Bradicardia y Fluoracilo Señal

2020
WHO Pharmaceuticals
NEWSLETTER No. 5
The WHO Pharmaceuticals Newsletter provides you

with the latest information on the safety of medicines
WHO Vision for Medicines Safety and legal actions taken by regulatory authorities around
No country left behind: the world. It also provides signals based on information
worldwide pharmacovigilance
for safer medicines, safer patients derived from the WHO global database of individual
case safety reports, VigiBase.
The aim of the Newsletter is

to disseminate regulatory
information on the safety of
pharmaceutical products,
based on communications
received from our network of
national pharmacovigilance centres
and other sources such as
specialized bulletins and journals,
as well as partners in WHO.
The information is produced in

the form of résumés in English,
full texts of which may be obtained
on request from:
Safety and Vigilance: Medicines,
EMP-HIS,
World Health Organization,
1211 Geneva 27, Switzerland, Contents
E-mail address: [email protected]
This Newsletter is also available at: Regulatory matters
http://www.who.int/medicines
Safety of medicines
Signal
WHO Pharmaceuticals Newsletter No. 5, 2020
ISBN 978-92-4-001453-4 (electronic version)

ISBN 978-92-4-001454-1 (print version)
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Table of Contents
Regulatory Matters
Alfuzosin ............................................................................................................... 4
Baricitinib .............................................................................................................. 4
Benidipine ............................................................................................................. 4
Canagliflozin ......................................................................................................... 4
Hydroxychloroquine .............................................................................................. 5
Opioid ................................................................................................................... 5
Pentoxifylline ......................................................................................................... 5
Piperacillin, Tazobactam ....................................................................................... 5
Relugolix ............................................................................................................... 5
Tinidazole ............................................................................................................. 6
Ulipristal acetate ................................................................................................... 6
X-ray contrast media ............................................................................................. 6
Safety of medicines
Allopurinol ............................................................................................................. 7
Beta-lactam antibiotics, non-steroidal anti-inflammatory drugs, intravenous iron
preparations and rocuronium ................................................................................. 7
Clozapine, other antipsychotics ............................................................................. 7
Cyproterone .......................................................................................................... 8
Denosumab ........................................................................................................... 8
Emollient ............................................................................................................... 8
Glecaprevir/pibrentasvir (combination) .................................................................. 8
Isotretinoin ............................................................................................................ 9
Topiramate ............................................................................................................ 9
Information Note
Sodium valproate ................................................................................................ 10
Signal
Everolimus and osteonecrosis of the jaw (ONJ) ................................................... 11
Fluorouracil and Bradycardia – national signal from Peru with potential global
relevance ............................................................................................................ 18
WHO Pharmaceuticals Newsletter No. 5, 2020 • 3

Regulatory Matters
Alfuzosin reported in clinical trials and in cases were evaluated by the

post-marketing use worldwide. SRP, PvPI, and IPC who found
Risk of palpitations There were 21 cases of a strong causal relationship
diverticulitis. between benidipine and
India. The National associated photosensitivity
For post-marketing use of
Coordination Centre - reaction.
baricitinib outside of clinical
Pharmacovigilance Programme trials, 35 spontaneous cases of Reference:
of India (NCC-PvPI) has made diverticulitis were reported Based on the communication
a recommendation to the worldwide up until 2019. Of from NCC-PvPI, IPC India
Central Drugs Standard Control these, 25 cases included a (ipc.gov.in)
Organisation (CDSCO) to medical history of diverticulitis
request that the patient and/or chronic use of NSAIDs,
information leaflet (PIL) for corticosteroids or opioids,
alfuzosin should be revised to which are known important risk
incorporate palpitations as a factors for diverticulitis. Canagliflozin
clinically significant adverse
drug reaction. Health-care professionals are Risk of amputations
advised to use baricitinib with
Alfuzosin is used for the removed
caution in patients with
treatment of benign prostatic diverticular disease and in
hyperplasia. USA. The US Food and Drug
those concomitantly treated Administration (FDA) has
Between July 2011 and with medications associated announced that the boxed
November 2019, the NCC-PvPI with an increased risk of warning about the risk of
received a total of three diverticulitis. amputation with the use of
individual case safety reports Also, health-care professionals canagliflozin (Invokana® and
(ICSRs) of alfuzosin associated should advise patients on Invokamet®) has been
palpitations. The cases were baricitinib to seek immediate removed from the prescribing
evaluated by the Signal Review medical care if they experience information.
Panel (SRP), PvPI, and Indian severe abdominal pain
Pharmacopeia Commission Canagliflozin is a sodium-
especially accompanied with glucose cotransporter-2
(IPC) who found a strong fever, nausea and vomiting or
causal relationship between (SGLT2) inhibitor. It lowers
other symptoms of blood sugar by causing the
alfuzosin associated diverticulitis.
palpitations. kidneys to remove sugar from
Reference: the body through the urine. It
Reference: Drug Safety Update, MHRA, is used to reduce the risk of
Based on the communication 26 August 2020 major heart-related events
from NCC-PvPI, IPC India (www.gov.uk/mhra) such as heart attack, stroke or
(ipc.gov.in) death in patients with type 2
diabetes, and to reduce the
risk of end-stage kidney
disease, worsening of kidney
Benidipine function, heart-related death,
Baricitinib and being hospitalized for heart
Risk of photosensitivity failure in certain patients with
Increased risk of reaction type 2 diabetes and diabetic
diverticulitis kidney disease.
India. The NCC-PvPI has made
United Kingdom. The The FDA’s review of new
a recommendation to the
Medicines and Healthcare clinical trial data demonstrated
CDSCO to request that the PIL
Products Regulatory Agency additional heart and kidney
for benidipine is revised to
(MHRA) has announced that related benefits.
incorporate photosensitivity as
the risk of diverticulitis has a clinically significant adverse Safety information from recent
been added to the product drug reaction. clinical trials also suggests that
information for baricitinib the risk of amputation, while
(Olumiant®). Benidipine is used for the
still increased with
treatment of hypertension and
Baricitinib is a Janus kinase canagliflozin, is lower than
long term prophylactic
inhibitor and is indicated for previously described. The FDA
management of angina
the treatment of moderate to has concluded that the boxed
pectoris.
severe active rheumatoid warning should be removed.
arthritis in adults. Between July 2011 and
Health-care professionals and
November 2019, the NCC-PvPI
A European review has patients should continue to
received a total of five ICSRs
assessed cases of diverticulitis recognize the importance of
reporting benidipine associated
associated with baricitinib preventative foot care and
photosensitivity reaction. The

Regulatory Matters
monitor for new pain, Opioid found a strong causal

tenderness, sores, ulcers and relationship between
infections in the legs and feet. Naloxone helps reverse pentoxifylline use and
palpitations.
Reference: opioid overdose
MedWatch, US FDA, 26 August Reference:
2020 (www.fda.gov) USA. The FDA has requested Based on the communication
that manufacturers of opioid from NCC-PvPI, IPC India
(See also WHO Pharmaceuticals Newsletter pain relievers and medicines to
No.3, 2020: Risk of diabetic ketoacidosis in (ipc.gov.in)
treat opioid use disorder
UK; No.1, 2020: Updated advice on
monitoring ketone bodies in Ireland) (OUD), add new
recommendations about
naloxone to the prescribing
information. Piperacillin,
Opioids have serious risks Tazobactam
Hydroxychloroquine including misuse and abuse,
addiction, overdose and death. Risk of acute generalised
Risk of prolonged QT, Naloxone is used to block the exanthematous pustulosis
ventricular tachycardia effects of opioids (e.g. (AGEP)
countering decreased
Japan. The Ministry of Health, breathing) and can help India. The NCC-PvPI has made
Labour and Welfare (MHLW) reverse opioid overdose to a recommendation to the
and the Pharmaceuticals and prevent death. CDSCO to request that the PIL
Medical Devices Agency
The FDA encourages health- for piperacillin/tazobactam is
(PMDA) have announced that
care professionals to raise revised to incorporate acute
the package insert for
awareness of the availability of generalised exanthematous
hydroxychloroquine
naloxone when they prescribe pustulosis (AGEP) as a clinically
(Plaquenil®) should be revised
opioid pain relievers or significant adverse drug
to include prolonged QT and
medicines to treat OUD. reaction.
ventricular tachycardia as
adverse drug reactions. Piperacillin/tazobactam is used
Health-care professionals
should educate patients on how for the treatment of moderate
Hydroxychloroquine is
to recognize respiratory to severe lower respiratory
indicated for cutaneous lupus
depression and how to tract infections.
erythematosus and systemic
lupus erythematosus. administer naloxone. Between July 2011 and
Reference: November 2019, NCC-PvPI
A total of four cases of
MedWatch, US FDA, 23 July received a total of six ICSRs
prolonged QT and ventricular
2020 (www.fda.gov) reporting
tachycardia (including torsades
piperacillin/tazobactam
de pointes) were reported in
associated AGEP. The cases
patients that used
were evaluated by the SRP,
hydroxychloroquine in Japan
PvPI, and IPC who found a
during the previous three
years. A causal relationship Pentoxifylline strong causal relationship
between
between the drug and event
Risk of palpitations piperacillin/tazobactam use
could not be established for
and AGEP.
any of these cases. One case of
patient mortality has been India. The NCC-PvPI has made
Reference:
reported and a causal a recommendation to the
Based on the communication
relationship could not be CDSCO to request the revision
from NCC-PvPI, IPC India
established for that case. of the PIL for pentoxyphylline
(ipc.gov.in)
to incorporate palpitations as a
The MHLW and PMDA have clinically significant adverse
concluded that a revision of the drug reaction.
package insert is necessary.
Pentoxifylline is a vasodilator
Reference: indicated for the treatment of Relugolix
Revision of Precautions, atrial and atriovenous
MHLW/PMDA, 8 September circulatory disorder. Risk of severe abnormal
2020 (www.pmda.go.jp/english/) uterine bleeding in patients
Between July 2011 and
with submucosal fibroid
November 2019, the NCC-PvPI
received a total of four ICSRs Japan. The MHLW and the
reporting palpitations PMDA have announced that the
associated with pentoxifylline package insert for relugolix
use. The cases were evaluated (Relumina®) should be revised
by the SRP, PvPI, and IPC who
Regulatory Matters
to include the risk of severe strong causal relationship No.3, 2020: Licence suspension due to liver
abnormal uterine bleeding in between tinidazole use and injury in UK; No.1, 2020: Risk of hepatic
patients with submucosal skin hyperpigmentation. injury in EU; No.5, 2018: New measures to
minimize risk of liver injury in EU and
fibroid in the careful
Reference: Canada)
administration section.
Based on the communication
Relugolix is indicated for relief from NCC-PvPI, IPC India
of menorrhagia, lower (ipc.gov.in)
abdominal pain, lumbar pain
and anaemia associated with X-ray contrast media
uterine fibroids.
Risk of contrast-induced
A total of 13 cases of severe Ulipristal acetate encephalopathy
abnormal uterine bleeding
were reported in patients using Revocation of marketing Japan. The MHLW and the
relugolix in Japan during the PMDA have announced that the
authorizations
previous three years. For 10 of package inserts for X-ray
the 13 cases, a causal
recommended
contrast media including
relationship between the drug Europe. The European iopamidol (Iopamiron®),
and event was reasonably Medicines Agency (EMA) has iohexol (Omnipaque®) and
possible. No patient mortalities announced that the meglumine iotroxate
have been reported. Pharmacovigilance Risk (Biliscopin®) should be revised
Patients should be carefully Assessment Committee (PRAC) to include contrast-induced
monitored and if any has recommended the encephalopathy as an adverse
abnormalities are observed, revocation of the marketing drug reaction.
appropriate measures should authorizations for ulipristal X-ray contrast media is
be taken. Patients should be acetate preparations (Esmya® indicated for several methods
instructed to immediately and generic medicines) when such as arteriography by digital
contact a medical institution if used to treat symptoms of X-ray method, computer-
they experience heavy bleeding uterine fibroids, due to the risk assisted tomography and
at one time. of liver injury. intravenous urography.
Reference: Ulipristal acetate is indicated A total of 11 cases of contrast-
Revision of Precautions, for the treatment of moderate induced encephalopathy in
MHLW/PMDA, 8 September to severe symptoms of uterine patients exposed to X-ray
2020 (www.pmda.go.jp/english/) fibroids in women who have contrast media have been
not reached the menopause. reported in Japan during the
Ulipristal acetate is also used previous three years, including
as a single-dose medicine for five cases for which a causal
emergency contraception. The relationship between the drug
Tinidazole recommendation does not and event was reasonably
apply for use of ulipristal as a possible.
Risk of skin contraception.
hyperpigmentation The MHLW and PMDA have
The PRAC considered all the concluded that a revision of the
available evidence including package inserts was necessary.
India. The NCC-PvPI has made
cases of serious liver injury.
a recommendation to the
Because it was not possible to Reference:
CDSCO to request that the PIL
identify which patients were Revision of Precautions,
for tinidazole is revised to
most at risk or measures that MHLW/PMDA, 20 July 2020
incorporate skin
could reduce the risk, the PRAC (www.pmda.go.jp/english/)
hyperpigmentation as a
concluded that the risks of the
clinically significant adverse
medicines outweighed the
drug reaction.
benefits and that they should
Tinidazole is used for the not be marketed in the EU.
treatment of amoebiasis and
The PRAC recommendation will
giardiasis in adult patients only
now be forwarded to EMA’s
and in the treatment of
Committee for Medicinal
anaerobic infections.
Products for Human Use
Between July 2011 and (CHMP), which will adopt the
November 2019, the NCC-PvPI EMA’s opinion.
received a total of 13 ICSRs of
Reference:
tinidazole associated skin
EMA, 4 September 2020
hyperpigmentation. The cases
(www.ema.europa.eu)
were evaluated by the SRP,
PvPI, and IPC who found a (See also WHO Pharmaceuticals Newsletter

Safety of Medicines
Allopurinol Beta-lactam MHRA has announced that

monitoring blood
Interaction with antibiotics, non- concentrations of clozapine
preparations (Clozaril®,
azathioprine or steroidal anti- Denzapine® and Zaponex®)
mercaptopurine: Bone
inflammatory drugs, for toxicity is advised in certain
marrow suppression clinical situations. Blood level
intravenous iron monitoring of other
New Zealand. The Medsafe
has announced that co- preparations and antipsychotics for toxicity may
also be helpful in certain
administration of allopurinol rocuronium circumstances.
with azathioprine or
mercaptopurine can lead to Risk of Kounis syndrome Clozapine and other
life-threatening bone marrow antipsychotic medicines are
suppression. New Zealand. The Medsafe indicated to treat symptoms
has reminded health-care related to psychosis, including
Allopurinol is a xanthine
professionals that Kounis schizophrenic disorders and
oxidase inhibitor used to
syndrome has been associated some forms of bipolar disorder.
reduce hyperuricaemia in
with a variety of medicines
patients with gout. The MHRA received two
including beta-lactam
Azathioprine is an separate reports raising
antibiotics, non-steroidal anti-
immunosuppressive agent, and concerns regarding the need
inflammatory drugs,
mercaptopurine is a cytotoxic for monitoring of clozapine
intravenous iron preparations
drug used in the treatment of blood levels in one report and
and rocuronium.
leukaemia. Azathioprine is monitoring antipsychotic blood
metabolized to Kounis syndrome is a levels during long-term high-
mercaptopurine, which is hypersensitivity reaction dose antipsychotic use in the
metabolized into an inactive affecting the coronary arteries. other.
compound by xanthine oxidase. The underlying mechanism for
Kounis syndrome is mast cell Expert Advisory Groups of the
Inhibition of xanthine oxidase Commission on Human
activation and release of
by allopurinol increases plasma Medicines considered safety
inflammatory mediators.
concentrations of the active data for clozapine and other
metabolites of azathioprine and The CARM recently received a antipsychotic drugs and
mercaptopurine, which may report of coronary artery advised that blood
lead to life-threatening spasm associated with the use concentrations of clozapine
leukopenia, thrombocytopenia of amoxicillin/clavulanic acid in should be monitored for
or pancytopenia. a male patient. toxicity in certain clinical
situations (e.g. a patients
Concomitant use of allopurinol Management of Kounis
stopping smoking, with
and azathioprine or syndrome involves removing
pneumonia, and/or with poor
mercaptopurine is not the offending allergen,
metabolism). The Groups also
recommended. If co- managing the acute coronary
advised that blood level
administration is necessary, vasospasm, and treating the
monitoring of other
the dose or azathioprine or allergic response. Careful
antipsychotic drugs may be
mercaptopurine should be selection and use of medicines
helpful in certain
reduced. are needed when managing the
circumstances.
acute condition to avoid further
Up to June 2020, the Centre
histamine release or Also, health-care professionals
for Adverse Reactions
exacerbation of coronary are advised that if blood
Monitoring (CARM) had
vasospasm. clozapine level monitoring is
received 14 cases describing an
carried out, this should be in
interaction between allopurinol Reference:
addition to the required blood
and azathioprine. In 13 of the Prescriber Update, Medsafe,
tests to manage the risk of
cases the patients experienced September 2020
agranulocytosis.
bone marrow suppression. Two (www.medsafe.govt.nz/)
recent cases reported Reference:
pancytopenia. Drug Safety Update, MHRA,
26 August 2020
Reference:
(www.gov.uk/mhra)
Prescriber Update, Medsafe, Clozapine, other
September 2020
(www.medsafe.govt.nz/) antipsychotics
(See also WHO Pharmaceuticals Newsletter
No.1, 2016: Interaction with 6-
Monitoring blood
mercaptopurine and azathioprine in concentrations advised
Australia)
United Kingdom. The

Safety of Medicines
Cyproterone stopping denosumab (Prolia®) the presence of a naked flame,

for osteoporosis. fabric with emollient dried on is
Risk of meningioma easily ignited. Although
Denosumab is indicated for
emollients are not flammable in
treatment of osteoporosis and
New Zealand. The Medsafe themselves or when on the
bone loss associated with
has announced that exposure skin, but when dried on to
hormone ablation in men with
to cyproterone may increase fabric they act as an
prostate cancer or with long-
the risk of meningioma. accelerant.
term systemic glucocorticoid
Cyproterone is an antiandrogen therapy in adult patients. In July 2020, the MHRA
treatment indicated for: launched a campaign to raise
From 2015 to June 2020, 44
inoperable carcinoma of the awareness of this important
cases of vertebral fracture,
prostate, reduction of drive in risk. A toolkit of resources is
including multiple fractures,
sexual deviations in men, and available for health and social
have been reported in the UK
for severe signs of care professionals to support
in post-marketing settings in
androgenisation in women. the safe use of emollients.
patients after stopping or
A recent cohort study in France delaying ongoing treatment Health-care professionals are
has demonstrated a dose- with denosumab. encouraged to inform patients
dependent association between and caregivers of the risks with
Health-care professionals
cyproterone acetate and the emollient products.
should evaluate a patient’s
risk of meningioma. This risk individual factors for benefits Reference:
increases as the cumulative and risks before initiating Drug Safety Update, MHRA,
dose rises. treatment with denosumab, 26 August 2020
Up until March 2020, the CARM particularly in patients at (www.gov.uk/mhra)
received two reports of increased risk of vertebral (See also WHO Pharmaceuticals Newsletter
meningioma associated with fractures (e.g. previous No.1, 2019; Risk of severe and fatal burns in
cyproterone. Both patients vertebral fracture). Patients UK; No.3, 2013: May cause skin irritation,
were women who had been should not stop denosumab particularly in children with eczema in UK)
treated with cyproterone for without specialist review.
more than 10 years. Reference:
Cyproterone is contraindicated Drug Safety Update, MHRA,
26 August 2020
in patients with a meningioma
(www.gov.uk/mhra)
Glecaprevir/
or a history of meningioma. If
a patient treated with (See also WHO Pharmaceuticals Newsletter
pibrentasvir
cyproterone is diagnosed with No.3, 2019: Risk of hypercalcaemia and (combination)
meningioma, treatment must multiple vertebral fractures in Japan; No.4,
be permanently stopped. 2018: Risk of multiple vertebral fractures in
Risk of hepatic toxicity
Japan)
Reference:
Prescriber Update, Medsafe, New Zealand. The Medsafe
September 2020 has announced that severity of
(www.medsafe.govt.nz/) liver disease should be
assessed before administrating
(See also WHO Pharmaceuticals Newsletter Emollient a combination of two direct-
No.4, 2020: Restrictions in use due to risk of acting antivirals (DAAs),
meningioma in Ireland and UK; No.3, 2020: Risk of severe and fatal
glecaprevir and pibrentasvir
Restrictions in use due to risk of burns (Maviret®).
meningioma in EU)
United Kingdom. The The combination of glecaprevir
MHRA has informed health-care and pibrentasvir is used for the
professionals of the recent treatment of chronic hepatitis
campaign to promote C. Glecaprevir and pibrentasvir
Denosumab awareness of the risk of severe are metabolized in the liver,
and fatal burns, and of the and therefore patients with
Increased risk of multiple availability of new resources to impaired liver function will be
vertebral fractures support safe use of emollients. exposed to increased levels of
these antivirals, increasing the
United Kingdom. The Emollients, known as skin
risk of adverse reactions.
MHRA has announced that the creams, are used to help
Commission on Human manage different dry skin In August 2019, the US FDA
Medicines’ Pharmacovigilance conditions such as eczema, warned about the rare
Expert Advisory Group psoriasis and ichthyosis. occurrence of serious liver
suggested that there is an injury with use of hepatitis C
Emollients can transfer from
increased risk of multiple medicines. This was based on
the skin onto clothing, bedding,
vertebral fractures after 63 reported cases of worsening
dressings and other fabrics. In
Safety of Medicines
liver function associated with dysfunction during treatment Topiramate is indicated to treat
DAA treatment, which and persistence of these epilepsy and to prevent
sometimes led to liver failure adverse effects for some time migraines.
and death. after discontinuation.
The CARM received a report of
The Medicines Adverse Depression, anxiety and patient who experienced pre-
Reactions Committee (MARC) psychotic symptoms, including seizure symptoms after
reviewed the risk of serious suicidal thoughts/attempts and changing brands of topiramate.
liver injury in patients taking suicide, have been reported in The Medsafe recommends
the drug to determine the patients treated with prescribers follow the MHRA’s
impact for New Zealand isotretinoin. All patients taking advice on switching brands of
prescribers and patients. isotretinoin should be antiepileptic medicines. Brand
monitored for signs of switches for topiramate must
Before starting treatment, the
depression by the prescriber be carefully considered, taking
patient’s liver function should
and referred for appropriate into consideration factors such
be assessed. The drug can be
treatment if necessary. Also, it as seizure frequency and
used in patients with mild liver
is important to remember that treatment history.
impairment, but is not
psychiatric symptoms may not
recommended in patients with Reference:
be fully alleviated after
moderate liver impairment and Prescriber Update, Medsafe,
discontinuation.
is contraindicated in patients September 2020
with severe liver impairment. Isotretinoin has also been (www.medsafe.govt.nz/)
associated with reports of
The CARM has not received any
sexual dysfunction,
reports of liver-related adverse
predominantly involving
reactions in association with
erectile dysfunction, decreased
Maviret®.
libido and vaginal dryness,
Reference: although they are currently
Prescriber Update, Medsafe, thought to be rare.
September 2020
Additionally, isotretinoin is a
(www.medsafe.govt.nz/)
powerful teratogen associated
(See also WHO Pharmaceuticals Newsletter with a high frequency of severe
No.2, 2019: Risk of hepatic impairment and and life-threatening birth
jaundice in Japan) defects if there is exposure in
utero. It is contraindicated in
women of childbearing
potential unless all the
conditions of the Pregnancy
Isotretinoin Prevention Programme are
met.
Risk of psychiatric reactions
and sexual dysfunction Reference:
Drug Safety Update, MHRA,
United Kingdom. The 26 August 2020
MHRA has reminded health- (www.gov.uk/mhra)
care professionals that (See also WHO Pharmaceuticals Newsletter
isotretinoin (Roaccutane®, No.5, 2018: Risk of obsessive compulsive
Reticutan® and Rizuderm®) disorder (OCD) in New Zealand; No.5, 2016:
should only be used to treat Potential risk of psychiatric adverse events
severe forms of acne that is in Australia; No.1, 2015: Possible risk of
resistant to adequate courses psychiatric disorders in UK)
of standard therapy due to the
risk of teratogenic effects,
potential psychiatric reactions
and sexual dysfunction.
Topiramate
Isotretinoin is indicated for
severe acne that is resistant to Brand change should be
adequate courses of standard avoided
antibacterial or topical therapy.
New Zealand. The Medsafe
The MHRA regularly reviews
has reminded health-care
the safety of isotretinoin, with
professionals that changing
the aim of examining the
brands of topiramate should be
available evidence for the
avoided.
possible risks of psychiatric
adverse reactions and sexual
Information Note
Sodium valproate
The WHO Pharmaceuticals Newsletter No. 5, 2019, provided some information on sodium valproate. Additional
information is provided below, outlining actions proposed by WHO.
Medicines containing valproate (e.g. sodium valproate, valproic acid, divalproex) should be avoided in
pregnant women or in females of child-bearing potential, unless alternative treatments are ineffective or not
tolerated, because of the high risk of birth defects (such as spina bifida, facial, skull, limb and heart
malformations) and developmental disorders in infants who are exposed to valproate in the womb. When
alternative treatments are not available or appropriate, female patients prescribed valproate medicines
should be made aware of the risk and use effective contraception methods.
Valproic acid (sodium valproate) is included on the WHO Model Lists of Essential Medicines for the treatment
of epilepsy in adults and children, and of bipolar disorder in adults.
In 2021, the listings for valproic acid on the Model Lists will be revised to include a cautionary note to better
highlight the safety risks associated with use in pregnant women and females of child-bearing potential.
WHO will be updating its current guidelines on epilepsy management in 2021. As part of this process, the
evidence review on question on “Management of epilepsy in women of child bearing age”, will be updated to
inform the revised recommendation on the role of pharmacological interventions, including valproate and
other antiseizure medicines.

Signal
A signal is defined by WHO as reported information on a possible causal relationship between an adverse event and a drug, the
relationship being unknown or incompletely documented previously. Usually more than a single report is required to generate a signal,
depending upon the seriousness of the event and the quality of the information. A signal is a hypothesis together with data and arguments
and it is important to note that a signal is not only uncertain but also preliminary in nature.
The signals in this Newsletter are based on information derived from reports of suspected adverse drug reactions available in the WHO
global database of individual case safety reports (ICSRs), VigiBase. The database contains over 23 million reports of suspected adverse
drug reactions, submitted by National Pharmacovigilance Centres participating in the WHO Programme for International Drug Monitoring.
VigiBase is, on behalf of the WHO, maintained by the Uppsala Monitoring Centre (UMC) and periodic analysis of VigiBase data is
performed in accordance with UMC’s current routine signal detection process. International pharmaceutical companies, when identified as
uniquely responsible for the drug concerned, are invited to comment on the signal text. Signals are thereafter communicated to National
Pharmacovigilance Centres, before being published in this Newsletter. Signal texts from UMC might be edited to some extent by WHO and
may differ from the original version. More information regarding the ICSRs, their limitations and proper use, is provided in the UMC Caveat
document available at the end of Signal (page 24). For information on the UMC Measures of Disproportionate reporting please refer to
WHO Pharmaceuticals Newsletter Issue No. 1, 2012.
UMC, a WHO Collaborating Centre, is an independent foundation and a centre for international service and scientific research within the
field of pharmacovigilance. For more information, on the UMC Measures of Disproportionate Reporting etc., visit www.who-umc.org. To
leave a comment regarding the signals in this Newsletter, please contact: the Uppsala Monitoring Centre, Box 1051, SE-751 40 Uppsala,
Sweden. E-mail: [email protected].
Everolimus and osteonecrosis of the jaw (ONJ)

Anna Hegerius, Uppsala Monitoring Centre
Summary angiogenesis inhibition, soft tissue toxicity, and

immunity dysfunction. Considering the mechanism
Osteonecrosis of the jaw (ONJ) is a rare but
of action of everolimus, it is reasonable to assume
potentially serious and painful condition, originally
that it may be involved in the development of ONJ.
associated with the use of bisphosphonates. In
recent years ONJ has been linked to several other Based on current data, the risk of ONJ due to
drugs, including the mTOR inhibitor everolimus, everolimus treatment alone seems very low.
used to treat advanced malignancies and to prevent However, combined with other drugs with a
transplant rejection. During a UMC signal detection potential to cause ONJ and risk factors such as
sprint, held in December 2018, the MedDRA diabetes or dental surgery, everolimus may act as a
preferred term ‘osteonecrosis of jaw’ was trigger. Further studies in this area are required
highlighted for the drug everolimus in VigiBase, the considering the increasing population of patients at
WHO global database of individual case safety risk of ONJ and the adverse impact on the quality of
reports (ICSRs). As of 3 February 2020, there were life for those affected.
117 reports for this drug–adverse drug reaction
(ADR) combination in VigiBase.
Introduction
ONJ is not labelled for everolimus, but related terms
such as stomatitis, jaw pain, oral pain, impaired The antineoplastic agent everolimus is indicated for
wound healing and mucositis are. Among the cases the treatment of various cancers (breast,
in VigiBase and the scientific literature, the vast pancreatic, gastrointestinal, lung, and renal) and is
majority concern patients with concurrent or past also used as an immunosuppressant to prevent
therapy with drugs known (or suspected) to cause transplant rejection. In breast cancer treatment,
ONJ, which makes it difficult to identify the everolimus is combined with the aromatase inhibitor
offending drug. However, there are a few case exemestane. Everolimus inhibits the activity of
reports where neither drugs nor risk factors mammalian target of rapamycin (mTOR), a serine-
associated with ONJ were involved, implicating threonine kinase involved in cell growth and
everolimus as an independent cause of ONJ. In 15 metabolism, resulting in a decrease of both
of the VigiBase cases, the reaction abated when the hypoxia-inducible factors and vascular endothelial
drug was withdrawn. growth factor (VEGF) levels, which reduces tumour
growth and angiogenesis. Furthermore, the mTOR
The exact pathophysiology of ONJ remains unclear,
and VEGF pathways play a key role in regulating
but several theories have been proposed and the
bone homeostasis and immune responses.1, 2
mechanism is likely multi-factorial. Factors that
Everolimus and temsirolimus (the other drug in the
may cause ONJ are: bone remodelling (osteoclast)
same class) are derivatives of sirolimus.
inhibition, bone infection/inflammation,

Signal
Osteonecrosis of the jaw (ONJ) is characterised as exemestane (54 cases), zoledronic acid (54),
oral lesions of exposed necrotic bone that persist for denosumab (38), capecitabine (11) and fulvestrant
at least eight weeks, with no previous history of (11). Zoledronic acid and denosumab are both
radiation or metastasis to the area. This oral known to cause ONJ. Exemestane is a potent
condition is rare but potentially serious and very oestrogen lowering agent, and a reduction in bone
painful. A number of drugs are known to cause ONJ mineral density and an increased fracture rate has
but it can also occur spontaneously.3 The condition been observed. Fulvestrant is an oestrogen receptor
was first described in 2003, in a case report antagonist and may also cause osteoporosis, but
including 36 patients who had been treated with there is no long-term data on the effects on bone.
two different bisphosphonates,4 and was later Most co-reported reactions were malignant
determined to be a drug class effect. In the neoplasm progression (13 cases), stomatitis (12),
following years, other drugs were also associated fatigue (11), pain (10) and metastasis to bone (9).
with the development of ONJ, such as the Stomatitis and metastasis to the bone (if located in
monoclonal antibodies denosumab and the jaw) may have contributed to the ONJ.
bevacizumab and the tyrosine kinase inhibitor
The vast majority of the patients were administered
sunitinib. More recently the mTOR inhibitor
everolimus due to breast cancer (73 cases) or renal
everolimus has also been implicated as a risk factor
cancer (28 cases), and the dose varied between 5
for ONJ.5 Hence the term ‘Medication Related
and 20 mg per day, with 10 mg being the most
Osteonecrosis of the Jaw’ (MRONJ) was established
common daily dose. Most cases had a reasonable
in 2009 by the American Association of Oral and
time to onset, with a median of 31 weeks, which is
Maxillofacial Surgeons (AAOMS).3 In addition to the
shorter than the median time to onset for
use of antiresorptive and antiangiogenic agents,
bisphosphonate-related ONJ (108 weeks) but longer
several other risk factors for ONJ have been
than the median time to onset for non-
identified. These include dental surgery (e.g. tooth
antiresorptive medications (20 weeks).11, 12 In 15
extraction), poor oral health, diabetes, smoking,
cases the reaction abated when the drug was
and concomitant use of steroids.6, 7
withdrawn.
The combination of antiangiogenics and
Since several other drugs are known to cause ONJ,
antiresorptives is known to increase the risk of ONJ
all cases with drugs that have ONJ labelled were
development,8, 9 but little is known about the risk of
excluded from the case series. This resulted in 27
developing ONJ with antiangiogenics alone.
remaining cases, but some of them could also be
excluded since the narratives revealed that the
patients had taken other ONJ-causing drugs. Some
Reports in VigiBase
cases had a medical history that may have
During a UMC signal detection sprint held in contributed to the development of ONJ, e.g.
December 2018, the MedDRA preferred term stomatitis, dental issues or bone metastasis.
‘osteonecrosis of jaw’ was highlighted for the drug
A selection of reports is presented in Table 1. Case
everolimus in VigiBase, the WHO global database of
1 concerns a female patient with metastatic breast
individual case safety reports (ICSRs).
cancer who developed ONJ five weeks after
As of 3 February 2020, there were 117 reports for initiating everolimus (and exemestane) treatment.
this drug–adverse drug reaction (ADR) combination Both drugs were withdrawn and the patient was
in VigiBase. Based on the overall reporting of recovering when the report was sent. According to a
adverse reactions for everolimus, and of the later publication of this case, the patient had no
adverse reaction ONJ in VigiBase, the expected relevant past dental history and metastasis was
value for the number of reports on the combination ruled out. The patient was treated with
was 35, and the association was highlighted as cephalosporin for two weeks and after two months
disproportionally reported, by IC analysis10. her condition had improved.13
The reports came from 15 countries across four In case 2, a female patient received everolimus for
continents: Europe (76 reports), the Americas (16), advanced breast cancer and after nine days
Asia (23), and Australia (1). More female than male experienced a range of adverse reactions including
patients were affected (75% women), since the aphthae, throat pain and difficulty swallowing. She
most common indication for everolimus in the case was also diagnosed with ONJ and had no relevant
series was breast cancer, and the age range was medical history or concomitant medication.
29-82 years, with a median of 64 years. Physicians Everolimus treatment was continued and most of
and other health professionals accounted for 95% the adverse reactions persisted, except for the
of the reports and the rest were submitted by aphthae which resolved after laser therapy. The
pharmacists and consumers/non-health time to onset was very short in this case, but not
professionals. More than 90% of the cases were implausible.12 The reporter assessed the events as
serious, including six fatalities (5%), but all were suspected to be related to the drug.
not caused by the ONJ.
Case 3 describes a female patient with metastatic
In 18 cases, everolimus was the only reported drug, breast cancer who received everolimus for 19 days
and in 26 cases it was the only suspected drug. The and then stopped the drug for one month due to a
most frequently co-reported drugs were tooth extraction. The treatment was then resumed

Signal
but again stopped after only two days due to ONJ recovering after the drug had been withdrawn. The
onset. The reporter suspected the drug to have patient had no related medical history nor past drug
caused the adverse reaction since the patient had therapy.
recovered substantially two weeks after drug
Case 5 presents a female patient of unknown age
withdrawal. However, tooth extraction is also a
who developed ONJ during treatment with
trigger event for ONJ.
everolimus for advanced breast cancer. The time to
Case 4 concerns a female patient with recurrent onset is unknown, but the drug was withdrawn and
breast cancer, treated with everolimus and a few the stomatitis resolved; the outcome of the ONJ
other drugs (see Table 1) who developed ONJ. The was unknown.
time to onset is unknown but the patient was
Table 1. Characteristics of a selection of case reports in VigiBase of everolimus in association with

osteonecrosis of jaw (ONJ)
Case Reporter Age/Sex Suspected (S) or Reactions (MedDRA Time to Action taken
concomitant (C) preferred terms) onset
drugs
1 Other health 76/F Everolimus (S) Osteonecrosis of jaw 5 weeks Drug withdrawn,
professional Exemestane (C) recovering
2 Other health 61/F Everolimus (S) Osteonecrosis of jaw, 9 days Dose not changed, not
professional aphthous ulcer, oropharyngeal recovered
pain, dysphagia, furuncle,
hepatotoxicity etc.
3 Physician 55/F Everolimus (S) Osteonecrosis of jaw 7 weeks* Drug withdrawn,
Exemestane (C) recovering
Pantoprazole (C)
Prednisone (C)
Tramadol (C)
Colecalciferol (C)
4 Physician 75/F Everolimus (S) Osteonecrosis of jaw Unknown Drug withdrawn,
Exemestane (S) recovering
Capecitabine (S) Rechallenge, outcome
Cyclophophamide (S) unknown
Fulvestrant (S)
5 Other health 75/F Everolimus (S) Osteonecrosis of jaw, Unknown Drug withdrawn,
professional stomatitis outcome unknown for
everolimus, recovered for
stomatitis
*The patient was treated with the drug for 19 days, halted treatment for a month due to a tooth extraction, and then resumed
treatment for only two days before the ONJ occurred and the drug was withdrawn.
Literature and labelling administered a bisphosphonate, these drugs

accumulate in bone and the effect may last more
ONJ is not labelled for everolimus (or temsirolimus)
than 10 years,18 which makes it reasonable to
in the most recent Summary of Product
assume that previous intake of these drugs may
Characteristics (SPC) in the United Kingdom but
still be relevant for the development of ONJ.
related terms such as stomatitis, jaw pain, oral
pain, impaired wound healing and mucositis are.14 However, in addition to case 1 above, there are a
ONJ has not been observed in clinical trials, but few other published case reports where
gingival swelling and jaw pain have been.6 bisphosphonates or monoclonal antibodies were not
Osteonecrosis is labelled for sirolimus, and since involved, implicating everolimus as an independent
everolimus mimics sirolimus, it is reasonable to cause of ONJ. One case concerns a female breast
assume that it might have a similar effect. cancer patient with no medical history of radiation,
and metastasis to the mandible was ruled out. The
In addition to the cases in VigiBase, there are
patient had a tooth extracted four months prior to
several case reports in the literature where
the ONJ diagnosis, which may have contributed to
everolimus is suspected of causing or contributing
the onset.19 Another case describes a male patient
to ONJ. However, in some of these cases, it is
who had taken everolimus for 1.5 years (after a
difficult to establish a causal link since the patient
kidney transplant) when he was diagnosed with
had also taken other drugs known to cause ONJ, for
ONJ. He had no recent dental trauma, but he had
example bisphosphonates.15-17 Even though many
taken steroids, which may also have contributed to
years may have passed since a patient was
the adverse reaction.20

Signal
There are also case reports where the other mTOR extractions. There are a few case reports of ONJ in
inhibitor temsirolimus has been combined with patients who neither taken other suspected drugs
denosumab or bevacizumab, resulting in ONJ, and nor had any known risk factors. Based on current
the authors describe a potential synergistic effect.21, data, the risk of ONJ due to everolimus treatment
22 alone, seems very low. However, combined with
other drugs with the potential to cause ONJ and risk
Furthermore, US FDA reviewed all ONJ cases in
factors such as diabetes or dental surgery,
FAERS on the drugs suspected to cause ONJ. This
everolimus may act as a trigger. Although it is
study was the first to show that the mTOR inhibitors
impossible to conclude what role everolimus played
everolimus and temsirolimus were also associated
in each reported case, VigiBase data and published
with the risk for ONJ, with 84 and 28 cases
case reports still point to a potential causal
respectively. However, compared to other drugs,
association where the drug may at least have
the risk of mTOR induced ONJ was low (<5%).23
contributed to the development of ONJ. Further
The exact pathophysiology of ONJ has still not been studies in this area are required considering the
fully understood but several theories have been increasing population of patients at risk of ONJ, the
proposed and the mechanism is likely to be multi- seriousness of this condition, and the adverse
factorial. Factors that may cause ONJ are: bone impact on the quality of life for those affected.
remodelling (osteoclast) inhibition, bone Close collaboration between medical doctors and
infection/inflammation, angiogenesis inhibition, soft dentists, as well as information to patients at risk,
tissue toxicity, and immunity dysfunction.24 In are important aspects for the prevention, prompt
relation to everolimus, pre-clinical studies have recognition and treatment of ONJ.27
shown that inhibition of mTOR decreases the
maturation of osteoclasts and increases their
apoptosis, which may explain how osteonecrosis References
may occur.1 Furthermore, when VEGF activity is
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inhibited, the healing of bone is impaired6. The
H, Hirao A, et al. Metabolic Regulation of
immunosuppression caused by everolimus explains
Osteoclast Differentiation and Function. J Bone
the impaired wound healing and the infection
Miner Res. 2013;28(11):2392-9.
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explained by several factors, for example the Aghaloo T, Mehrotra B, et al. American
potency, route of administration, and cumulative Association of Oral and Maxillofacial Surgeons
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Falagas ME, Tsakalos G, et al. Combination of
19. Lee CYS, Lee KL, Hirata KY, Suzuki JB.
Bisphosphonates and Antiangiogenic Factors
Medication-Related Osteonecrosis of the Jaw
Induces Osteonecrosis of the Jaw More
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Acid and Everolimus: A Case Report. Ann
Response from Novartis
1 Introduction Transplant) under brand names Afinitor, Votubia

and Certican/Zortress, respectively.
On 26 March 2020, Novartis received a request to
provide comments on osteonecrosis of the jaw
(ONJ) in association with everolimus. Everolimus is
2 Novartis response
marketed by Novartis for three broad indications
(Oncology, Tuberous Sclerosis complex (TSC) and 2.1 Everolimus indicated for Oncology and TSC

Signal
Novartis has been monitoring and providing last PSUR.

analysis of ONJ as part of periodic safety update
2.1.1.1 Novartis global safety database
reports (PSURs) in both TSC (since 2014) and
oncology indications (since 2017). The Between 31 Mar 2019 and 31 March 2020, eight
Pharmacovigilance Risk Assessment Committee cases were retrieved (seven cases of ONJ and one
(PRAC) in its most recent assessment report case of necrosis) using the same MedDRA search
(EMEA/H/C/PSUSA/00010268/201703) concurred strategy with PTs Chondronecrosis, Necrosis,
with Novartis analysis (cut-off date 31 March 2019) Osteonecrosis and Osteonecrosis of jaw to the
that there is no conclusive evidence of causal PSURs. All cases were reported in oncology
association between ONJ and everolimus in indications.
oncology and TSC settings and concluded that there
was no sufficient data to warrant an update of the Noteworthy case definition: Well-documented cases
SmPC for ONJ. The PRAC requested Novartis to with a HCP-confirmed diagnosis of ONJ with no
continue monitoring ONJ and present updated alternative explanation (concomitant drugs,
analysis in the next PSUR. risk/predisposing factors).
2.1.1 Methodology The cases retrieved are presented in Table 2-1

below
Novartis is presenting the results of the evaluation
of ONJ cases received since the cut-off date of the
Table 2-1 Case reports of ONJ
Case Reporter Age /sex Suspected drugs Dose Action taken PT TTO
(days)
1 non-HCP/SR 65/M Everolimus UKN UKN Osteonecrosis of NR
Mycophenolate jaw
Mofetil,
Prednisolone
2 HCP/SR 67/F Afinitor UKN Treatment Osteonecrosis of 44
Discontinued jaw
3 HCP/PMS 35/F Everolimus, UKN Treatment Osteonecrosis of 394
Zoledronic Acid Discontinued jaw
4 HCP/Lit 67/F Paclitaxel, 2.5 mg UKN Osteonecrosis of NR
Carboplatin, jaw
Zoledronic Acid
Everolimus
5 HCP/PMS 52/M Everolimus 5 mg NR Necrosis NR
Lenvatinib
6 HCP/PMS 64/M Pazopanib 10mg , Treatment Osteonecrosis of 1669
Nivolumab 5 mg Discontinued jaw
Lenvatinib
Zoledronic Acid
Everolimus
7 HCP/Lit 46/F Zoledronic Acid UKN NR Osteonecrosis of 455
Everolimus, jaw
Exemestane
8 non-HCP/SR 60/F Everolimus 5mg NR Osteonecrosis of NR
Lenvatinib jaw
HCP= Health Care Professional; Lit= Literature, SR=Spontaneous Report, PMS= Post marketing surveillance, PT=Preferred
Term, NR=Not reported, UNK= unknown; TTO=Time to onset
Of the eight cases, two were non-HCP and one was not be established. The review of the new cases is
necrosis of unknown location. Four cases were consistent with the conclusion presented in previous
confounded by use of bisphosphonates. Anti- PSURs. Novartis will continue to monitor ONJ cases
angiogenic agent lenvatinib was a co-suspected in subsequent PSURs.
medication in three cases. Furthermore the cases
lacked sufficient information for a meaningful
medical assessment. None of the eight cases met 2.1.1.2 Empirica Signal
noteworthy criteria and hence a causal role could

Signal
Table 2-2 Measure of disproportionality

Drug Event SOC SP+Lit+POP SP+Lit+POP
Total N EB05
Afinitor Osteonecrosis of jaw Musculoskeletal and 104 0.617
connective tissue disorders
Votubia Osteonecrosis of jaw Musculoskeletal and 2 0.146
Afinitor Osteonecrosis Musculoskeletal and 20 0.617
Votubia Osteonecrosis Musculoskeletal and 1 0.11
*SOC=System Organ Class, SP: Lit: POP=Spontaneous: Literature: Patient Oriented Program, EB05= The EB05
is the lower bound of the 90% confidence interval for the EBGM (Empiric Bayes Geometric Mean)
The EB05 (lower bound of the 90% confidence everolimus, Empirica Signal and Novartis Global
interval for the EBGM (Empiric Bayes Geometric Safety Database search for ONJ was performed,
Mean) score was less than one. with a cut-off date of 31 Mar 2020, in transplant
patients treated with everolimus by using the
2.2 Everolimus indicated for prophylaxis of
MedDRA version 22.1 with the PT Osteonecrosis of
rejection of transplanted organs
jaw.
2.2.1 Methodology
2.2.1.1 Empirica Signal
In order to assess the association between ONJ and
Table 2-3 Measure of disproportionality
Drug Event SOC SP+Lit+POP SP+Lit+POP

Total N EB05
Certican Osteonecrosis of Musculoskeletal and connective 3 0.06
jaw tissue disorders
SOC=System Organ Class, SP=Spontaneous: LT=Literature: POP=Patient Oriented Program, EB05=lower bound
of the 90% confidence interval for the EBGM (Empiric Bayes Geometric Mean)
2.2.1.2 Novartis Global Safety Database clinical trial or spontaneous reporting cases were
retrieved.
The search retrieved three LT cases for ONJ. No
Table 2-4 Case reports of ONJ

Case Reporter Age/Sex Suspected drugs Dose Action PT TTO
taken
1 HCP 69/M Everolimus NR NA PTLD NR
Prednisolone NR Unknown Epstein-Barr virus infection NR
Osteonecrosis of jaw 4 month
Rituximab NR Unknown
Kidney transplant rejection NR
Methylprednisolone NR NA
2 HCP 65/M Everolimus 10 mg BD TD Osteonecrosis of jaw 18 month
Pain in jaw 18 month
Prednisolone 10 mg OD Ongoing Exposed bone in jaw 18 month
3 HCP 65/M Everolimus 1mg BD TD Osteonecrosis of jaw NR
and 0.75 Pain NR
mg BD Hypophagia NR
Weight decreased NR
Resorption bone increased NR
Prednisolone NR Unknown Sinus perforation NR
Oroantral fistula NR
NR=Not reported, NA=Not applicable, TD=treatment discontinued, PTLD=Post-transplant lymphoproliferative disorders,
TTO=Time to onset

Signal
In above indicated cases, there is limited a causal association of everolimus to the event of
information regarding TTO, as well as alternative ONJ could not be established.
explanations such as concomitant suspected drugs
and/or risk factors (prednisolone in all three cases,
rituximab in the first case (1), teeth extractions 3 References (available on request)
history in the second case (2), and history of teeth
extractions and parathyroidectomy in the third case 1. Keribin P. Guerrot D, Jardin F. Osteonecrosis of
(3)), therefore, a causal association could not be the Jaw in a Patient Presenting With Post-
established. Transplantation Lymphoproliferative Disorder
Treated With Rituximab: A Case Report.
Up to date, there is no confirmed clinical evidence American Association of Oral and Maxillofacial
of an effect of ONJ with everolimus (indicated for Surgeons J Oral Maxillofac Surg -:1-7, 2017
prophylaxis of rejection of transplanted organs)
alone. 2. Akkach S, et al. Everolimus-induced
osteonecrosis of the jaw in the absence of
Discussion and Conclusion bisphosphonates: a case report. Br J Oral
Maxillofac Surg. 2019
Everolimus has been marketed for more than 10
years worldwide. The cumulative post-marketing 3. Law M, Walker R, Basu G. Everolimus associated
patient exposure in oncology setting is over osteonecrosis of the jaw in kidney transplant
208,393 PTY, in TSC is over 23,522 PTY and in recipient. Kidney International Reports (2019) 4,
Transplant setting is over 638,081 PTY. Based on S1-S437
analysis of years of clinical and post-marketing data
Fluorouracil and Bradycardia – national signal from Peru with potential

global relevance
César Luis Avalos Capristán, Pharmacovigilance and Technovigilance National Center of Peru
1. Abstract the global network for consideration.

Fluorouracil is the third most used
chemotherapeutic agent in the treatment of solid
2. Introduction
malignant tumours worldwide. It has many side
effects, including on the cardiovascular system. In a Fluorouracil belongs to a class of drugs called
signal detection workshop focussing on Latin antimetabolites. It is administered intravenously
American data in VigiBase, the WHO global and acts by reducing or stopping the growth of
database of individual case safety reports, a signal cancerous cells in the body. Fluorouracil is generally
related to fluorouracil and bradycardia was detected used in combination with other chemotherapeutic
from Peruvian data using quantitative signal drugs to treat cancer of the colon or rectum, certain
detection methods. Thirteen cases were observed types of breast cancer, pancreatic cancer, and
where only 0.3 were statistically expected to be stomach cancer, where the dosing varies between
seen. The review found that although bradycardia one and five days, often once monthly.1
has been described as an adverse reaction in
literature reports, it is not included in the summary Among listed adverse events associated with the
of product characteristics (SmPC) or national fact use of fluorouracil are diarrhoea, hand-foot
sheets in Peru, nor in those of regulatory agencies syndrome (a.k.a. palmar-plantar
in the USA, Spain, or Canada. The more general erythrodysesthesia), myelosuppression, mucositis,
term of arrythmia is mentioned in some SmPCs, and cardiotoxicities.2 Among listed cardiac side
and tachycardias sometimes appear. The literature, effects are chest pain, myocardial infarction, sudden
including an observational study and a case series, cardiac death, pericarditis, and changes in the ECG,
supports the finding of bradycardia in patients e.g. ST-T changes and arrhythmia, sometimes
undergoing chemotherapy. To summarise, in Peru specified as atrial fibrillation or tachycardia.3 The
we have suggested including bradycardia in the appearance of the specific term bradycardia is not
sections on adverse reactions, warnings and listed among the adverse effects associated with
precautions in our national drug fact sheet for the fluorouracil in the summary of product
product, and here we share this information with characteristics of fluorouracil in the USA or the UK.
Bradycardia means a slow heart rhythm, often
Signal
defined as a frequency of less than 60 beats per identified in a signal detection workshop focussing
minute.4 on Latin American data in VigiBase, carried out in
May 2019. It was detected using disproportionality
analysis where the expected number of cases in
Peru was calculated to be 0.3 while the number
observed was 13 (IC025: 3.2). The data referred to
3. VigiBase reports in Table 1 includes the characteristics of all the 13
The combination of bradycardia and fluorouracil was Peruvian reports which formed the basis of the
signal analysis.
N° Age Sex Indication Drugs Doses ADRs Time to Positive Positive

(years) mg reported onset (days) dechallenge Rechallenge
1 66 F Colon Fluorouracil (S) 960mg Bradycardia 0 Yes Yes
adenocarcinoma
2 76 M Colon cancer Fluorouracil (S) - Bradycardia 1 No -
3 56 M Gastric cancer Fluorouracil (S) - Bradycardia 1 Yes -
4 56 F Gastric cancer Fluorouracil (S)) - Bradycardia 1 Yes Yes
5 30 F Rectal cancer Fluorouracil (S) 500 mg Bradycardia 2 Yes -

Oxaliplatin (C) 130 mg
Calcium folinate (C) 250 mg
6 55 M Gastric malignant Fluorouracil (S) 1650 mg Bradycardia 0 Yes -
neoplasm Oxaliplatin (C) 114 mg
7 69 M Malignant Fluorouracil (S) 3440 mg Bradycardia 1 - -
neoplasm of the Oxaliplatin (C) 280 mg Peripheral
colon neuropathy
8 89 M Malignant Fluorouracil (S) 1000 mg Bradycardia 1 - -
neoplasm of the Oxaliplatin (C) 85 mg Hypertension
colon Ondansetron (C) 24 mg
9 63 F Malignant Fluorouracil (S) 1000 mg Bradycardia 3 Yes -
neoplasm of the Cisplatin (C) 100 mg
vagina
10 68 M Gastric malignant Fluorouracil (S) 900 mg Bradycardia 0 - -
neoplasm Cisplatin (C) -
11 42 F Gastric cancer Fluorouracil (S) 1580 mg Bradycardia 0 Yes Yes
Cisplatin (C) 58 mg Headache
Docetaxel (C) 75 mg
12 53 F Gastric malignant Fluorouracil (S) 3920 mg Bradycardia 3 Yes -
neoplasm Cisplatin (C) 98 mg
Docetaxel (C) 98 mg
13 58 M Malignant Fluorouracil (S) 3060 mg Bradycardia 1 Yes -
neoplasm of the Irinotecan (C) 220 mg
cecum
Table 1 includes four reports (1, 2, 3 and 4) that docetaxel, neither of which give bradycardia as an
give fluorouracil as the only administered drug; the acknowledged adverse drug reaction.10,11,12,13,14,15
diagnoses for which fluorouracil was administered One of the four reports described the concomitant
were in these cases colon adenocarcinoma, colon administration of ondansetron, and development of
cancer and gastric cancer. bradycardia as an infrequent adverse reaction.16,17
The information shown in the reports indicates that
Some of the other cases mention concomitantly
administration of fluorouracil and its concomitants
used drugs which potentially could have caused or
(oxaliplatin, ondansetron) was on the same day,
contributed to the event: Four other reports
but not specifying a more detailed time for each one
describe the concomitant administration of
in relation to the event.
oxaliplatin, a drug with the capacity to cause
adverse cardiac effects.5,6,7,8,9 In the case of Four reports included the administration of cisplatin,
oxaliplatin the development of bradycardia which in its labelling has bradycardia as an adverse
associated with overdose is noted in the prescribing reaction,18 and in two of these, docetaxel was also
information.8,9 One of the four reports (Case 5) administered. In three of the four reports
described concomitant administration of calcium fluorouracil and the concomitant drugs were
folinate, and two other (11 and 12) included administered on the same day, but the exact hour
Signal
of administration of each drug is not specified. In findings. In three cases (1, 3 and 11) the level of
two of the four reports the bradycardia occurred on bradycardia ranged between 40 and 54 beats per
the same day that administration of fluorouracil and minute. No cases reported additional symptoms of
the concomitant drugs was started; equally, in the the bradycardia and only three cases (7, 8 and 11)
other two reports the bradycardia started three gave any additional adverse drug reaction:
days after administration of fluorouracil began. In headache, hypertension and peripheral neuropathy.
addition, in these four cases fluorouracil was the
Five of the Peruvian reports (Cases 6, 7, 8, 12 and
only drug reported as suspected.
13) came from the same doctor while each of the
Case 13 in Table 1 had concomitant administration others came from a different reporter.
of irinotecan and fluorouracil. The information in the
In VigiLyze, the combination bradycardia-
fact sheet for irinotecan describes the appearance
fluorouracil results in 139 reports from 23 countries
of bradycardia in the section on adverse reactions.19
worldwide, with Peru third after the USA (34
The report only states that the administration of
reports) and India (18 reports). Table 2 shows the
both drugs was carried out on the same day but
main characteristics of these cases (including the
does not specify the exact time of administration.
ones from Peru).
Onset of bradycardia was on day 1-3 in all the
Peruvian cases. None of the cases give any ECG
Table 2. Case series characteristics of 139 global reports on bradycardia with fluorouracil in
VigiBase
Feature N° of reports (%)
Male / Female/ Information missing 80 (58) / 52 (37) / 7 (5)
0-17y /18-44y / 45-64y /65-74 y / 75+y/ information missing 1 (1) / 26 (19) / 50 (36) / 40 (29) / 9 (6) / 13 (9)
Serious case* 71 (51)
Fatal outcome 6 (4)
Sole reported drug 31 (22)
Time to onset 0-7 days / > 7 days/ information missing 77 (55) / 26 (19) / 36 (26)
Positive dechallenge / Positive rechallenge 41 (29) / 4 (3)
*Some countries cannot report seriousness to VigiBase due to limitations in their reporting format, so the true proportion of
serious cases may be higher.
There were 13 global reports with a VigiBase fluorouracil intravenously for a diagnosis of an
completeness score of 1.00; here we illustrate four unknown neoplasm. The patient presented with
of these cases: bradycardia on the third day of administration,
so the treatment was discontinued, with the
1. France: a male patient aged 53 was
patient's recovery being observed. The report
administered fluorouracil intravenous 6300
only indicates the administration of fluorouracil.
mg/cycle to treat oropharyngeal cancer. On the
third day of treatment the patient presented An expanded search was performed in VigiBase to
with bradycardia, hypotension, bradypnea and retrieve additional cases of bradycardia but coded
allergic shock. The report indicates that the otherwise. Among the terms considered were
patient recovered after the suspension of the atrioventricular block (complete, first degree and
treatment. second degree), cardiac arrest, abnormal
electrocardiogram, sudden death. The few
2. India: a 20-year-old, 52 kg male patient was
additional cases retrieved were, after assessment,
given 900 mg/24 hr intravenously for a
not considered relevant for the signal.
diagnosis of nasopharynx malignancy; with only
fluorouracil administration reported. On the
second day of treatment the patient presented
4. Literature and labelling
with bradycardia, observing recovery two days
later, without having reported any suspension The information sheets/labelling of some
of treatment. international regulatory agencies set out
information on heart disorders or events associated
3. India: a 36-year-old male patient, 54 kg, who
with the use of fluorouracil. However, bradycardia is
was given intravenous fluorouracil 1000 mg/24
not listed in the section of adverse drug reactions,
hr for nasal cavity neoplasia. The patient
nor warnings and precautions in the country
presented with bradycardia on the fifth day
sources that were checked, such as the USA (Food
after administration, with recovery being
and Drug Administration - FDA), Spain (Agencia
observed the same day. The report only
Española de Medicamentos y Productos Sanitarios -
indicates the administration of fluorouracil.
AEMPS) and Canada (Health Canada).
4. India: a 41-year-old male patient, 68 kg and
Three peer-reviewed publications describing cases
168 cm, who was given 750 mg/24 hr
Signal
or case series of bradycardia in relation to cardiotoxicity was not significantly different

fluorouracil use were found: between patients with or without pre-existing
cardiovascular disease (p = 0.095). Cardiotoxicities
Talapatra K et al20 discussed a series of cases of six
were more common with continuous infusion of
patients (aged 38-59 years) who developed
fluorouracil, when radiotherapy was given
transient asymptomatic bradycardia (heart rate
concurrently with fluorouracil, and when fluorouracil
≤50/minute) in a group of 207 patients who
was used in combination with cisplatin.
received chemotherapy with injectable fluorouracil
and cisplatin (dose: cisplatin 75-100 mg/m2 and
injectable 5-fluorouracil 750-1000 mg / m2 day one
5. Discussion and conclusion
and with continued 5-fluorouracil infusion during
day 2-5 of the treatment). None of the six patients There is a variety of probable causes for the
had any comorbidities, except one with appearance of cardiotoxicity in general associated
hypertension. The assessment of the six patients with the use of fluorouracil, among which are the
indicated that there were no associated symptoms, dose and method of administration, use of
such as chest pain, giddiness or sweating at the concomitant chemotherapeutic agents with
time of the bradycardia. The serum electrolytes cardiotoxic potential, and concurrent radiotherapy.
were checked in the patients during the episodes of Moreover, the clinical characteristics of the patients
bradycardia, observing normal results. The authors (presence of pre-existing coronary lesions, arterial
concluded that the case series shows a tendency for disease, or traditional cardiovascular risk factors)
the development of asymptomatic bradycardia in and variability in the definitions of cardiotoxicity
patients undergoing treatment with infusion of should be considered. Cardiotoxicity with
fluorouracil. It may be argued that cisplatin and fluoropyrimidines tends to occur in association with
hydration of the patient had a part to play in the the first cycle of administration. An average time of
development of bradycardia but since the onset of symptoms is observed up to 12 hours after
development of bradycardia appeared after the the start of the infusion, although heart conditions
third day in all the patients, the authors consider may occur at any time during the infusion or even
that this makes it likely that fluorouracil was a more up to 1-2 days after the infusion, as observed in the
plausible cause. cases reported for bradycardia in Peru (84.6%) and
globally (39.5%).23
Nakajima T et al21 described a male patient of
Japanese origin, aged 78 years with a medical The cardiotoxicity associated with the use of
history that included hypertension, and diagnosed fluorouracil is well known and has been reported:
with stage III oesophageal cancer, who received a atrial fibrillation, ST-T changes and chest pain being
combination of cisplatin and fluorouracil. The the most frequently observed symptoms.
patient experienced episodes of bradycardia on the Cardiotoxicity in relation to the use of fluorouracil
first day after cisplatin administration, and due to it requires close clinical supervision and, if it occurs,
being asymptomatic it was decided to continue the treatment may require suspension of the drug. The
planned 2-5 days of continuous infusion of effect of fluorouracil withdrawal (positive
fluorouracil. On treatment day 4 his heart rate fell dechallenge) is evidenced in the cases of
to 22 beats/min without other objective findings or bradycardia reported in Peru (62%), as well as
subjective symptoms. With atropine treatment the worldwide (29%).24
rate temporarily improved. The treatment was
interrupted, and a gradual improvement of the Khan et al. concluded that bradycardia events were
patient’s heart rate ensued. Within two days of more common with a continuous infusion of
stopping the treatment the rate had returned to fluorouracil, radiotherapy concurrent with
normal. The authors discuss the pharmacokinetics fluorouracil, and when fluorouracil was used in
of the two drugs and speculate that the second combination with cisplatin.22
phase of a biphasic elimination curve of the cisplatin While information on adverse cardiac reactions is
with a half-life of >100 hours could have acted found in the fact sheets of countries such as the
synergistically with fluorouracil to adversely affect USA (Food and Drug Administration - FDA), Spain
cardiomyocytes and the cardiac conduction system (Agencia Española de Medicamentos y Productos
resulting in the bradycardia observed during its Sanitarios - AEMPS) and Canada (Health
infusion. They conclude that while the combination Canada)5,6,7 including in some cases information on
chemotherapy is a useful treatment for this type of increased heart rate, tachycardia; they do not
cancer it may induce severe bradycardia and point describe bradycardia in the sections on adverse
out the need for carefully monitoring patients. reactions, warnings and precautions.
Khan MA et al22 carried out research on Cisplatin, ondansetron, oxaliplatin and irinotecan,
cardiotoxicities, especially bradycardia, in cancer which were observed as concomitant drugs in some
patients treated with chemotherapy regimens based of the Peruvian cases, include information about the
on fluorouracil in the Pakistani population. development of bradycardia, notably for oxaliplatin
Symptomatic cardiotoxicity was noted in 60 and irinotecan, only in association with overdose
(19.9%) out of 301 patients. Bradycardia was the cases8,9 or as part of the appearance of cholinergic
most common cardiotoxicity and was observed in diarrhoea or reaction.19
36 (12.0%) of the patients. The incidence of

Signal
The administration of fluorouracil and the perfusión EFG. [updated February 2019].
concomitant drugs is performed cyclically in Available at:
different doses and ways.25 However, in the https://cima.aemps.es/cima/dochtml/ft/71868/
Peruvian cases, the information regarding the exact FT_71868.html
moment of administration of each drug in relation
6. Health Canada [Internet]. Product monograph:
to the event is not clear, making it difficult to fully
Fluorouracil Injection USP 50 mg/mL (5 g/100
assess the causal relationship of each individual
mL). [updated 17 April 2018]. Available at:
drug to the adverse reaction.
https://pdf.hres.ca/dpd_pm/00044861.PDF
Capecitabine, another anticancer agent, is a
7. Dailymed [Internet]. LABEL: FLUOROURACIL-
prodrug to fluorouracil which is metabolised to
fluorouracil injection, solution. [updated 23
fluorouracil in the body.26 International regulatory
February 2017]. Available at:
agencies (eg. FDA, AEMPS and EMA) include
https://dailymed.nlm.nih.gov/dailymed/drugInf
information referring to the development of
o.cfm?setid=66d451fe-2436-494c-80c5-
bradycardia with the administration of
4528c8e34369
capecitabine.27,28,29 Taking this into account, it is
relevant to consider including bradycardia as an 8. Health Canada [internet]. Product monograph:
adverse reaction associated with the use of PrOXALIPLATIN Oxaliplatin Injection, Pfizer
fluorouracil in relevant drug information documents. Standard 5 mg/mL oxaliplatin. [updated 19
November 2018]. Available at:
Peru has 10 registered pharmaceutical products
that contain fluorouracil, none of which include
bradycardia as an adverse reaction or a warning. It 9. Food and Drug Administration – FDA [Internet].
is therefore suggested to include in Peru ELOXATIN (oxaliplatin) injection for intravenous
bradycardia in the sections on adverse reactions, use. [updated September 2018]. Available at:
warnings and precautions in the national drug fact https://www.accessdata.fda.gov/drugsatfda_do
sheet, and we would like to inform the global cs/label/2015/021759s019lbledt.pdf
network for consideration at national level.
10. Agencia Española de Medicamentos y Productos
The analysis and writing of the signal were Sanitarios-AEMPS [Internet]. FOLINATO
performed with kind peer review by colleagues from CÁLCICO NORMON 50 mg Polvo y disolvente
the Uppsala Monitoring Centre who participated in para solución inyectable EFG / FOLINATO
the workshop mentioned in the text; Birgitta CÁLCICO NORMON 350 mg Polvo para solución
Grundmark, Lovisa Sandberg, and Elki Sollenbring. inyectable EFG. Available at:
https://cima.aemps.es/cima/dochtml/ft/70340/
FT_70340.html
References:
11. Food and Drug Adminsitration-FDA [internet].
1. MedlinePlus [Internet]. U.S. National Library of LevoLeucovorin injection. [updated November
Medicine. [updated 30 December 2019]. 2013]. Available at:
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8.html
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Medicine. [updated 23 February 2017]. Label: INJECTION 10 mg/mL USP. [updated August
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4528c8e34369#L8a71c005-1a49-46d2-a01a-
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DOCETAXEL INJECTION, for intravenous use.
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Khodadadi , Muneeb Rehman , Ronstan Lobo ,

Signal
CAVEAT DOCUMENT
Statement of reservations, limitations and conditions relating to data released from
VigiBase, the WHO global database of individual case safety reports (ICSRs).
Understanding and accepting the content of this document are formal conditions for the use of
VigiBase data.
Uppsala Monitoring Centre (UMC) in its role as the World For these reasons, interpretations of adverse effect
Health Organization (WHO) Collaborating Centre for data, and particularly those based on comparisons
International Drug Monitoring receives reports of between medicinal products, may be misleading.
suspected adverse reactions to medicinal products from The data comes from a variety of sources and the
National Centres in countries participating in the WHO likelihood of a causal relationship varies across
Programme for International Drug Monitoring. The reports. Any use of VigiBase data must take these
information is stored in VigiBase, the WHO global significant variables into account.
database of individual case safety reports (ICSRs). It is
Prohibited use of VigiBase Data includes, but is not
important to understand the limitations and qualifications
limited to:
that apply to this information and its use.
• patient identification or patient targeting
Tentative and variable nature of the data
• identification, profiling or targeting of general
Uncertainty: The reports submitted to UMC generally
practitioners or practice
describe no more than suspicions which have arisen from
observation of an unexpected or unwanted event. In most Any publication, in whole or in part, of information
instances it cannot be proven that a specific medicinal obtained from VigiBase must include a statement:
product is the cause of an event, rather than, for example,
(i) recording ‘VigiBase, the WHO global database of
underlying illness or other concomitant medication.
individual case safety reports (ICSRs)’ as the source
Variability of source: Reports submitted to national of the information
centres come from both regulated and voluntary sources.
(ii) explaining that the information comes from a variety
Practice varies: some national centres accept reports only
of sources, and the probability that the suspected
from medical practitioners; others from a broader range of
adverse effect is drug-related is not the same in all
reporters, including patients, some include reports from
cases
pharmaceutical companies.
(iii) affirming that the information does not represent the
Contingent influences: The volume of reports for a
opinion of the UMC or the World Health Organization.
particular medicinal product may be influenced by the
extent of use of the product, publicity, the nature of the Omission of this statement may exclude the
adverse effects and other factors. responsible person or organization from receiving
further information from VigiBase.
No prevalence data: No information is provided on the
UMC may, in its sole discretion, provide further
number of patients exposed to the product, and only a
instructions to the user, responsible person and/or
small part of the reactions occurring are reported.
organization in addition to those specified in this
Time to VigiBase: Some national centres make an statement and the user, responsible person and/or
assessment of the likelihood that a medicinal product organization undertakes to comply with all such
caused the suspected reaction, while others do not. Time instructions.
from receipt of an ICSR by a national centre until
submission to UMC varies from country to country. Uppsala Monitoring Centre (UMC)
Information obtained from UMC may therefore differ from Box 1051, SE-751 40 Uppsala, Sweden
that obtained directly from national centres. Tel: +46-18-65 60 60, E-mail: [email protected]
www.who-umc.org

Bradicardia y Fluoracilo Señal

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2020

The WHO Pharmaceuticals Newsletter provides you

The aim of the Newsletter is

The information is produced in

ISBN 978-92-4-001453-4 (electronic version)

© World Health Organization 2020

WHO Pharmaceuticals Newsletter No. 5, 2020 • 3

Alfuzosin reported in clinical trials and in cases were evaluated by the

WHO Pharmaceuticals Newsletter No. 5, 2020 • 4

monitor for new pain, Opioid found a strong causal

WHO Pharmaceuticals Newsletter No. 5, 2020 • 6

Allopurinol Beta-lactam MHRA has announced that

WHO Pharmaceuticals Newsletter No. 5, 2020 • 7

Cyproterone stopping denosumab (Prolia®) the presence of a naked flame,

WHO Pharmaceuticals Newsletter No. 5, 2020 • 10

Everolimus and osteonecrosis of the jaw (ONJ)

Summary angiogenesis inhibition, soft tissue toxicity, and

WHO Pharmaceuticals Newsletter No. 5, 2020 • 11

WHO Pharmaceuticals Newsletter No. 5, 2020 • 12

Table 1. Characteristics of a selection of case reports in VigiBase of everolimus in association with

Literature and labelling administered a bisphosphonate, these drugs

WHO Pharmaceuticals Newsletter No. 5, 2020 • 13

Agents: Results of an Italian Multicenter Study Stomatol (Roma). 2014;5(2 Suppl):26-.

Response from Novartis

1 Introduction Transplant) under brand names Afinitor, Votubia

WHO Pharmaceuticals Newsletter No. 5, 2020 • 15

Novartis has been monitoring and providing last PSUR.

2.1.1 Methodology The cases retrieved are presented in Table 2-1

Table 2-1 Case reports of ONJ

WHO Pharmaceuticals Newsletter No. 5, 2020 • 16

Table 2-2 Measure of disproportionality

Table 2-3 Measure of disproportionality

Drug Event SOC SP+Lit+POP SP+Lit+POP

Table 2-4 Case reports of ONJ

WHO Pharmaceuticals Newsletter No. 5, 2020 • 17

Fluorouracil and Bradycardia – national signal from Peru with potential

1. Abstract the global network for consideration.

N° Age Sex Indication Drugs Doses ADRs Time to Positive Positive

5 30 F Rectal cancer Fluorouracil (S) 500 mg Bradycardia 2 Yes -

or case series of bradycardia in relation to cardiotoxicity was not significantly different

WHO Pharmaceuticals Newsletter No. 5, 2020 • 21

PrJAMP-ONDANSETRON ONDANSETRON Sakti Chakrabarti , Joerg Herrmann , Amir

WHO Pharmaceuticals Newsletter No. 5, 2020 • 23

WHO Pharmaceuticals Newsletter No. 5, 2020 • 24

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