Download New preclinical findings on Oseltamivir Case report of Cushing`s

continued from Page 1 • Case report of Cushing’s syndrome with traditional medicine (Pil Ajaib®)
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
manufacturer’s 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 Cushing’s 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
D
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.
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.
5 • Adverse Drug Reaction News • March 2004 • Vol. 6 No. 1
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.
(TGA) received 46 suspected reports of
oesophagitis and 49 suspected reports of
oesophageal ulceration associated with
this drug 2.
Local ADR reports
Endoscopic view of oseophagitis
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
Package insert amendments reflecting safety issues
labelling. The purchase of these products
from unreliable sources could pose
additional safety problems if they are
adulterated with western medicines.
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.
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.
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 patient’s 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.
(Tegretol ® ;
4. Carbamazepine
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.
(Sandimmun ® ;
5. Ciclosporin
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 (Clexane®; Aventis Pharma)
New precautionary statements on percutaneous
coronary revascularisation procedures,
bleeding and information on lab tests have
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.
(Flixonase®;
8. Fluticasone propionate
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 Cushing’s 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.
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.
11. Lactated Ringer’s Injection USP (Baxter)
Frequency of allergic reactions or anaplylactoid
symptoms has been reported to be higher in
women during pregnancy.
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.
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.
18. Temozolomide (Temodal ® ; ScheringPlough) New ADRs have been added:
lymphopenia (very common) and rare cases of
opportunistic infections including Pneumocystis
carinii pneumonia (PCP).
(Celance®,
13.Pergolide mesylate
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
n
Published by the Centre for Drug Administration, HSA and the Pharmacovigilance Advisory Committee
Editor-in-Chief
Ms Chan Cheng Leng BSc (Pharm) Hons
Executive Editor Ms Ang Pei San BSc (Pharm)
Staff Editors
Ms Tan Bee Him BSc (Pharm)
Dr Ting Kang Nee BPharm (Hons), PhD
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
w
s
n e w s
• ISSN: 0219 – 2152 • March 2004 • Vol. 6 No. 1
Oseltamivir is not recommended for infants
less than 1 year of age
O
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.
New preclinical findings
Roche has recently released the findings
from its preclinical study carried out in
juvenile rats (7-day old) and highlighted
the concerns to the regulatory authorities
regarding the use of Tamiflu® in infants.
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®.
HSA’s 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 Cushing’s 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
(Diovan ® ;
19. Valsartan
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.
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.
Adverse Drug Reaction News is produced by the Centre for Drug Administration, HSA and the Pharmacovigilance Advisory Committee
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
e
New preclinical findings on Oseltamivir
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: [email protected]
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.
continued on Page 5
Content
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 Cushing’s syndrome may be precipitated by
consumption of exogenous steroids.
Oseltamivir treatment of
influenza in children
Cushing’s 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.
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.
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.
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.
No. of ADR reports
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.
300
257 (23.4%)
250
208 (18.9%)
200
No. of
ADRs
% of total
no. of ADRs
887
361
136
86
62
42
41
33
26
26
46.2
18.8
7.1
4.5
3.2
2.2
2.1
1.7
1.4
1.4
* 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)
50
0
Blood
disorders
(19)
WHO ADR
preferred
term
Agranulocytosis /
Leucopenia /
Neutropenia /
Pancytopenia
136 (12.4%)
150
100
98 (8.9%)
38 (3.4%)
<1
1-12
13-24
25-44
45-60
>60
Age (years)
Table 1: Top 15 drugs (by active ingredients) suspected of causing ADRs.
Active ingredient*
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).
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)
350
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.
Description
Table 3: Examples of some serious suspected ADRs received in 2003
363 (33%)
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)
2 • Adverse Drug Reaction News • March 2004 • Vol. 6 No. 1
No. of
reports
% of the total no. of
suspected active ingredients
100
67
67
51
50
48
42
28
24
24
22
21
21
21
20
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
Hepatic
dysfunction
(21)
Table 2: Top 10 ADRs by system-organ classes*
Chart 1: Breakdown of no. of patients who experienced ADRs by age group (n = 1,100)
400
Description
(Total no. of
reactions)
Body as a
whole (11)
Central
nervous
system
disorders
(17)
Suspected
drug
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)
Methaemoglobinaemia / Monocytosis
/ Thrombocythaemia
Ciprofloxacin or phenytoin (1)
Dapsone (1)
Paroxetine (1)
Thrombocytopenia
Carbamazepine (2)
Gefitinib (1)
Anaphylactic
reactions
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)
Encephalopathy
Clonazepam or imipramine or
risperidone (1)
Febrile convulsions /
Fits / Seizure anoxic
/ Spasms / Tonicclonic convulsions
Chlorpromazine (1)
DTP Vaccine (1)
Imipenem plus cilastin (1)
Infanrix IPV-HIB® inj (2)
Suxamethonium or
asparaginase (1)
Description
(Total no. of
reactions)
Central
nervous
system
disorders
(17)
Endocrine
disorders
(6)
Gastrointestinal
disorders
(5)
Hepatic
dysfunction
(21)
WHO ADR
preferred
term
Clonazepam or imipramine or
risperidone (1)
Haloperidol (1)
Psychosis
Chloroquine (1)
Optic atrophy
Hydroxychloroquine (1)
Brachial neuritis
Hepatitis B inj (1)
Motor activity
retarded / Ataxia
Celecoxib (1)
Paroxetine (1)
Hemiparesis
Oxaliplatin (1)
Intraventricular
haemorrhage
Warfarin (1)
Serotonin syndrome
Paroxetine (1)
Acute pancreatitis
Lovastatin (2)
Adrenal insufficiency
/ Cushing’s syndrome
Complementary medicine or
prednisolone (1)
Complementary medicine (1)
Syndrome of
inappropriate ADH
secretion
Indapamide (1)
Diabetes mellitus
Olanzapine (1)
Duodenal ulcer /
Perforated duodenal
ulcer / GI ulcer /
GI perforation
Aspirin (1)
Carbamazepine or
hydrochlorothiazide (1)
Clopidogrel (1)
Co-trimoxazole or cefuroxime (1)
Warfarin (1)
Allopurinol (3)
Complementary medicine (1)
Ciclosporin (1)
Moxifloxacin (1)
Suspected
drug
Abnormal hepatic
function / Increased
hepatic enzymes /
Jaundice
Nimesulide (1)
Sodium valproate (2)
Phenytoin or piperacillin plus
tazobactam (1)
Fatty liver
Sodium valproate (1)
Hepatic failure
Allopurinol (1)
Complementary medicine (1)
Isoniazid or pyrazinamide or
rifampicin (1)
Phenobarbitone (1)
Hepatitis
Allopurinol (2)
Complementary medicine (2)
Complementary medicine or
isoniazid or pyrazinamide or
rifampicin (1)
Sodium valproate (1)
Musculoskeletal
disorders
(3)
Rhabdomyolysis
Chlorpromazine (1)
Lovastatin (1)
Simvastatin (1)
Renal
dysfunction
(9)
Acute / Chronic
renal failure
Diclofenac (1)
Losartan (1)
Lovastatin (1)
Rofecoxib (2)
Teicoplanin or imipenem plus
cilastin (1)
Suspected
drug
Neuroleptic
malignant
syndrome
Abnormal hepatic
function / Increased
hepatic enzymes /
Jaundice
WHO ADR
preferred
term
Respiratory
disorders
(28)
Skin
reactions
(32)
Interstitial nephritis /
Proteinuria
Rofecoxib (1)
Nephropathy
Rituximab (1)
Pulmonary fibrosis
Atovaquone plus proguanil (1)
Breathing difficulty /
Shortness of breath /
Stridor / Hypoxia
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)
Bronchospasm /
Wheezes
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)
Exfoliative dermatitis
Hydrochlorothiazide (1)
Imipenem plus cilastin or
vancomycin (1)
Rifampicin (1)
Stevens Johnson
Syndrome
Allopurinol (2)
Amitriptyline or
carbamazepine (1)
Amoxicillin (1)
Amoxicillin or complementary
medicine or ibuprofen (1)
Description
(Total no. of
reactions)
Skin
reactions
(32)
Cardiovascular
disorders
(16)
Others (11)
WHO ADR
preferred
term
Suspected
drug
Stevens Johnson
Syndrome
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)
Toxic epidermal
necrolysis
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)
Cardiac failure
Rosiglitazone (1)
Hypotension /
Hypertension
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)
Myocardial infarction
Rosiglitazone (1)
Diabetes mellitus
Suxamethonium or
asparaginase (1)
Hydrocephalus
Warfarin (1)
Hypokalaemia /
Hyponatraemia
Amiloride plus
hydrochlorothiazide (2)
Carbamazepine (1)
Citalopram (1)
Hydrochlorothiazide (1)
Hydrochlorothiazide plus
losartan (1)
Indapamide (1)
Losartan (1)
Rofecoxib (1)
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.
Adverse Drug Reaction News • March 2004 • Vol. 6 No. 1 • 4
continued from Page 1 • Case report of Cushing’s syndrome with traditional medicine (Pil Ajaib®)
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
manufacturer’s 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 Cushing’s 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
D
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.
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.
5 • Adverse Drug Reaction News • March 2004 • Vol. 6 No. 1
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.
(TGA) received 46 suspected reports of
oesophagitis and 49 suspected reports of
oesophageal ulceration associated with
this drug 2.
Local ADR reports
Endoscopic view of oseophagitis
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
Package insert amendments reflecting safety issues
labelling. The purchase of these products
from unreliable sources could pose
additional safety problems if they are
adulterated with western medicines.
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.
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.
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 patient’s 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.
(Tegretol ® ;
4. Carbamazepine
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.
(Sandimmun ® ;
5. Ciclosporin
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 (Clexane®; Aventis Pharma)
New precautionary statements on percutaneous
coronary revascularisation procedures,
bleeding and information on lab tests have
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.
(Flixonase®;
8. Fluticasone propionate
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 Cushing’s 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.
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.
11. Lactated Ringer’s Injection USP (Baxter)
Frequency of allergic reactions or anaplylactoid
symptoms has been reported to be higher in
women during pregnancy.
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.
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.
18. Temozolomide (Temodal ® ; ScheringPlough) New ADRs have been added:
lymphopenia (very common) and rare cases of
opportunistic infections including Pneumocystis
carinii pneumonia (PCP).
(Celance®,
13.Pergolide mesylate
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
n
Published by the Centre for Drug Administration, HSA and the Pharmacovigilance Advisory Committee
Editor-in-Chief
Ms Chan Cheng Leng BSc (Pharm) Hons
Executive Editor Ms Ang Pei San BSc (Pharm)
Staff Editors
Ms Tan Bee Him BSc (Pharm)
Dr Ting Kang Nee BPharm (Hons), PhD
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
w
s
n e w s
• ISSN: 0219 – 2152 • March 2004 • Vol. 6 No. 1
Oseltamivir is not recommended for infants
less than 1 year of age
O
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.
New preclinical findings
Roche has recently released the findings
from its preclinical study carried out in
juvenile rats (7-day old) and highlighted
the concerns to the regulatory authorities
regarding the use of Tamiflu® in infants.
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®.
HSA’s 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 Cushing’s 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
(Diovan ® ;
19. Valsartan
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.
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.
Adverse Drug Reaction News is produced by the Centre for Drug Administration, HSA and the Pharmacovigilance Advisory Committee
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
e
New preclinical findings on Oseltamivir
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: [email protected]
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.
continued on Page 5
Content
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 Cushing’s syndrome may be precipitated by
consumption of exogenous steroids.
Oseltamivir treatment of
influenza in children
Cushing’s 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
continued from Page 1 • Case report of Cushing’s syndrome with traditional medicine (Pil Ajaib®)
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
manufacturer’s 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 Cushing’s 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
D
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.
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.
5 • Adverse Drug Reaction News • March 2004 • Vol. 6 No. 1
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.
(TGA) received 46 suspected reports of
oesophagitis and 49 suspected reports of
oesophageal ulceration associated with
this drug 2.
Local ADR reports
Endoscopic view of oseophagitis
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
Package insert amendments reflecting safety issues
labelling. The purchase of these products
from unreliable sources could pose
additional safety problems if they are
adulterated with western medicines.
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.
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.
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 patient’s 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.
(Tegretol ® ;
4. Carbamazepine
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.
(Sandimmun ® ;
5. Ciclosporin
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 (Clexane®; Aventis Pharma)
New precautionary statements on percutaneous
coronary revascularisation procedures,
bleeding and information on lab tests have
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.
(Flixonase®;
8. Fluticasone propionate
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 Cushing’s 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.
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.
11. Lactated Ringer’s Injection USP (Baxter)
Frequency of allergic reactions or anaplylactoid
symptoms has been reported to be higher in
women during pregnancy.
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.
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.
18. Temozolomide (Temodal ® ; ScheringPlough) New ADRs have been added:
lymphopenia (very common) and rare cases of
opportunistic infections including Pneumocystis
carinii pneumonia (PCP).
(Celance®,
13.Pergolide mesylate
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
n
Published by the Centre for Drug Administration, HSA and the Pharmacovigilance Advisory Committee
Editor-in-Chief
Ms Chan Cheng Leng BSc (Pharm) Hons
Executive Editor Ms Ang Pei San BSc (Pharm)
Staff Editors
Ms Tan Bee Him BSc (Pharm)
Dr Ting Kang Nee BPharm (Hons), PhD
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
w
s
n e w s
• ISSN: 0219 – 2152 • March 2004 • Vol. 6 No. 1
Oseltamivir is not recommended for infants
less than 1 year of age
O
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.
New preclinical findings
Roche has recently released the findings
from its preclinical study carried out in
juvenile rats (7-day old) and highlighted
the concerns to the regulatory authorities
regarding the use of Tamiflu® in infants.
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®.
HSA’s 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 Cushing’s 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
(Diovan ® ;
19. Valsartan
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.
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.
Adverse Drug Reaction News is produced by the Centre for Drug Administration, HSA and the Pharmacovigilance Advisory Committee
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
e
New preclinical findings on Oseltamivir
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: [email protected]
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.
continued on Page 5
Content
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 Cushing’s syndrome may be precipitated by
consumption of exogenous steroids.
Oseltamivir treatment of
influenza in children
Cushing’s 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