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Adverse Drug Reaction
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Published by the Centre for Drug Administration, HSA and the Pharmacovigilance Advisory Committee
Advisory on the use of cough and
cold medicines in children
n view of concerns raised on the recent recall in the United
States of over-the-counter cough and cold products
marketed for infants and toddlers, and the ensuing
recommendations from the public advisory committee meeting
convened by the US Food & Drug Administration (FDA) on
the safe use of these medicines in young children, HSA has
provided an interim advisory to healthcare professionals on
the appropriate use of these products while we continue to
review the scientific data. These recommendations were
included in the Dear Healthcare Professional Letter issued on
30 October 2007 and posted at the MOH Health Professional
portal at http://www.hpp.moh.gov.sg.
Table 1: Interim recommendations on use of cough and cold medicines
in various age groups of children
Category /
Drug
Under
6 months
6 months to
2 years
2 years &
above
Promethazine
Contraindicated
Not
recommended
Use with
caution
Antihistamines1
Not
recommended
Use only
when benefits
have been
assessed to
outweigh risks
Use with
caution
Cough
suppressants 2
Not
recommended
Use only
when benefits
have been
assessed to
outweigh risks
Use with
caution
Cold and flu
products 3
Not
recommended
Use only
when benefits
have been
assessed to
outweigh risks
Use with
caution
Active ingredients discussed during the meeting between US FDA
and its expert panel for which adverse event reports were analysed:
1 Brompheniramine,chlorpheniramine,diphenhydramine
2 Codeine, dextromethorphan, diphenhydramine
3 Ephedrine, guaifenesin, phenylephrine, pseudoephedrine
ISSN: 0219 – 2152
December 2007
Vol.9 No.3
CONTENTS
Background
The recent recall in the US in October 2007 involved 14 brands
of cough and cold preparations (containing antihistamines
and decongestants) targeted for infants and very young
children. They were voluntarily recalled by drug companies
due to the danger of overdosage and misuse in this group of
patients. Examples of such products are Concentrated Infants'
Tylenol Drops Plus Cold & Cough, Dimetapp Decongestant
Plus Cough Infant Drops, and Decongestant Infant Drops.
HSA confirms that these products are not licensed for sale or
use in Singapore.
The US FDA also convened an expert advisory committee in
October to deliberate on the efficacy and safety of cough and
cold products when used in children under six years of age.
In view of the lack of efficacy data in young children balanced
against the occurrences of rare but serious adverse drug
reactions (ADRs) associated with the use of these products,
the expert panel recommended stronger cautionary labels on
these products and not to use them in children under six years
old. FDA will deliberate on the panel’s recommendations
before coming to a conclusion on this issue.
continued on Page 2
1
Advisory on the use of cough and cold
medicines in children
5
Reports of adverse reactions to Beauty Express®
Miracle Pigmentation Scar Cream
2
Association of salbutamol and myocardial
ischaemia in premature labour
5
Summary of advisories issued by HSA and companies
6
Package insert amendments reflecting safety issues
Gadolinium-based contrast agents
– Important safety information
7
Package insert amendments reflecting safety issues
7
Voluntary withdrawal of clobutinol (Silomat®) cough syrup
8
Voluntary suspension of sales of aprotinin (Trasylol®)
3
4
Risk of torsade de pointes and QT
prolongation with haloperidol
Association of
salbutamol and
myocardial ischaemia
in premature labour
identified for the development of ischaemic events besides
preterm labour. In four of the cases, it was specifically stated
that the patients had no known risk factors. One patient had
a paternal history of cardiovascular disease while another
had a possible pre-existing coronary vascular occlusion.
laxoSmithKline (GSK) has issued a Dear Healthcare
Professional Letter to alert our healthcare professionals
on reports of myocardial ischaemia associated with the use
of salbutamol (Ventolin®) as a tocolytic agent. GSK also
advised healthcare professionals to exercise caution when
using salbutamol for premature labour, to carefully monitor
patient’s cardiovascular function including ECG, and to
discontinue the drug if signs of myocardial ischaemia develop.
Background
Salbutamol, a selective beta2-adrenoreceptor agonist, is
available in several dosage forms with varied uses. Parenteral
preparations of salbutamol are registered for the management
of uncomplicated premature labour in the last trimester of
pregnancy though it is known that salbutamol tablets may
sometimes be used for this purpose.
The advice by GSK follows a company-initiated review of the
available data from published literature, clinical trials and
spontaneous reports of myocardial ischaemia in association
with salbutamol. The review found eight spontaneously
reported cases in the company database and nine reports in
published literature, suggestive of a causal association with
myocardial ischaemia when salbutamol was given for the
treatment of premature labour.
Summary of spontaneous reports and literature
The reported events included myocardial ischaemia, myocardial
infarction, chest pain and ECG abnormalities indicative of
myocardial ischaemia. All the events were reported with the
use of intravenous salbutamol except one which was reported
with the use of salbutamol tablets. Five cases required
hospitalisation and one was considered life-threatening.
The time to onset ranged between 1.5 hours to 4 days with
most of the cases occurring within the same day as treatment
initiation. No significant pre-disposing factors could be
About half of the cases reported a positive dechallenge
on salbutamol discontinuation. One case documented
ST depression on the re-introduction of salbutamol one year
after the first incident of myocardial ischaemia. However,
most of the cases did not provide information on rechallenge.
Where specified in the reports, actions taken after the
occurrence of the adverse event include the discontinuation
of salbutamol and treatment with nifedipine, heparin, aspirin,
nitroglycerin and verapamil.
Conclusions and recommendations
Although the effects of sympathomimetics may be exaggerated
in preterm labour due to high background sympathetic drive,
hyperventilation, dehydration and haemodilution through the
use of intravenous fluids, the association between myocardial
ischaemia with salbutamol use in preterm labour cannot be
ruled out as the reported cases were well-documented and
contained no significant pre-disposing factors for the
development of ischaemic events other than preterm labour.
To date, HSA has not received any spontaneous local ADR
report of myocardial ischaemia associated with the use of
salbutamol in preterm labour. Nevertheless, healthcare
professionals are advised to be cautious when using
salbutamol for this purpose, and to report any serious adverse
reactions suspected to be due to its use in pregnancy to the
Pharmacovigilance Unit of HSA. The local package inserts of
parenteral and oral Ventolin® products has been updated to
include this new safety information.
References
1. Aust N Z J Obstet Gynaecol 1981; 21:1-4.
2. Eur J Obstet Gynecol Reprod Biol 2001; 98:177-185.
3. Singapore J Obstet Gynaecol 1986; 17:54-58.
4. Arch Mal Coeur 1997; 90:1651-1654.
5. Acta Obstet Gynecol Scand 1987; 66:417-420.
6. Am J Obstet Gynecol 1989; 161:318-321.
7. Circulation 2006; 113: 1564-1571.
continued on Page 1 - Advisory on the use of cough and cold medicines in children
Review of data by US FDA
Local situtation
A review of the adverse reports from the US FDA
associated with the antihistamines (diphenhydramine,
brompheniramine and chlorpheniramine), and the
decongestants (pseudoephedrine, phenylephrine, and
ephedrine) over 1969–2006 revealed that most of the ADRs
occurred in children under two years old and overdosage and
drug toxicities were the common causes. A further analysis
of the adverse events associated with pseudoephedrine,
chlorpheniramine, diphenhydramine and dextromethorphan
from 2002–2007 showed that serious events and deaths
related to the nervous system (e.g. seizures), cardiac
and respiratory system were associated with both overdoses
as well as labeled doses of cough and cold medicines.
There is also a potential risk of overdose when using multiple
cough and cold products.
HSA has not received any local reports of fatal adverse
drug reactions associated with cough and cold medicines.
However, taking into consideration the findings by US FDA
and the lack of efficacy data of cough and cold medicines
used in children, HSA has provided healthcare professionals
with an interim advisory on the use of cough and
cold medicines in young children. This advisory takes into
consideration guidelines developed by other regulatory
agencies, and the previous review conducted by HSA
and its Pharmacovigilance Advisory Committee in 2005 on
the use of promethazine in children under two years of age.
Adverse Drug Reaction News • December 2007 • Vol.9 No.3
Gadolinium-based contrast agents
– Important safety information
Omniscan® and Magnevist® contraindicated in patients with severe renal failure
rising from the emerging concerns associated
with gadolinium-based contrast agents (GBCAs)
and the protential increased risk of nephrogenic fibrosing
dermopathy
(NFD)
and
nephrogenic
systemic
fibrosis (NSF), the Health Sciences Authority (HSA)
and its Pharmacovigilance Advisory Committee have
reviewed the safety profile and use of these products,
particularly in patients with renal dysfunction.
Brief overview
Gadolinium-based contrast agents (GBCAs) are approved by
HSA for use in magnetic resonance imaging (MRI).
Seven GBCAs are registered in Singapore: gadodiamide
(Omniscan®, GE Healthcare), gadopentetate dimeglumine
(Magnevist®, Bayer Schering Phama), gadoterate
Summary of recommendations
meglumine
gadobutrol
• Use of Omniscan® or Magnevist® is contraindicated in
(Gadovist®, Bayer Schering Phama), gadobenate dimeglumine
patients with severe renal failure (GFR < 30mL/min/1.72m2).
(Dotarem®,
Guerbet),
(Multihance®, IDS Pharmaceutical Division), gadoversetamide
(Optimark®, Tyco Healthcare) and gadoxetic acid
(Primovist®, Bayer Schering Phama).
• The risk for the development of NFD/NSF in patients with
moderate renal impairment is unknown, therefore
Omniscan® and Magnevist® should be used with
HSA has been closely monitoring the association of NFD/NSF
caution in patients with moderate renal impairment
with these contrast agents since May 2006, following the
(GFR 30–59mL/min/1.73m2), especially if any gadolinium-
first alert by GE Healthcare on NFD/NSF reported with the use
based contrast media have been previously administered.
of Omniscan® in patients with severe renal impairment. An
article was published in July 2006 issue of the Adverse Drug
Reaction News Bulletin to alert healthcare professionals
• Omniscan® and Magnevist® should be used in neonates
and infants only if the benefits outweigh the risks as
these patients have immature kidney functions.
of these adverse reactions.
• The other GBCAs should be used in patients with severe
Following the first alert on Omniscan®, more global reports
renal impairment (GFR < 30mL/min) only when absolutely
of NFD/NSF were subsequently received for Omniscan®
necessary where the benefits outweigh their risks. Any
(more than 150 cases), as well as Magnevist® (78 cases)
possible alternative imaging tests that do not require GBCA,
and Optimark® (11 cases). More recently, isolated cases
the clinical need for GBCA use, the relative risk for the
associated with other GBCAs were also reported. All these
patient, the type of agent to be used and any history of prior
reports occurred only in patients with renal dysfunction and
GBCA exposure should be considered when using the other
is associated with swelling and tightening of the skin
GBCAs in severe renal impaired patients.
in the extremities which may develop over a period of days
to several weeks. The mechanism by which a GBCA can
cause NFD/NSF has not been elucidated but the current
understanding is that GBCAs are associated with different
levels of NFD/NSF risk based on their physicochemical
and pharmacokinetic properties.
• There is no robust evidence to show that haemodialysis
can prevent or treat the development of NFD/NSF, but
haemodialysis shortly after GBCAs administration in
patients currently receiving haemodialysis may be useful
in removing the agent from the body, and there is some
preliminary evidence that suggests NFD/NSF is less likely
HSA has issued a Dear Healthcare Professional Letter (DHCPL)
to develop in patients receiving early and adequate
in December 2007 to all registered physicians to alert
haemodialysis. If it is to be performed, the US and European
them to the above safety information, as well as advise on
authorities have recommended that at least two episodes
appropriate use of these drugs. For details of the DHCPL,
of haemodialysis, the first commencing within 24 hours
please log on to the MOH Health Professionals Portal at
of administration of GBCA, performed in patients
http://www.hpp.moh.gov.sg.
at risk who receive any of the GBCAs.
Adverse Drug Reaction News • December 2007 • Vol.9 No.3
Risk of torsade de
pointes and QT
prolongation
with haloperidol
a search of their Benefit Risk Management worldwide
safety database. The results revealed 73 cases of TdP,
of which 11 of these cases led to fatalities. Eight of these
fatalities involved the IV administration of haloperidol.
The second study involved a post-marketing investigation
that examined reports of cardiac events that involved
haloperidol received by the company as of 30 July 2005.
Thirteen of these haloperidol related cardiac events reported
involved the occurrence of TdP, QT prolongation, ventricular
arrhythmia and/or sudden death.
Label amendments in the US
aloperidol is a butyrophenone antipsychotic agent and
its indications include the management of psychoses,
schizophrenia and manic states and management of
aggressive and agitated behavior. Haloperidol injection
has been registered in Singapore since 1994 and is licensed
only for intramuscular administration.
Based on these recent findings, the labelling of Haldol®
products in the US were revised to include the following
warnings:
• Higher doses and IV administration of haloperidol
appear to be associated with a higher risk of QT
prolongation and TdP.
• Although cases of sudden death, TdP and QT prolongation
have been reported even in the absence of predisposing
factors, particular caution is advised in treating patients
using any formulation of haloperidol who:
• have other QT prolonging conditions, including
electrolyte imbalance (particularly hypokalaemia and
hypomagnesemia),
• have underlying cardiac abnormalities, hypothyroidism,
or familial long QT syndrome, or
• are taking drugs known to prolong the QT interval.
Recent safety alert issued by the US FDA
The US Food and Drug Administration (FDA) has recently
issued a safety alert which highlights the potential increased
risk of QT prolongation and torsade de pointes (TdP) with the
• Because of this risk of TdP and QT prolongation,
ECG monitoring is recommended if haloperidol is
given intravenously.
Additionally, Johnson & Johnson’s recent amendments to
Haldol®’s labelling now include that Haldol® is not approved
for intravenous administration.
use of intravenous (IV) administration of haloperidol.
Conclusion
Although injectable haloperidol is approved by the FDA only
to be used as an intramuscular injection, there is considerable
evidence from the medical literature that IV haloperidol is a
relatively common ‘off-label’ clinical practice, primarily to
treat cases of severe agitation in intensive care units.
There are at least 28 case reports of QT prolongation and TdP
in the medical literature, some with fatal outcome in the
context of off-label IV administration of haloperidol.
HSA has not received any local reports of prolonged QTc
or TdP involving the use of haloperidol, and will continue
to monitor the situation. The FDA, in its safety update, stated
that based on case reports alone, it was unable to estimate
the frequency with which QT prolongation or TdP occur
following administration of haloperidol and will continue to
monitor post-marketing reports for such adverse events and
further regulatory actions and communications will be effected
as additional information becomes available.
Additionally, case control studies performed have
demonstrated a dose-response relationship between
intravenous haloperidol dosing and subsequent TdP.
It advised that healthcare professionals should take into
consideration the above new safety information when making
individual treatment decisions for their patients.
Johnson & Johnson (sponsor of the proprietary brand of
haloperidol, Haldol® in the US) recently conducted two
post-marketing studies analysing QT prolongation and
TdP with the administration of haloperidol (both oral and
injectable). In the first study, Johnson & Johnson performed
Adverse Drug Reaction News • December 2007 • Vol.9 No.3
References
1. FDA information for healthcare professionals, 17 September 2007.
http://www.fda.gov/Cder/drug/InfoSheets/HCP/haloperidol.htm
2. Reuter s. FDA warns of heart risks with schizophrenia drug.
http://www.reuters.com/article/governmentFilingsNews/idUSWBT00759220070917
Reports of adverse reactions to Beauty
Express® Miracle Pigmentation Scar Cream
he Pharmacovigilance Unit, HSA has received local
reports of adverse reactions resulting from use of
adulterated cosmetic products. The cases below relate to the
experience of some patients.
Local case reports
The cosmetic product,
Beauty Express® Miracle
Pigmentation Scar Cream
was tested by HSA to
contain betamethasone
dipropionate 0.023%,
a potent steroid, following
reports of adverse drug
reactions to the product.
A few female patients who
purchased the product from a retail shop in Singapore as skin
whitener for skin pigmentation developed rashes, redness
and skin sensitivity on their face after using the creams for
several years. These patients became very dependent on the
cream and suffered flares of skin redness and soreness
whenever they stopped application of the creams. Clinically,
the rashes on their face were very suggestive of “steroid
facies” as the skin on their face were red and atrophied with
surface telangiectasia. The reporting physician suspected
steroid facies and symptoms of steroid withdrawal syndrome
when they stopped using the cream. Steroid facies is caused
by prolonged use of fluorinated topical steroids on the face.
Other side effects of topical fluorinated steroids on the face
include perioral and periorbital dermatitis (which manifest as
acneiform eruptions around the mouth and eyes).
Betamethasone dipropionate is a very potent corticosteroid
as compared to other topical corticosteroids such as
hydrocortisone and betamethasone valerate. It can result in
Cushing's syndrome, skin atropy and hyperglycaemia.
Prolonged and widespread use may also result in reversible
hypothalamic-pituitary-adrenal (HPA) axis suppression.
The local company marketing Beauty Express® Miracle
Pigmentation Scar Cream was prosecuted by HSA for
adulterating the product with betamethasone dipropionate.
When diagnosing an adverse reaction in patients, healthcare
professionals are encouraged to take a detailed medical
history which may take into consideration the patient’s
use of cosmetic products.
Summary of advisories issued by HSA and companies
Summary of Dear Healthcare Professional Letters issued by HSA and/or pharmaceutical companies from January 2006 to November 2007.
For details, please log on to http://www.hpp.moh.gov.sg using your professional board register number or Singpass.
– Rosiglitazone (Avandia® or Avandamet®):
Rare reports of macular oedema
24 May 2007 – Zolendronic acid (Zometa®): Reports of
atrial fibrillation observed in clinical study
14 Feb 2006 – Aprotinin (Trasylol®): Literature reports on
the possible risk of serious renal and
cardiovascular toxicity following Trasylol®
administration to patients undergoing
coronary artery bypass grafting surgery
(CABG)
11 Jun 2007 – Nimesulide: Suspension of sales following
signals of liver toxicities
9 Jan 2006
22 Feb 2006 – Gatifloxacin (Tequin®): Safety update and
product labelling changes of serious cases of
hypoglycaemia and hyperglycaemia
23 Jun 2006 – Lamotrigine (Lamictal®): Risk of oral clefts
21 Jun 2006 – Infliximab (Remicade®): Risk of hepatosplenic
T-cell lymphoma
8 Feb 2007
– Ranibizumab (Lucentis®): Risk of stroke
21 Feb 2007 – Entecavir (Baraclude®): Risk of developing
HIV resistance cannot be excluded with
entecavir therapy in HIV/HBV co-infected
patients not receiving HAART
12 Mar 2007 – Rosiglitazone (Avandia®): Clinical trial
observation of an increased incidence
of fractures in female patients receiving
long-term treatment with rosiglitazone for
type 2 diabetes mellitus
3 Apr 2007
– Tegaserod (Zelmac®): Temporary withdrawal
of sales
9 May 2007 – Bevacizumab (Avastin®): Risk of tracheoesophageal fistula
14 Jun 2007 – Deferasirox (Exjade®): Risk of acute renal
failure and blood cytopenias
5 Jul 2007
– Tegaserod (Zelmac®)/ Restrictions on the
supply of tegaserod and special access for
patients who have no therapeutic alternatives
21 Aug 2007 – Rosiglitazone (Avandia®)/ Rosiglitazone and
metformin (Avandamet®): Advisory for
patients with congestive heart failure
23 Aug 2007 – Lopinavir and ritonavir (Kaletra®): Accidental
overdose in children
04 Sep 2007 – Clobutinol (Silomat®): Withdrawal of sales
07 Sep 2007 – Salbutamol: Risk of myocardial ischaemia
when used during premature labour in
pregnant women
30 Oct 2007 – Advisory on the use of cough and cold
medicines in children
7 Nov 2007 – Aprotinin (Trasylol®): Temporary suspension
of sales
9 Nov 2007 – Mycophenolate mofetil (Cellcept®): Increased
risk of congenital malformations observed
following use in pregnancy
Adverse Drug Reaction News • December 2007 • Vol.9 No.3
Package insert amendments reflecting safety issues
HSA has approved the following package insert changes due to safety updates from June 2007 to October 2007. Please note that due to space constraints, the list
published is not exhaustive and you are encouraged to refer to the following website for the complete listing with details: www.hsa.gov.sg/safetyinfo_and_recalls.
Please also note that there might be a time lag in the availability of the package insert which reflects the latest change(s).
1. Adefovir (Hepsera®, GSK) Caution: Elderly. Warning: Lactic acidosis (in the
absence of hypoxemia), sometimes fatal, usually associated with severe
hepatomegaly & hepatic steatosis may occur, hence treatment with nucleoside
analogues should be discontinued when rapidly elevating aminotransferase
levels, progressive hepatomegaly or metabolic lactic acidosis of unknown
etiology occur & caution should be exercised when prescribing nucleoside
analogues to any patient (particularly obese women) with hepatomegaly, or
other known risk factors for liver disease. New ADRs: Vomiting, mild to
moderate increases in serum creatinine levels, hypophosphatemia & a decrease
in carnitine concentrations.
2. Alendronate (Fosamax®, MSD) Cautions: Discontinuation should be considered
in patients with osteonecrosis of jaw (ONJ) based on individual benefit / risk
assessment, especially for patients requiring invasive dental surgery.
Dental surgery may exacerbate ONJ. Known risk factors for ONJ include
co-morbid disorders like periodontal disease.
3. Anagrelide (Agrylin®, IDS) Elderly patients had twice the incidence of serious
adverse events, mainly cardiac-related events. Contraindication:
Moderate/severe hepatic impairment or moderate/severe renal
impairment (ClCr <50ml/min). Potential risks & benefits of anagrelide
therapy in patients with mild hepatic impairment should be assessed
before treatment is started. Warning: Cardiomegaly & congestive
heart failure reported. Cautions: Patients with known or suspected
heart disease. Pre-treatment cardiovascular examination (echocardiography,
electrocardiogram) & continued monitoring of CV function is recommended.
Not recommended in patients with elevated transaminases (>5 times ULN).
Concomitant use with other PDE III inhibitors such as milrinone, amrinone,
enoximone, olprinone & cilostazol is not recommended. Potential risks &
benefits of concomitant use of anagrelide with acetylsalicylic acid in patients
with a platelet count >1500 x 109/L &/or a history of haemorrhage should be
assessed before starting treatment. Patients with rare hereditary problems
of galactose intolerance, Lapp lactase deficiency or glucose-galactose
malabsorption should not be given with anagrelide.
4. Baclofen (Lioresal®, Novartis) Signs & symptoms of overdosage have been
reported with doses >5mg/day in patients undergoing chronic haemodialysis
as baclofen concentrations in plasma are elevated. Cautions: i) Patients
suffering from depressive, manic disorders or Parkinson's disease;
ii) Discontinuation or cases of overdosage as lowering of convulsion
threshold may occur & seizures have occasionally been reported; iii) Abrupt
withdrawal as dyskinesia & hyperthermia have been reported.
Clinical characteristics of withdrawal of intrathecal Lioresal® may resemble
autonomic dysreflexia, infection (sepsis), malignant hyperthermia, neuroleptic
malignant syndrome, or other conditions associated with a hypermetabolic
state or widespread rhabdomyolysis.
Drug interactions: Synthetic opiates, alcohol, morphine & levodopa. Careful
monitoring of respiratory & cardiovascular functions is essential, especially
cardiopulmonary disease & respiratory muscle weakness. ADRs: Hypothermia,
pollakiuria & erectile dysfunction.
5. Cabergoline (Dostinex®, Pfizer) Warnings: Chest x-ray is recommended when
new clinical symptoms of respiratory disorders are presented. Discontinue
therapy in the case of x-ray signs of pleural effusion/pulmonary fibrosis or in
the diagnosis of valvulopathy. Pathological gambling, increased libido &
hypersexuality (reversible upon reduction of dose or treatment discontinuation)
reported. ADRs: Alopecia, aggression & psychotic disorder.
6. Carbamazepine (Tegretol®, Novartis) Warning: Toxic epidermal necrolysis &
SJS have been rarely reported with Tegretol®. Drug interactions: Paroxetine
& levetiracetam. ADR: Hypogammaglobulinaemia.
7. Ceftibuten (Cedax®, Schering-Plough) Ceftibuten can rarely lead to
prolonged prothrombin time (PT), especially in patients previously
stabilised on oral anticoagulant therapy. PT or INR should be monitored
in patients at risk & treated as required. ADRs: Bronchospasm, dyspnoea,
rash, urticaria, photosensitivity reaction, pruritus, angioneurotic oedema &
pseudomembranous colitis.
8. Cholestyramine (PMS-Cholestyramine®, Apotheca) Caution: May cause
steatorrhea or accentuate pre-existing steatorrhea & this may require reduction
& adjustment of dosage.
Drug interactions: Digitalis & estrogens that undergo enterohepatic
recirculation. Cholestyramine has been shown to reduce the bioavailability
of HMG-CoA reductase inhibitors; the clinical cholesterol-lowering effects
of an HMG-CoA reductase inhibitor & cholestyramine have been shown
to be additive. ADRs: Dental bleeding, diuresis, weight loss/gain, increased
libido, swollen glands, edema & dental caries.
9. Ciclosporin (Sandimmun Neoral®, Novartis) Warnings: Avoid excess UV light
exposure; monitor renal function in elderly. There is only limited experience
with the use in children with endogenous uveitis.
Drug interactions: Oxcarbazepine, bosentan, voriconazole & colchicine.
Methotrexate exhibits nephrotoxic synergy with ciclosporin.
Following concomitant administration of ciclosporin & lercanidipine,
AUC of lercanidipine was increased 3 times & AUC of ciclosporin
was increased 21%. Concomitant use of potassium sparing drugs e.g.
p o t a s s i u m s p a r i n g d i u r e t i c s , AC E i n h i b i t o r s , a n g i o t e n s i n I I
receptor antagonists or potassium containing drugs may lead to
significant increases in serum potassium.
Adverse Drug Reaction News • December 2007 • Vol.9 No.3
10. Clobetasol (Univate®, Apex Pharmacy) Contraindication: Treatment of
dermatoses, peri-anal & genital pruritus in children <1yr, including
dermatitis& nappy eruption. Severe ADRs are likely to happen if
application of more than 50g/week is used.
11. Diclofenac (Cataflam®, Novartis) Caution: Breastfeeding. Drug interactions:
Concomitant use of topical diclofenac & topical steroids in patients with
significant pre-existing corneal inflammation may increase risk of developing
corneal complications. ADRs: Conjunctival hyperaemia, allergic conjunctivitis,
eyelid erythema, urticaria, rash, eczema, erythema, pruritus, hypersensitivity,
cough & rhinitis.
12. Diphtheria, haemophilius influenzae, pertussis, polio & tetanus (InfanrixIPV+Hib®, GSK) Warning: For children with progressive neurological disorders
like infantile spasms, uncontrolled epilepsy or progressive encephalopathy,
to defer pertussis immunization until condition is corrected. ADRs: Local or
diffuse swelling at injection site, sometimes involving adjacent joint.
Large swelling reactions more likely when children primed with acellular
pertussis vaccines vs whole cell vaccine; local swelling & diffuse swelling
may be more frequent when booster dose is administered between
4 & 6 years, resolving over an average of 4 days. Swelling of the entire
injected limb has been reported.
13. Eletriptan (Relpax®, Pfizer) Caution: Co-administering with other drugs having
serotonergic activity, such as SNRIs & SSRIs due to possible development of
serotonin syndrome. Thus, careful observation of the patient is warranted
particularly during treatment initiation or dose increase of either eletriptan
or SSRIs/SNRIs. Concomitant use with potent CYP3A4 inhibitors
e.g. ketoconazole, itraconazole, erythromycin, clarithromycin & protease
inhibitors is not recommended.
14. Epoetin alfa (Eprex®, Johnson & Johnson) Warnings: Monitor haemoglobin
(Hb) levels closely due to a potential increased risk of thromboembolic events
& fatal outcomes when patients are treated at Hb levels above the target
for the indication of use. In patients with chronic renal failure, maintenance
Hb concentration should not exceed the upper limit of the target Hb
concentration. Hb levels >12g/dL may be associated with a higher risk of
cardiovascular events, including death. ADRs: Increase in blood pressure,
aggravation of existing hypertension, myalgia, hypertensive crisis with
encephalopathy & seizures, shunt thromboses, & porphyria.
15. Estramustine (Estracyt®, Pfizer) Warnings: Patients with prostate cancer &
osteoblastic metastases are at risk for hypocalcemia. Monitor calcium levels.
16. Etoricoxib (Arcoxia®, MSD) Warnings: Long-term administration of NSAIDs
has resulted in renal papillary necrosis & other renal injury. Perforations,
ulcers or bleeds can occur at any time during use & without warning
symptoms though the results of the MEDAL Program demonstrate that risk
of GI toxicity in patients treated with Arcoxia® 60mg or 90mg once daily
is significantly less than with diclofenac 150mg daily. ADR: Shock. Serious
skin reactions, some of them fatal, may occur.
17. Gadoxetic acid (Primovist®, Zuellig) Warnings: Occurrence of nephrogenic
systemic fibrosis (NSF) / nephrogenic fibrosing dermopathy (NFD) in patients
with severe renal impairment (GFR <30ml/min/1.73m 2 ) were reported.
No robust evidence that haemodialysis can prevent or treat the development
of NSF but haemodialysis shortly after Primovist® administration in patients
currently recently receiving haemodialysis may be useful at removing
Primovist® from the body. No evidence to support the initiation of
haemodialysis for prevention or treatment of NSF in patients not already
undergoing haemodialysis.
18. Ibandronic acid (Bonviva®, Roche) Osteonecrosis of the jaw, associated with
tooth extraction &/or local infection has been reported in cancer patients
receiving mainly IV bisphosphonates & in patients with osteoporosis receiving
oral bisphosphonates. Consider dental examination with appropriate preventive
dentistry in those with concomitant risk factors e.g. cancer, chemotherapy,
radiotherapy, corticosteroids, & poor oral hygiene. Avoid in patients with rare
hereditary problems of galactose intolerance, the Lapp lactase deficiency or
glucose-galactose malabsorption.
19. Isradipine (Dynacirc SRO®, Novartis) Warnings: Angina pectoris may occur,
predominantly in patients with pre-existing coronary artery disease.
In patients with pre-existing angina pectoris, frequency, duration & severity
of anginal attacks may be increased by rapid dosage increments or
at the start of treatment. Food interaction: Grapefruit juice may increase
bioavailability of isradipine. ADRs: Polyuria, malaise, weight increased,
stroke, syncope, transient ischaemic attack, lethargy, dry mouth,
constipation, diarrhoea, insomnia, & chest pain.
20. Lansoprazole (Prevacid®, Luen Wah Medical) Contraindication: Patients on
atazanavir therapy. Drug interactions: Theophylline & atazanavir.
ADRs: Anaphylactic reactions, dyspnea, shock, toxic epidermal necrolysis
(Lyell syndrome), oculomucocutaneous syndrome, Stevens Johnson
syndrome, severe hepatic dysfunction with jaundice, hepatitis,
agranulocytosis, pancytopenia, haemolytic anaemia, nausea,
vomiting, anorexia, abdominal pain, candidiasis, stomatitis, glossitis,
taste abnormality, interstitial nephritis, acute renal failure, interstitial pneumonia,
gynaecomastia, blurred vision, oedema, weakness, malaise, numbness
of tongue or lips, numbness of limbs, arthralgia, muscle pain, & alopecia.
continued on Page 7
Package insert amendments reflecting safety issues
HSA has approved the following package insert changes due to safety updates from June 2007 to October 2007. Please note that due to space constraints, the list
published is not exhaustive and you are encouraged to refer to the following website for the complete listing with details: www.hsa.gov.sg/safetyinfo_and_recalls.
Please also note that there might be a time lag in the availability of the package insert which reflects the latest change(s).
Discontinue lansoprazole in the following cases: i) Diarrhoea persists.
ii) Abdominal pain & frequent diarrhoea occurring in H.pylori eradication.
iii) Abnormalities in renal function test values e.g. increases in BUN, creatinine,
etc. iv) Fever, coughing, dyspnoea, abnormal lung sound (crepitation) etc.
When such symptoms arise, chest X-ray should be performed immediately
& patient treated with corticosteroid.
21. Lopinavir & ritonavir (Kaletra®, Abbott) Precautions: Coadministration
of ritonavir & digoxin may result in significantly increased digoxin levels,
therefore monitoring of serum digoxin levels is recommended.
Drug interactions: Rifampin, fluticasone & tipranavir. ADRs: Myocardial
infarct, hepatomegaly, liver fatty deposit, liver tenderness, joint
disorder, myasthenia, extrapyramidal syndrome, increased cough,
neoplasm, skin striae, & impotence.
22. Naftidrofuryl (Praxilene®, Merck) Contraindication: History of hyperoxaluria.
Warnings: Taking Praxilene® without liquid before going to bed
may cause local oesophagitis. Recommended to drink large volumes
of liquid during the whole treatment period to maintain an adequate
level of diuresis and to reduce the formation of calcium oxalate
kidney stones. ADRs: Nausea & hepatitis.
23. Nifedipine (Adalat LA®, Bayer) Warnings: Bezoars can occur rarely &
may require surgical intervention. ADRs: Anaphylactoid reaction, anxiety
reactions, migraine, par-/dysaesthesia, visual disturbances, palpitations,
nosebleed, nasal congestion, GI & abdominal pain, erythema, joint
swelling, & erectile dysfunction.
24. Octreotide (Sandostatin LAR® & Sandostatin multidose®, Novartis)
Warnings: Uncommon cases of bradycardia have been reported hence dose
adjustments of drugs like beta blockers, calcium channel blockers,
or agents to control fluid & electrolyte balance may be necessary.
Octreotide may alter absorption of dietary fats in some patients. Depressed
vitamin B12 levels & abnormal Schilling's tests observed in some
patients on octreotide hence to monitor vitamin B12 levels in patients on
Sandostatin LAR® & who have a history of vitamin B12 deficiency.
ADRs: Anaphylaxis, tachycardia, dyspnoea, cholecystitis, thyroid
dysfunction, dyspepsic signs, symptoms & episodes of arrhythmia,
ECG changes e.g. QT prolongation.
25. Oxybutynin (Lyrinel®, J&J) Warnings: Monitor patients for signs of
anticholinergic CNS effects, particularly in the first few months after beginning
treatment or increasing the dose. ADRs: Psychotic disorder & agitation.
26. Paricalcitol (Zemplar®, Abbott) Chronic renal failure subjects showed a
decreased clearance & increased half-life of paricalcitol. ADRs: Facial
& oral oedema.
27. Pimecrolimus (Elidel®, Novartis) Use of Elidel® cream in patients <2 yrs old
is not recommended until further data becomes available. ADRs:
Anaphylactic reactions, alcohol intolerance (flushing, rash, burning, itching
or swelling), allergic reactions & skin discoloration (e.g. hypopigmentation,
hyperpigmentation).
28. Pneumococcal 7-valent conjugate (Prevenar®, Wyeth) When Prevenar®
is co-administered with hexavalent vaccines (DTaP-Hib-IPV-HepB), the rate
of febrile reactions was higher compared to that occurring following
administration of hexavalent vaccines alone. Reactions were mostly
moderate (≤39oC) & transient. ADR: Urticaria-like rash.
29. Procaterol (Meptin®, Luen Wah Medical) Precautions: Pregnancy. Use only as
additional therapy for patients whose symptoms are not adequately controlled
& not as a substitute for inhaled corticosteroids & other anti-inflammatory
agents. Use short-acting inhaled beta2 stimulants in episodes of acute asthma.
30. Raloxifene (Evista®, Eli Lilly) Caution: Postmenopausal women with a history
of stroke or other significant stroke factors such as transient ischaemic attack
or atrial fibrillation. ADRs: Thrombocytopenia, peripheral oedema, venous &
arterial thromboembolic reaction.
31. Ropinirole (Requip®, GSK) Warnings: Compulsive behaviours such as
pathological gambling & hypersexuality have been reported in
Parkinson's disease patients treated with ropinirole, especially at high
doses & were generally reversible upon dose reduction or treatment
discontinuation. In some cases, other factors like a history of compulsive
behaviours or concurrent dopaminergic treatment were present.
ADRs: Constipation, peripheral oedema & hypersexuality.
32. Sulfasalazine (PMS-Sulfasalazine®, IDS) Contraindications: Intestinal & urinary
obstructions. Not to be used in patients in whom acute asthmatic attacks,
urticaria, rhinitis or other allergic manifestations are precipitated by ASA
or other NSAIDs as fatal anaphylactic reactions have occurred in such
individuals. Cautions: Patients with hepatic or renal damage, blood dyscrasias,
severe allergy or bronchial asthma. Pancreatitis has been observed in some
susceptible individuals. Deaths associated with the use of sulfasalazine
have been reported from hypersensitivity reactions, agranulocytosis, aplastic
anemia, other blood dyscrasias, renal & liver damage, irreversible
neuromuscular & CNS changes & fibrosing alveolitis. Presence of clinical
signs like sore throat, fever, pallor, purpura or jaundice may be indications
of serious blood disorders. Bone marrow depression has been reported usually
within the first 3 months of starting treatment & is usually reversible on
stopping sulfasalazine. A full blood count, including differential white blood
cell count, should be carried out before starting therapy & monitored closely
during the first few months of treatment, thereafter patients should be
screened if their condition changes or if they have symptoms of infection.
Oligospermia with infertility have been observed in men treated with
sulfasalazine. Adequate fluid intake must be maintained in order to prevent
crystalluria & stone formation.
33. Ziprasidone (Zeldox®, Pfizer) Cautions: Patients with severe hepatic insufficiency;
concomitant use with other centrally acting agents & drugs acting on the
dopaminergic & serotonergic systems. Warnings: Rare post-marketing reports
of torsade de pointes in patients with multiple confounding risk factors taking
ziprasidone reported. Discontinue drug if signs of neuroleptic malignant
syndrome occurred. Zeldox® is not approved for elderly patients with
dementia-related psychosis. Women of childbearing potential receiving
ziprasidone should use an appropriate contraceptive.
ADRs: Seizures, body weight gain & loss, transient elevation of prolactin,
mania/hypomania, serotonin syndrome, syncope, torsade de pointes,
angioedema, galactorrhea, & priapism.
34. Zoledronic acid (Zometa®, Novartis) Warnings: Renal deterioration,
progression to renal failure & dialysis have been reported in patients after
the initial dose or a single dose of Zometa®. ADRs: Atrial fibrillation,
somnolence & bronchoconstriction.
Voluntary withdrawal of
clobutinol (Silomat®) cough syrup
lobutinol (Silomat®, Boehringer Ingelheim) was licenced
in Singapore in 1999. It is an orally active non-opioid
antitussive agent, and is indicated for the treatment of
irritable, non-productive cough and inflammatory disorders
of the airways.
In September 2007, Boehringer Ingelheim voluntarily
withdrew Silomat® from the Singapore market as a
precautionary measure due to concerns of a potential
increased risk of cardiac arrhythmias that could be associated
with the active ingredient.
Published experimental data have indicated the potential of
clobutinol affecting the hERG (human ether-a-go-go related
gene) potassium channels. Preliminary findings from
a recent clinical trial with clobutinol in adult healthy
volunteers have shown a prolongation of the QTc interval in
the ECG. As clobutinol is indicated for a non-serious disease
condition and in view of the potentially life-threatening
adver se effects, HSA agreed with the actions of
Boehringer Ingelheim to withdraw clobutinol from the
worldwide market. A Dear Healthcare Professional Letter
(DHCPL) was issued by the company to alert healthcare
professionals to the findings and the decision to recall and
suspend the sales of Silomat®. For details of the DHCPL,
please log on to the Health Professionals Portal at
http://www.hpp.moh.gov.sg.
Adverse Drug Reaction News • December 2007 • Vol.9 No.3
Voluntary suspension
of sales of
aprotinin (Trasylol®)
International measures
As a result of the findings of the BART study, and in consultation
with the German Federal Institute for Drugs and Medical
Devices (BfArM), the US Food and Drug Administration (FDA),
Health Canada and other regulatory authorities, Bayer
protinin (Trasylol®, Bayer HealthCare) is an
antifibrinolytic agent used to reduce blood loss and
the need for blood transfusion in adult patients at risk of blood
HealthCare® decided to temporarily suspend the worldwide
sales of Trasylol® until the final data from the study can be
compiled and evaluated.
loss who are undergoing cardiopulmonary bypass in the
course of coronary artery bypass graft surgery. It has been
HSA’s action and advisory
In consultation with the Health Sciences Authority (HSA), the
registered in Singapore since 1994.
sales of Trasylol® was temporarily suspended in Singapore
Recent safety findings
on 6 November 2007 pending further evaluation of information
Recent findings have raised concerns regarding the safety
from the BART study. A final regulatory decision on Trasylol®
issues associated with the use of aprotinin in cardiac surgery.
will be made in due course and healthcare professionals
Earlier observational studies have suggested that aprotinin
will be informed accordingly.
may increase the risk of mortality when compared against
other antifibrinolytic agents. The latest Canadian study,
As an interim measure, HSA has worked with Bayer to allow
BART (Blood conservation using antifibrinolytics: A randomized
supply of Trasylol® through restricted access under certain
trial in high risk cardiac surgery patients), a trial comparing
conditions, to a small group of patients who have been
the safety and efficacy of aprotinin (2 million units bolus + 2
assessed by their physicians to have no other therapeutic
million units in pump prime + 2 million units via infusion over
options, and where the benefits of the drug may outweigh its
4 hours) against epsilon-aminocaproic acid (10g bolus + 250
risks. Physicians are required to discuss the risks associated
mL NaCl in pump prime + 2g/hr infusion) or tranexamic acid
with using Trasylol® and obtain written consent from either
(30mg/kg bolus + 2mg/kg/hr in pump prime + 16mg/kg/hr
the patient or the next of kin should the patient be incapable
infusion) suggested an increase in all-cause mortality among
or incompetent in doing so before prescribing Trasylol®.
patients in the aprotinin arm of the study compared to the
other two drugs: the 30 days mortality of aprotinin compared
References
to the two drugs were relative risks of 1.5 at p=0.06 and p=0.08.
1. FDA early communication about an ongoing safety review aprotinin injection,
Although statistical significance was not reached, a trend
25 October 2007. http://www.fda.gov/cder/drug/early_comm/aprotinin.htm
towards an increase in mortality in the aprotinin-treated group
2. N Engl J Med Jan 2006; 354(4):353-65.
was present throughout most of the trial.
3. Transfusion Mar 2006; 46(3):327-338.
Editor-in-Chief
Enquiries, comments and suggestions to:
Ms Chan Cheng Leng, BSc (Pharm) Hons
Executive Editor
Ms Ang Pei San, BSc (Pharm)
Staff Editors
Mr Choong Chih Tzer, BPharm
Dr Yvonne Koh, BSc (Pharm) Hons, PhD
Ms Adena Lim, BSc (Pharm) Hons, MPharm (Clin Pharm)
Ms Belinda Tan, BSc (Pharm)
Pharmacovigilance Unit
Centre for Drug Administration
Health Products Regulation Group
Health Sciences Authority
11 Biopolis Way, #11-03,
Helios, Singapore 138667
The contents are not to be reproduced in part or in whole,
without prior written approval from 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.
Editorial Board
Clinical Prof. Goh Chee Leok
Prof. Edmund Lee Joo Deoon
Tel: (65) 6866 3538
Fax: (65) 6478 9069
Clinical A/Prof. Chng Hiok Hee
Clinical A/Prof. Gilbert Lau Kwang Fatt
Dr Lee Kheng Hock
Website: http://www.hsa.gov.sg
Email: [email protected]
Adverse Drug Reaction News • December 2007 • Vol.9 No.3
Copyright© 2007 Health Sciences Authority of Singapore.
All Rights Reserved.