WHO Pharmaceuticals Newsletter No 3 2023 1693146010

2023
WHO Pharmaceuticals
NEWSLETTER No. 3
WHO Vision for Safety of

Medicinal Products
The WHO Pharmaceuticals Newsletter provides you
No country left behind: with the latest information on the safety of medicinal
worldwide pharmacovigilance products and regulatory actions taken by authorities
for safer medicinal products, around the world.
safer patients
In addition, this issue of the newsletter includes a brief
overview of the Vaccine Safety Net (VSN), a global
network of websites established by WHO to provide
reliable information on the safety of vaccines.
The aim of the Newsletter is

to disseminate regulatory
information on the safety of
medicinal 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:
Pharmacovigilance, Contents
MHP/RPQ,
World Health Organization, Regulatory Matters
1211 Geneva 27, Switzerland,
E-mail address:
pvsupport@who.int Safety of Medicinal products
This Newsletter is also available at: Features

https://www.who.int/teams/regula
tion-prequalification
WHO Pharmaceuticals Newsletter No. 3, 2023
ISBN 978-92-4-007805-5 (electronic version)

ISBN 978-92-4-007806-2 (print version)
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Table of Contents
Regulatory Matters
Antitubercular agents ...............................................................................................4
Bosutinib ................................................................................................................4
Cephalosporins ........................................................................................................4
COVID-19 vaccine Janssen (Ad26.COV2-S) .................................................................5
Diazoxide ................................................................................................................5
Janus kinase (JAK) inhibitors .....................................................................................5
Losartan .................................................................................................................6
Nirmatrelvir-ritonavir and immunosuppressants ...........................................................6
Opioids ...................................................................................................................7
Paracetamol ............................................................................................................7
Piperacillin ..............................................................................................................7
Piroxicam ................................................................................................................8
Propofol ..................................................................................................................8
Terlipressin .............................................................................................................8
Voriconazole ............................................................................................................9
Safety of Medicinal Products

Amlodipine ............................................................................................................ 10
Folic acid .............................................................................................................. 10
Ibuprofen .............................................................................................................. 10
Isotretinoin ........................................................................................................... 11
Lactulose .............................................................................................................. 11
Levofloxacin .......................................................................................................... 12
Nitrofurantoin ........................................................................................................ 12
Pneumococcal Polysaccharide Vaccine (23-Valent) ..................................................... 13
Prednisolone.......................................................................................................... 13
Prednisone ............................................................................................................ 14
Scopolamine and butylscopolamine .......................................................................... 14
Sitagliptin ............................................................................................................. 15
Valproic acid (sodium valproate) .............................................................................. 15
Features
National Regulatory Authorities welcome to join Vaccine Safety Net....................... 17
All the previous issues of the WHO Pharmaceuticals Newsletter can be accessed from our
website.
3
Regulatory Matters
Antitubercular event may occur with other drugs within the

irrespective of the types of tyrosine kinase inhibitors
agents antitubercular agents. (TKIs) class (dasatinib,
Taking into account the imatinib, and nilotinib), and
Potential risk of situation in Japan where has agreed that a causal
paradoxical drug health-care professionals relationship between
reaction who have experienced TB bosutinib use and
treatments will decrease occurrence of ILD is
Japan. The Ministry of due to low prevalence, it plausible. The MAH should
Health, Labour and Welfare was concluded that such amend the product’s
(MHLW) and the warnings for all the information to include this
Pharmaceuticals and antitubercular agents are risk.
Medical Devices Agency necessary.
(PMDA) have announced Health-care professionals Reference:
that the product are advised that if PRAC recommendations on
information for worsening of existing signals, EMA, 6 March 2023
antitubercular agents (all tuberculosis or new onset (link to the source within
products marketed in Japan of tuberculosis symptoms is www.ema.europa.eu)
as listed in the link) observed after initiating the
should be revised to treatment, the decision to Cephalosporins
include a warning of the continue administration
potential risk of paradoxical should be determined Risk of neurotoxicity
drug reaction. based on drug
New Zealand. The
Paradoxical drug reaction in susceptibility tests or other
Medsafe has announced
the tuberculosis (TB) measures.
that it is working with the
treatment refers to events Reference: sponsors of cephalosporin
such as increased shadows Revision of Precautions, products to update the
on chest radiographs, MHLW/PMDA, 23 March data sheets to include the
appearance of new 2023 (link to the source within risk of neurotoxicity.
shadows, pleural effusions www.pmda.go.jp/english/)
and swollen or enlarged Cephalosporins are broad-
mediastinal or cervical spectrum beta-lactam
lymph nodes after starting Bosutinib antibiotics used in primary
treatment, despite the and secondary care to treat
reduction or negativity of Risk of interstitial lung a range of infections.
TB bacteria in the sputum. disease Cephalosporins are
grouped into five
The review by the MHLW
Europe. The generations based on their
and PMDA was triggered by
Pharmacovigilance Risk antibacterial properties and
the revision of the
Assessment Committee their discovery.
Prescribing Information for
(PRAC) of the European
some of the antitubercular Case report and case series
Medicines Agency (EMA)
agents in the US. In ICSRs reviews found that
has recommended a
reported in Japan, there compared with other
change to the product
were in total 39 case cephalosporins, cefepime
information for bosutinib to
reports where a causal was associated with the
include the risk of
relationship between most reports of
interstitial lung disease
several antitubercular neurotoxicity
(ILD).
agents and an adverse internationally. However,
event was reasonably The PRAC has considered neurotoxicity has been
possible. The mechanism of the available evidence from reported with all
the event is attributed to clinical studies, post- generations of
allergy to a bacterial cell of marketing cases, literature cephalosporins. Reports of
Mycobacterium reports and the already neurotoxicity with
tuberculosis; therefore, the known association of ILD cephalosporins are mainly
4
Regulatory Matters
characterized by vaccination. cases assessed, six were in

encephalopathy, myoclonus infants and children. Of the
An additional revision to
and/or seizures. Risk eight cases, two were
the product information
factors include older age found to be probably linked
includes facial paralysis
groups, renal impairment, to the use of diazoxide,
(including Bell’s Palsy) that
underlying central nervous four were found to be
have been reported during
system disorders and if possibly linked and two
post-authorization use.
intravenous route of were unlikely to be linked.
administration is used. Reference: It was concluded that there
US FDA Roundup: March is a possible link between
The New Zealand Medicines 14, 2023 (link1 and link2 to the use of diazoxide and
Adverse Reaction the source within www.fda.gov) the risk of pericardial
Committee effusion.
(MARC) recommended that
health professionals should Health Canada is working
Diazoxide
consider cephalosporin- with the manufacturer to
induced neurotoxicity in update the CPM for
Risk of pericardial
patients with the above risk diazoxide with a warning
effusion
factors and an unexplained, about cases of pericardial
new onset neurological Canada. Health Canada effusion having been
condition. In such cases, has announced the update observed, including in
withdrawal of the medicine of the Canadian Product infants and children.
may be appropriate. Monographs (CPM) to
Reference:
include the risk of
Reference: Summary safety review,
pericardial effusion with the
Prescriber Update, Health Canada, 24 March
use of diazoxide
Medsafe, 23 March 2023 2023 (link to the source within
(link to the source within (Proglycem®).
www.hc-sc.gc.ca)
www.medsafe.govt.nz) Diazoxide is authorized to
manage low blood sugar
(hypoglycaemia) in infants,
Janus kinase
COVID-19 vaccine children and adults caused (JAK) inhibitors
Janssen by a higher-than-normal
amount of insulin in the Risks of major
(Ad26.COV2-S)
blood (hyperinsulinism) cardiovascular events,
Potential risks of associated with specific malignancy, venous
myocarditis and tumours, surgeries, thromboembolism,
pericarditis, and facial maternal or foetal medical serious infections and
paralysis conditions, delivery-related increased mortality
complications, or genetic
United States. The US conditions, when other United Kingdom. The
Food and Drug medical therapy or surgical Medicines and Healthcare
Administration (FDA) has management have been Products Regulatory
announced that the product Agency (MHRA) has
unsuccessful or are not
information for COVID-19 feasible.
informed health-care
vaccine Janssen professionals of new risk
(Ad26.COV2-S) was The safety review was minimization measures for
revised to include a triggered by published JAK inhibitors used to treat
Warning conveying that cases in the scientific chronic inflammatory
disorders.
adverse events following literature. Health Canada
use of the vaccine reported reviewed eight Janus kinase (JAK)
suggest increased risks of international cases of inhibitors are a class of
myocarditis and pericardial effusion in medicines that include
pericarditis, particularly patients taking diazoxide abrocitinib (Cibinqo®),
within the period 0 through from the Canada Vigilance filgotinib (Jyseleca®) ,
7 days following database. Of the eight baricitinib (Olumiant®),
5
Regulatory Matters
upadacitinib (Rinvoq®) , Following the MHRA’s Reference:

and tofacitinib (Xeljanz®). review, changes are being Based on the
They are used in the made to the product communication from IPC,
treatment of chronic information for all JAK India, April 2023 (link to the
inflammatory disorders inhibitor medicines source within ipc.gov.in)
such as rheumatoid authorized for
arthritis, psoriatic arthritis, inflammatory diseases to
juvenile idiopathic arthritis, note the updated risk Nirmatrelvir-ritonavir
ankylosing spondylitis, characterization and and
non-radiographic axial expanded risk minimization
immunosuppressants
spondyloarthritis, ulcerative measures. The MHRA has
colitis, Crohn’s disease, sent a DHPC letter to Risk of adverse events
atopic dermatitis, and advise of these changes. from drug-drug
alopecia areata.
Reference: interaction
This new risk minimization Drug Safety Update, MHRA,
Canada. Health Canada
measures are consistent 26 April 2023 (link to the
with the measures has announced that the
source within
introduced for tofacitinib www.gov.uk/mhra) product information for
(Xeljanz®) in 2020 and nirmatrelvir-ritonavir
2021. The MHRA’s review (See also WHO Pharmaceuticals (Paxlovid®) has been
Newsletter No.1, 2023: Janus updated to include the risk
found that risks of
kinase (JAK) inhibitors and Risks of
increased incidence of of drug-drug interaction
cardiovascular conditions, blood
malignancy, major adverse clots, cancer, serious infections in with immunosuppressants
cardiovascular events Europe and Singapore) (including cyclosporine,
(MACE), serious infections, everolimus, sirolimus and
venous thromboembolism Losartan tacrolimus).
(VTE) and mortality, are
considered class effects Risk of muscle spasm Nirmatrelvir-ritonavir is
across JAK inhibitors used indicated for the treatment
for chronic inflammatory India. The Central Drugs of COVID-19 and is an
disorders. Standard Control inhibitor of cytochrome
Organization (CDSCO) has P450 (CYP) 3A. Tacrolimus
Therefore, it is advised to
approved the is metabolized by CYP3A
avoid prescribing these
medicines unless there are recommendation from the and has a narrow
no suitable alternatives in National Coordination therapeutic index.
patients with the following Centre – Pharmacovigilance
risk factors: age 65 years Programme of India (NCC- Canadian cases of serious
or older; current or past PvPI), Indian adverse events following a
long-time smoking; other Pharmacopoeia drug-drug interaction
risk factors for Commission (IPC) to revise between nirmatrelvir-
cardiovascular disease or the prescribing information ritonavir and tacrolimus
malignancy. leaflet (PIL) for losartan to have been reported. In
include muscle spasm as some cases, the tacrolimus
In addition to the results of
an adverse drug reaction. levels were observed to go
studies for tofacitinib and
up rapidly and to very high
baricitinib which suggested Losartan is indicated for
levels, which can lead to
an increased risk of major the treatment of mild to
adverse effects such as
cardiovascular events, the moderate hypertension.
acute kidney injury and
latest review conducted by
The NCC-PvPI, IPC increased susceptibility to
the EMA looked at the
reviewed 10 Individual severe infections due to
available mechanistic and
Case Safety Reports over-immunosuppression.
safety data for each of the
(ICSRs) of losartan Cases have also been
five JAK inhibitors and
associated muscle spasm reported in the literature
concluded that the effects
and a causal relationship from other countries.
could be considered a class
between them was found.
effect.
Health-care professionals
6
Regulatory Matters
are advised to avoid use of persistent pain that relationship between them
nirmatrelvir-ritonavir in requires an extended was found.
patients taking treatment period with a
Reference:
immunosuppressants when daily opioid pain medicine
Based on the
close monitoring of and for which alternative
communication from IPC,
immunosuppressant treatment options are
India, April 2023 (link to the
concentrations is not inadequate. source within ipc.gov.in)
feasible. If co-
The updates also include a
administered, dose
new warning about opioid-
adjustment, monitoring of
induced hyperalgesia (OIH) Piperacillin
concentrations and adverse
which is a condition where
reactions for levels of Risk of haemophagocytic
opioids cause an increase
immunosuppressants are lymphohistiocytosis
in pain (hyperalgesia) or an
recommended.
increased sensitivity to pain (HLH)
Reference: (allodynia).
Health Product InfoWatch: Malaysia. The National
This action is part of the
March 2023, Health Pharmaceutical Regulatory
implementation of FDA
Canada, (link to the source Agency (NPRA) has
Overdose Prevention
within www.hc-sc.gc.ca) announced that the product
Framework.
safety information for
Reference: piperacillin will be updated
Opioids CDER Statement, US FDA, to include a warning
13 April 2023 (link to the regarding the risk of
New safety label
source within www.fda.gov) haemophagocytic
changes lymphohistiocytosis (HLH).
United States. The US Piperacillin belongs to the
FDA is requiring several Paracetamol
ß-lactam antibiotics which
updates to the prescribing are active against a range
Risk of fixed drug
information for immediate- of gram-positive and gram-
release (IR) and extended-
eruption
negative aerobic and
release/long-acting (ER/LA) India. The CDSCO has anaerobic bacteria and
opioid analgesics. approved the often combined with a ß-
The required safety recommendation from the lactamase inhibitor such as
labelling changes include: National Coordination tazobactam to enhance the
• the risk of overdose Centre – Pharmacovigilance activity against many of
increases as the dosage Programme of India (NCC- those resistant organisms.
increases for all opioid PvPI), Indian
pain medicines Pharmacopoeia HLH is a life-threatening
• IR opioids should not be Commission (IPC) to revise syndrome caused by
used for an extended the prescribing information pathologic over-activation
period unless a patient’s leaflet (PIL) for of the immune system,
pain remains severe paracetamol to include with clinical features of
enough to require them fixed drug eruption as an extreme systemic
and alternative treatment adverse drug reaction. inflammation, such as
options continue to be fever, skin rashes,
Paracetamol is indicated for
inadequate hepatosplenomegaly,
the symptomatic treatment
• many acute pain cytopenias,
of pain and fever.
conditions treated in the hyperferritinaemia,
outpatient setting require The NCC-PvPI, IPC hypertriglyceridaemia,
no more than a few days reviewed 480 Individual hypofibrinogenaemia, and
of an opioid pain medicine Case Safety Reports haemophagocytosis.
• it is recommended to (ICSRs) of paracetamol
reserve ER/LA opioid pain associated fixed drug The NPRA has reviewed the
medicines for severe and eruption and a causal available information on
7
Regulatory Matters
cases of haemophagocytic Risk of fixed drug to include “For single use in

lymphohistiocytosis eruption one patient. Risk of sepsis
reported internationally as in multiple use” and “Use
well as relevant scientific India. The CDSCO has immediately after
literature. HLH has high approved the opening”. In case of
mortality rates and a delay recommendation from the insufficient space on the
in diagnosis of HLH is often National Coordination immediate packaging, the
the greatest barrier to Centre – Pharmacovigilance National Competent
favourable outcomes owing
Programme of India (NCC- Authorities may decide to
to the rarity of HLH, variety
PvPI), Indian omit parts of the warning
of clinical presentations,
Pharmacopoeia on the immediate
and non-specific clinical
and laboratory findings. In Commission (IPC) to revise packaging.
a published case series, the prescribing information
leaflet (PIL) for piroxicam The PRAC has considered
clinical symptoms of HLH in
to include fixed drug the available evidence in
three children were
eruption as an adverse EudraVigilance, literature
reported to have improved
following cessation of drug reaction. and the responses of the
piperacillin/tazobactam in MAHs for this decision.
Piroxicam is indicated for
combination with
the treatment of Reference:
corticosteroid therapy
(e.g., intravenous rheumatoid arthritis, PRAC recommendations on
prednisolone/methylprednis osteoarthritis, ankylosing signals, EMA, 11 April 2023
olone), one of which spondylitis, cervical (link to the source within
involved the addition of spondylitis and other www.ema.europa.eu)
Intravenous human musculoskeletal disorder.
immunoglobulin (IVIG).
The NCC-PvPI, IPC
Considering the complexity
reviewed 31 Individual Terlipressin
and severity of the
condition the NPRA deems Case Safety Reports
(ICSRs) of Piroxicam Risk of respiratory
it necessary to alert health-
care professionals about associated fixed drug failure and septic shock
the potential risk of HLH eruption and a causal
United Kingdom. The
following the use of relationship between them
MHRA has alerted health-
piperacillin-containing was found.
care professionals that in
products.
Reference: patients with type 1
Health-care professionals Based on the hepatorenal syndrome
are also reminded that communication from IPC, terlipressin may cause
early detection of HLH India, April 2023 (link to the serious or fatal respiratory
manifestations followed by source within ipc.gov.in) failure at a frequency
timely intervention and higher than previously
treatment are crucial for known, and that
minimising morbidity and Propofol terlipressin increases the
mortality.
risk of sepsis and septic
Medication errors that shock.
Reference: could potentially lead to
Safety Alert, NPRA, 1 Terlipressin is a synthetic
life threatening/fatal
November 2022 (link to the pituitary hormone. It is
cases
source within authorized for treatment of
www.npra.gov.my) Europe. The PRAC of the bleeding from dilated veins
(See also WHO Pharmaceuticals
EMA has recommended in the food pipe leading to
Newsletter No.2, 2023: tazobactam
and piperacillin risk of that MAHs for propofol the stomach (bleeding
haemophagocytic containing products should oesophageal varices) and
lymphohistiocytosis) submit a variation to for emergency treatment of
amend the product type 1 hepatorenal
information of the outer syndrome (rapidly
Piroxicam and immediate packaging progressive renal failure in
8
Regulatory Matters
patients with liver cirrhosis Newsletter No.1, 2023: terlipressin may be required to check
and risks of respiratory failure,
(scarring of the liver) and that the medicines are still
sepsis in Europe)
ascites (fluid accumulation having the desired effect.
in the abdomen)). The
Reference:
advice in this article relates
only to use of terlipressin Voriconazole PRAC recommendations on
for type 1 hepatorenal signals, EMA, 11 April 2023
syndrome. Drug interaction with (link to the source within
www.ema.europa.eu)
flucloxacillin leading to
A recent European
subtherapeutic
review into the benefits
and risks of terlipressin voriconazole levels
treatment, which was
Europe. The PRAC of the
triggered by the CONFIRM
EMA has recommended a
trial findings, concluded
change to the product
that new measures were
information for
required to reduce the risk
voriconazole to include
of respiratory failure and
drug interaction with
sepsis when terlipressin is
flucloxacillin leading to
used in patients with type 1
subtherapeutic
hepatorenal syndrome. The
voriconazole levels.
Pharmacovigilance Expert
Advisory Group of the The PRAC has considered
UK’s Commission on the evidence from the
Human Medicines agreed literature, the responses
with the recommendations, from the MAH and has
while also highlighting the agreed that the MAHs for
benefits of terlipressin voriconazole and
treatment when an flucloxacillin-containing
appropriate assessment of medicinal products should
the benefits and risks has submit a variation to
been made. Changes will amend the product
be made to the product information as described
information for terlipressin below: Flucloxacillin has
medicines authorized for been reported to
type 1 hepatorenal significantly decrease
syndrome to note the plasma voriconazole
individual benefits and risks concentrations. If
when initiating terlipressin concomitant administration
treatment, especially for of flucloxacillin with
those with severe renal or voriconazole cannot be
hepatic impairment and avoided, monitor for
monitor all patients closely potential loss of
during terlipressin voriconazole effectiveness
treatment. A Direct (e.g., by therapeutic drug
Healthcare Professional monitoring); increasing the
Communication letter has dose of voriconazole may
also been sent to UK be needed.
health-care professionals.
Patients are advised to
Reference: inform their doctor if they
Drug Safety Update, MHRA, are taking medicinal
23 March 2023 (link to the products containing
source within voriconazole and
www.gov.uk/mhra) flucloxacillin, as a dose
(See also WHO Pharmaceuticals adjustment or monitoring
9
Amlodipine causality assessment of the unlikely). Additionally, the

reported cases and data mining for this
Potential risk of literature might support a drug/ADR combination
Hyperkalaemia relationship between provided positive statistical
Amlodipine and association (IC=1.1) at
Saudi Arabia. The Saudi hyperkalaemia. This signal that point of time.
Food & Drug Authority needs further investigation
The SFDA’s investigation
(SFDA) has released a to confirm the risk, and
concluded that the current
safety signal concerning health-care professionals
available evidence from
amlodipine and risk of should be aware of this
assessment of the ICSRs
hyperkalaemia. potential adverse reaction.
and data mining might
Amlodipine is an Reference: support a relationship
antihypertensive drug Safety Alert, SFDA, 16 May between folic acid and
belonging to the group of 2023 (link to the source within constipation. This signal
drugs called www.sfda.gov.sa) needs further investigation
dihydropyridine calcium to confirm the risk,
channel blockers. however, health-care
Hyperkalemia is defined as professionals should be
Folic acid
a serum or plasma aware of this potential
potassium level above the adverse reaction.
Potential risk of
upper limits of normal.
constipation Reference:
In 2023, the SFDA has Safety Alert, SFDA, 1
Saudi Arabia. The SFDA
detected a signal of March 2023 (link to the
has released a safety signal
Amlodipine and source within www.sfda.gov.sa)
concerning folic acid and
hyperkalaemia and
the risk of constipation.
reviewed all the evidence
available on the association Folic acid or Folate (vitamin
Ibuprofen
between them. The SFDA B-9) is important in red
found one local case and blood cell formation and for Potential risk of renal
225 international cases in healthy cell growth and
tubular acidosis
VigiBase (the WHO global function. The nutrient is
database of ICSRs) and crucial during early Saudi Arabia. The SFDA
applied WHO-UMC causality pregnancy to reduce the has released a safety signal
assessment criteria on risk of birth defects of the concerning ibuprofen and
thirty cases with highest brain and spine. its potential risk of renal
completeness score. It Constipation is generally tubular acidosis.
resulted in two probable described as having fewer
cases, sixteen possible than three bowel Ibuprofen is a non-steroidal
cases, six unlikely case and movements a week. anti-inflammatory
six cases not assessable. The SFDA detected a medication that indicated
Data mining of this domestic case-report of for its analgesia and anti-
drug/ADR has been constipation and 157 inflammatory effects.
estimated using international cases in In 2023, the SFDA has
Information component VigiBase and extracted the detected a signal of
(IC= 1) which revealed a top 30 cases from VigiLyze ibuprofen and renal tubular
positive statistical that have completeness acidosis and reviewed all
association. Furthermore, a score of 1.0 in order to the evidence available on
case report was found in apply the WHO causality the association between
the literature that support assessment criteria on them.
the association. them. As a result, majority The SFDA reviewed
of the cases were possibly VigiBase and found 116
linked to Folic acid (21 ICSRs internationally at
cases were possible and that point of time. The
available evidence from
the other nine cases were SFDA has extracted cases
10
with completeness score of Reticutan®) treatment. associated with

0.5 (n=10 cases) in order Recommendations include isotretinoin. This included
to apply the causality the addition of new suspected side effects
assessment criteria on warnings for the risk of reported to the MHRA,
them. As a result, all the sexual dysfunction, research into the risks and
assessable cases of renal including the possibility of the biological mechanisms
tubular acidosis were either persistence after treatment that may explain these
probably or possibly linked discontinuation, and advice events, from published
to ibuprofen. Data mining for health-care studies about patients
of this drug/ADR has been professionals to ask taking isotretinoin,
estimated using patients about symptoms information on how
Information component or signs of sexual isotretinoin safety is
(IC=4.2) which reflect dysfunction prior to managed in other
strong positive statistical starting treatment with countries, and result of a
association. isotretinoin and to monitor public call for information.
patients for the
The SFDA’s investigation Reference:
development of new sexual
concluded that the current Drug Safety Update, MHRA,
disorders during treatment.
available evidence from 26 April 2023 (link to the
Recommendations also
assessment of the ICSRs, source within
include the development of
class effect and literature www.gov.uk/mhra)
consistent monitoring
might support a
requirements for potential
relationship between of (See also WHO Pharmaceuticals
psychiatric and sexual side Newsletter No.5, 2020: isotretinoin
ibuprofen and renal tubular
effects in all patients and risks of psychiatric reactions
acidosis. This signal needs
throughout treatment. The and sexual dysfunction in UK)
further investigation to
initiation of treatment in
confirm the risk, and
patients younger than 18 Lactulose
health-care professionals
years will require two
should be aware of this Potential risk of Pruritus
prescribers to agree a
potential adverse reaction.
patient’s acne is severe and
Reference: that there is no other
Safety Alert, SFDA, 21 effective treatment before
concerning lactulose and its
March 2023 (link to the initiation of isotretinoin
potential risk of pruritus.
source within www.sfda.gov.sa) therapy.
Lactulose is a synthetic
(See also WHO Pharmaceuticals Isotretinoin is indicated for
sugar used to treat
Newsletter No.1, 2020: Ibuprofen severe forms of acne (such
and Risk of renal toxicity in New constipation. It is broken
as nodular or conglobate
Zealand) down in the colon into
acne or acne at risk of
products that pull water
permanent scarring)
Isotretinoin out from the body and into
resistant to adequate
the colon resulting in
courses of standard
Risk of sexual softening the stools.
therapy with systemic anti-
dysfunction Lactulose is also used to
bacterials and topical
reduce the amount of
United Kingdom. The therapy.
ammonia in the blood of
MHRA has announced that patients with liver disease.
The MHRA has formed an
the Isotretinoin Expert
Implementation Advisory
Working Group (IEWG) of In 2023, the SFDA has
Group to advise on the
the Commission on Human detected a signal of
implementation of these
Medicines (CHM) lactulose and pruritus and
recommendations.
recommended new reviewed all the evidence
measures to strengthen the The IEWG considered the available on the association
safety of isotretinoin available information on between them. The SFDA
(capsule form, psychiatric and sexual side initiated this investigation
Roaccutane® and effects suspected to be following a local case-
11
report of pruritus. The the SFDA reviewed all the pulmonary and hepatic
SFDA looked into the evidence available on the adverse drug reactions and
VigiBase and found 340 association between them. advise patients to be
ICSRs internationally. The The SFDA found one local vigilant for the signs and
SFDA has extracted the top case and 857 international symptoms in need of
30 cases with cases in VigiBase and further investigation.
completeness score of 1.0 applied WHO-UMC causality
Nitrofurantoin is a broad-
in order to apply the assessment criteria on
spectrum antibacterial
causality assessment ICSRs with completeness
agent, which has been
criteria on them. As a score 1.0 (n=30). Among
available since the 1950s.
result, most of the them, 29 cases were either
It is indicated in adults,
assessed cases provides probably or possibly
children and infants over
positive linkage to associated with
three months old for the
Lactulose (14 probable, 11 levofloxacin. Evidence from
treatment and prophylaxis
possible, and five unlikely literature found that
of acute or recurrent
cases). support the signal, as the
uncomplicated urinary tract
risk of dry mouth was
The SFDA’s investigation infections (UTIs) and acute
reported in a published
concluded that the current or recurrent uncomplicated
randomized double-blind
available evidence from pyelitis. The potential for
controlled trial of
assessment of the ICSRs acute pulmonary damage
levofloxacin.
might support a with nitrofurantoin is well-
relationship between of documented in the product
lactulose and pruritus. This information.
signal needs further
available evidence from The MHRA has advised
investigation to confirm the
assessment of the ICSRs health-care professionals
risk, and health-care
and literature might as follows:
professionals should be
support a relationship
aware of this potential • patients and caregivers to
between levofloxacin and
adverse reaction. be vigilant for new or
dry mouth. This signal
needs further investigation worsening respiratory
Reference:
to confirm the risk, and symptoms while taking
Safety Alert, SFDA, 1
health-care professionals nitrofurantoin and
March 2023 (link to the
source within www.sfda.gov.sa) should be aware of this promptly investigate any
potential adverse reaction. symptoms that may
indicate a pulmonary
Reference: adverse reaction.
Levofloxacin Safety Alert, SFDA, 21 • immediately discontinue
March 2023 (link to the nitrofurantoin on the
Potential risk of dry source within occurrence of new or
mouth www.sfda.gov.sa) worsening symptoms
Saudi Arabia. The SFDA indicative of pulmonary
has released a safety signal damage.
concerning levofloxacin and
Nitrofurantoin • be vigilant for symptoms
its potential risk of dry and signs of liver
mouth. dysfunction in patients
Risks of pulmonary and
hepatic adverse drug taking nitrofurantoin for
Levofloxacin is a broad- any duration, but
reactions
spectrum, third-generation particularly with long-
fluoroquinolone antibiotic United Kingdom. The term use, and monitor
used to treat bacterial MHRA has reminded patients periodically for
infections. healthcare professionals signs of hepatitis and for
that prescribing changes in biochemical
In 2023, the SFDA detected
nitrofurantoin should be tests that would indicate
a signal of levofloxacin and
alert to the risks of hepatitis or liver injury.
dry mouth. Furthermore,
12
• use caution when least to the joints extensive swelling of

prescribing nitrofurantoin immediately above and vaccinated limb within a
in patients with below the injection site or short period after
pulmonary disease or that may cross one or more administration of PPV 23
hepatic dysfunction, joints. Alternatively, ELS and to report all suspected
which may mask the can be defined as swelling ELS events following
signs and symptoms of of the limb that results in immunisation with PPV 23.
adverse reactions. twice the normal size of the
Reference:
limb circumference.
Reference: Safety Alert, NPRA, 20
Extensive swelling of
Drug Safety Update, MHRA, December 2022 (link to the
vaccinated limb is a known
26 April 2023 (link to the
adverse event to some source within
source within www.npra.gov.my)
other vaccines, such as
www.gov.uk/mhra)
Comirnaty® (COVID-19
(See also WHO Pharmaceuticals mRNA vaccine) and Prednisolone
Newsletter No.2, 2020: diphtheria/tetanus
nitrofurantoin and Risk of toxoids/acellular pertussis Potential risk of
pulmonary and hepatic impairment
vaccine (adsorbed hypomagnesaemia
and peripheral neuropathy in New
Zealand) paediatric) (DTaP), while
the reporting rate differs
substantially among
Pneumococcal vaccines.
concerning prednisolone
and its potential risk of
Polysaccharide The NPRA has reviewed
available information on hypomagnesaemia.
Vaccine (23- cases reported
Prednisolone is a
Valent) internationally for
corticosteroid used to treat
suspected adverse events
a wide range of health
Potential risk of and data from the scientific
conditions including
extensive swelling of literature. The EMA
allergies, blood disorders,
requested that the package
vaccinated limb skin diseases,
insert for all PPV 23
inflammation, infections
products be updated with
Malaysia. The NPRA has and certain cancers and to
the risk of extensive
issued a Safety Alert about prevent organ rejection.
swelling of vaccinated limb
the potential risk of Hypomagnesemia is an
in 2022. In the NRPA’s
extensive swelling of electrolyte disturbance
view, it is possible that
vaccinated limb with caused by a low serum
these events may be
pneumococcal magnesium level in the
overlooked due to the
polysaccharide vaccine (23- blood.
regular occurrence of
valent) or PPV 23.
injection site inflammation In 2023, the SFDA has
PPV 23 containing purified following immunisation. detected a signal of
capsular polysaccharides of Besides, extensive swelling prednisolone and
the 23 most prevalent or of vaccinated limb might be hypomagnesaemia and
invasive pneumococcal misdiagnosed as cellulitis reviewed all the evidence
types of Streptococcus or erysipelas in the lack of available on the association
pneumonia is indicated for bacteriological information, between them. The SFDA
children from 2 years of which could result in found 28 international
age, adolescents, and unnecessary antibiotic cases in VigiBase and
adults in whom there is an treatment. applied WHO-UMC causality
increased risk of assessment criteria on all
Health-care professionals
pneumococcal disease. cases. Almost half of them
are advised to be aware
(13 cases) were possibly
Extensive limb swelling and inform vaccine
linked to prednisolone
(ELS) is defined as limb recipients about the
(other 13 cases were not
swelling that extends at possible occurrence of
13
assessable + two cases them. The SFDA found one of medication errors of
were unlikely). Data local case and 1037 administration of
mining of this drug/ADR international cases in scopolamine instead of
has been estimated using VigiBase. The SFDA applied butylscopolamine resulting
Information component WHO-UMC causality in serious adverse
(IC= 0.6) which showed a assessment criteria on reactions.
positive statistical ICSRs with completeness
The Spanish
association for the score 1.0 (n=30). Twenty
Pharmacovigilance System
drug/ADR combination. cases provided positive
(SEFV-H) has received five
association (one probable
cases of serious adverse
The SFDA’s investigation and nineteen possible
reactions related to the
concluded that the current cases). Eight cases were
erroneous administration of
available evidence from unlikely and two cases
scopolamine instead of
assessment of the ICSRs were not assessable. Data
butylscopolamine. The
might support a mining of this drug/ADR
affected patients required
relationship between was estimated using
medical assistance. The
prednisolone and Information component
errors detected indicate
hypomagnesaemia. This (IC= 4.0), which showed a
that confusion may occur in
signal needs further strong positive statistical
the prescription, dispensing
investigation to confirm the association for the
and administration of the
risk, and health-care drug/ADR combination.
drug.
professionals should be
aware of this potential The SFDA’s investigation The very similar name of
adverse reaction. concluded that the current the two active ingredients
available evidence from makes them susceptible to
Reference:
assessment of the ICSRs confusion. However, their
Safety Alert, SFDA, 30 April
and data mining might indications and dosage are
2023 (link to the source within
indicate a relationship very different. Butyl-
www.sfda.gov.sa) between prednisone and scopolamine bromide
osteonecrosis. This signal (formerly called
needs further investigation scopolamine butylbromide),
Prednisone to confirm the risk, and because of its chemical
health-care professionals structure as a quaternary
Potential risk of should be aware of this ammonium salt, does not
osteonecrosis potential adverse reaction. cross the blood-brain
barrier. It is indicated for
Saudi Arabia. The SFDA Reference: the treatment of acute
has released a safety signal Safety Alert, SFDA, 21 spasms of the
concerning prednisone and March 2023 (link to the gastrointestinal, biliary and
its potential risk of source within www.sfda.gov.sa)
genitourinary tracts.
osteonecrosis. Scopolamine
Prednisone is a synthetic, hydrobromide, on the other
Scopolamine and hand, has a tertiary amine
anti-inflammatory
structure so it crosses the
glucocorticoid that derives butylscopolamine
from cortisone. blood-brain barrier and is
Risk of medication errors indicated as a
Osteonecrosis is the death
of bone cells due to premedication in
resulting in serious
decreased blood flow. anesthesia to reduce
adverse reactions
excessive salivation and
In 2023, the SFDA has secretions from the
detected a signal of Spain. The Spanish Agency respiratory tract.
prednisone and for Medicines and Health
osteonecrosis and reviewed Products (AEMPS) is The administration by
all the evidence available alerting health-care mistake of scopolamine at
on the association between professionals about the risk doses of butylscopolamine
14
involves an overdose that investigation following a valproic acid (and its

can cause anticholinergic local case-report of fatigue. sodium salt, sodium
adverse reactions at the The SFDA looked into valproate) for the
level of the central nervous VigiBase and found 629 treatment of epilepsy and
system with serious ICSRs and extracted bipolar disorder in women
consequences. international cases with and girls of childbearing
Characteristic signs and completeness score of 1.0 potential contained in the
symptoms of scopolamine (n=19 cases) in order to addendum to the mhGAP
overdose are headache, apply the causality intervention guide
nausea, vomiting, blurred assessment criteria on (mhGAP-IG) and mhGAP
vision, confusion, them. As a result, seven humanitarian intervention
disorientation, memory cases of fatigue were either guide (mhGAP-HIG). The
loss, and hallucinations. probably or possibly linked addenda have been issued
to sitagliptin. Literature in advance of an update to
Health-care professionals evidence found supportive the mhGAP guideline for
are advised to pay detailed in a published article. non-specialist health-care
attention to the possible Additionally, the risk is providers which is due to
confusion between written in reference safety be released later this year,
scopolamine and information of medications and was discussed at the
butylscopolamine, both in from the same class. meeting of the WHO
the prescription and in the Advisory Committee for the
dispensing and The SFDA’s investigation Safety of Medicinal
administration of the concluded that the current products (ACSoMP) on 14
medicinal product. available evidence from December 2022.
assessment of the ICSRs,
Prescription of valproic acid
Reference: class effect and literature
(sodium valproate) for
Security Notes, AEMPS, 17 might support a
women and girls of
April 2023 (link to the source relationship between of
childbearing potential:
within www.aemps.gob.es) sitagliptin and fatigue. This
signal needs further • Valproic acid (sodium
Sitagliptin
investigation to confirm the valproate) should not
risk, and health-care be prescribed because
Potential risk of fatigue
professionals should be of the high risk of birth
aware of this potential defects and
Saudi Arabia. The SFDA developmental
adverse reaction.
has released a safety signal disorders in children
concerning sitagliptin and Reference: exposed to valproic
its potential risk of fatigue. Safety Alert, SFDA, 1 acid (sodium valproate)
March 2023 (link to the in the womb.
Sitagliptin is dipeptidyl • Lamotrigine or
source within
peptidase-4 (DPP-4) levetiracetam should
www.sfda.gov.sa)
inhibitor indicated for the be offered as first line
treatment of patients with monotherapy for both
T2D. generalized onset
seizures and focal
Valproic acid
Fatigue is a term that onset seizures.
refers to a general feeling (sodium valproate) • For women and girls of
of exhaustion or a lack of childbearing potential
energy. Risks of birth defects currently prescribed
and developmental valproic acid (sodium
In 2023, the SFDA detected valproate):
disorders in children
a signal of sitagliptin and • Advice should be
fatigue and reviewed all the provided on use of
evidence available on the WHO. WHO has issued a effective contraception,
association between them. safety statement to alert without interruption,
The SFDA initiated this stakeholders to the revised during the entire
guidance on the use of duration of treatment.
15
Information must be women should consider • A specialist should

provided on risks alternative treatment periodically review
associated with valproic options. Women should whether valproic acid
acid (sodium valproate) be advised to consult (sodium valproate) is
use during pregnancy, their physician as soon the most suitable
pregnancy prevention as they are planning treatment for the
and refer for pregnancy and the person.
contraceptive advice if need to urgently
they are not using consult their physician Reference:
effective contraception. in case of pregnancy. Safety alert, WHO, 2 May
• Individual • Every effort should be 2023 (link to the source within
circumstances should made to switch to www.who.int)
be evaluated in each appropriate alternative
(See also WHO Pharmaceuticals
case when choosing the treatment prior to Newsletter No.1, 2023: Valproate
contraception method conception. If switching and risks in pregnancy and
and involving the is not possible, the potential risks in male patients in
woman in shared woman should receive UK and No.2, 2023: summary of
decision making. further counselling ACSoMP meeting on 14 December
• If a woman is planning regarding the risks of 2022)
to become pregnant, a valproic acid (sodium
person trained in the valproate) for the
management of unborn child to support
epilepsy/bipolar her informed decision-
disorder in pregnant making.
Call for Submissions

We are very keen to make this newsletter even more useful to all our readers. We are calling out
to all national medical products regulatory authorities to send us the latest information on
safety and regulatory actions on medicinal products from their countries.
We also welcome short reports on any recent events or achievements in pharmacovigilance in

your country.
All submissions will be reviewed for relevance and subject to the WHO internal selection,
editorial review, and clearance process.
Please send your submissions or questions to: pvsupport@who.int
16
Features
National Regulatory Authorities welcome to join Vaccine Safety Net
Background information
The Vaccine Safety Net (VSN) is a global network of websites, established by the World Health
Organization, that provide reliable information on vaccine safety.
Due to the success of immunization, some diseases are no longer perceived as a threat. Certain
groups have even questioned the utility of vaccination despite its proven success in controlling
disease. In recent years, several websites providing unbalanced, misleading and alarming vaccine
safety information have been established, which can lead to undue fears, particularly among parents
and patients.
Acknowledging the above-mentioned issues and urged by governments, key non-governmental
organizations and the United Nations Children's Fund (UNICEF), WHO initiated, in 2003, the Vaccine
Safety Net Project (VSN).
A key player in the Project is the Global Advisory Committee on Vaccine Safety (GACVS), established
by WHO in 1999, to respond promptly, efficiently, and with scientific rigor to vaccine safety issues of
potential global importance.
VSN criteria
GACVS developed four categories of criteria for good information practices - regarding credibility,
content, accessibility and design to which digital resources providing information on vaccine safety
should adhere. The WHO Pharmacovigilance (PVG) team uses the criteria to evaluate candidate
websites and to re-evaluate existing VSN member websites. There are 44 formal assessment criteria,
divided into 4 broad categories. Each category is designated as mandatory or desired. The criteria
are grouped as follows:
• credibility (25 mandatory criteria);
• content (quality and quantity) (7 mandatory and 1 desired criteria);
• accessibility (2 mandatory and 4 desired criteria);
• design (2 mandatory and 3 desired criteria).
You can find detailed VSN criteria on the WHO website.
The network is continuously expanding. To date, 104 websites, from 44 countries provide
information in 36 languages.
National Regulatory Authorities (NRAs)’ websites are welcome to apply for VSN membership to
ensure that reliable, understandable, evidence-based information on the safety of vaccines is
available to the public.
If you feel that your site meets the GACVS criteria outlined above, please kindly send a request for a
site evaluation to pvsupport@who.int. The WHO PVG team will then conduct an assessment of your
website and will send you feedback regarding any areas that require clarification or improvements in
order to meet the GACVS criteria as well as a set of recommendations to assist you in meeting these
criteria. Once the identified issues have been addressed to the satisfaction of the evaluators, WHO
will add your website to the list of VSN members.
17

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WHO Pharmaceuticals Newsletter No 3 2023 1693146010

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2023

WHO Vision for Safety of

The aim of the Newsletter is

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This Newsletter is also available at: Features

ISBN 978-92-4-007805-5 (electronic version)

© World Health Organization 2023

Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris.

Safety of Medicinal Products

Antitubercular event may occur with other drugs within the

characterized by vaccination. cases assessed, six were in

upadacitinib (Rinvoq®) , Following the MHRA’s Reference:

cases of haemophagocytic Risk of fixed drug to include “For single use in

Amlodipine causality assessment of the unlikely). Additionally, the

with completeness score of Reticutan®) treatment. associated with

• use caution when least to the joints extensive swelling of

involves an overdose that investigation following a valproic acid (and its

Information must be women should consider • A specialist should

Call for Submissions

We also welcome short reports on any recent events or achievements in pharmacovigilance in

Please send your submissions or questions to: pvsupport@who.int

National Regulatory Authorities welcome to join Vaccine Safety Net

• credibility (25 mandatory criteria);

• content (quality and quantity) (7 mandatory and 1 desired criteria);

• accessibility (2 mandatory and 4 desired criteria);

• design (2 mandatory and 3 desired criteria).

You can find detailed VSN criteria on the WHO website.

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