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Published by the Health Products Regulation Group, HSA and the HSA Pharmacovigilance Advisory Committee
Sulphur Allergy – A common misnomer in ADR reporting
T
he Pharmacovigilance Branch, HSA has received six serious
adverse drug reactions (ADR) reports and 246 non-serious
reports of patients who were labelled as being allergic
to sulphur over the period July 2007 to July 2008. Some
patients who have suffered hypersensitivity to sulphonamide
antimicromials such as co-trimoxazole may have been
labelled as hypersensitive to sulphur. As there are important
distinctions between sulphonamide antimicrobials,
sulphonamide non-antimicrobials, sulphites, sulphates and
sulphur allergy, this article is intended to clarify this misnomer
and to discourage the use of the term as it may be imprecise
and misleading.
These differences form the basis for classification of
sulphonamide drugs (see Table 1 for details).
Differentiating sulphur compounds
I. Elemental sulphur
Sulphur is a natural element and exists in a yellow crystalline
form. Elemental sulphur is usually not the allergenic agent and
is mainly used as a precursor to other chemicals. In traditional
medicine, sulphur has been used mainly as part of creams to
alleviate various conditions such as psoriasis, eczema and acne.
Fig 1. This shows the basic form of a sulphonamide antimicrobial. Besides
the SO 2 –NH 2 moiety, other important structures unique to the
sulphonamide antibiotics and not found in non-antimicrobial
sulphonamides are shown.
II. Sulphur compounds
Sulphates are commonly found in drugs, soaps and cosmetics.
Examples of common sulphates include glucosamine sulphate,
ferrous sulphate, heparin sulphate and sodium lauryl sulphate.
Sulphites are present as preservatives in food, beverages and
pharmaceuticals. Examples of common sulphite preservatives
are sodium sulphite (Na 2 SO 3), sodium bisulphite (NaHSO 3 ),
and sodium metabisulphite (Na2S2O3).
Patients sensitive to sulphites frequently have underlying
allergic or asthmatic conditions. In rare cases, sulphites can
cause anaphylaxis. However, these responses are mediated by
different mechanisms and different antigenic sites as those
of sulphonamide antimicrobials making cross reactivity highly
unlikely.
III. Sulphonamides
A sulphonamide is any compound with a SO 2–NH 2 moiety.
Sulphonamide antimicrobials contain an aromatic amine
(arylamine) at the N4 position and a five or six member heterocyclic
ring with one or more nitrogen at the sulphonamide N1 position.
(see Fig. 1). Sulphonamide non-antimicrobials do not have both
components.
Fig 2. This is a selection of non-antimicrobial sulphonamides with the
SO2–NH2 moiety labelled. It is clear that, besides the SO2–NH2 moiety,
there is no resemblance with sulphonamide antimicrobials.
continued on Page 2
ISSN: 0219 - 2152
1
5
December 2008
Vol.10 No.3
Sulphur allergy – A common misnomer
in ADR reporting
2
CPE accreditation of ADR News
Bulletin
6
3
Abacavir hypersensitivity reactions
associated with HLA-B*5701 allele
4
Slimming health products (Relacore &
Lami) adulterated with sibutramine
CONTENTS
8pp_ADR_News_Dec2008_Vol10_No3.p65
1
6
7
8
Fentanyl transdermal patch & overseas
reports of fatality
Haemorrhagic or necrotizing pancreatitis
associated with Byetta®
Summary of advisories issued by HSA &
pharmaceutical companies
Package insert amendments reflecting
safety issues
Biosimilar products
11/18/2008, 3:22 PM
2
Adverse Drug Reaction News
December 2008
Vol.10
No.3
Continuing Professional Education (CPE) accreditation
of the HSA ADR News Bulletin for pharmacists
T
More about the bulletin
he editorial team of the HSA
Adverse Drug Reactions (ADR)
News Bulletin is pleased to
a n n o u n c e t h a t t h e S i n g a p o re
Pharmacy Council has approved the
inclusion of the news bulletin to
the list of publications which
pharmacists can read to obtain their
Continuing Professional Education
(CPE) points.
The HSA ADR News Bulletin, produced
three times a year, was first published
in 1999 and is now in its tenth year of
publication. The main objectives of the
bulletin are to increase awareness of
adverse drug reactions (ADRs) among
healthcare professionals and to
promote ADR reporting. Additionally,
the bulletin also covers current
topics of relevance to healthcare
professionals such as safety concerns
that have significant impact on clinical
practice, new safety information,
emerging safety concerns, product
withdrawals and suspensions,
and safety-related package insert
amendments.
Pharmacists can apply for one
p a t i e n t - c a re C P E p o i n t u n d e r
category 3A for reading each issue
of the news bulletin. The CPE points
can be logged in via the Singapore
Pharmacy Council website at
http://www.spc.gov.sg
continued from Page 1
Sulphur allergy – A common misnomer in ADR reporting
toxic epidermal necrolysis (TEN). The oxidative formation of these metabolites occurs
by means of the cytochrome P450 system. These reactive metabolites act by forming
immunogenic structures for antibodies or T cells and also by direct cytotoxicity to
lymphocytes and other immune cells.3
Although non-antimicrobial sulphonamides have the potential to cause allergic
reactions, the predominance of scientific evidence suggests that cross-reactivity with
antimicrobial sulphonamides is unlikely. However, patients with sulphonamide
antimicrobial allergies may develop subsequent allergies to a sulphonamide nonantimicrobial. This association appears to be due to a predisposition of such patients
to allergic reactions rather than to cross- reactivity with sulphonamide antimicrobial.7
Fig 3. Two sulphonamide antimicrobials and the
common site that interacts with IgE antibodies.
All illustrations (Figs 1-3) are abstracted with
permission from Dr Leong KP’s article published
in the Medical Digest: The Truth about Sulpha
Drug Allergy. 1
Allergic mechanism and cross-reactivity
between sulphonamide drugs
Sulphonamide antimicrobials are second only
to the ß-lactams as the most common cause
of drug allergy.2 Cross-allergenicity between
sulphonamide antimicrobials is possible
based on their structural similarities.
Table 1
Drug groups
(and examples of drugs in these groups)
1. Aromatic amides
a. Sulphonamide antimicrobials:
sulphadiazine, sulphamethoxazole,
sulphisoxazole
b. Sulphonamide antivirals: amprenavir,
fosamprenavir
2. Nonaromatic amides
a. Diuretics: hydrochlorothiazide,
chlorthiazide, furosemide, bumetanide
b. Sulphonylureas: chlorpropamide,
tolbutamide, glibenclamide, glipizide
c. Carbonic anhydrase inhibitors :
acetazolamide
d. COX-2 selective inhibitors: celecoxib
Type I hypersensitivity reactions (immediatetype hypersensitivity) are IgE-mediated and
can manifest as urticaria, angioedema,
bronchospasm and anaphylaxis. The N1
heterocyclic ring moiety has been found to
be the epitope for these IgE antibodies.
Conclusion
Nearly all hypersensitivity responses to
sulphonamide antimicrobials are not type I
and appear to be mediated by cytotoxic
or immunogenic hydroxylamine and
nitrosoamine metabolites involving the N4
arylamine rather than by the sulphonamide
moiety itself. Examples of non-type 1
hypersensitivity reactions are maculopapular
rash, Stevens-Johnson Syndrome and
Accurate reporting of ADRs is crucial in the
management of allergies. Being labelled as
allergic to sulphur often creates confusion
for both the patient and the attending
healthcare professional. The term ‘sulphur
allergy’ should thus be avoided. Instead,
the specific drug name should be
identified.
8pp_ADR_News_Dec2008_Vol10_No3.p65
2
Cross-reactivity with
sulphonamide antimicrobial
Cross-reactivity within this group is
likely based on structural similarities
Based on current information, there is
lack of documentation for cross-reactivity
between the two drug groups,
i.e. aromatic amides and nonaromatic
amides. Allergies when they do occur
appears to be due to a predisposition
of the patient to allergic reactions rather
than cross-reactivity between these
two groups of drugs
References
1. Medical Digest. Tan Tock Seng Hospital,
Oct-Dec 2001; 14-16.
2. Ann Allergy Asthma Immunol 2008 Feb;
100(2):91-100; quiz 100-3, 111.
3. Australian Prescriber Vol 31 No: 1 Feb 2008
http://www.australianprescriber.com/
upload/pdf/articles/933.pdf
4. Pharmacotherapy 2004;24(7):857-70.
5. Ann Pharmacother 2006 Jun;40(6):1040-6.
6. Drug Safety 2001;24(4):239-47.
7. N Eng J Med 2003; 349:1628-35.
11/18/2008, 3:22 PM
December 2008
Vol.10
No.3
Adverse Drug Reaction News
Abacavir hypersensitivity reactions associated
with HLA-B*5701 allele
A
bacavir is a nucleoside reverse
transcriptase inhibitor (NRTI)
used in the treatment of
infection caused by the human
immunodeficiency virus (HIV). There are
two licensed products carrying abacavir
namely Ziagen® (GlaxoSmithKline),
which contains abacavir only and
Kivexa® (GlaxoSmithKline) which
contains a combination of abacavir
and lamivudine.
HLA-B*5701 associated Abacavir
Hypersensitivity Reactions (HSR)
Recently, the US Food and Drug
Administration (FDA) issued an alert
informing healthcare professionals
that serious and sometimes fatal
hypersensitivity reactions caused by
abacavir therapy are significantly
more common in patients with the
human leukocyte antigen (HLA) allele,
HLA-B*5701. This alert was based on
the review of two studies, PREDICT-1
and SHAPE, which supported the
recommendation for pre-therapy
screening for the presence of
HLA-B*5701 allele and the selection of
alternative therapies in positive subjects.
3
HLA-B*5701 resulted
in a reduction in
the incidence of
clinically-suspected
HSR of approximately
60% compared with
no screening.
The SHAPE study
is a retrospective,
case-control study
designed to evaluate
Prospective screening for relevant alleles
the sensitivity of
HLA-B*5701 allele with respect to abacavir HSR in black and white subjects in the
United States. In this study, the data supports the strong association between
HLA-B*5701 and clinically-suspected abacavir HSR in both black and white patients as
well as the pre-screening for the HLA-B*5701 allele in the broader United States
population to improve the safety profile of abacavir.
International regulatory actions
Following the safety alert by FDA, the US package inserts of abacavir and abacavircontaining medications were updated to include recommendation to test patients
for HLA-B*5701 allele before starting or restarting these medications. The US
abacavir medication guide for patients was also updated to highlight the safety
information on the increase risk of abacavir HSR in patients with the HLA-B*5701
allele carriage. Similar warnings on strong association between HLA-B*5701
allele carriage and abacavir HSR and the recommendation to do pre-therapy
HLA-B*5701 screening have also been updated in the European package inserts for
abacavir containing medications.
Abacavir Hypersensitivity Reactions
Local situation
Abacavir HSR is a multi-organ syndrome
characterized by two or more clinical signs
and symptoms that include fever, rash,
gastrointestinal symptoms, respiratory
symptoms and constitutional symptoms.
Symptoms can occur any time during
treatment with abacavir but usually
appear within the first six weeks (median,
11 days).
HSA has not received any local reports pertaining to abacavir HSR. However,
physicians who prescribe abacavir-containing medications are encouraged to
advise their patients to look out for signs and symptoms of abacavir hypersensitivity
reactions. If they develop signs and symptoms suggestive of hypersensitivity
reactions, they should be advised to stop their medication and seek prompt medical
attention. Although our Asian population has a low prevalence of the HLA-B*5701
allele, it is important to bear in mind the potential risk of abacavir HSR associated
with this allele.
Details of the studies
PREDICT-1 is a prospective, randomized,
double-blind study that evaluates the
clinical utility of pre-therapy HLA-B*5701
screening compared to no screening on
the incidence of abacavir HSR in
abacavir-naïve patients infected with
HIV type 1. Data from PREDICT-1 estimates
that 61% of HLA-B*5701 positive
subjects will develop abacavir HSR
during treatment with abacavir compared
with 4.5% of HLA-B*5701 negative
subjects. Screening of HIV-1 infected
subjects
for
the
presence
of
8pp_ADR_News_Dec2008_Vol10_No3.p65
3
The local package insert for Ziagen® has recently been updated to reflect the safety
information on HLA-B*5701 allele associated abacavir HSR and the recommendation
to do pre-therapy screening for this allele. The package insert of Kivexa® is in the
process of being updated with this safety information. Healthcare professionals are
encouraged to report suspected adverse drug reactions associated with abacavir to
the Pharmacovigilance Branch of HSA.
References
1. FDA alert. Information for Healthcare Professionals Abacavir (marketed as Ziagen) and
Abacavir-containing Medications.
http://www.fda.gov/cder/drug/InfoSheets/HCP/abacavirHCP.htm.
2. European Public Assessment Report for Abacavir (Ziagen®)
http://www.emea.europa.eu/humandocs/PDFs/EPAR/Ziagen/101999en8b.pdf.
3. N Eng J Med 2008 Feb 7;358:568-79
4. CID 2008 Apr 1; 46: 1111-8
11/18/2008, 3:22 PM
4
Adverse Drug Reaction News
December 2008
Vol.10
No.3
Slimming health products (Relacore & Lami)
adulterated with sibutramine
I
n recent months, the
Pharmacovigilance
Branch, HSA has
received three reports
of
adverse
drug
re a c t i o n s
(ADR)
associated with two
slimming
health
p ro d u c t s . O n f u r t h e r
investigation,
the
p ro d u c t s
n a m e l y,
‘Relacore’ and ‘Lami’,
w e re
found
to
contain sibutramine, an
u n d e c l a re d w e s t e r n
drug ingredient used as an appetite
s u p p re s s a n t i n t h e m a n a g e m e n t o f
obesity.
B) Lami
Case report
A 2 9 y e a r- o l d f e m a l e p re s e n t e d t o a
general practitioner’s clinic with symptoms
of palpitation, breathlessness, auditor y
hallucination and labile mood after taking
a traditional Jamu supplement labelled as
‘Lami’. The patient has been taking ‘Lami’
since 2007. Adverse symptoms manifested
when she took eight capsules of the
product, which was four times above the
dose of two capsules/day
recommended on the label.
T h e p a t i e n t p ro v i d e d t h e
sample, which was also tested
by HSA to contain sibutramine.
Sibutramine-induced
psychosis
A) Relacore
I n J u n e 2 0 0 8 , H S A i s s u e d a p re s s
statement to alert the public of the
a d u l t e r a t e d p ro d u c t l a b e l l e d a s
‘Relacore’. This was prompted by two
ADR reports involving two adult patients
(a male and female) in their early 20s,
that were brought to HSA’ s attention
by doctors at a hospital. Noteworthy was
that both patients admitted to purchasing
the slimming product over the Internet. One of the patient
provided samples of ‘Relacore’, which was ordered from a
Chinese website. The product was subsequently tested by
H S A’ s a n a l y t i c a l l a b o r a t o r y t o c o n t a i n 1 2 . 2 2 m g o f
sibutramine in each capsule.
The adulterated product labelled as ‘Relacore’ (could be a
counterfeit of the product sold in the US) was promoted as a
dietary supplement and claimed to contain “stress mitigating
compound” for “belly fat and stress control”.
Details of one case report
The male patient mentioned above, presented with symptoms
of psychosis, including hallucination and palpitation at the
emergency department. On further probing by the doctor,
he admitted to taking ‘Relacore’ for three months at a dose
of 3–4 capsules daily, which was beyond the dose of two
capsules recommended on the product’s label. Based on the
amount of sibutramine found in each capsule, the patient
had unwittingly consumed 36–48 mg of sibutramine daily
(maximum daily dose of subitramine is 15 mg). This could
explain the adverse reactions observed in the patient, taking
into consideration the close temporal relationship between
the onset of adverse reaction and date of ingestion of the
adulterated product.
8pp_ADR_News_Dec2008_Vol10_No3.p65
4
Sibutramine is a noradrenaline
a n d s e ro t o n i n re u p t a k e
inhibitor indicated for weight
loss. The commonly reported
a d v e r s e re a c t i o n s i n c l u d e
insomnia, headache and
a n x i e t y. Ta c h y c a rd i a a n d
hypertension have also been
reported in some patients.
Sibutramine is also known to exhibit significant dopamine
reuptake inhibition and some authors have postulated that
this could possibly lead to the development of psychotic
symptoms, especially in the event of an overdose. 1 This is
based on the postulation that the dopamine reuptake
inhibition could result in excess dopamine in the synaptic
c l e f t s a n d a c o n s e q u e n t i n c re a s e d d o p a m i n e rg i c
neurotransmission, in line with the dopamine hypothesis of
psychosis. 2, 3
Be mindful of Internet purchase of drug and health
products
Given the increasing trend of consumers turning to the
I n t e r n e t f o r p u rc h a s e o f h e a l t h p ro d u c t s , h e a l t h c a re
professionals are encouraged to ask patients about the
consumption of such complementary medicines or health
supplements. Very often, patients may not regard these
products as medicines and will not mention it to their doctors.
The information may be important to physicians in making a
differential diagnosis of the adverse events experienced by
patients.
References
1. J Psychosom Res. 2008 Jan;64(1):107-9.
2. Am J Psychiatry. 2000 Dec;157(12):2057-8.
3. J Clin Psychopharmacol. 2007 Jun;27(3):315-7.
11/18/2008, 3:22 PM
December 2008
Vol.10
No.3
Adverse Drug Reaction News
Fentanyl transdermal patch and overseas reports of fatality
Fatal adverse reactions relating to drug abuse, misuse and overdose reported
H
SA would like to update healthcare
professionals on the overseas
cases of life-threatening and fatal
adverse events reported with the use of
fentanyl transdermal patch.
Fentanyl is a potent opioid analgesic which
should be used only in patients who have
previously tolerated opioids as there is a risk
of significant respiratory depression in
opioid-naïve patients. In Singapore, fentanyl
transdermal patch (Durogesic®, JanssenCilag) is licensed as a controlled drug for
the management of chronic and intractable
pain requiring opioid analgesia that involves
continuous opioid administration for an
extended period of time. It is only licensed
for use in adults and in opioid-tolerant
children aged two years and above.
Reports received by UK MHRA
Recently, reports of life-threatening adverse
reactions and death have been received by
the UK Medicines and Health products
Regulatory Agency (MHRA) from healthcare
professionals, patients and caregivers of
patients who were using fentanyl patches
for malignant and non-malignant pain
control. These were found to be possibly
related to unintentional overdose such as
dosing errors, accidental exposure (in
children) and exposure of the patch to a
heat source, potentially resulting in an
increase in fentanyl absorption. Some of the
reports also reflected the use of fentanyl
patches for unlicensed indications and in
opioid-naïve patients. In the UK, fentanyl
products include Durogesic® Dtrans®,
Durogesic®, Matrifen® and Tilofyl®.
5
overdose, intentional
overdose or suicide,
drug interactions with
CYP 3A4 inhibitors
(eg. grapefruit juice,
ketoconazole,
erythromycin,
diltiazem) and the
sharing of the patch
with another patient
who
was
not
prescribed
the
treatment.
Fentanyl transdermal
products available in
Canada include Duragesic®, Ratio-Fentanyl® and Ran-Fentanyl®. The Health Canada had
in earlier warnings issued in 2004 and 2005 described fatal outcomes in opioid-naïve
adolescents and when fentanyl patches were abused by adolescents, leading the agency
to revise the Canadian product monograph for Duragesic® to emphasize the safe and
appropriate use of the patch.
Reports received by US FDA
In December 2007, the US Food and Drug Administration (FDA) issued a public health
advisory to alert patients, caregivers and healthcare professionals to adverse reactions
arising from the prescribing of the fentanyl patch to patients for inappropriate indications
such as acute pain following surgery, for headaches and occasional mild pain. The agency
also received reports on patients who replaced the patch more frequently than was directed
in the product label, applying more patches than prescribed, or applying a heat source to
the patch, all of which may lead to exceedingly high fentanyl levels in the blood. Both
Durogesic® and generic versions of the product are marketed in the US.
Local situation
To date, no adverse reaction of the nature described above has been reported to the
Pharmacovigilance Branch of HSA. However, due to the seriousness and occurrence of
fatalities associated with the inappropriate use and abuse of the patch reported overseas,
healthcare professionals are advised to be aware of the potential serious and fatal adverse
effects associated with the use of fentanyl patches. They are also advised to instruct patients
and caregivers on the appropriate and safe use of fentanyl patches as well as educate
them on the signs and symptoms of fentanyl overdose (see table 1 for list of symptoms).
Reports received by Health Canada
Similarly, Health Canada received 105
adverse reactions suspected to be associated
with fentanyl transdermal patches between
January 1992 to December 2007 where a
fatal outcome was reported. In 33 of the
105 reports, the cause of death was
reported to be unrelated to the fentanyl
patches and in 20 cases, insufficient
information was provided in the reports.
Among the remaining 52 reports,
intentional drug abuse accounted for almost
half the cases. The other factors related to
the fatal adverse reactions included
inappropriate dose initiation and titration
including use in opioid-naïve patients,
inappropriate application of patches by
patients (applying more than prescribed) or
healthcare professionals, accidental
8pp_ADR_News_Dec2008_Vol10_No3.p65
5
Healthcare professionals are also encouraged to report all adverse events suspected to be
associated with fentanyl patches to the Pharmacovigilance Branch of HSA.
Table 1: Some signs and symptoms of fentanyl overdose
■
■
■
■
■
■
■
Troubled breathing or shallow breathing
Slow heartbeat
Cold, clammy skin
Tiredness
Extreme sleepiness or sedation
Inability to think, walk or talk normally
Feeling faint, dizzy or confused
References
1. Drug Safety Update Vol. 2 Issue 2 September 2008 from MHRA and CHM
2. Canadian Adverse Reaction Newsletter Vol. 18, Issue 3, July 2008
3. Dear Healthcare Professional Letter issued by Health Canada on Duragesic®, September 13, 2005.
4. Canadian Adverse Reaction Newsletter Vol. 15, Issue 3, July 2005
5. Canadian Adverse Reaction Newsletter Vol. 14, Issue 4, Oct 2004
6. http://www.fda.gov/cder/drug/infopage/fentanyl/default.htm
11/18/2008, 3:22 PM
6
Adverse Drug Reaction News
December 2008
Vol.10
No.3
Haemorrhagic or necrotizing pancreatitis
associated with Byetta®
Actions taken in the US
E
xenatide (Byetta®,
Eli Lilly) is an incretin
mimetic agent that
mimics the enhancement of
glucose-dependent insulin
secretion and several other
antihyperglycaemic actions
of incretins. It is licensed as
an adjunctive therapy in the
treatment of patients with
type 2 diabetes mellitus and
was recently registered in
Singapore in May 2008.
Post-marketing reports
of pancreatitis
Since its market introduction in June 2005,
the US Food and Drug Administration (FDA)
has been receiving post-marketing adverse
event reports describing acute pancreatitis in
patients treated with Byetta®. In the FDA’s
review of 30 post-marketing reports of acute
pancreatitis in patients treated with Byetta®,
majority of patients had at least one risk factor
for acute pancreatitis such as gallstones, severe
hypertriglyceridaemia and alcohol use. In six
patients, symptoms of pancreatitis began or
worsened after the dose of Byetta® was
doubled. Five patients developed serious
complications including dehydration, renal
failure, suspected ileus, phlegmon and ascites.
Recently, Byetta® was linked to six new cases
of haemorrhagic or necrotizing pancreatitis,
of which there were two fatalities and four
cases of deaths in patients with pancreatitis.
The US FDA issued a safety alert to warn
healthcare professionals of the potential
risk of acute pancreatitis associated with
Byetta®, following its review of the 30 postmarketing reports of acute pancreatitis in
patients treated with Byetta®. The package
insert for Byetta® was also updated
to include the post-marketing findings
of acute pancreatitis. With the recent
six cases of haemorrhagic or necrotizing
pancreatitis, FDA has requested the
company to add stronger and more
prominent warnings in the package insert
about the risk of acute haemorrhagic or
necrotizing pancreatitis. Healthcare professionals and patients were advised to maintain
vigilance for signs and symptoms of acute pancreatitis associated with the use of Byetta®.
Local situation and HSA’s advisory
To date, HSA has not received any local reports of acute pancreatitis associated with Byetta®.
However, physicians are encouraged to advise their patients taking Byetta® to look out for
signs and symptoms of acute pancreatitis and to seek prompt medical attention should they
experience unexplained, persistent, severe abdominal pain, which may be accompanied by
nausea and vomiting. If pancreatitis is suspected, Byetta® should be discontinued.
In June 2008, the company issued a Dear Healthcare Professional Letter to inform local
healthcare professionals of the potential risk of acute pancreatitis associated with Byetta®.
HSA is currently working with the company to update the local package insert to reflect
these recent post-marketing findings of acute pancreatitis. Healthcare professionals are
also encouraged to report any serious adverse drug reactions suspected to be associated
with the use of Byetta® to the Pharmacovigilance Branch of HSA.
References
1. FDA information for healthcare professionals: Exenatide (marketed as Byetta®).
http://www.fda.gov/cder/drug/InfoSheets/HCP/exenatide2008HCP.htm
2. Important prescribing information on Byetta®, 2007 Oct.
http://www.fda.gov/medwatch/safety/2007/byetta_dhcp-letter.pdf
Summary of advisories issued by HSA
and pharmaceutical companies
S
ummary of Dear Healthcare Professional Letters issued
by HSA and/or pharmaceutical companies from
November 2007 to October 2008. For details, please log
on to http://www.hpp.moh.gov.sg using your professional
board register number or Singpass.
1 Apr 2008
15 Apr 2008
22 Apr 2008
27 Nov 2007
11 Dec 2007
13 Dec 2007
26 Dec 2007
31 Jan 2008
14 Feb 2008
25 Feb 2008
17 Mar 2008
1 Apr 2008
Important safety information on perflutren
lipid microsphere (Definity®) [Research Biolabs]
Important safety warnings for gadolinium-based
contrast agents
Reclassification of hydroquinone – containing
products for skin-bleaching
Suspension of sales of nimesulide in Singapore:
HSA’ s update
Mycophenolic acid as sodium salt (Myfortic®) –
Labeling update on teratogenic risk [Novartis]
HSA
warns
about
an
illegal
product
“Power 1 Walnut
”
Reports of hepatic failure with deferasirox (Exjade®)
[Novartis]
Telbivudine (Sebivo®) in the treatment of chronic
hepatitis B - Adverse event “Peripheral neuropathy”
seen with the treatment of telbivudine combination
with pegylated interferon alfa-2A [Novartis]
Lapatinib (Tykerb®) and new safety information on
hepatotoxicity
(predominantly
transaminase
elevations) [GSK]
8pp_ADR_News_Dec2008_Vol10_No3.p65
6
26 May 2008
12 Jun 2008
14 Jul 2008
18 Sep 2008
19 Sep 2008
7 Oct 2008
20 Oct 2008
Update on risk of suicidal ideation and behaviour with
lamotrigine (Lamictal®) tablets and chewable dispersable
tablets [GSK]
HSA alerts on wider spread of harmful illegal health
products
Reports of progressive multifocal leukoencephalopathy
(PML) in mycophenolate mofetil (Cellcept®) treated
patients [Roche]
Abacavir sulphate-containing medicinal products
(Ziagen® tablets and oral solution; Kivexa® tablets;
Trizivir® tablets) – communication on results pertaining
to abacavir from the D:A:D study [GSK]
Important prescribing information on exenatide
(Byetta®) [Eli Lilly]
Safety information regarding the combined use
of bevacizumab (Avastin®) and sunitinib malate
Direct healthcare professional communication
on
a
report
of
progressive
multifocal
leukoencephalopathy (PML) in a patient with
rheumatoid arthritis treated with rituximab
(Mabthera®) [Roche]
US FDA’ s actions on products manufactured by two
of Ranbaxy’s manufacturing plants in India
New formulation of Eltroxin® (Levothyroxine) tablets
[GSK]
Recall of hot/cold packs
11/18/2008, 3:22 PM
December 2008
Vol.10
No.3
Adverse Drug Reaction News
Package insert amendments reflecting safety issues
H
SA has approved the following
package insert changes due to
safety updates from May 2008
to September 2008. 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:
http://www.hsa.gov.sg/
safetyinfo_and_recalls. Please also note
that there might be some lag time
in the availability of the package insert
which reflects the latest change(s).
1
Carbamazepine (Tegretol®, Novartis) Special
warning: Strong correlation between SJS/TEN
associated with carbamazepine & presence of Human
Leukocyte Antigen (HLA)-B*1502 allele found in Han
Chinese. Consider testing for allele in genetically
at-risk patients with Asian ancestry. Avoid use of
carbamazepine, anti-epileptic drugs & other drugs
associated with SJS/TEN in patients positive for
HLA-B*1502.
2
3
4
5
6
7
Cefepime (Maxipime® injection, Bristol-Myers)
Caution: Hypersensitivity to beta-lactam antibiotics,
GI disease esp. colitis, neutropenia, renal-impairment,
& in the elderly. New ADRs: Urticaria, renal dysfunction,
hepatic dysfunction including cholestasis.
Cyproterone, ethinylestradiol (Diane-35®,
Schering), Drospirenone, ethinylestradiol
(Yasmin®, Schering) & Levonorgestrel,
ethinylestradiol (Microgynon®, Schering)
Special warning: The most important risk factor for
cervical cancer is persistent HPV infection. Long term
COC use may further increase this risk. The extent
to which this finding is attributable to factors
e.g. cervical screening & sexual behaviour
remains controversial. Interactions: HIV protease
inhibitors (e.g. ritonavir), non-nucleoside reverse
transcriptase inhibitors (e.g. nevirapine) & combinations
may affect hepatic metabolism, increasing plasma &
tissue concentrations of cyclosporine & decreasing
lamotrigine concentrations. New ADRs: May induce
or exacerbate symptoms of angioedema in women
with hereditary angioedema.
Dactinomycin (Lyovac Cosmegen®, Merck)
New ADRs: Neutropenia, febrile neutropenia.
Duloxetine (Cymbalta®, Eli Lilly) Special warnings:
Caution in patients whose conditions are compromised
by increased heart rate or blood pressure. Suicidal
ideation & behaviours reported during therapy or early
after discontinuation. Not for patients < 18 years old.
Hyponatremia may occur as a result of SIADH. Patients
at risk include the elderly, those taking diuretics and
those with volume depletion. New ADRs: Creatine
phosphokinase increased, blood cholesterol increased,
atrial fibrillation, akathisia, palpitations, tachycardia,
dyskinesia, gastroenteritis, myoclonus convulsions,
acute liver injury, tinnitus, angioneurotic oedema.
Erythromycin (Eryc®, Hospira) Warning: Prolonged
QT observed in elderly. Precautions: Infantile
hypertrophic pyloric stenosis (IHPS) reported.
Erythromycin may aggravate the weakness of patients
with myasthenia gravis. Interactions: Uncorrected
electrolyte disorders (hypokalaemia), QTc interval
prolonged or drugs that prolong the QTc interval.
Monitor closely when oral erythromycin & quinidine
are administered concomitantly as QT prolongation,
torsades de pointes & cardiac arrest have been
reported. Myalgia, neutropenia & fever reported with
concurrent administration of erythromycin &
vinblastine. ADRs: Pancreatitis, QT prolongation
ventricular arrhythmias & convulsions.
Etanercept (Enbrel® injection, Wyeth) New ADRs:
Erythema multiforme, Stevens Johnson syndrome,
toxic epidermal necrolysis.
8pp_ADR_News_Dec2008_Vol10_No3.p65
7
8
Ezetimibe, simvastatin (Vytorin®, MSD) Precautions:
Risk of myopathy/rhabdomyolysis increased by
concomitant use of Vytorin® with danazol, fibrates,
niacin or fusidic acid. When used with gemfibrozil, dose
of Vytorin® should not exceed 10/10mg (ezetimibe/
simvastatin) daily. Monitor INRs If Vytorin® is added to
coumarin anticoagulant, or fluindione therapy. New
ADRs: Cholelithiasis, cholecystitis, depression, increased
creatine phosphokinase, elevations of liver
transaminases, anaphylaxis, hepatic failure.
16
17
9
Fentanyl (Durogesic® Transdermal System,
Janssen-Cilag) Special warnings: Patients at increased
risk of opioid abuse may be treated with modified-release
opioid formulations but monitor for signs of misuse,
abuse or addiction. Withdrawal symptoms possible
when converting from previous opioid analgesic to
Durogesic® or if therapy is abruptly stopped. Avoid
exposing application site to tanning lamps &
prolonged hot baths. New ADRs: Anaphylactic shock,
anaphylactic reaction, anaphylactoid reaction, drug
withdrawal syndrome. Pregnancy: Neonatal withdrawal
syndrome reported in newborn infants with chronic
maternal use of Durogesic® during pregnancy.
10
11
12
Fluvastatin (Lescol®, Novartis) ADR: Anaphylactic
reactions.
Glipizide (Glucotrol® XL, Pfizer) Special warning:
Treatment of patients with G6PD-deficiency may lead to
haemolytic anaemia. Interaction: Voriconazole.
Hydroxyzine (Atarax®, UCB) Contraindications:
1) Hypersensitivity to cetirizine, piperazine derivatives,
aminophylline, ethylenediamine, 2) porphyria,
3) pregnancy & breast-feeding. Special warnings:
Caution in young children with increased potential for
convulsions, glaucoma, bladder outflow obstruction,
decreased GI motility, myasthenia gravis, or dementia,
when used simultaneously with CNS depressants or
anticholinergics. Avoid alcohol. Caution in patients with
predisposing factor to cardiac arrhythmia, or those
concomitantly treated with a potentially arrhythmogenic
drug. Reduce dosage in elderly, patients with hepatic
dysfunction & moderate/severe renal impairment.
Stop treatment at least 5 days before allergy testing
or metacholine bronchial challenge. Interactions:
CNS depressants, anticholinergics, alcohol, betahistine,
anticholinesterase drugs, MAOIs, adrenaline,
cimetidine. Pregnancy & lactation: Hypotonia,
movement disorders (extrapyramidal disorders, clonic
movements), CNS depression, neonatal hypoxic
conditions, or urinary retention observed in neonates
of mothers who received Atarax® during late
pregnancy &/or labour. New ADRs: Tachycardia,
accommodation disorder, blurred vision , pyrexia,
hypersensitivity, anaphylactic shock, liver function test
abnormal, insomnia, dyskinesia, agitation, confusion,
disorientation, hallucination, urinary retention,
bronchospasm, hypotension, dermatitis, fixed drug
eruption, increased sweating.
13
Iloprost Trometamol (Ventavis®, Berlimed SA)
Special warnings: Inhalation might induce
bronchospasm. Patients with concomitant acute
pulmonary infections, COPD, & severe asthma should
be carefully monitored. Not for pregnant or lactating
women. Women of child bearing potential should use
effective contraceptive measures during treatment.
New ADRs: Pain in jaw, back pain, vomiting, dizziness,
diarrhoea, dyspnoea, bronchospasm, wheezing.
14
Influenza
vaccine
(Fluad®,
Novartis)
Contraindication: Children & elderly patients on
warfarin.
15
Laronidase (Aldurazyme®, Genzyme) Warning: Lifethreatening anaphylactic reactions up to 3 hours after
infusions. In patients with Mucopolysaccharidosis I, preexisting upper airway obstruction may have contributed
to severity of reactions. Patients with acute illness at time
of infusion may be at greater risk for infusion-related
reactions. New ADRs: Chills, vomiting, nausea,
arthralgia, diarrhoea, tachycardia, abdominal pain,
blood pressure increased, decreased oxygen saturation.
18
19
7
Levonorgestrel, ethinylestradiol (Nordette®,
Wyeth) Contraindications: Hereditary or acquired
thrombophilias, headache with focal neurological
symptoms (such as aura) & undiagnosed vaginal
bleeding. Precautions: adverse lipid changes. Elevations
of plasma triglycerides may lead to pancreatitis & other
complications. Interaction: Lamotrigine.
Lorazepam (Ativan®, Wyeth) Special warnings:
Severe & potentially fatal anaphylactic/anaphylactoid
reactions reported. Reports of angioedema
involving the tongue, glottis or larynx after first or
subsequent doses & sometimes dyspnoea, throat
closing, or nausea & vomiting. Such patients should
not be rechallenged. Dependence potential of
lorazepam reduced when used at appropriate
dose for short duration. Withdrawal symptoms
can appear after discontinuation of one week of
therapy. Avoid abrupt discontinuation after extended
therapy. Convulsions more common in patients
with pre-existing seizures disorders or in those
taking drugs that lower convulsive threshold.
Possible tolerance to sedative effects. Abuse
potential esp. in patients with a history of drug &/
or alcohol abuse. Precaution: Compromised respiratory
function. Pregnancy: Increased risk of congenital
malformations during 1st trimester. New ADRs:
Angioedema, diplopia, blurred vision.
Mesalazine (Salofalk®, IDS) Special warnings:
Caution in hepatic dysfunction. Do not administer
to patients with renal dysfunction Monitor renal
function for possibility of mesalazine-induced
nephrotoxicity during treatment. Not for children
<6 years old. Mesalazine suppositories may cause
contact dermatitis. Interaction: Possible potentiation
of the myelosuppressive effects of azathioprine or
6-mercaptopurine. ADRs: Acute & chronic interstitial
nephritis, renal insufficiency, allergic exanthema,
pancolitis, elevated parameters of cholestasis,
cholestatic hepatitis, alopecia. Pregnancy & lactation:
Report of renal failure in neonate born to woman
on long-term treatment with 2–4g/day oral doses
during pregnancy. Stop breastfeeding if infant
develops diarrhoea as hypersensitivity reactions
may occur in infant.
Mycophenolic acid (Myfortic®, Novartis)
Special warning: Occasional fatal cases of progressive
multifocal leukoencephalopathy (PML) reported.
Risk factors: immunosuppressant therapies & immune
deficiency. Consider reducing total immunosuppression
in patients with PML. In transplant patients, reduced
immunosuppression may place graft at risk.
20
Pramipexole (Sifrol®, Boehringer Ingelheim)
New ADRs: Amnesia, compulsive shopping,
restlessness, visual disturbance including blur
vision & reduced visual acuity, vomiting, weight loss.
21
Simvastatin (Zocor®, MSD) Precaution: Concomitant
administration with fusidic acid may increase risk of
myopathy. Consider temporary suspension of
simvastatin. New ADR: Hepatic failure.
22
Telmisartan (Micardis®, Boehringer Ingelheim)
Interactions: Treatment with NSAIDs associated
with potential for acute renal insufficiency in
dehydrated patients. Reduced effect during
combined treatment with NSAIDs. New ADRs:
Cystitis, syncope/faint, abnormal hepatic function/
liver disorder, renal impairment including acute
renal failure, hyperkalaemia, anaemia, angioneurotic
oedema, increased blood creatine phosphokinase.
23
Vardenafil (Levitra®, Bayer) Special warnings:
With alpha blockers besides tamsulosin, separate timing
of dose. When used with clarithromycin, do not exceed
5mg of vardenafil. Interaction: nicorandil. New ADRs:
Sudden deafness or loss of hearing, transient global
amnesia, seizures.
24
Zanamivir (Relenza®, GSK) Special warning: Seizures,
delirium, hallucination & abnormal behaviour observed
mainly early in the therapy & often has an abrupt onset
& rapid resolution.
11/18/2008, 3:22 PM
8
Adverse Drug Reaction News
December 2008
Vol.10
No.3
Biosimilar products
A regulatory update
A
biosimilar medicine is a medicinal product which is similar
to a biological medicine that has already been registered
with a drug regulatory authority and is submitted for
medicinal product registration by an independent applicant after
the patent period for the original product has expired.
As the cost of innovative biological products are generally high,
thereby limiting their use, the expiration of the patents on many
biological products such as human growth hormone and
erythropoietin has prompted the development and licensing of
biosimilar products. A biosimilar product would have an abbreviated
non-clinical and clinical development programme leveraging on
the existing information of the original product and focusing on
demonstration of similarity with the original product, also known
as the reference product.
Biosimilar products such as Valtropin® and Omnitrope® (both are
somatropin) and Binocrit® (which contains epoetin alpha) are
registered in the European Union. There are no biosimilar products
registered in Singapore as yet but such products will eventually
enter the market, subject to approval by HSA. This article serves to
provide healthcare professionals with more information on
biosimilars and what to take note of when prescribing and reporting
ADRs associated with biosimilar products when these products
become available locally in the future.
Why are biosimilar products different from generic
chemical products?
Biosimilar products may commonly be mistaken for generic versions
of the reference biological product. Unlike generic chemical drugs,
whereby the chemical structure is identical to that of the reference
chemical product, a biosimilar product does not usually have an
identical structure to the reference biological product. Hence, even
though these biological/biotechnology-derived proteins may be
approved by regulatory authorities to be similar in terms of quality,
safety and efficacy to a reference biological medicine to which it
has been compared with, there is a chance that these products
may cause adverse reactions which may be different from that of
their reference products. One such adverse reaction may be differing
immunological response of the patient.
How are biosimilar products assessed?
Biosimilar products are assessed based on comparability data
between the biosimilar products and the reference products in
terms of quality of product, non-clinical studies (e.g. animal
pharmacodynamic studies and toxicity studies) and clinical
studies (e.g. pharmacokinetic and pharmacodynamic studies in
human subjects). The eventual approval for the biosimilar product
may be for the same indications and patient groups as that of the
corresponding reference product registered in Singapore, or it
may be for more restricted indications and patient groups.
How should a biosimilar product be prescribed and
dispensed?
The decision by a doctor whether to prescribe a biosimlar product
or the innovator biological product is dependent on factors relevant
Editor-in-Chief
Ms Chan Cheng Leng,
BSc (Pharm) Hons
Executive Editor
Ms Adena Lim,
BSc (Pharm) Hons, MPharm
Editorial Board
Clinical Prof. Goh Chee Leok
Prof. Edmund Lee Joo Deoon
Clinical Prof. Chng Hiok Hee
Clinical A/Prof. Gilbert Lau Kwang Fatt
Dr Lee Kheng Hock
8pp_ADR_News_Dec2008_Vol10_No3.p65
8
Staff Editors
Ms Ang Pei San, BSc (Pharm)
Mr Choong Chih Tzer, BPharm
Ms Christine Ho, BSc (Pharm) Hons
Dr Yvonne Koh, BSc (Pharm) Hons, PhD
Ms Belinda Tan, BSc (Pharm)
Ms Liesbet Tan, BSc (Pharm) Hons
Ms Tan Siew Har, BSc (Pharm)
Ms Tan Wei Chuen, BSc (Pharm)
to the patient and the institution which he practises in. However
when prescribing such products, it is important to use the brand
name of the selected product. A biosimilar product may have the
same international non-proprietary name (INN) as the reference
biological product but they should not be presumed to be identical.
Using the brand name will help avoid the issue of automatic
substitution of the product when dispensed in the pharmacy, or
during administration of the product.
How do I report adverse drug reactions (ADRs) to
biosimilars?
In view of the complexity of biological molecules and for the reasons
mentioned above, it is pertinent to report the brand name of the
biosimilar which is suspected to cause an ADR rather than the name
of the substance (e.g. Genotropin® instead of somatropin), together
with the batch number of the product used.
Biosimilar products are similar but NOT identical to an existing
biological product.
■
A biosimilar product may have the same or a more restricted
indication for use compared to the existing biological product
■
When prescribing a biosimilar product, the brand name of
the product should be clearly stated on the prescription
■
When dispensing/administering a biosimilar product,
only the product with the correct brand name
should be dispensed/administered. There should NOT
be any substitution with another product with the same
international non-proprietary name without seeking
clarification with the prescribing doctor
■
When reporting an adverse reaction, the brand name and
batch number of the product should be clearly stated
References
1. http://www3.niaid.nih.gov/research/resources/DAIDSClinRsrch/
Glossary.htm
2. Drug Safety Update Vol. 1, Issue 7 February 2008 from MHRA and CHM
Enquiries, comments and
suggestions to:
Tel: (65) 6866 3538
Fax: (65) 6478 9069
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.
Website: http://www.hsa.gov.sg
Email: [email protected]
Copyright © 2008 Health Sciences Authority of
Singapore. All Rights Reserved.
Pharmacovigilance Branch
Health Products Regulation Group
Health Sciences Authority
11 Biopolis Way, #11-03,
Helios, Singapore 138667
11/18/2008, 3:22 PM