutramine found in each capsule, the patienthad unwittingly consumed 36–48 mg of sibutramine daily(maximum daily dose of subitramine is 15 mg). This couldexplain the adverse reactions observed in the patient, takinginto consideration the close temporal relationship betweenthe onset of adverse reaction and date of ingestion of theadulterated product.

B) Lami

Case report

A 29 year-o ld fema le presented to ageneral practitioner’s clinic with symptomsof palpitat ion, breathlessness, auditoryhallucination and labile mood after takinga traditional Jamu supplement labelled as‘Lami’. The patient has been taking ‘Lami’since 2007. Adverse symptoms manifestedwhen she took e ight capsu les o f theproduct, which was four times above the

dose o f two capsu les/dayrecommended on the label.The pat ient prov ided thesample, which was also testedby HSA to contain sibutramine.

S i b u t r a m i n e - i n d u c e dpsychosis

Sibutramine is a noradrenalineand seroton in reuptakeinhibitor indicated for weightloss. The commonly reportedadverse reac t ions inc ludeinsomnia , headache andanx ie ty. Tachycard ia andhypertension have also beenreported in some patients.

Sibutramine is also known to exhibit significant dopaminereuptake inhibition and some authors have postulated thatthis could possibly lead to the development of psychoticsymptoms, especially in the event of an overdose.1 This isbased on the postulat ion that the dopamine reuptakeinhibition could result in excess dopamine in the synapticc le f t s and a consequent increased dopaminerg icneurotransmission, in line with the dopamine hypothesis ofpsychosis. 2, 3

Be mindful of Internet purchase of drug and healthproducts

Given the increasing trend of consumers turning to theInternet for purchase of hea l th products , hea l thcareprofessionals are encouraged to ask patients about theconsumption of such complementary medicines or healthsupplements. Very often, patients may not regard theseproducts as medicines and will not mention it to their doctors.The information may be important to physicians in making adifferential diagnosis of the adverse events experienced bypatients.

References1. J Psychosom Res. 2008 Jan;64(1):107-9.2. Am J Psychiatry. 2000 Dec;157(12):2057-8.3. J Clin Psychopharmacol. 2007 Jun;27(3):315-7.

Slimming health products (Relacore & Lami)adulterated with sibutramine



Fentanyl transdermal patch and overseas reports of fatalityFatal adverse reactions relating to drug abuse, misuse and overdose reported

HSA would like to update healthcare professionals on the overseas cases of life-threatening and fatal

adverse events reported with the use offentanyl transdermal patch.

Fentanyl is a potent opioid analgesic whichshould be used only in patients who havepreviously tolerated opioids as there is a riskof significant respiratory depression inopioid-naïve patients. In Singapore, fentanyltransdermal patch (Durogesic®, Janssen-Cilag) is licensed as a controlled drug forthe management of chronic and intractablepain requiring opioid analgesia that involvescontinuous opioid administration for anextended period of time. It is only licensedfor use in adults and in opioid-tolerantchildren aged two years and above.

Reports received by UK MHRARecently, reports of life-threatening adversereactions and death have been received bythe UK Medicines and Health productsRegulatory Agency (MHRA) from healthcareprofessionals, patients and caregivers ofpatients who were using fentanyl patchesfor malignant and non-malignant paincontrol. These were found to be possiblyrelated to unintentional overdose such asdosing errors, accidental exposure (inchildren) and exposure of the patch to aheat source, potentially resulting in anincrease in fentanyl absorption. Some of thereports also reflected the use of fentanylpatches for unlicensed indications and inopioid-naïve patients. In the UK, fentanylproducts include Durogesic® Dtrans®,Durogesic®, Matrifen® and Tilofyl®.

Reports received by Health CanadaSimilarly, Health Canada received 105adverse reactions suspected to be associatedwith fentanyl transdermal patches betweenJanuary 1992 to December 2007 where afatal outcome was reported. In 33 of the105 reports, the cause of death wasreported to be unrelated to the fentanylpatches and in 20 cases, insufficientinformation was provided in the reports.Among the remaining 52 reports,intentional drug abuse accounted for almosthalf the cases. The other factors related tothe fatal adverse reactions includedinappropriate dose initiation and titrationincluding use in opioid-naïve patients,inappropriate application of patches bypatients (applying more than prescribed) orhealthcare professionals, accidental

overdose, intentionaloverdose or suicide,drug interactions withCYP 3A4 inhibitors(eg. grapefruit juice,k e t o c o n a z o l e ,e r y t h r o m y c i n ,diltiazem) and thesharing of the patchwith another patientwho was notprescribed thetreatment.

Fentanyl transdermalproducts available inCanada include Duragesic®, Ratio-Fentanyl® and Ran-Fentanyl®. The Health Canada hadin earlier warnings issued in 2004 and 2005 described fatal outcomes in opioid-naïveadolescents and when fentanyl patches were abused by adolescents, leading the agencyto revise the Canadian product monograph for Duragesic® to emphasize the safe andappropriate use of the patch.

Reports received by US FDAIn December 2007, the US Food and Drug Administration (FDA) issued a public healthadvisory to alert patients, caregivers and healthcare professionals to adverse reactionsarising from the prescribing of the fentanyl patch to patients for inappropriate indicationssuch as acute pain following surgery, for headaches and occasional mild pain. The agencyalso received reports on patients who replaced the patch more frequently than was directedin the product label, applying more patches than prescribed, or applying a heat source tothe patch, all of which may lead to exceedingly high fentanyl levels in the blood. BothDurogesic® and generic versions of the product are marketed in the US.

Local situationTo date, no adverse reaction of the nature described above has been reported to thePharmacovigilance Branch of HSA. However, due to the seriousness and occurrence offatalities associated with the inappropriate use and abuse of the patch reported overseas,healthcare professionals are advised to be aware of the potential serious and fatal adverseeffects associated with the use of fentanyl patches. They are also advised to instruct patientsand caregivers on the appropriate and safe use of fentanyl patches as well as educatethem on the signs and symptoms of fentanyl overdose (see table 1 for list of symptoms).

Healthcare professionals are also encouraged to report all adverse events suspected to beassociated with fentanyl patches to the Pharmacovigilance Branch of HSA.

Table 1: Some signs and symptoms of fentanyl overdose

■ Troubled breathing or shallow breathing■ Slow heartbeat■ Cold, clammy skin■ Tiredness■ Extreme sleepiness or sedation■ Inability to think, walk or talk normally■ Feeling faint, dizzy or confused

References1. Drug Safety Update Vol. 2 Issue 2 September 2008 from MHRA and CHM2. Canadian Adverse Reaction Newsletter Vol. 18, Issue 3, July 20083. Dear Healthcare Professional Letter issued by Health Canada on Duragesic®, September 13, 2005.4. Canadian Adverse Reaction Newsletter Vol. 15, Issue 3, July 20055. Canadian Adverse Reaction Newsletter Vol. 14, Issue 4, Oct 20046. http://www.fda.gov/cder/drug/infopage/fentanyl/default.htm



Haemorrhagic or necrotizing pancreatitisassociated with Byetta®

Exenatide (Byetta®,Eli Lilly) is an incretinmimetic agent that

mimics the enhancement ofglucose-dependent insulinsecretion and several otherantihyperglycaemic actionsof incretins. It is licensed asan adjunctive therapy in thetreatment of patients withtype 2 diabetes mellitus andwas recently registered inSingapore in May 2008.

Post-marketing reportsof pancreatitisSince its market introduction in June 2005,the US Food and Drug Administration (FDA)has been receiving post-marketing adverseevent reports describing acute pancreatitis inpatients treated with Byetta®. In the FDA’sreview of 30 post-marketing reports of acutepancreatitis in patients treated with Byetta®,majority of patients had at least one risk factorfor acute pancreatitis such as gallstones, severehypertriglyceridaemia and alcohol use. In sixpatients, symptoms of pancreatitis began orworsened after the dose of Byetta® wasdoubled. Five patients developed seriouscomplications including dehydration, renalfailure, suspected ileus, phlegmon and ascites.

Recently, Byetta® was linked to six new casesof haemorrhagic or necrotizing pancreatitis,of which there were two fatalities and fourcases of deaths in patients with pancreatitis.

Actions taken in the USThe US FDA issued a safety alert to warnhealthcare professionals of the potentialrisk of acute pancreatitis associated withByetta®, following its review of the 30 post-marketing reports of acute pancreatitis inpatients treated with Byetta®. The packageinsert for Byetta® was also updatedto include the post-marketing findingsof acute pancreatitis. With the recentsix cases of haemorrhagic or necrotizingpancreatitis, FDA has requested thecompany to add stronger and moreprominent warnings in the package insertabout the risk of acute haemorrhagic or

necrotizing pancreatitis. Healthcare professionals and patients were advised to maintainvigilance for signs and symptoms of acute pancreatitis associated with the use of Byetta®.

Local situation and HSA’s advisoryTo date, HSA has not received any local reports of acute pancreatitis associated with Byetta®.However, physicians are encouraged to advise their patients taking Byetta® to look out forsigns and symptoms of acute pancreatitis and to seek prompt medical attention should theyexperience unexplained, persistent, severe abdominal pain, which may be accompanied bynausea and vomiting. If pancreatitis is suspected, Byetta® should be discontinued.

In June 2008, the company issued a Dear Healthcare Professional Letter to inform localhealthcare professionals of the potential risk of acute pancreatitis associated with Byetta®.HSA is currently working with the company to update the local package insert to reflectthese recent post-marketing findings of acute pancreatitis. Healthcare professionals arealso encouraged to report any serious adverse drug reactions suspected to be associatedwith the use of Byetta® to the Pharmacovigilance Branch of HSA.

References1. FDA information for healthcare professionals: Exenatide (marketed as Byetta®).

http://www.fda.gov/cder/drug/InfoSheets/HCP/exenatide2008HCP.htm2. Important prescribing information on Byetta®, 2007 Oct.

http://www.fda.gov/medwatch/safety/2007/byetta_dhcp-letter.pdf

Summary of advisories issued by HSAand pharmaceutical companies

1 Apr 2008 Update on risk of suicidal ideation and behaviour withlamotrigine (Lamictal®) tablets and chewable dispersabletablets [GSK]

15 Apr 2008 HSA alerts on wider spread of harmful illegal healthproducts

22 Apr 2008 Reports of progressive multifocal leukoencephalopathy(PML) in mycophenolate mofetil (Cellcept®) treatedpatients [Roche]

26 May 2008 Abacavir sulphate-containing medicinal products(Ziagen® tablets and oral solution; Kivexa® tablets;Trizivir® tablets) – communication on results pertainingto abacavir from the D:A:D study [GSK]

12 Jun 2008 Important prescribing information on exenatide(Byetta®) [Eli Lilly]

14 Jul 2008 Safety information regarding the combined useof bevacizumab (Avastin®) and sunitinib malate

18 Sep 2008 Direct healthcare professional communicationon a report of progressive multifocalleukoencephalopathy (PML) in a patient withrheumatoid arthritis treated with rituximab(Mabthera®) [Roche]

19 Sep 2008 US FDA’ s actions on products manufactured by twoof Ranbaxy’s manufacturing plants in India

7 Oct 2008 New formulation of Eltroxin® (Levothyroxine) tablets[GSK]

20 Oct 2008 Recall of hot/cold packs

Summary of Dear Healthcare Professional Letters issuedby HSA and/or pharmaceutical companies fromNovember 2007 to October 2008. For details, please log

on to http://www.hpp.moh.gov.sg using your professionalboard register number or Singpass.

27 Nov 2007 Important safety information on perflutrenlipid microsphere (Definity®) [Research Biolabs]

11 Dec 2007 Important safety warnings for gadolinium-basedcontrast agents

13 Dec 2007 Reclassification of hydroquinone – containingproducts for skin-bleaching

26 Dec 2007 Suspension of sales of nimesulide in Singapore:HSA’ s update

31 Jan 2008 Mycophenolic acid as sodium salt (Myfortic®) –Labeling update on teratogenic risk [Novartis]

14 Feb 2008 HSA warns about an il legal product“Power 1 Walnut ”

25 Feb 2008 Reports of hepatic failure with deferasirox (Exjade®)[Novartis]

17 Mar 2008 Telbivudine (Sebivo®) in the treatment of chronichepatitis B - Adverse event “Peripheral neuropathy”seen with the treatment of telbivudine combinationwith pegylated interferon alfa-2A [Novartis]

1 Apr 2008 Lapatinib (Tykerb®) and new safety information onhepatotoxicity (predominantly transaminaseelevations) [GSK]



Levonorgestrel, ethinylestradiol (Nordette®,Wyeth) Contraindications: Hereditary or acquiredthrombophilias, headache with focal neurologicalsymptoms (such as aura) & undiagnosed vaginalbleeding. Precautions: adverse lipid changes. Elevationsof plasma triglycerides may lead to pancreatitis & othercomplications. Interaction: Lamotrigine.

Lorazepam (Ativan®, Wyeth) Special warnings:Severe & potentially fatal anaphylactic/anaphylactoidreactions reported. Reports of angioedemainvolving the tongue, glottis or larynx after first orsubsequent doses & sometimes dyspnoea, throatclosing, or nausea & vomiting. Such patients shouldnot be rechallenged. Dependence potential oflorazepam reduced when used at appropriatedose for short duration. Withdrawal symptomscan appear after discontinuation of one week oftherapy. Avoid abrupt discontinuation after extendedtherapy. Convulsions more common in patientswith pre-existing seizures disorders or in thosetaking drugs that lower convulsive threshold.Possible tolerance to sedative effects. Abusepotential esp. in patients with a history of drug &/or alcohol abuse. Precaution: Compromised respiratoryfunction. Pregnancy: Increased risk of congenitalmalformations during 1st trimester. New ADRs:Angioedema, diplopia, blurred vision.

Mesalazine (Salofalk®, IDS) Special warnings:Caution in hepatic dysfunction. Do not administerto patients with renal dysfunction Monitor renalfunction for possibil ity of mesalazine-inducednephrotoxicity during treatment. Not for children<6 years old. Mesalazine suppositories may causecontact dermatitis. Interaction: Possible potentiationof the myelosuppressive effects of azathioprine or6-mercaptopurine. ADRs: Acute & chronic interstitialnephritis, renal insufficiency, allergic exanthema,pancolit is, elevated parameters of cholestasis,cholestatic hepatitis, alopecia. Pregnancy & lactation:Report of renal failure in neonate born to womanon long-term treatment with 2–4g/day oral dosesduring pregnancy. Stop breastfeeding if infantdevelops diarrhoea as hypersensitivity reactionsmay occur in infant.

Mycophenolic acid (Myfortic®, Novartis)Special warning: Occasional fatal cases of progressivemultifocal leukoencephalopathy (PML) reported.Risk factors: immunosuppressant therapies & immunedeficiency. Consider reducing total immunosuppressionin patients with PML. In transplant patients, reducedimmunosuppression may place graft at risk.

Pramipexole (Sifrol®, Boehringer Ingelheim)New ADRs: Amnesia, compulsive shopping,restlessness, visual disturbance including blurvision & reduced visual acuity, vomiting, weight loss.

Simvastatin (Zocor®, MSD) Precaution: Concomitantadministration with fusidic acid may increase risk ofmyopathy. Consider temporary suspension ofsimvastatin. New ADR: Hepatic failure.

Telmisartan (Micardis®, Boehringer Ingelheim)Interactions: Treatment with NSAIDs associatedwith potential for acute renal insufficiency indehydrated patients. Reduced effect duringcombined treatment with NSAIDs. New ADRs:Cystitis, syncope/faint, abnormal hepatic function/liver disorder, renal impairment including acuterenal failure, hyperkalaemia, anaemia, angioneuroticoedema, increased blood creatine phosphokinase.

Vardenafil (Levitra®, Bayer) Special warnings:With alpha blockers besides tamsulosin, separate timingof dose. When used with clarithromycin, do not exceed5mg of vardenafil. Interaction: nicorandil. New ADRs:Sudden deafness or loss of hearing, transient globalamnesia, seizures.

Zanamivir (Relenza®, GSK) Special warning: Seizures,delirium, hallucination & abnormal behaviour observedmainly early in the therapy & often has an abrupt onset& rapid resolution.

HSA has approved the following package insert changes due to safety updates from May 2008

to September 2008. Due to spaceconstraints, the list published is notexhaustive and you are encouraged torefer to the following website forthe complete listing with details:h t t p : / / w w w . h s a . g o v . s g /safetyinfo_and_recalls. Please also notethat there might be some lag timein the availability of the package insertwhich reflects the latest change(s).

14

15

16

17

18

20

21

22

1

2

3

45

6

7

8

9

101112

13

Package insert amendments reflecting safety issues

19

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Carbamazepine (Tegretol®, Novartis) Specialwarning: Strong correlation between SJS/TENassociated with carbamazepine & presence of HumanLeukocyte Antigen (HLA)-B*1502 allele found in HanChinese. Consider testing for allele in geneticallyat-risk patients with Asian ancestry. Avoid use ofcarbamazepine, anti-epileptic drugs & other drugsassociated with SJS/TEN in patients positive forHLA-B*1502.

Cefepime (Maxipime® injection, Bristol-Myers)Caution: Hypersensitivity to beta-lactam antibiotics,GI disease esp. colitis, neutropenia, renal-impairment,& in the elderly. New ADRs: Urticaria, renal dysfunction,hepatic dysfunction including cholestasis.

Cyproterone, ethinylestradiol (Diane-35®,Schering), Drospirenone, ethinylestradiol(Yasmin®, Schering) & Levonorgestrel,ethinylestradiol (Microgynon®, Schering)Special warning: The most important risk factor forcervical cancer is persistent HPV infection. Long termCOC use may further increase this risk. The extentto which this finding is attributable to factorse.g. cervical screening & sexual behaviourremains controversial. Interactions: HIV proteaseinhibitors (e.g. ritonavir), non-nucleoside reversetranscriptase inhibitors (e.g. nevirapine) & combinationsmay affect hepatic metabolism, increasing plasma &tissue concentrations of cyclosporine & decreasinglamotrigine concentrations. New ADRs: May induceor exacerbate symptoms of angioedema in womenwith hereditary angioedema.

Dactinomycin (Lyovac Cosmegen®, Merck)New ADRs: Neutropenia, febrile neutropenia.

Duloxetine (Cymbalta®, Eli Lilly) Special warnings:Caution in patients whose conditions are compromisedby increased heart rate or blood pressure. Suicidalideation & behaviours reported during therapy or earlyafter discontinuation. Not for patients < 18 years old.Hyponatremia may occur as a result of SIADH. Patientsat risk include the elderly, those taking diuretics andthose with volume depletion. New ADRs: Creatinephosphokinase increased, blood cholesterol increased,atrial fibrillation, akathisia, palpitations, tachycardia,dyskinesia, gastroenteritis, myoclonus convulsions,acute liver injury, tinnitus, angioneurotic oedema.

Erythromycin (Eryc®, Hospira) Warning: ProlongedQT observed in elderly. Precautions: Infantilehypertrophic pyloric stenosis (IHPS) reported.Erythromycin may aggravate the weakness of patientswith myasthenia gravis. Interactions: Uncorrectedelectrolyte disorders (hypokalaemia), QTc intervalprolonged or drugs that prolong the QTc interval.Monitor closely when oral erythromycin & quinidineare administered concomitantly as QT prolongation,torsades de pointes & cardiac arrest have beenreported. Myalgia, neutropenia & fever reported withconcurrent administration of erythromycin &vinblastine. ADRs: Pancreatitis, QT prolongationventricular arrhythmias & convulsions.

Etanercept (Enbrel® injection, Wyeth) New ADRs:Erythema multiforme, Stevens Johnson syndrome,toxic epidermal necrolysis.

Ezetimibe, simvastatin (Vytorin®, MSD) Precautions:Risk of myopathy/rhabdomyolysis increased byconcomitant use of Vytorin® with danazol, fibrates,niacin or fusidic acid. When used with gemfibrozil, doseof Vytorin® should not exceed 10/10mg (ezetimibe/simvastatin) daily. Monitor INRs If Vytorin® is added tocoumarin anticoagulant, or fluindione therapy. NewADRs: Cholelithiasis, cholecystitis, depression, increasedcreatine phosphokinase, elevations of l ivertransaminases, anaphylaxis, hepatic failure.

Fentanyl (Durogesic® Transdermal System,Janssen-Cilag) Special warnings: Patients at increasedrisk of opioid abuse may be treated with modified-releaseopioid formulations but monitor for signs of misuse,abuse or addiction. Withdrawal symptoms possiblewhen converting from previous opioid analgesic toDurogesic® or if therapy is abruptly stopped. Avoidexposing application site to tanning lamps &prolonged hot baths. New ADRs: Anaphylactic shock,anaphylactic reaction, anaphylactoid reaction, drugwithdrawal syndrome. Pregnancy: Neonatal withdrawalsyndrome reported in newborn infants with chronicmaternal use of Durogesic® during pregnancy.

Fluvastatin (Lescol®, Novartis) ADR: Anaphylacticreactions.

Glipizide (Glucotrol® XL, Pfizer) Special warning:Treatment of patients with G6PD-deficiency may lead tohaemolytic anaemia. Interaction: Voriconazole.

Hydroxyzine (Atarax®, UCB) Contraindications:1) Hypersensitivity to cetirizine, piperazine derivatives,aminophyll ine, ethylenediamine, 2) porphyria,3) pregnancy & breast-feeding. Special warnings:Caution in young children with increased potential forconvulsions, glaucoma, bladder outflow obstruction,decreased GI motility, myasthenia gravis, or dementia,when used simultaneously with CNS depressants oranticholinergics. Avoid alcohol. Caution in patients withpredisposing factor to cardiac arrhythmia, or thoseconcomitantly treated with a potentially arrhythmogenicdrug. Reduce dosage in elderly, patients with hepaticdysfunction & moderate/severe renal impairment.Stop treatment at least 5 days before allergy testingor metacholine bronchial challenge. Interactions:CNS depressants, anticholinergics, alcohol, betahistine,anticholinesterase drugs, MAOIs, adrenaline,cimetidine. Pregnancy & lactation: Hypotonia,movement disorders (extrapyramidal disorders, clonicmovements), CNS depression, neonatal hypoxicconditions, or urinary retention observed in neonatesof mothers who received Atarax® during latepregnancy &/or labour. New ADRs: Tachycardia,accommodation disorder, blurred vision , pyrexia,hypersensitivity, anaphylactic shock, liver function testabnormal, insomnia, dyskinesia, agitation, confusion,disorientation, hallucination, urinary retention,bronchospasm, hypotension, dermatitis, fixed drugeruption, increased sweating.

Iloprost Trometamol (Ventavis®, Berlimed SA)Special warnings: Inhalation might inducebronchospasm. Patients with concomitant acutepulmonary infections, COPD, & severe asthma shouldbe carefully monitored. Not for pregnant or lactatingwomen. Women of child bearing potential should useeffective contraceptive measures during treatment.New ADRs: Pain in jaw, back pain, vomiting, dizziness,diarrhoea, dyspnoea, bronchospasm, wheezing.

Influenza vaccine (Fluad®, Novartis)Contraindication: Children & elderly patients onwarfarin.

Laronidase (Aldurazyme®, Genzyme) Warning: Life-threatening anaphylactic reactions up to 3 hours afterinfusions. In patients with Mucopolysaccharidosis I, pre-existing upper airway obstruction may have contributedto severity of reactions. Patients with acute illness at timeof infusion may be at greater risk for infusion-relatedreactions. New ADRs: Chills, vomiting, nausea,arthralgia, diarrhoea, tachycardia, abdominal pain,blood pressure increased, decreased oxygen saturation.



Editor-in-ChiefMs Chan Cheng Leng,

BSc (Pharm) Hons

Executive EditorMs Adena Lim,

BSc (Pharm) Hons, MPharm

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 BranchHealth Products Regulation GroupHealth Sciences Authority

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

Tel: (65) 6866 3538Fax: (65) 6478 9069

Website: http://www.hsa.gov.sgEmail: [email protected]

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 EditorsMs Ang Pei San, BSc (Pharm)

Mr Choong Chih Tzer, BPharm

Ms Christine Ho, BSc (Pharm) Hons

Dr Yvonne Koh, BSc (Pharm) Hons, PhD

Ms Belinda Tan, BSc (Pharm)

Ms Liesbet Tan, BSc (Pharm) Hons

Ms Tan Siew Har, BSc (Pharm)

Ms Tan Wei Chuen, BSc (Pharm)

Abiosimilar medicine is a medicinal product which is similarto a biological medicine that has already been registered with a drug regulatory authority and is submitted for

medicinal product registration by an independent applicant afterthe patent period for the original product has expired.

As the cost of innovative biological products are generally high,thereby limiting their use, the expiration of the patents on manybiological products such as human growth hormone anderythropoietin has prompted the development and licensing ofbiosimilar products. A biosimilar product would have an abbreviatednon-clinical and clinical development programme leveraging onthe existing information of the original product and focusing ondemonstration of similarity with the original product, also knownas the reference product.

Biosimilar products such as Valtropin® and Omnitrope® (both aresomatropin) and Binocrit® (which contains epoetin alpha) areregistered in the European Union. There are no biosimilar productsregistered in Singapore as yet but such products will eventuallyenter the market, subject to approval by HSA. This article serves toprovide healthcare professionals with more information onbiosimilars and what to take note of when prescribing and reportingADRs associated with biosimilar products when these productsbecome available locally in the future.

Why are biosimilar products different from genericchemical products?Biosimilar products may commonly be mistaken for generic versionsof the reference biological product. Unlike generic chemical drugs,whereby the chemical structure is identical to that of the referencechemical product, a biosimilar product does not usually have anidentical structure to the reference biological product. Hence, eventhough these biological/biotechnology-derived proteins may beapproved by regulatory authorities to be similar in terms of quality,safety and efficacy to a reference biological medicine to which ithas been compared with, there is a chance that these productsmay cause adverse reactions which may be different from that oftheir reference products. One such adverse reaction may be differingimmunological response of the patient.

How are biosimilar products assessed?Biosimilar products are assessed based on comparability databetween the biosimilar products and the reference products interms of quality of product, non-clinical studies (e.g. animalpharmacodynamic studies and toxicity studies) and clinicalstudies (e.g. pharmacokinetic and pharmacodynamic studies inhuman subjects). The eventual approval for the biosimilar productmay be for the same indications and patient groups as that of thecorresponding reference product registered in Singapore, or itmay be for more restricted indications and patient groups.

How should a biosimilar product be prescribed anddispensed?The decision by a doctor whether to prescribe a biosimlar productor the innovator biological product is dependent on factors relevant

to the patient and the institution which he practises in. Howeverwhen prescribing such products, it is important to use the brandname of the selected product. A biosimilar product may have thesame international non-proprietary name (INN) as the referencebiological product but they should not be presumed to be identical.Using the brand name will help avoid the issue of automaticsubstitution of the product when dispensed in the pharmacy, orduring administration of the product.

How do I report adverse drug reactions (ADRs) tobiosimilars?In view of the complexity of biological molecules and for the reasonsmentioned above, it is pertinent to report the brand name of thebiosimilar which is suspected to cause an ADR rather than the nameof the substance (e.g. Genotropin® instead of somatropin), togetherwith the batch number of the product used.

Biosimilar products are similar but NOT identical to an existingbiological product.

■ A biosimilar product may have the same or a more restrictedindication for use compared to the existing biological product

■ When prescribing a biosimilar product, the brand name ofthe product should be clearly stated on the prescription

■ When dispensing/administering a biosimilar product,only the product with the correct brand nameshould be dispensed/administered. There should NOTbe any substitution with another product with the sameinternational non-proprietary name without seekingclarification with the prescribing doctor

■ When reporting an adverse reaction, the brand name andbatch number of the product should be clearly stated

References1. http://www3.niaid.nih.gov/research/resources/DAIDSClinRsrch/

Glossary.htm2. Drug Safety Update Vol. 1, Issue 7 February 2008 from MHRA and CHM

Biosimilar productsA regulatory update


ADR News Dec2008 Vol10 No3

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