ADR News Feb2003 Vol5No1

7/29/2019 ADR News Feb2003 Vol5No1

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Published by the Centre for Pharmaceutical Administration, HSA and the Expert Panel on Adverse Drug React

efazodone (Serzone® , Bristol MyersSquibb) was licensed in Singapore in1997 and is indicated for the treatment

of depression. It inhibits re-uptake of serotoninand also selectively blocks serotonin receptors.

As of December 2002, worldwide data shows that there havebeen 28 reports of liver failure, 15 of which resulted in deaths.These were suspected to be associated with nefazodone sinceit became available in 1994. The Pharmacovigilance (PV)Unit has received one local adverse drug reaction (ADR)report in April 2002 of a 54-years-old female patient whodeveloped mildly elevated ALT suspected to be due tonefazodone.

Recent developments in the international arenaIn January 2002, the US FDA added a Black Box Warningand strengthened the warnings of the label for Serzone® toinclude the reports of liver failure. The reported rate in theUS is about 1 case of liver failure resulting in death or transplant per 250,000 – 300,000 patient-years of Serzone® treatment.

In January 2003, Bristol Myers Squibb announced thedecision to voluntarily withdraw nefazodone in all Europeancountries for commercial reasons. The drug continues to beavailable in countries such as the US and Australia.

Package insert amendmentsThe local package inserts for Serzone® have been amendedin February 2002 to include the black box and warning onhepatic adverse effect:■ Nefazodone is not recommended for use in patients with

acute liver disease or elevated baseline serum transaminases.■ Patients should be advised to be alert for signs and symptoms

of liver dysfunction, and to report them to their doctor immediately if they occur.

■ Nefazodone should be discontinued if signs or symptomssuggest liver failure, or if patient develops evidence of hepatocellular injury. Such patients should be assumed tobe at increased risk of developing liver injury if nefazodoneis restarted, and therefore this should not be considered.

These amendments and warnings of rare cases of liver failurehave been brought to the attention of our physicians througha Dear Healthcare Professional Letter issued by themanufacturer in February 2002.

The Unit is closely monitoring the safety of nefazodone andthe measures taken by the other regulatory agencies such asthose in the US and Australia. Healthcare professionals areencouraged to report every case of suspected ADRs tonefazodone to the PV Unit ■

February 2003 • Vo1 5 No.1 ISSN : 0219-2152

ADVERSE DRUG REACTIO

NHealthcare professionals are encouraged to report suspected cases of liver dysfunction associated with nefazodone NEFAZODONE AND LIVER FAILURE

Photo courtesy of National Kidney Foundation

E

Pr ovi de us wi th your f ul l n ame an d emai l addr ess to r ecei ve HSA dr ug saf ety i n f or mati on . Emai l us at [email protected]

continued on page 4

CONTENTSNefazodone and liver failure 1Update on Eprex ® and pure red cell aplasia 1

Analysis of ADR reports for year 2002 2Careful use of isotretinoin 4

UPDATE ON EPREX®

AND PURE REDCELL APLASIA Amendment of product labelling information to advise only IV adminstration of Eprex ® in CRF patients

poetin alfa (Eprex ®, J a n s s e n - C i l a g ) was licensed in

Singapore in 1988 for the treatment of anaemiaassociated with chronicrenal failure (CRF),

cancer chemotherapy,autologous blood donationand during major electiveorthopaedic surgery. It can be administered

via the subcutaneous (SC) and intravenous (IV) route.In August 2002, due to the emergence of reports of pure red cell aplasia (PRCA) in CRF patients suspectedto be associated with SC Eprex ®, the company amendedits package insert to advise that the IV route beadministered in these patients wherever feasible.

Update on number of PRCA cases

By the end of September 2002, there were 179 cases of PRCA suspected to be associated with Eprex ®, reported worldwide in CRF patients. Of these, 155 were confirmedby bone marrow biopsy and 112 were anti-erythropoietinantibodies positive. All cases of antibody-positive PRCA had administration of Eprex ® by the SC route. Theincidence of antibody-positive PRCA for Eprex ® isestimated by the company to be rare, occurring at lessthan 1:1,000 patient years.

Local PRCA reportsIn Singapore, the PV Unit has received 10 local reports of PRCA, 7 of which were suspected to be associated with Eprex ®

and 3 in which combinations of Eprex ® and Recormon®

(epoetin beta) were used. Eight of the cases had bone marrow biopsy done and antibodies tested positive to erythropoietin.Of the 7 cases where the gender was identified, 4 weremales and 3 were females. Ninety percent of the patients were Chinese. Their median age was 64.5 years (range 46 –71 years). The dose of erythropoietin ranged from SC 2000IU twice weekly to 4000 IU thrice weekly. The duration of treatment with erythropoietin to the time of diagnosis of PRCA ranged from 6 months to 2 years.


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ANALYSIS OF ADR RE

T

Spontaneous ADR reporting by our healthcare professionalsis very important in ensuring that the HSA receives timely signal of potential drug problems.

he Pharmacovigilance (PV) Unit of the Centre for Pharmaceutical Administration, Health Sciences

Authority (HSA) is responsible for the collation andreview of all spontaneous adverse reports submitted by our healthcare professionals. This activity forms part of HSA’soverall post-marketing surveillance program in ensuring thesafety of all marketed medicinal products in Singapore.

Review of ADR reports

For the year 2002, a total of 801 ADR reports were submittedby our healthcare professionals. This represented an increaseof more than 40% of reports received in 2001. The publicsector hospitals contributed 68.5% of the reports followedby the private hospitals/health institutions (14.4%), themanufacturers (11.7%), general practitioners (8.7%) andothers (0.7%).The ethnic distribution of the patients in the reports was similar to that of the local population, comprising 70% Chinese,10% Malays and 6% Indians. Females appear to be moresusceptible to ADRs than males. There were 1.8 times more ADR reports received in the female gender compared to themale.

Serious adverse drug reactions comprised 22% of the totalreports. There were 6 fatal cases suspected to be directly caused or precipitated by the offending drug(s). Eighteenpercent of the patients were hospitalised following the ADRs,

and in another 34% of the reports, the patients were already hospitalised when the adverse event occurred■

Figure 2: Breakdown of ADR reports by age groups (n = 801)

N u m

b e r o

f A D R r e p o r t s

0

50

100

150

200

250

300

Age (years)

44 (5.4%)59 (7.4%)

102 (12.7%)

288 (35.8%)

178 (22.5%)

130 (16.2%)

<1 1-12 13-24 25-44 45-60 >60

Figure 1: Breakdown of ADR reports by ethnic group(n = 801)

Chinese563 (70%)

Indian45 (6%)

Malay83 (10%)

Others35 (4%)

Unknown75 (9%)

Male to female ratio is 1 : 1.8

Table 2: Top 10 ADRs

Description No of ADRsRash and urticaria1 417 Facial oedema and angioedema2 209Raised hepatic enzyme levels and other liver disorders3 68 Acute respiratory disorders4 42Gastrointestinal disorders5 42Thyroid disorders6 41Haematological disorders7 41Palpitations and chest discomfort 30Musculoskeletal disorders8 27 Renal disorders9 13

NB: More than one ADR may be described in an ADR report

1 - Erythema, erythematous rash, macular rash, maculopapular rash, papular rash, petechial rash, rash, vasculitic rash, wheals; itching, pruritus, urticaria

2 - Angioedema, eyelid oedema, face oedema, periorbital oedema3 - Abnormal hepatic function, cholestasis, fatty liver, hepatic damage/failure,

hepatitis, jaundice, hepatic cell damage, raised liver function tests4 - Asthma, breathing difficulty/dyspnoea, bronchospasm, respiratory distress,

shortness of breath, stridor, wheezes5 - Abdominal distension/pain, bloating, diarrhoea, duodenal ulcer, epigastric

pain, gastric irritation, haematemesis and melaena, nausea, peptic ulcer, vomiting

6 - Abnormal thyroid function tests, hyperthyroidism, thyrotoxicosis7 - Agranulocytosis, anaemia, decreased haemoglobin, decreased platelet count,

haemoglobinaemia, leucopenia, marrow hypoplasia, neutropenia,pancytopenia, pure red cell aplasia, thrombocytopenia

8 - Arthralgia, back pain, increased creatine kinase, joint ache, muscle ache/

stiffness, myalgia, myopathy, myositis, numbness, rhabdomyolysis, musclespasms9 - Abnormal renal function, abnormal urine output, acute renal failure, interstitial

nephritis, nephropathy, proteinuria, urinary frequency, urine discolouration

Table 1: Top 15 drugs suspected of causing ADRs(by active ingredients)

Active ingredient * No of reportsNaproxen 54Diclofenac 47 Ceftriaxone 34Iopamidol 30Mefenamic acid 28Ciprofloxacin 22Paracetamol 22 Varicella zoster vaccine 21 Amoxicillin 15Cefazolin 15 Alendronate 13 Allopurinol 13

Cloxacillin 13Co-trimoxazole 13Rofecoxib 12

* May or may not be the sole suspected drug



ORTS FOR YEAR 2002Table 3: Examples of some serious suspected ADRs

Description(Total no. of WHO preferred Suspectedreactions) term active ingredient

Blood Agranulocytosis Carbimazole tab (1)disorders (34) Ticlopidine tab (1)

Traditional Chinese medicine (1)Idiopathic Carbimazole tab (1)thrombocytopenicpurpuraLeucopenia Ticlopidine tab (1)Neutropenia Celecoxib cap or hydrochlorothiazide /

losartan tab or atorvastatin tab (1)Cloxacillin inj or penicillin G inj (1)Imipenem inj (1)Phenytoin cap (1)Ticlopidine tab (5)

Pancytopenia Ciprofloxacin inj or metronidazoleinj (1)Imatinib cap (2)Linezolid tab (1)Rifampicin cap (1)Ticlopidine tab (1)

Pure red cell aplasia Epoetin alfa inj (7)Epoetin alfa or epoetin beta inj (3)

Thrombocytopenia Abciximab inj (1) Allopurinol tab (1)Sodium valproate tab (1)Ticlopidine tab (1)

Body as a Anaphylactic reactions Amoxicillin cap (1) whole (5) Ceftriaxone inj (2)

Oxaliplatin inj (1)Orphenadrine / paracetamol tab (1)

Central nervous Encephalopathy Traditional Chinese medicine (2)system Extrapyramidal Chlorpheniramine tab or codeinedisorders (16) disorders phosphate / promethazine syr (1)

Febrile DTP® inj (3)convulsions / Infanrix HIB® inj (1)Seizure anoxic / Infanrix IPV+HIB® inj (2)Tonic-clonic Pneumovax ® inj (1)convulsions / Fits / Prochlorperazine inj (1)Spasms Tetract-HIB® inj (1)Neuroleptic Zuclopenthixol inj (1)malignant syndrome Thioridazine tab or trifluoperazine

tab (1)Paroxetine tab (1)

Psychosis Bromocriptine tab or entacaponetab (1)

Endocrine Acute pancreatitis Gabapentin cap (1)disorders (19) Adrenal crisis Traditional Malay medicine (1)

Thyroid disorders Traditional Chinese medicine (17)Gastrointestinal Duodenal ulcer / Aspirin tab (1)disorders (5) Perforated Aspirin tab or rofecoxib tab (1)

duodenal ulcer / Rofecoxib tab (2)Gastrointestinalulcer Haematemesis, Celecoxib cap (1)melaena

Hepatic Abnormal hepatic Co-trimoxazole tab (1)dysfunction (22) function / Increased Danazol cap (1)hepatic enzymes / L-asparaginase inj (1) Jaundice Traditional Chinese medicine (3)Cholestasis Traditional Chinese medicine (1)Hepatic damage Carbamazepine tab (1)

Hepatic failure Amiodarone tab (1)Bupropion tab (1)Gemtuzumab ozogamicin inj (1)Traditional Chinese medicine (4)

Hepatitis Allopurinol tab (1)Isoniazid tab or pyrazinamide tabor rifampicin cap (1)Isoniazid tab or rifampicin cap (2)Leflunomide tab (1)Traditional Chinese medicine (2)

Musculoskeletal Rhabdomyolysis Pravastatin tab (1)disorders (4) Simvastatin tab (3)

Renal Abnormal renal Amikacin inj or piperacillin /dysfunction (7) function tazobactam inj (1)

Acute renal failure Rofecoxib tab (1)Traditional Chinese medicine (2)

Interstitial nephritis, Rofecoxib tab (1)proteinuriaNephropathy Traditional Chinese medicine (1)

Respiratory Acute respiratory Asparaginase inj (1)disorders (19) distress Iohexol inj (1)

Apnoea Infanrix HIB® inj (1)Breathing difficulty / Alendronate tab (1)Shortness of breath Aspirin tab (1)/ Stridor Ceftriaxone inj (2)

Coamoxiclav tab (1)Ketoprofen cap (1)

Ketorolac inj (1)Omeprazole tab (1)Oxaliplatin inj (1)Paclitaxel inj (1)

Bronchospasm / Diclofenac inj (1) Wheezes Iohexol inj (1)

Ketorolac inj (1)Naproxen cap (1)

Laryngeal oedema Iohexol inj (1)Traditional Chinese medicine (1)

Skin Stevens-Johnson Allopurinol tab (1)reactions (14) Syndrome Carbamazepine tab or phenytoin

cap (1)Ciprofloxacin tab or vancomycininj (1)Co-trimoxazole tab (2)Orphenadrine / paracetamol tab (1)Phenytoin cap (2)Piroxicam cap (1)Salofalk ® tab (1)Sibutramine cap (1)Traditional Jamu medicine (1)

Toxic epidermal Erythromycin tab (1)necrolysis Omeprazole cap (1)

Others (4) Allopurinol Allopurinol tab (4)hypersensitivity syndrome

Description(Total no. of WHO preferred Suspectedreactions) term active ingredient

The above data cannot be used to measure the frequency of an ADR in Singapore as ADR reporting is associated with an unknown and a variable degree of under-reporting. The submission of a suspected ADR report also does not necessarily mean that it was caused by the drug. Many factors have to taken into account inassessing causal relationships including temporal association, the possible contribution of concomitant medication and the underlying disease.



sotretinoin (Roaccutane®, Roche), has been available inSingapore since 1984 and is used for the treatment of severenodular cystic acne and acne which has failed to respond to

other therapies.

a) Teratogenicity Isotretinoin is a known teratogen and treatment with

isotretinoin during pregnancy is contraindicated. The risksinclude an incidence of 15% of major malformations, 5% of perinatal mortality, 16% of premature birth and 40% of spontaneous abortion.

Since Accutane® (brand name of isotretinoin in the US) wasapproved in the US in 1982, Roche has received nearly 2,000reports of pregnant women exposed to the drug; 70% of theseoccurred even after the company launched the Pregnancy Prevention Programme in 1988. As part of the risk management programme for isotretinoin, physicians are reminded to gothrough the following checklist before prescribing isotretinoin:■ Exclude pregnancy before initiating treatment for female

patients of childbearing potential. Effective contraception isrequired for at least four weeks before starting treatment,throughout therapy, and for four weeks after stopping;

■ Advise patients that it could damage the foetus and to informphysician if pregnancy should occur;

■ Ensure that patients receive a copy of the patient informationleaflet and understand the information provided;

■ Ensure that patients sign the consent form and understand thepossible risks involved.

b) Psychiatric problemsCausal linkage between isotretinoin treatment and psychiatricevents cannot be established from the observations in post-

marketing reports due to under-reporting, the high incidenceof psychiatric illness in the population and the incomplete natureof spontaneous reports. Nonetheless these observations serveas important signals of a potential drug safety problem.

Based on the post-marketing surveillance reports received by Roche, as of April 2000, there has been 5,665 serious adverseevent reports reported with Accutane®. Psychiatric disordersconstitute 18.8% of these reports.

Update on Eprex and Pure Red cell Aplasia continued from page 1

New labelling amendmentsBased on the current data, the company has amended thepackage insert of Eprex ® to indicate that only the IV route shouldbe used in CRF patients, haemodialysis and peritoneal dialysispatients. The SC administration of Eprex ® can still be used for the treatment of anaemia in other patient populations e.g. thoseundergoing cancer chemotherapy and elective orthopaedicsurgery, as there have been no reports of antibody-mediated

PRCA in these patients.

Prescribe with care in women of childbearing age and in people prone to depressionCAREFUL USE OF ORAL ISOTRETINOIN

I

Whilst the company continues in its investigation into the causesof PRCA by Eprex ®, all healthcare professionals who areinvolved in the handling of Eprex ® are reminded that proper cold-chain handling of Eprex ® is important in ensuring stability of the product. It is advised not to keep Eprex ® outside of 2 – 8degree Celsius for more than one hour.

Please report any cases of PRCA associated with erythropoietinto the Pharmacovigilance (PV) Unit ■

Adverse Drug Reaction News is produced by the Centre for Pharmaceutical Administration, Health Sciences Authority and the Expert Panel on Adverse Drug Reactions

Its contents are not to be reproduced in part or in whole, without prior written approval to the editor. Whilst every effort is made in compiling the content of this publication, the publishers,editors and authors accept no liability whatsoever for the consequences of any inaccurate or misleading data, opinions or statements. The mention of any product by the authors does notimply any official endorsement of the product by the Health Sciences Authority. Copyright ® 2003 Health Sciences Authority of Singapore. All Rights Reserved.

Editorial Board

Clinical Professor Goh Chee Leok, Clinical Assoc. Professor Chng Hiok Hee, Dr Gilbert Lau,Clinical Professor Ng Han Seong, Professor Vernon Oh

Editor-in-Chief

Ms Chan Cheng Leng, BSc (Pharm) HonsExecutive Editor

Ms Ang Pei San, BSc (Pharm) Enquiries, comments and suggestions to:Pharmacovigilance Unit, Centre for Pharmaceutical Administration, Health Sciences Authority

2 Jalan Bukit Merah Singapore 169547 Tel: (65) 6325 5604, Fax: (65) 6325 5448 Website: http://www.hsa.gov.sg Email: [email protected]

The US FDA hasperformed an analysis onthe reports of suicidesand hospitalised cases of depression, suicidalideation and suicideattempts in US patients onisotretinoin for the period 1982 to May 2000. In total, there

were 147 cases reported of suicide and hospitalised depression. Among these, 38% had a previous psychiatric history, 33% hadnone, and information was unknown for 29%.

Thirty-seven of these persons committed suicide during or after isotretinoin use. The median age was 17 years and 84% of the37 reports were male. The median time from starting use of isotretinoin to suicide was about three months. Eighty-Fivepersons were hospitalised for depression, suicidal ideation, and/or suicide attempt during or shortly after isotretinoin use, and25 persons reported being hospitalised for these conditions after stopping isotretinoin. Of these reports, 56% of the patients werefemale. The median time for onset of the adverse effects fromuse of isotretinoin to hospitalisation was about one month, and18% experienced persistent problems after isotretinoin wasstopped.

In Singapore, the PV Unit has received one report of depressionin a young Chinese male who was prescribed Roaccutane®.However, the patient did not experience any suicidal ideation.

Physicians are advised to be alert for any adverse mood changesin their patients taking isotretinoin and to withdraw the drug if these occur or refer patients to a psychiatric specialist. The

warnings on psychiatric and behavioural disorders have beenincluded in the local package insert ■

References:1. Drug Information for the Healthcare Professional. Isotretinoin. USPDI

2002, 22nd edition pg 1784-9. Micromedex Thomson Healthcare.Quebecor World, Taunton, Massachusetts.

2. Clinical executive summary, Appendix I (http://www.fda.gov/ohrms/dockets/ac/00/backgrd/3639b1e_01.DOC)

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