Safety news - World Health Organization

WHO Drug Information Vol. 32, No. 1, 2018

Safety news

Safety warnings                                  several hours after administration. In some
                                                 patients the onset was after several months
Edoxaban:                                        of treatment.(1)
Interstitial lung disease                           An overview of the risks of teriparatide
J a p a n – The PMDA has informed health         —including hypercalcaemia, a range of
professionals that cases of interstitial         side effects due to dilatation of vessels, and
pneumonia have been observed in patients         osteosarcoma reported in animal toxicity
treated with the anti-clotting agent             studies and leading to suspension of initial
edoxaban (Lixiana®) in Japan. Based on           clinical trials—has been published in the
the PMDA’s investigation the MHLW has            independent drug bulletin of the Japan
recommended updates to the product               Institute of Pharmacovigilance. The authors
information of this medicine. Patients           conclude that the benefit/risk balance is
should be carefully monitored. If signs          negative in the treatment of osteoporosis.(2)
and symptoms such as cough, shortness of         ►► (1) PMDA Summary of investigation
breath, dyspnoea, fever or abnormal chest           results and MHLW Revision of precautions
sound are observed, examinations including          (teriparatide acetate, teriparatide genetical
                                                    recombination), 11 January 2018.
chest X-ray, chest CT scan, and serum
marker test should be done immediately.             (2) Med-Check– The Informed Prescriber
If interstitial lung disease is suspected,          (TIP). December 2017; 3(9): 34-5.
administration of edoxaban should be
discontinued and appropriate measures such       Clarithromycin:
as administration of corticosteroid taken.       Risk of cardiovascular events
►► PMDA Summary of investigation results and     U n i t e d S t a t e s o f A m e r i c a – The FDA has
   MHLW Revision of precautions, 11 January      advised caution in the use of the antibiotic
                                                 clarithromycin in patients with heart disease,
                                                 even for short periods. Clarithromycin is
Teriparatide:                                    associated with a potential increased risk of
Shock and loss of consciousness                  heart problems or death that can occur years
J a p a n – Following reported cases of loss     later. This safety issue was first observed in
of consciousness and acute hypotension           a large clinical trial, and was confirmed in
in patients treated with the osteoporosis        a 10-year follow-up study in patients with
medicine teriparatide in Japan, leading to       coronary heart disease.
cardiac arrest and/or respiratory arrest in         Health care professionals should weigh
some cases, the PMDA has recommended             the benefits and risks of clarithromycin and
that clearer warnings should be added to         consider prescribing other antibiotics in
the product information about the risk of        patients with heart disease. If such patients
seizures, shock and loss of consciousness        are given clarithromycin they should be
associated with the use of teriparatide. These   alerted to the risks and advised to seek
events may occur immediately or up to            medical care immediately if they experience

WHO Drug Information Vol. 32, No. 1, 2018                                             Safety news

any signs and symptoms of a cardiovascular          Iomeprol, iohexol:
problems such as a heart attack or stroke.          Severe skin reactions
The product information has been updated.           J a p a n – Following reports of
►► FDA Drug safety communication, 22 February       acute generalized exanthematous
   2018.                                            pustulosis (AGEP) in patients treated with
                                                    the iodinated contrast media iomeprol
Atezolizumab:                                       and iohexol, the PMDA has recommended
Myocarditis                                         updates to the product information to warn
C a n a d a – The marketing authorization           about this potential adverse effect.
holder, in agreement with Health Canada,            ►► PMDA Summary of investigation results,
has informed health professionals that severe          13 February 2018.
cases of myocarditis have been reported
in patients treated with the anti-cancer            Saccharomyces boulardii probiotics:
medicine atezolizumab (Tecentriq®) in               Do not use in critically ill or
clinical trials. Healthcare professionals should    immunocompromised patients
monitor patients on atezolizumab for signs          E s t o n i a – The marketing authorization
and symptoms of myocarditis. Treatment              holder, in agreement with the regulatory
should be withheld in patients with Grade 2         authority of Estonia, has informed health
myocarditis, and permanently discontinued           professionals that Saccharomyces boulardii-
in patients with Grade 3 or 4 myocarditis.          containing probiotic products should not be
Patients on atezolizumab who develop                used in critically ill or immunocompromised
myocarditis should receive corticosteroids          patients, as they can cause fungaemia in very
and/or additional immunosuppressive agents          rare cases. Also, special care should be taken
as clinically indicated.                            when handling of S. boulardii medicinal
   The Canadian product information has             products in the presence of patients mainly
been updated to include this new safety             with central venous catheters, but also with
information.                                        peripheral catheters, in order to avoid any
►► Health Canada Advisory, 14 February 2018.        contamination by touch and the spread
                                                    of microorganisms by air. The product
Lenvatinib:                                         information has been updated to include
Gallbladder inflammation                            these warnings.(1)
J a p a n – The PMDA has informed health               S. boulardii is a replacement for intestinal
professionals that cases of acute cholecystitis     flora. It is used for adjuvant symptomatic
have been reported in patients treated              treatment of diarrhoea as well as for
with the anti-cancer medicine lenvatinib            prophylaxis and treatment of antibiotic-
mesilate (Lenvima®) in Japan and in other           associated diarrhoea and recurrence of
countries. Two of the cases observed in             Clostridium difficile disease in addition to
Japan had a fatal outcome. A warning has            vancomycin and metronidazole. The update
been added to the product information,              follows a review and recommendation by the
recommending that patient should be                 EMA’s Pharmacovigilance Risk Assessment
monitored and appropriate measures taken            Committee (PRAC).(2)
—such as stopping the medicine—if any               ►► (1) Ravimiamet (Estonian medicines agency).
abnormalities are observed.                            Safety announcement, 13 February 2018.
►► PMDA Summary of investigation results and
   MHLW Revision of precautions, 11 January 2018.      (2) PRAC meeting minutes, September 2017.

Safety news                                                WHO Drug Information Vol. 32, No. 1, 2018

Artemisia annua soft gel capsules:                        of a rare type of salmonella associated
Reports of liver damage                                   with kratom-containing capsules, teas
N e w Z e a l a n d – Medsafe has alerted                 and powders. This underscores the risk
consumers that Artemisia annua extract may                that unapproved products, which are not
pose a risk of harm to the liver. A. annua                subject to manufacturing controls, may be
extract is marketed in New Zealand as a                   contaminated with harmful bacteria.
natural dietary supplement for maintaining                ►► FDA News release, 21 February 2018.
and supporting joint health and mobility.
The warning follows reports of liver toxicity
received by the Agency’s Centre for Adverse               To be withdrawn from the market
Reactions Monitoring (CARM). All the
reports involved patients taking a specific               Hydroxyethyl starch:
product presented as soft gel capsules. Since             Earlier restrictions not sufficient
the chemical composition of the A. annua                  E u r o p e a n U n i o n – The EMA has
extract in that product was not disclosed                 endorsed the recommendation by its
it is not clear if other products containing              Pharmacovigilance Risk Assessment
A. annua extract could have similar effects.              Committee (PRAC) to suspend the
►► Medsafe Alert communication, 15 February               marketing authorizations for hydroxyethyl-
   2018.                                                  starch solutions for infusion across the EU.
                                                          These solutions are used as plasma volume
Mitragyna speciosa (kratom):                              replacement following acute blood loss to
Opioid-like substance to                                  treat hypovolaemia in case cristalloids are
be recalled in the U.S.                                   not sufficient to stabilize the patient.
U n i t e d S t a t e s o f A m e r i c a – The FDA has      Restrictions had been introduced in the
received numerous reports of adverse events               EU in 2013 to reduce the risks of these
associated with the use of food supplement                products for critically ill patients and those
products containing kratom (Mitragyna                     with sepsis and kidney injury. The PRAC has
speciosa), including 44 reported deaths.                  reviewed the results of two drug utilization
Such products are not authorized in the                   studies together with other available data
U.S. The FDA has encouraged companies                     and feedback from stakeholders and
supplying kratom-containing products to                   experts, and has concluded that the earlier
organize a destruction and recall, and to                 restrictions have not been sufficiently
submit data for evaluation of the products                effective.
through the applicable regulatory pathway.                ►► EMA Press release, 12 January 2018.
Kratom is a plant that grows in Thailand,
Malaysia, Indonesia and Papua New Guinea.                 Daclizumab:
The FDA has reviewed data suggesting that                 Cases of inflammatory brain disorders
compounds in kratom share structural                      E u r o p e a n U n i o n – The EMA has
similarities with controlled opioid analgesics            recommended the immediate suspension
and have significant risks of abuse and                   and recall of the multiple sclerosis medicine
adverse effects.                                          daclizumab (Zinbryta®). This follows
   In addition the FDA and the U.S. Centers               12 cases of serious inflammatory brain
for Disease Control and Prevention (CDC)                  disorders worldwide, including encephalitis
are monitoring a nationwide outbreak                      and meningoencephalitis. Three of the

WHO Drug Information Vol. 32, No. 1, 2018                                                    Safety news

cases were fatal. The company that markets           Known risks
the medicine has voluntarily requested the
withdrawal of the marketing authorization            Obeticholic acid:
and has informed EMA of its decision to              Liver decompensation or failure in
stop ongoing clinical studies.                       incorrectly dosed patients
   No new patients should start treatment            U n i t e d S t a t e s o f A m e r i c a – In an update
with daclizumab. Healthcare professionals            to its communication of September
should immediately contact patients on               2017, the FDA has added its most
daclizumab and should stop their treatment           prominent “Boxed Warning” and other
and consider alternatives. Patients stopping         updates to the product information for
treatment must be followed up for at least           obeticholic acid (Ocaliva®) to clarify the
6 months.(1)                                         recommendations for screening, dosing and
   In November 2017 the EMA had tightened            monitoring based on the patient’s Child-
its restrictions on the use of daclizumab            Pugh score of liver impairment and any
introduced in July 2017 because of the risk of       prior decompensation event. Obeticholic
serious liver damage.(2) Available evidence          acid is used for the treatment of primary
also indicates that daclizumab could be              biliary cholangitis (PBC), a rare chronic liver
linked to other immune-mediated disorders,           disease. It has been incorrectly dosed daily
such as blood dyscrasias, thyroiditis or             instead of weekly in patients with moderate
glomerulonephritis. An urgent review is              to severe PBC, increasing the risk of serious
under way (see page 26).                             liver injury. The FDA is also requiring a
►► (1) EMA Press release, 7 March 2017.              medication guide for patients.
   (2) WHO Drug Information, Issues 3 and 4 of       ►► FDA Drug safety communication, 2 February
   2017.                                                2018.

Flupirtine:                                          Loperamide:
Serious liver problems                               Packaging changes for safe use
E u r o p e a n U n i o n – The EMA’s                U n i t e d S t a t e s o f A m e r i c a – Despite
Pharmacovigilance Risk Assessment                    earlier warnings, the FDA continues
Committee (PRAC) has recommended that                to receive reports about serious heart
the marketing authorization for the analgesic        problems occurring with excessive doses
flupirtine be withdrawn. Following an earlier        of the antidiarrhoeal medicine loperamide.
review, restrictions had been introduced             Most cases are linked to abuse or misuse
in 2013 to limit the use of flupirtine to no         of loperamide, for example to increase
more than two weeks in patients with acute           its euphoric effects by combining it with
pain who could not use other analgesics,             other drugs, or to treat symptoms of opioid
subject to weekly liver function tests. These        withdrawal. The maximum daily dose of
recommendations have not been sufficiently           loperamide for adults approved in the U.S.
followed in clinical practice, and the PRAC          is 8 mg per day for over-the-counter use and
could not identify any further measures              16 mg per day for prescription use. The FDA
that would adequately reduce the risk of             is working with manufacturers to use blister
liver problems associated with the use of            packs or other single dose packaging and to
flupirtine.                                          limit the number of doses in a package.
►► EMA. Article 31 referral: Flupirtine-containing   ►► FDA Drug Safety Communication, 30 January
   medicinal products. 9 February 2018.                 2018.

Safety news                                         WHO Drug Information Vol. 32, No. 1, 2018

Retinoid-containing medicines:                     clinical study, which has found that an
Updated measures to avoid use in                   increased blood concentration of efavirenz
pregnancy, neuropsychiatric disorders              was associated with prolongation of the
E u r o p e a n U n i o n – The EMA’s              QT interval. The product information for
Pharmacovigilance Risk Assessment                  efavirenz has been updated.
Committee (PRAC) has recommended                      The product information approved in the
updated measures to avoid the use of               EU and the U.S. states that QTc prolongation
retinoids in pregnancy as they can have            has been observed with efavirenz, and that
harmful effects on the unborn child,               alternatives to efavirenz should be considered
and to warn about the possible risk of             in patients taking other medicine with a
neuropsychiatric disorders.                        known risk of Torsade de Pointes, and in
   The recommended pregnancy prevention            patients at increased risk of Torsade de
measures depend on the type of retinoid.           Pointes.
Oral medicines containing acitretin,               ►► PMDA Summary of investigation results,
alitretinoin or isotretinoin must be used in          13 February 2018.
line with an updated pregnancy prevention
programme, and the marketing authorization         Ipilimumab:
holders will conduct a study and a survey to       Myositis
assess the effectiveness of the new measures.      J a p a n – The PMDA has recommended to
For oral bexarotene and tretinoin, which           include a warning about the risk of muscle
are used under strict medical supervision to       inflammation (myositis) in the product
treat certain cancers, the current pregnancy       information for the skin cancer medicine
prevention measures are considered                 ipilimumab (Yervoy®) in order to align it
appropriate. For topical retinoids the PRAC        with the product information approved in
adopted a precautionary approach: Although         the EU and the U.S.
their absorption is very low it could be           ►► PMDA Summary of investigation results,
increased by excessive use or skin lesions, and       11 January 2018.
their use is not recommended in pregnancy
or in women planning to have a baby.
   A warning about the risk of                     Nintedanib:
neuropsychiatric disorders, such as                Liver injury
depression, anxiety and mood changes, will         N e w Z e a l a n d , C a n a d a – The marketing
be added to the prescribing information            authorization holders, in agreement
of oral retinoids. These events may be due         with Medsafe, have informed health
to the medicine as well as the nature of the       professionals that cases of drug-induced
disease itself. No additional warning was          liver injury (DILI), including one fatal case,
considered necessary for topical retinoids.        have been reported in patients treated with
►► EMA. Article 31 referral: Retinoid-containing   nintedanib (Ofev®) in the post-marketing
   medicinal products. 9 February 2018.            setting.(1, 2) Most of these events occurred
                                                   in the first three months of treatment.
Efavirenz:                                            Nintedanib is indicated for the treatment
QT interval prolongation                           of idiopathic pulmonary fibrosis. The
J a p a n – The PMDA has informed health           product information is being updated to
professionals about the outcomes of a              reflect the observed increased severity of

WHO Drug Information Vol. 32, No. 1, 2018                                                       Safety news

DILI and to provide further guidance on the          Opioid cough and cold medicines:
monitoring schedule of hepatic laboratory            Labelling changes
testing. Similar updates have been included          U n i t e d S t a t e s o f A m e r i c a – The FDA
in the product information approved in the           is requiring updates to the product
U.S., the EU and Japan.                              information for prescription cough and
►► (1) Dear Healthcare Professional Letter, posted   cold medicines containing codeine or
   on Medsafe website on 5 December 2017.            hydrocodone to limit the use of these
   (2) Health Canada Advisory, 11 January 2018.      products to adults 18 years and older and
                                                     to provide information about the risks of
Valproate:                                           misuse, abuse, addiction, overdose, death,
Updated measures to avoid use in                     and slowed or difficult breathing. The
pregnancy                                            updates are based on the outcome of an FDA
E u r o p e a n U n i o n – The EMA’s                review communicated in April 2017 and the
Pharmacovigilance Risk Assessment                    recommendations of an expert panel.
Committee (PRAC) has recommended                     ►► FDA Drug safety communication, 11 January
additional measures to avoid the use                    2018.
of valproate in pregnant women. The
medicine should only be used in women of             Idarucizumab:
childbearing age if the conditions of a new          Second dose may be needed
pregnancy prevention programme are met.              N e w Z e a l a n d – Following the outcome of a
New visual warnings, a patient reminder              full cohort study, Medsafe has alerted health
card and updated educational materials               professionals that some patients may need a
will also be introduced to warn about the            second dose of idarucizumab (Praxbind®) to
risk of malformations and developmental              reverse the effects of dabigatran (Pradaxa®).
problems in infants exposed to valproate             The timing of the second dose depends on
in the womb. The PRAC recognized that                the timing of the recurrence of bleeding
for some pregnant women with epilepsy it             and the measurement of the elevated
may not be possible to stop valproate, and           coagulation tests. More information
determined that they can continue treatment          is shown in the product’s data sheet.
with appropriate specialist care.                    Idarucizumab is indicated in patients treated
   Valproate is used in the EU to treat              with dabigatran when rapid reversal of
epilepsy and bipolar disorder. In some               dabigatran’s anticoagulant effect is required
EU member states it is also authorized to            for emergency surgery/urgent procedures or
prevent migraine headaches. The measures             in life-threatening or uncontrolled bleeding.
taken following an earlier review have               ►► Medsafe Prescriber Update. March 2018.
not been sufficient to mitigate the risks of            39(1): 2.
valproate in pregnancy. The strengthened
warnings were adopted following a second             Gadolinium-based contrast agents
review with wide consultation, including a           U n i t e d S t a t e s o f A m e r i c a – Based on results
public hearing.                                      of an additional review the FDA is requiring
►► EMA Press release, 9 February 2018.               a new class warning for gadolinium-based
                                                     contrast agents, alerting health professionals
                                                     and patients to the risks caused by long-
                                                     term gadolinium retention in the body. A

Safety news                                              WHO Drug Information Vol. 32, No. 1, 2018

patient medication guide will be introduced,            recommended only in individuals with a past
and manufacturers have been requested to                dengue infection, as documented either by a
conduct further human and animal safety                 diagnostic test or by a documented medical
studies.(1)                                             history of past dengue illness. This follows a
  In the EU a final decision on restrictions            review of preliminary results provided by the
for linear gadolinium-based contrast agents             manufacturer. Further WHO guidance on the
has been published following the conclusion             matter is expected no earlier than April 2018.
of the EMA’s regulatory review in July 2017.               In 2016 the WHO Strategic Advisory
The restrictions recommended earlier were               Group of Experts on Immunization (SAGE)
maintained.(2)                                          had recommended the vaccine for use in
►► (1) FDA Drug safety communication,                   endemic areas with a seroprevalence over
   19 December 2017.                                    70%.(2) A theoretical elevated risk of dengue
     (2) EMA’s final opinion confirms restrictions on   in vaccinated seronegative individuals was
     use of linear gadolinium agents in body scans.     noted, prompting additional research by the
     23 November 2017.
                                                        manufacturer. Preliminary findings suggest
                                                        that the subset of trial participants who had
Interim recommendations                                 not been exposed to dengue virus prior
                                                        to vaccination had a higher risk of more
Ulipristal:                                             severe dengue and hospitalizations than
No new treatment courses to be started                  unvaccinated participants. This increased
E u r o p e a n U n i o n – The EMA’s                   risk was seen after an initial protective period
Pharmacovigilance Risk Assessment                       and persisted over the observation period of
Committee (PRAC) has recommended that,                  up to 66 months after primary vaccination.
pending the outcome of its ongoing review                  Dengvaxia® has been introduced in
of ulipristal (Esmya®), no patients should              subnational programmes in the Philippines
start new or repeat treatment courses with              and Brazil targeting about one million
ulipristal for uterine fibroids. In women               individuals in total. It is otherwise available
currently on treatment, liver function should           on the private market in countries where
be monitored at least once a month. If liver            there is a marketing authorization. The
enzyme levels are more than twice the upper             manufacturer has proposed a labelling change
limit of normal, treatment should be stopped            to the national regulatory authorities in the
and the patient closely monitored, and                  countries where Dengvaxia® is licensed.
the liver function tests should be repeated             ►► (1) WHO. Updated Questions and Answers
2–4 weeks after stopping treatment.                        related to the dengue vaccine Dengvaxia® and
   Ulipristal is under EMA review following                its use. 22 December 2017.
reports of serious liver injury, including liver           (2) WHO. Dengue vaccine: WHO. position
                                                           paper – July 2016. Weekly Epidemiological
failure leading to transplantation.                        Record, No. 30, 29 July 2016.
►► EMA Press release, 9 February 2018.

Recombinant live-attenuated                             Radium-223 dichloride:
dengue vaccine                                          Must not be used with abiraterone and
WHO has published its interim position on               prednisone / prednisolone
the use of the recombinant, live-attenuated             E u r o p e a n U n i o n – The EMA has
dengue vaccine Dengvaxia®.(1) Vaccination is            recommended contraindicating the

WHO Drug Information Vol. 32, No. 1, 2018                                                Safety news

use of the prostate cancer medicine             mycophenolate-containing medicines to
radium-223 dichloride (Xofigo®) with            prevent rejection of transplanted organs.
abiraterone (Zytiga®) and prednisone /          The previous recommendation that male
prednisolone due to an increased risk of        patients should use condoms in addition to
death and fractures. Healthcare professionals   their female partners using a highly effective
should stop this combination in men             method of contraception has been removed.
currently treated with it and review the        Either the male patient or his female partner
treatment for these patients. The safety        should use reliable contraception during
and efficacy of radium-223 in combination       mycophenolate treatment and for at least
with second-generation androgen receptor        90 days after stopping treatment. Female
antagonists, such as enzalutamide (Xtandi®),    patients who can become pregnant must use
have not been established.                      at least one reliable form of contraception
   The contraindication was introduced          before, during and for 6 weeks after stopping
by the EMA’s Pharmacovigilance Risk             treatment. Two forms of contraception are
Assessment Committee (PRAC) as                  preferred but no longer mandatory.
a temporary measure in view of the              ►► EMA Press release, 15 December 2017.
seriousness of the events reported in a
clinical trial. An in-depth review of the       Combination treatments for asthma:
benefits and risks of radium-223 is ongoing.    Warning removed
►► EMA Press release, 9 March 2018.             U n i t e d S t a t e s o f A m e r i c a – An FDA review
                                                of four large clinical safety trials has shown
                                                that treating asthma with long-acting beta
Warnings softened                               agonists (LABAs, e.g. salmeterol, vilanterol,
                                                formoterol) in combination with inhaled
Direct-acting antivirals:                       corticosteroids (ICS, e.g. fluticasone,
Effect on blood glucose not confirmed           mometasone, budesonide) does not result
N e w Z e a l a n d – Medsafe has provided an   in significantly more serious asthma-related
update on its monitoring communication          side effects than treatment with an ICS
issued in March 2017, which highlighted a       alone. The Boxed Warning about asthma-
possible blood glucose-lowering effect of       related death has been removed from the
the direct acting antivirals Viekira Pak® and   product information of medicines that
Viekira Pak-RBV® when used in patients          contain both an ICS and LABA.
with type 2 diabetes. No further cases were        Using LABAs alone to treat asthma
reported in New Zealand, and the effect         without an ICS to treat lung inflammation is
could not be confirmed.                         associated with an increased risk of asthma-
►► Medsafe monitoring communication,            related death. The warnings stating this will
   31 January 2018.                             remain in the product information of the
                                                relevant medicines.
Mycophenolate:                                  ►► FDA Drug safety communication, 20 December
Updated recommendations for                        2017.
E u r o p e a n U n i o n – The EMA has
updated its recommendations for
contraception in men and women taking

Safety news                                          WHO Drug Information Vol. 32, No. 1, 2018

Reviews started

Medicine        Use            Concerns                                       Reference
Daclizumab      Treatment      Cases of serious inflammatory brain            ►► EMA Press release,
(urgent         of multiple    disorders, including 3 fatal cases. Linked        7 March 2017.
review)         sclerosis      to potentially fatal immune-mediated
(Zinbryta®)                    liver injury in a 2017 review. Possible risk
                               of other immune-mediated disorders.
                               To be recalled (see page 20).
Dabigatran      Anti­          Possible risk of gout or gout-like             ►► Medsafe Monitoring
(Pradaxa®)      thrombotic     symptoms (one case report in New                  Communication,
                                                                                 31 January 2018.
                agent          Zealand, and reports in WHO’s VigiBase)

Compliance with good practices                      integrity and other GMP failures during an
                                                    inspection of the company’s site located at
Svizera Labs Pvt Ltd:                               No. 10, Longhai Avenue, in Qinhuangdao,
Notice of Concern withdrawn                         Hebei Province, China.
Following corrective actions taken by                  A WHO inspection of the site in
Svizera Labs Pvt Ltd and the clarifications         December 2017 revealed that the company
provided being considered acceptable, and           had only partly addressed the FDA’s
considering the outcome of an additional            observations. A follow-up WHO inspection
on-site inspection on 25–29 June 2017, the          is planned for October 2018 to verify that
WHO Prequalification Team - Medicines has           the company has implemented its corrective
withdrawn the Notice of Concern (NOC)               and preventive action (CAPA) plan as
for Svizera Labs Pvt Ltd Mumbai, India. The         submitted to WHO.
NOC had been issued on 2 September 2015                Qinhuangdao Zizhu manufactures
after an inspection of the company’s site at        three prequalified active pharmaceutical
Turbhe, Navi Mumbai, India.                         ingredients (APIs) – levonorgestrel,
►► WHO Prequalification News, 1 February 2018.      mifepristone and ethinylestradiol – and
                                                    supplies levonorgestrel for two prequalified
                                                    finished products. To date WHO has not
Qinhuangdao Zizhu Pharmaceutical                    received any complaints relating to the
Co Ltd:                                             quality of prequalified levonorgestrel
Corrective action under way                         tablets. WHO is working closely with the
G e n e v a – The WHO Prequalification              manufacturers of prequalified levonorgestrel
Team–Medicines has provided an update               tablets to identify alternative API sources,
on the level of compliance with good                and has requested them to take additional
manufacturing practices (GMP) by                    measures to ensure that all API batches
Qinhuangdao Zizhu Pharmaceutical Co Ltd.            from Qinhuangdao Zizhu meet their
On 8 March 2017 the U.S. FDA had placed             specifications.
an import alert on the company, following           ►► WHO Prequalification Team–Medicines.
observations of serious breaches of data               Position paper, 13 February 2018.

WHO Drug Information Vol. 32, No. 1, 2018                                                   Safety news

Falsified medicines

  Falsified cefixime products circulating in the Democratic Republic of
  the Congo
  The WHO Medical Product Alert No. 1/2018 relates to two versions of falsified cefixime
  products that have been identified in the eastern part of the Democratic Republic of the
  Congo (South Kivu) and were reported to WHO in late 2017. Cefixime is used to treat a
  range of bacterial infections and is listed as a WHO Essential Medicine.
    The products were sent for quality assurance laboratory testing and the results shared
  with WHO (see table). Both products are presented in standard white plastic containers of
  100 tablets. The tablets of both products are round, small, and without any embossing. The
  labels of both products have spelling mistakes. Product details are shown below.
                                                  Product 1                        Product 2
  Product name:                                   CEFIXIME                   Cifixime Trihydrate
  Batch number:                                     4734                           Et078776
  Expiry date:                                     12/2019                         DEC 2018
  Manufacturing date:                              01/2016                         Nov 2014
  Stated active pharmaceutical ingredient:         Cefixime                   Cifixime Trihydrate
  Manufacturer name stated on the label:       MERCK & CO. INC.              HOLDEN MEDICAL
                                                                            THE NETHERLANDS
                                             2.5% of declared content
  Assay result:                                                              No cefixime detected
                                                   of cefixime
  Both stated manufacturers have confirmed they did not manufacture either of these
  products. No adverse reactions to either product have been reported to WHO at this stage.
  ►► WHO Medical Product Alert No. 1/2018 (includes photographs).

  Falsified “Augmentin” circulating in Cameroon
  The WHO Medical Product Alert No. 2/2018 relates to a falsified version of
  Augmentin (amoxicillin + clavulanate potassium) identified in Cameroon. WHO was
  informed in early 2018 by an NGO that this product was available in a street market
  in Douala. The packaging of the falsified product appears to be a close imitation of
  the genuine product manufactured by GlaxoSmithKline (GSK). The writing on the
  packaging has some spelling errors. GSK has confirmed that they did not manufacture
  this product.
    Samples were sent for quality assurance testing and the results shared with WHO. The
  laboratory analysis did not identify any of the expected active ingredients.
    The source of the falsified product has not yet been identified. No adverse reactions
  have been reported to WHO at this stage.
  ►► WHO Medical Product Alert No. 2/2018 (includes photographs).

     Report suspected falsified products to the competent national regulatory authority and/or
     pharmacovigilance centre, and notify WHO at

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