n

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

n e w s ISSN: 0219 2152 March 2004 Vol. 6 No. 1

New preclinical findings on Oseltamivir

Oseltamivir is not recommended for infants less than 1 year of age

seltamivir (Tamiflu , Roche) was recently licensed for the treatment of uncomplicated illness due to influenza infections in children 1 year of age and older who have been symptomatic for no more than 2 days. It has been licensed for use in adults since October 2000. We highlight the findings of a recent preclinical study which alerts to the potential concerns pertaining to the use of Tamiflu in very young children.

the concerns to the regulatory authorities regarding the use of Tamiflu in infants.

New preclinical findings

Roche has recently released the findings from its preclinical study carried out in juvenile rats (7-day old) and highlighted

Juvenile rats that were treated with a single dose of 1000 mg/kg oseltamivir (about 250 times the recommended total daily dose) died due to the unusually high levels of oseltamivir and its phosphate salt found in the brain of these young animals. The concentrations of oseltamivir phosphate were approximately 1,500 times those seen in adult rats given the same dose. It is likely that these high exposures are related to an immature blood brain barrier of the juvenile rats. Studies showed no death or other

significant effects in older juvenile rats given the same or higher doses of Tamiflu.

HSAs recommendation / action

The clinical significance of these data to human infants is uncertain. Due to the uncertainty in predicting the exposures in infants with immature blood brain barrier, prescribers are advised that Tamiflu should not be given to children under 1 year of age. The above findings have been included in the package insert of Tamiflu.

Case report of Cushings syndrome with traditional medicine (Pil Ajaib)

Healthcare professionals are encouraged to ask if their patients are consuming complementary medicine when taking medical history

Local case report

he Pharmacovigilance Unit recently received an ADR report of Cushing's syndrome suspected to be associated with Pil Ajiab, a traditional medicine which is labelled to contain herbs and spices. The patient has been taking this product which was purchased from outside of Singapore for her joint pain for two years. The purported indications of the product include relief of various pain and numbness.
continued on Page 5

Content

Oseltamivir treatment of influenza in children

Cushings syndrome due to adulterated traditional medicine

Analysis of ADR reports for 2003

Doxycycline and oesophagitis

Labelling changes Safety update

Repor ting Made Easy: Online adverse drug reaction repor ting is available at http://www.hsa.gov.sg/ADR_online

Analysis of ADR reports for year 2003

T
he reporting of spontaneous adverse drug reactions (ADR) by our healthcare professionals to the Health Sciences Authority (HSA) is one of the most effective tools that we have at HSA to monitor the safety of a marketed drug / health product in Singapore. In an effort to improve the signals obtained from the spontaneous reports, HSA has stepped up its effort to promote ADR reporting amongst our healthcare professionals. Over the last year, more than 15 roadshows targeted at our doctors and pharmacists were conducted to promote the relevance of ADR reporting. HSA also organised its 1st HSA Drug Safety Seminar on 1st November 03 which focussed on the clinical aspects of ADR. To faciliate the reporting of ADRs, new yellow ADR reporting forms were distributed to all registered clinics and pharmacies in Singapore. In addition, the frequency of the ADR news bulletin was increased to 3 issues a year from the previous of 2. The female to male ratio of the patients in the reports was 1.6 : 1 (672 vs 423 reports). The most common age group reported with ADRs was the 25 44 years age group. This formed 33% of the total patient cohort. Chart 1 shows the breakdown of the no. of patient by age group. NSAIDs and antibiotics were the most commonly reported drugs causing ADRs in our local patients (See Table 1). The top 3 reported ADRs (by system-organ class) include skin, body as a whole (general) and gastrointestinal disorders. Refer to Table 2 for further information. The serious ADRs constituted 18.8% of the total reports. Examples of some serious suspected ADRs received in 2003 are listed in Table 3. There were 2 fatal cases suspected to be directly caused or precipitated by the offending drug(s). Seventeen percent of the patients were hospitalised due to ADRs and in another 30% of the reports, the patients were already hospitalised when the adverse reaction occurred. Chart 1: Breakdown of no. of patients who experienced ADRs by age group (n = 1,100)
Table 2: Top 10 ADRs by system-organ classes* Description
Skin disorders Body as a whole - general disorders Gastrointestinal system disorders Respiratory system disorders Nervous system disorders Cardiovascular disorders Haematological disorders Raised hepatic enzyme levels and other liver disorders Musculoskeletal system disorders Metabolic and nutritional disorders

Description (Total no. of reactions)

WHO ADR preferred term

Suspected drug

Description (Total no. of reactions)

WHO ADR preferred term

Suspected drug

Hepatic dysfunction (21)

Abnormal hepatic function / Increased hepatic enzymes / Jaundice Fatty liver Hepatic failure

Nimesulide (1) Sodium valproate (2) Phenytoin or piperacillin plus tazobactam (1) Sodium valproate (1) Allopurinol (1) Complementary medicine (1) Isoniazid or pyrazinamide or rifampicin (1) Phenobarbitone (1) Allopurinol (2) Complementary medicine (2) Complementary medicine or isoniazid or pyrazinamide or rifampicin (1) Sodium valproate (1) Chlorpromazine (1) Lovastatin (1) Simvastatin (1) Diclofenac (1) Losartan (1) Lovastatin (1) Rofecoxib (2) Teicoplanin or imipenem plus cilastin (1) Rofecoxib (1) Rituximab (1) Atovaquone plus proguanil (1) Alka-seltzer or ketoprofen (1) Allopurinol or enalapril(1) Cefazolin or diclofenac (1) Co-trimoxazole (1) Diclofenac (1) Iohexol (2) Naproxen (1) Paracetemol or tolbutamide (1) Prochlorperazine (1) Streptokinase (1) Teicloplanin or vancomycin (1) Vitamin K (1) Atracurium or propofol (1) Bromhexine or cefalexin (1) Cefazolin or diclofenac (1) Ceftriaxone (3) Ciprofloxacin (1) Ciclosporin (1) Diclofenac (4) Iohexol (1) Mepivacaine (1) Sulfasalazine (1) Hydrochlorothiazide (1) Imipenem plus cilastin or vancomycin (1) Rifampicin (1) Allopurinol (2) Amitriptyline or carbamazepine (1) Amoxicillin (1) Amoxicillin or complementary medicine or ibuprofen (1)

Skin reactions (32)

Stevens Johnson Syndrome

No. of ADRs
887 361 136 86 62 42 41 33 26 26

% of total no. of ADRs

46.2 18.8 7.1 4.5 3.2 2.2 2.1 1.7 1.4 1.4

Hepatitis

Amoxicillin or nimesulide or spiramycin (1) Aspirin or Alka-seltzer or cotrimoxazole or diclofenac (1) Carbamazepine (3) Carbamazepine or hydrochlorothiazide (1) Cefadroxil (1) Cefalexin or chloramphenicol (1) Coamoxiclav or carbamazepine (1) Complementary medicine (2) Co-trimoxazole or phenytoin or sulfasalazine(1) Lamotrigine (1) Trimethoprim (1) Amoxicillin (2) Ampicillin or ceftriaxone or vancomycin (1) Coamoxiclav (1) Coamoxiclav or ceftriaxone (1) Co-trimoxazole (1) Co-trimoxazole or cefuroxime (1) Levofloxazin (1) Mefenamic acid (1) Nitrofurantoin (1) Rosiglitazone (1) Amifostine (1) Ampicillin or propofol (1) Bromhexine or cefalexin (1) Cefaclor (1) Ceftriaxone (1) Cisplatin (1) Complementary medicine (1) Etoposide (1) Mepivacaine (1) Ondansetron (1) Orphenadrine or paracetemol or Panadeine (1) Paclitaxel (2) Paroxetine (1) Streptokinase (1) Rosiglitazone (1) Suxamethonium or asparaginase (1) Warfarin (1) Amiloride plus hydrochlorothiazide (2) Carbamazepine (1) Citalopram (1) Hydrochlorothiazide (1) Hydrochlorothiazide plus losartan (1) Indapamide (1) Losartan (1) Rofecoxib (1)

Toxic epidermal necrolysis

Musculoskeletal disorders (3) Renal dysfunction (9)

Rhabdomyolysis

* The system-organ class refers to the adverse reaction terminology developed by the WHO. (NB: More than one ADR may be described in an ADR report)

Acute / Chronic renal failure

Table 3: Examples of some serious suspected ADRs received in 2003

400
363 (33%) Description (Total no. of reactions) 257 (23.4%) 208 (18.9%) 136 (12.4%) 98 (8.9%) 38 (3.4%) WHO ADR preferred term Suspected drug Description (Total no. of reactions) WHO ADR preferred term Suspected drug

No. of ADR reports

350 300 250 200 150 100 50 0

Blood disorders (19)

Agranulocytosis / Leucopenia / Neutropenia / Pancytopenia

<1

1-12

13-24

25-44

45-60

>60 Methaemoglobinaemia / Monocytosis / Thrombocythaemia Thrombocytopenia

Overview of reports
From our analysis, the number of ADR reports received by the Pharmacovigilance Unit from 1997 to 2003 has been increasing steadily at an average of 20% per annum. For 2003, the unit received 1,100 reports; this represented a 38% increase over the number of reports received in 2002. The public hospitals contributed the majority of the reports (60.3%), followed by the private clinics (14.3%), public health institutions (10.3%), private hospitals/ health institutions (8.1%), pharmaceutical companies (4.2%), polyclinics (2.3%) and retail pharmacies (0.5%). Three-quarter of the reporters were doctors but reports from pharmacists have increased (197 reports for 2003 compared to 137 in 2002).

Age (years)

Amantadine or peginterferon alpha-2b or ribavirin (1) Carbamazepine (2) Carbimazole (2) Ciprofloxacin or phenytoin (1) Clopidogrel (1) Doxorubicin (1) Meropenem (1) Ranitidine or sodium valproate or vancomycin (1) Ticlopidine (1) Ticlopidine or imipenem plus cilastin (1) Vancomycin (1) Ciprofloxacin or phenytoin (1) Dapsone (1) Paroxetine (1) Carbamazepine (2) Gefitinib (1) Alka-seltzer or ketoprofen (1) Amoxicillin or diclofenac (1) Atracurium or morphine (1) Bromhexine or cefalexin (1) Cefaclor (1) Cefazolin or diclofenac (1) Ceftriaxone (1) Iohexol (1) Mepivacaine (1) Orphenadrine or paracetemol or Panadeine (1) Sultamicillin (1) Clonazepam or imipramine or risperidone (1) Chlorpromazine (1) DTP Vaccine (1) Imipenem plus cilastin (1) Infanrix IPV-HIB inj (2) Suxamethonium or asparaginase (1)

Central nervous system disorders (17)

Neuroleptic malignant syndrome Psychosis Optic atrophy Brachial neuritis Motor activity retarded / Ataxia Hemiparesis Intraventricular haemorrhage Serotonin syndrome

Clonazepam or imipramine or risperidone (1) Haloperidol (1) Chloroquine (1) Hydroxychloroquine (1) Hepatitis B inj (1) Celecoxib (1) Paroxetine (1) Oxaliplatin (1) Warfarin (1) Paroxetine (1) Lovastatin (2) Complementary medicine or prednisolone (1) Complementary medicine (1) Indapamide (1) Respiratory disorders (28)

Interstitial nephritis / Proteinuria Nephropathy Pulmonary fibrosis Breathing difficulty / Shortness of breath / Stridor / Hypoxia

Cardiovascular disorders (16)

Cardiac failure Hypotension / Hypertension

Myocardial infarction Others (11) Diabetes mellitus Hydrocephalus Hypokalaemia / Hyponatraemia

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

Active ingredient*
Diclofenac Co-trimoxazole Naproxen Ceftriaxone Mefenamic acid Amoxicillin Paracetamol Aspirin Ciprofloxacin Coamoxiclav Cefalexin Cefazolin Erythromycin Ibuprofen Cloxacillin
* May or may not be the sole suspected drug(s)

No. of reports
100 67 67 51 50 48 42 28 24 24 22 21 21 21 20

% of the total no. of suspected active ingredients

6.8 4.5 4.5 3.5 3.4 3.3 2.9 1.9 1.6 1.6 1.5 1.4 1.4 1.4 1.4

Body as a whole (11)

Anaphylactic reactions

Endocrine disorders (6)

Acute pancreatitis Adrenal insufficiency / Cushings syndrome Syndrome of inappropriate ADH secretion Diabetes mellitus

Bronchospasm / Wheezes

Olanzapine (1) Aspirin (1) Carbamazepine or hydrochlorothiazide (1) Clopidogrel (1) Co-trimoxazole or cefuroxime (1) Warfarin (1) Allopurinol (3) Complementary medicine (1) Ciclosporin (1) Moxifloxacin (1) Skin reactions (32) Exfoliative dermatitis

Central nervous system disorders (17)

Encephalopathy Febrile convulsions / Fits / Seizure anoxic / Spasms / Tonicclonic convulsions

Gastrointestinal disorders (5)

Duodenal ulcer / Perforated duodenal ulcer / GI ulcer / GI perforation

Stevens Johnson Syndrome

Hepatic dysfunction (21)

Abnormal hepatic function / Increased hepatic enzymes / Jaundice

NB: 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 be taken into account in assessing causal relationships including temporal association, the possible contribution of concomitant medication and the underlying disease.

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continued from Page 1 Case report of Cushings syndrome with traditional medicine (Pil Ajaib)

On admission to the hospital for other medical conditions, the attending doctor noted that the patient was clinically cushingnoid. The patient who was not on any other medications also complained of weight gain, multiple joint pains and lethargy. Further tests conducted suggested that the Cushings syndrome may be precipitated by consumption of exogenous steroids.

labelling. The purchase of these products from unreliable sources could pose additional safety problems if they are adulterated with western medicines. As part of medical history taking, healthcare professionals are encouraged to ask if their patients are also taking complementary medicine. Healthcare professionals are encouraged to report any suspected ADRs arising from consumption of complementary medicines to the Pharmacovigilance Unit at HSA. If adulterations with western drugs are suspected, samples may be forwarded together with the report for further investigations.

HSA investigations
The analysis of the samples of Pil Ajaib revealed that it was adulterated with indomethacin 15.42 mg/capsule and dexamethasone 0.22 mg/capsule. Based on the manufacturers recommended dose of 4 capsules per day, the total intake of indomethacin and dexamethasone per day are about 60 mg and 0.88 mg respectively. These are therapeutic doses of the two drugs. The presentation of Cushings syndrome in this patient is consistent with the effects of prolonged consumption of dexamethasone.

Conclusion
Herbal medicinal products are generally perceived by the public to be safer than conventional western medicines. However the safety of some unlicensed herbal products may be compromised by lack of suitable quality control and inadequate

Doxycycline Oesophagitis
Take doxycycline with food or a large glass of water while in an upright position

&

(TGA) received 46 suspected reports of oesophagitis and 49 suspected reports of oesophageal ulceration associated with this drug 2.

oxycycline is the most commonly reported tetracycline analogue that causes oesophagitis. More than 70 drugs have been reported in the literature to induce oesophageal disorders, however antibacterials such as doxycycline, tetracycline and clindamycin account for more than 50% of cases 1.

Local ADR reports

To-date, the Pharmacovigilance Unit, HSA has received four local reports of retrosternal pain suspected to be associated with the intake of oral doxycycline. In all 4 cases, there was no indication that the adverse reaction progressed to oesophageal ulceration. These cases involved patients between 20 to 24 years of age, who took the antibacterial agent for acne vulgaris or upper respiratory tract infection from two days to 3.5 months. The ADRs were not considered serious in nature by the reporting doctors.

Endoscopic view of oseophagitis

Mechanism of action
Patients who have difficulty in swallowing solid dosage forms of medications are more susceptible to doxycycline-induced oesophagitis. When the doxycyline tablet /capsule transits down the oesophageal lumen, it dissolves to form an acidic solution. High local concentrations of the acidic solution resulting from increased transit time or when the drug gets lodged in the oesophagus can cause mucosal lesions. In addition, reflux of the medication which can occur when a patient lies down soon after taking the drug can also cause similar problems. Symptoms of reflux oesophagitis include heartburn, retrosternal pain and regurgitation.

Doxycycline-induced oesophagitis is often self-limiting upon discontinuation of the drug. However, in severe cases, symptomatic treatment may be required.

Overseas reports
The WHO ADR database (which captures the spontaneous ADR reports from more than 60 countries participating in the WHO International Drug Monitoring Program) has 352 suspected reports of doxycyclineinduced oesophagitis for the period 1969 to 2003. The New Zealand Pharmacovigilance Centre has received 46 suspected reports of oesophagitis associated with doxycycline for the period up to October 2003 and the Australia Therapeutic Goods Administration

Advice to patients
To minimise this risk, patients should be advised to take doxycycline in an upright position, with food or with a large glass of water and to also avoid taking it just before bedtime.
References 1. Jaspersen D. Drug-induced oesophageal disorders: pathogenesis, incidence, prevention and management. Drug Saf. 2000 Mar; 22(3): 237-49. 2. Medical Editorial Team. Oesophagitis with doxycycline and others. Prescriber Update 2003;24(2):30

5 Adverse Drug Reaction News March 2004 Vol. 6 No. 1

Package insert amendments reflecting safety issues

Labelling amendments made between August and November 2003 are listed below. For details, please refer to the updated package inserts (PI).
1. Alendronate (Fosamax; MSD) Prescribers are advised to monitor patients serum calcium levels and symptoms of hypocalcaemia in those with mineral metabolism disorders. An acute phase response (myalgia, malaise and rarely, fever) has been reported with Fosamax. Severe skin reactions including Stevens Johnson syndrome and toxic epidermal necrolysis have been reported rarely. 2. Betamethasone as 17-valerate (Betnovate; GSK) Warning that use of topical steroids may be hazardous in psoriasis has been added. Local skin burning and pruritus are now listed as common ADRs. 3. Bupropion (Zyban; GSK) Instructions for use in renal and liver impaired patients have been included. New ADRs have been added based on post-marketing experience. These include palpitation, dystonia, hallucination, urinary frequency and/or retention, hepatitis and symptoms of serum sickness. 4. Carbamazepine (Tegretol ; Novartis) Women of childbearing age are advised to use alternative forms of birth control while taking Tegretol. Lists of drugs that may raise or decrease Tegretol levels have been included. New adverse events including very rare (<0.01%) occurrence of hepatic failure, pancreatitis and angioedema has been added. 5. Ciclosporin (Sandimmun ; Novartis) Warnings of increased risks of developing malignancies and infections have been added. Statement that treatment using multiple immunosuppressants could lead to the development of lymphoproliferative disorders and solid tumours (with reports of fatalities) was included. New drugs that interact with ciclosporin and the various complications have been listed. New ADRs reported include motor polyneuropathy (rare), anorexia, nausea, vomiting, abdominal pain, diarrhoea (common), hyperlipidaemia (very common) and gynecomastia (rare). 6. Enoxaparin Aventis Pharma) New precautionary statements on percutaneous coronary revascularisation procedures, bleeding and information on lab tests have (Clexane; rapid dose reduction, withdrawal of, or changes in antiparkinson therapy. Fibrotic and serosal inflammatory disorders have been reported after prolonged usage. Signs and symptoms to look out for in these disorders are listed in the PI. Patients should be advised to exercise caution while driving or operating machinery during treatment with pergolide because of reported cases of somnolence and episodes of sudden sleep onset. 14. Pneumococcoal 7-valent conjugate (Prevenar; Wyeth) ADRs from post-marketing experience including blood, lymphatic & immune disorders have been added. Adverse events reported with overdose have been reported with recommended single dose of Prevenar 15. Rofecoxib (Vioxx ; MSD) VIGOR study has been included in the PI to reflect the higher risk of cardiovascular thromboembolism in patients taking Vioxx compared to naproxen. The side effects list has been updated with new post-marketing reports including bronchospasm, anaphylactic reactions, hypertensive crisis, hepatic failure, peptic ulcers, aplastic anaemia and toxic epidermal necrolysis. 16. Sibutramine (Reductil ; Abbott Lab) Reports of bleeding disorders have been included. ADRs list has been updated with new postmarketing reports. 17. Sildenafil (Viagra; Pfizer) Clinical data showing simultaneous administration of sildenafil and doxazosin may lead to hypotension has been included. Additional clinical data on patients taking multiple antihypertensive agents was also elaborated. 18. Temozolomide (Temodal ; ScheringPlough) New ADRs have been added: lymphopenia (very common) and rare cases of opportunistic infections including Pneumocystis carinii pneumonia (PCP). 19. Valsartan (Diovan ; Novartis) Postmarketing reports of very rare cases of impaired renal function, angioedema, rash, pruritus and hypersensitivity/allergic reaction (including serum sickness & vasculitis) have been included.

been included. Details on the risk of patients (including pregnant women) with mechanical prosthetic valves are elaborated. Major haemorrhage cases including retroperitoneal and intracranial bleeding, some of which were fatal, have been included. 7. Epoetinum alfa (Eprex ; Johnson & Johnson) An increased incidence of thrombotic events in cancer patients has been reported. 8. Fluticasone propionate (Flixonase; GSK) New precautionary statements on interaction with ritonavir that can greatly increase fluticasone plasma levels resulting in markedly reduced serum cortisol concentrations. Postmarketing reports of this systemic corticosteroid effects including Cushings syndrome and adrenal suppression have been included in the PI. Headache has been added as a new common ADR. 9. Haemaccel Infusion Solution (Aventis Pharma) Very rare cases of air embolism have been reported. Instructions to expel air for infusion under pressure are included. 10. Ketoprofen (Fastum Gel; Pharmaforte) Under the contraindications section, hypersensitivity to other related products was elaborated. Patients are warned to avoid direct sunlight (including sunbeds) during treatment. Postmarketing experience of isolated but severe cases of erythema, burns, pruritus, dermatitis, urticaria and boil reactions have been reported. 11. Lactated Ringers Injection USP (Baxter) Frequency of allergic reactions or anaplylactoid symptoms has been reported to be higher in women during pregnancy. 12. Paroxetine (Seroxat; GSK) Statements on the lack of efficacy in children with major depressive disorder have been included. A new section on adverse events arising from paediatric clinical trials has been added. 13.Pergolide mesylate (Celance, Eli Lilly) Advice on gradual discontinuation of pergolide has been included. A complex symptom resembling the neuroleptic malignant syndrome (NMS) has been reported in association with

Adverse Drug Reaction News is produced by the Centre for Drug Administration, HSA and the Pharmacovigilance Advisory Committee
Editor-in-Chief Ms Chan Cheng Leng BSc (Pharm) Hons Editorial Board Clinical Prof. Goh Chee Leok Prof. Edmund Lee Jon Deoon A/Prof. Chia Kee Seng Clinical A/Prof. Chng Hiok Hee Dr Gilbert Lau Kwang Fatt Dr Lee Kheng Hock Enquiries, comments and suggestions to: Pharmacovigilance Unit, Centre for Drug 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

Executive Editor Ms Ang Pei San BSc (Pharm) Staff Editors Ms Tan Bee Him BSc (Pharm) Dr Ting Kang Nee BPharm (Hons), PhD

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 2004 Health Sciences Authority of Singapore. All Rights Reserved.