February 2003 Vo1 5 No.

ISSN : 0219-2152

ADVERSE DRUG REACTION NEWS

cases of liver dysfunction associated with nefazodone
efazodone (Serzone , Bristol Myers Squibb) was licensed in Singapore in 1997 and is indicated for the treatment of depression. It inhibits re-uptake of serotonin and also selectively blocks serotonin receptors. As of December 2002, worldwide data shows that there have been 28 reports of liver failure, 15 of which resulted in deaths. These were suspected to be associated with nefazodone since it 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 who developed mildly elevated ALT suspected to be due to nefazodone. Recent developments in the international arena In January 2002, the US FDA added a Black Box Warning and strengthened the warnings of the label for Serzone to include the reports of liver failure. The reported rate in the US 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 the decision to voluntarily withdraw nefazodone in all European countries for commercial reasons. The drug continues to be available in countries such as the US and Australia. Package insert amendments The local package inserts for Serzone have been amended in February 2002 to include the black box and warning on hepatic adverse effect:
Nefazodone is not recommended for use in patients with

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

NEFAZODONE AND LIVER FAILURE UPDATE ON EPREX AND PURE RED Healthcare professionals are encouraged to report suspected CELL APLASIA

Amendment of product labelling information to advise only IV adminstration of Eprex in CRF patients

poetin alfa (Eprex, Janssen-Cilag) was licensed in Singapore in 1988 for the treatment of anaemia associated with chronic renal failure (CRF), cancer chemotherapy, autologous blood donation and during major elective orthopaedic surgery. It can be administered Photo courtesy of National Kidney Foundation 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 suspected to be associated with SC Eprex , the company amended its package insert to advise that the IV route be administered 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 confirmed by bone marrow biopsy and 112 were anti-erythropoietin antibodies positive. All cases of antibody-positive PRCA had administration of Eprex by the SC route. The incidence of antibody-positive PRCA for Eprex is estimated by the company to be rare, occurring at less than 1:1,000 patient years. Local PRCA reports In 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 were males 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 2000 IU 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.
continued on page 4

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 symptoms suggest liver failure, or if patient develops evidence of hepatocellular injury. Such patients should be assumed to be at increased risk of developing liver injury if nefazodone is restarted, and therefore this should not be considered.

These amendments and warnings of rare cases of liver failure have been brought to the attention of our physicians through a Dear Healthcare Professional Letter issued by the manufacturer in February 2002. The Unit is closely monitoring the safety of nefazodone and the measures taken by the other regulatory agencies such as those in the US and Australia. Healthcare professionals are encouraged to report every case of suspected ADRs to nefazodone to the PV Unit

CONTENTS
Nefazodone and liver failure Update on Eprex and pure red cell aplasia Analysis of ADR reports for year 2002 Careful use of isotretinoin 1 1 2 4

Provide us with your full name and email address to receive HSA drug safety information. Email us at HSA_DRUGSAFETY@hsa.gov.sg 1

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

ANALYSIS OF ADR REP

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

Active ingredient *

No of reports 54 47 34 30 28 22 22 21 15 15 13 13 13 13 12

he Pharmacovigilance (PV) Unit of the Centre for Pharmaceutical Administration, Health Sciences Authority (HSA) is responsible for the collation and review of all spontaneous adverse reports submitted by our healthcare professionals. This activity forms part of HSAs overall post-marketing surveillance program in ensuring the safety of all marketed medicinal products in Singapore. Review of ADR reports For the year 2002, a total of 801 ADR reports were submitted by our healthcare professionals. This represented an increase of more than 40% of reports received in 2001. The public sector hospitals contributed 68.5% of the reports followed by the private hospitals/health institutions (14.4%), the manufacturers (11.7%), general practitioners (8.7%) and others (0.7%).

Naproxen Diclofenac Ceftriaxone Iopamidol Mefenamic acid Ciprofloxacin Paracetamol Varicella zoster vaccine Amoxicillin Cefazolin Alendronate Allopurinol Cloxacillin Co-trimoxazole Rofecoxib
* May or may not be the sole suspected drug

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 more susceptible to ADRs than males. There were 1.8 times more ADR reports received in the female gender compared to the male. Serious adverse drug reactions comprised 22% of the total reports. There were 6 fatal cases suspected to be directly caused or precipitated by the offending drug(s). Eighteen percent 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 1: Breakdown of ADR reports by ethnic group (n = 801)
Unknown Others
35 (4%) 75 (9%)

Table 2: Top 10 ADRs

Description Rash and urticaria

1 2

No of ADRs 417 209 68 42 42 41 41 30 27 13

Facial oedema and angioedema Acute respiratory disorders Gastrointestinal disorders5 Thyroid disorders
6 4

Raised hepatic enzyme levels and other liver disorders3

Haematological disorders7 Palpitations and chest discomfort Musculoskeletal disorders8 Renal disorders
9

Malay
83 (10%)

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

Indian
45 (6%)

Chinese
563 (70%)

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 oedema 3 - Abnormal hepatic function, cholestasis, fatty liver, hepatic damage/failure, hepatitis, jaundice, hepatic cell damage, raised liver function tests 4 - Asthma, breathing difficulty/dyspnoea, bronchospasm, respiratory distress, shortness of breath, stridor, wheezes 5 - Abdominal distension/pain, bloating, diarrhoea, duodenal ulcer, epigastric pain, gastric irritation, haematemesis and melaena, nausea, peptic ulcer, vomiting 6 - Abnormal thyroid function tests, hyperthyroidism, thyrotoxicosis 7 - 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, muscle spasms 9 - Abnormal renal function, abnormal urine output, acute renal failure, interstitial nephritis, nephropathy, proteinuria, urinary frequency, urine discolouration

Male to female ratio is 1 : 1.8

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

288 (35.8%)

300
Number of ADR reports

250 200 150 100

44 (5.4%) 59 (7.4%) 178 (22.5%) 130 (16.2%) 102 (12.7%)

50 0
<1 1-12 13-24 25-44 Age (years) 45-60 >60

Adverse Drug Reaction News, Vol 5 No.1

PORTS FOR YEAR 2002

Table 3: Examples of some serious suspected ADRs Description (Total no. of reactions) Blood disorders (34) WHO preferred term Agranulocytosis Suspected active ingredient Carbimazole tab (1) Ticlopidine tab (1) Traditional Chinese medicine (1) Carbimazole tab (1) Description (Total no. of reactions) WHO preferred term Hepatic failure Suspected active ingredient Amiodarone tab (1) Bupropion tab (1) Gemtuzumab ozogamicin inj (1) Traditional Chinese medicine (4) Allopurinol tab (1) Isoniazid tab or pyrazinamide tab or rifampicin cap (1) Isoniazid tab or rifampicin cap (2) Leflunomide tab (1) Traditional Chinese medicine (2) Pravastatin tab (1) Simvastatin tab (3) Amikacin inj or piperacillin / tazobactam inj (1) Rofecoxib tab (1) Traditional Chinese medicine (2) Rofecoxib tab (1) Traditional Chinese medicine (1) Asparaginase inj (1) Iohexol inj (1) Infanrix HIB inj (1)

Idiopathic thrombocytopenic purpura Leucopenia Neutropenia

Hepatitis

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

Musculoskeletal disorders (4) Renal dysfunction (7)

Rhabdomyolysis Abnormal renal function Acute renal failure Interstitial nephritis, proteinuria Nephropathy

Pancytopenia

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)

Respiratory disorders (19)

Acute respiratory distress Apnoea

Body as a whole (5)

Anaphylactic reactions Amoxicillin cap (1) Ceftriaxone inj (2) Oxaliplatin inj (1) Orphenadrine / paracetamol tab (1) Encephalopathy Extrapyramidal disorders Febrile convulsions / Seizure anoxic / Tonic-clonic convulsions / Fits / Spasms Traditional Chinese medicine (2) Chlorpheniramine tab or codeine phosphate / promethazine syr (1) DTP inj (3) Infanrix HIB inj (1) Infanrix IPV+HIB inj (2) Pneumovax inj (1) Prochlorperazine inj (1) Tetract-HIB inj (1) Skin reactions (14)

Central nervous system disorders (16)

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 / Wheezes Diclofenac inj (1) Iohexol inj (1) Ketorolac inj (1) Naproxen cap (1) Iohexol inj (1) Traditional Chinese medicine (1) Allopurinol tab (1) Carbamazepine tab or phenytoin cap (1) Ciprofloxacin tab or vancomycin inj (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) Erythromycin tab (1) Omeprazole cap (1) Allopurinol tab (4)

Laryngeal oedema Stevens-Johnson Syndrome

Neuroleptic Zuclopenthixol inj (1) malignant syndrome Thioridazine tab or trifluoperazine tab (1) Paroxetine tab (1) Psychosis Endocrine disorders (19) Gastrointestinal disorders (5) Acute pancreatitis Adrenal crisis Thyroid disorders Duodenal ulcer / Perforated duodenal ulcer / Gastrointestinal ulcer Haematemesis, melaena Bromocriptine tab or entacapone tab (1) Gabapentin cap (1) Traditional Malay medicine (1) Traditional Chinese medicine (17) Aspirin tab (1) Aspirin tab or rofecoxib tab (1) Rofecoxib tab (2)

Toxic epidermal necrolysis Others (4) Allopurinol hypersensitivity syndrome

Celecoxib cap (1) Co-trimoxazole tab (1) Danazol cap (1) L-asparaginase inj (1) Traditional Chinese medicine (3) Traditional Chinese medicine (1) Carbamazepine tab (1)

Hepatic Abnormal hepatic dysfunction (22) function / Increased hepatic enzymes / Jaundice Cholestasis Hepatic damage

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 underreporting. 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 in assessing causal relationships including temporal association, the possible contribution of concomitant medication and the underlying disease.
Adverse Drug Reaction News, Vol 5 No.1

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

New labelling amendments Based on the current data, the company has amended the package insert of Eprex to indicate that only the IV route should be used in CRF patients, haemodialysis and peritoneal dialysis patients. The SC administration of Eprex can still be used for the treatment of anaemia in other patient populations e.g. those undergoing cancer chemotherapy and elective orthopaedic surgery, as there have been no reports of antibody-mediated PRCA in these patients.

Whilst the company continues in its investigation into the causes of PRCA by Eprex, all healthcare professionals who are involved 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 8 degree Celsius for more than one hour. Please report any cases of PRCA associated with erythropoietin to the Pharmacovigilance (PV) Unit

CAREFUL USE OF ORAL ISOTRETINOIN

Prescribe with care in women of childbearing age and in people prone to depression

sotretinoin (Roaccutane, Roche), has been available in Singapore since 1984 and is used for the treatment of severe nodular 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 risks include an incidence of 15% of major malformations, 5% of perinatal mortality, 16% of premature birth and 40% of spontaneous abortion.

The US FDA has performed an analysis on the reports of suicides and hospitalised cases of depression, suicidal ideation and suicide attempts in US patients on isotretinoin 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% had none, 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 the 37 reports were male. The median time from starting use of isotretinoin to suicide was about three months. Eighty-Five persons were hospitalised for depression, suicidal ideation, and/ or suicide attempt during or shortly after isotretinoin use, and 25 persons reported being hospitalised for these conditions after stopping isotretinoin. Of these reports, 56% of the patients were female. The median time for onset of the adverse effects from use of isotretinoin to hospitalisation was about one month, and 18% experienced persistent problems after isotretinoin was stopped. In Singapore, the PV Unit has received one report of depression in 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 changes in 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 been included 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. Clinical executive summary, Appendix I (http://www.fda.gov/ohrms/ dockets/ac/00/backgrd/3639b1e_01.DOC)

Since Accutane (brand name of isotretinoin in the US) was approved in the US in 1982, Roche has received nearly 2,000 reports of pregnant women exposed to the drug; 70% of these occurred even after the company launched the Pregnancy Prevention Programme in 1988. As part of the risk management programme for isotretinoin, physicians are reminded to go through the following checklist before prescribing isotretinoin:
Exclude pregnancy before initiating treatment for female patients of childbearing potential. Effective contraception is required 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 inform physician if pregnancy should occur; Ensure that patients receive a copy of the patient information leaflet and understand the information provided; Ensure that patients sign the consent form and understand the possible risks involved.

b) Psychiatric problems Causal linkage between isotretinoin treatment and psychiatric events cannot be established from the observations in postmarketing reports due to under-reporting, the high incidence of psychiatric illness in the population and the incomplete nature of spontaneous reports. Nonetheless these observations serve as 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 adverse event reports reported with Accutane. Psychiatric disorders constitute 18.8% of these reports.

2.

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

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

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

Executive 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: HSA_DRUGSAFETY@hsa.gov.sg

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 not imply any official endorsement of the product by the Health Sciences Authority. Copyright 2003 Health Sciences Authority of Singapore. All Rights Reserved.

Adverse Drug Reaction News, Vol 5 No.1