NEW RECOMMENDATIONS ON THE USE OF DOMPERIDONE Key

Published by the Health Products Regulation Group, HSA and the HSA Product Vigilance Advisory Committee

ISSN: 0219 - 2152 May 2017 Vol.19 No.1

NEW RECOMMENDATIONS ON THE

USE OF DOMPERIDONE

Key Points

The use of domperidone for treatment of dyspepsia,

nausea and vomiting is associated with a potential risk

of serious cardiovascular events

Precautionary measures to mitigate the risk include

contraindicating the use in patients with high risk of

cardiotoxicity and use of lowest possible dose for the

shortest possible duration

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Contents

 New recommendations on the use 1-2

of domperidone

 Risk of hepatitis B virus reactivation 2-3

with direct-acting antivirals

 Analysis of adverse event (AE) reports 3-5

for the year 2016

 Highlights of local safety signals 6-7

for the year 2016

 List of Dear Healthcare Professional Letters 7

 Risk of falsely elevated oestradiol levels due 8

to cross-reactivity of fulvestrant with oestradiol

immunoassays

Background

Domperidone is a pro-kinetic and anti-emetic drug registered in

Singapore for the treatment of dyspepsia, as well as nausea and

vomiting due to various conditions.

HSA has recently completed a re-assessment to determine

if additional measures are necessary to further mitigate the

cardiovascular (CV) risk associated with the use of domperidone.

This follows an earlier assessment in 2012, which resulted in the

strengthening of the package inserts (PIs) of domperidone to

include warnings of increased risk of ventricular arrhythmia (VA)

and sudden cardiac death (SCD), especially in patients older than

60 years old or those taking oral doses of more than 30 mg daily.

International regulatory actions

Several other drug regulatory agencies have also carried out

assessments on domperidone and issued recommendations on

its use. The European Medicines Agency (EMA)

removed the

indication for dyspepsia due to insufcient long-term efcacy data

supporting this indication, and restricted the maximum oral daily

dose to 30 mg for its use to treat nausea and vomiting.

Health

Canada retained the use in gastritis and nausea and vomiting

at a maximum daily dose of 30 mg as well as strengthened the

safety warnings in the PI to highlight the risk of CV events.

HSA’s beneﬁt-risk re-assessment

Domperidone is a well-established pro-kinetic drug used in

the treatment of nausea, vomiting and dyspepsia. HSA has

reassessed its risk-benet following a review of ve epidemiology

studies, which suggested an association with increased risk of

VA and SCD.

3-4

The identied cardiotoxicity risk factors included advanced age

(>60 years old), underlying CV conditions, high domperidone

dose (>30 mg/day) and concomitant use with QT prolongation

drugs and CYP3A4 inhibitors. Local reports of cardiotoxicity

associated with domperidone use were found to be isolated.

From 2006 to 2016, HSA received two cases of QT prolongation

associated with domperidone. Considering the long history of use

in local clinical setting and the relatively low incidence of locally

reported cardiac-related adverse events, HSA, in consultation

with its Medicines Advisory Committee, concluded that the

benet-risk prole of domperidone remains favourable when

used appropriately for the above indications. Additional measures

were recommended to mitigate the risk of cardiotoxicity, which

included restricting its use in high risk patients and strengthening

the CV warnings in the PI.

Adverse Drug Reaction News • May 2017 • Vol.19 • No.1

References

1. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/

referrals/Domperidone-containing_medicines/human_referral_prac_000021.

jsp&mid=WC0b01ac05805c516f

2. http://www.hc-sc.gc.ca/dhp-mps/medeff/reviews-examens/domperidone-eng.php

3. Drug Saf. 2010; 33: 1003-1014.

4. Pharmacoepidemiology and Drug Safety 2010; 19: 881-888.

Key Points

There have been overseas reports of hepatitis B virus

(HBV) reactivation in patients who received treatment

with direct-acting antivirals (DAAs) for hepatitis C virus

(HCV) infection

Healthcare professionals are encouraged to be vigilant for

HBV reactivation in patients who have a past or current

HBV infection, and who are prescribed DAA-containing

products for the treatment of HCV infection

Overseas cases of hepatitis B virus (HBV) reactivation have been

reported in patients who were treated with direct-acting antivirals

(DAAs) for hepatitis C virus (HCV) infection. In some cases, the

HBV reactivation had led to serious outcomes such as hepatic

failure and death. This risk has been observed with the use of

DAA regimens that are interferon-free.

DAAs are a class of drugs used for the treatment of HCV

infection. They inhibit viral replication, thus reducing the amount

of HCV in the body. DAAs not requiring use in combination

with interferon are registered in Singapore either as single-

ingredient or combination products. They include asunaprevir

(Sunvepra

, Bristol-Myers Squibb (Singapore) Pte Ltd),

daclatasvir (Daklinza

, Bristol-Myers Squibb (Singapore) Pte

Ltd), sofosbuvir (Sovaldi®, Gilead Sciences Singapore Pte Ltd),

simeprevir (Olysio®, Johnson & Johnson Pte Ltd), sofosbuvir/

ledipasvir (Harvoni®, Gilead Sciences Singapore Pte Ltd), and

dasabuvir/ombitasvir/paritaprevir/ritonavir (Viekira Pak

, Abbvie

Pte Ltd).

International regulatory actions

a) European Medicines Agency (EMA)

In March 2016, the EMA’s Pharmacovigilance Risk Assessment

Committee (PRAC) initiated a review to assess the extent of HBV

reactivation in patients treated with DAAs for HCV infection. The

review was triggered by reports of HBV reactivation in patients

co-infected with HBV and HCV, and who were receiving treatment

with DAAs for HCV infection. Approximately 30 cases of HBV

reactivation were identied by the PRAC during its review. As co-

infection with HCV is known to suppress HBV replication, it was

suggested that reactivation of HBV could be a consequence of

the rapid treatment-induced reduction in HCV and the DAAs’ lack

of activity against HBV.

The PRAC concluded its review in December 2016, and

recommended for all patients to be screened for HBV before

starting treatment with DAAs for HCV infection. It also

recommended that patients co-infected with HBV and HCV

should be monitored and managed according to current clinical

guidelines.

b) US Food & Drug Administration (FDA)

The US FDA also conducted a review on this safety issue, and

issued a safety communication in October 2016 to warn about the

risk of HBV reactivation in patients co-infected with HCV, while

RISK OF HEPATITIS B VIRUS

REACTIVATION WITH DIRECT-

ACTING ANTIVIRALS

HSA’s advisory

Healthcare professionals are advised of the following, when

considering the use of domperidone:

• Domperidone is contraindicated in patients with existing

prolongation of cardiac conduction intervals, particularly

QTc, patients with signicant electrolyte disturbances or

underlying cardiac disease and when co-administrated with

QT-prolonging medicines or potent CYP3A4 inhibitors.

• An increased risk of cardiotoxicity was observed in patients

older than 60 years.

• Domperidone should be used at the lowest effective dose for

the shortest possible duration.

• In adults and children aged ≥ 12 years old weighing ≥ 35 kg,

the recommended maximum oral daily dose is 30 mg, given

in doses of 10 mg up to three times daily. Taking into account

the pharmacokinetic studies and bioavailability of rectal

suppositories, the recommended rectal suppository dose is

30 mg twice daily.

• In children aged < 12 years old and those aged ≥ 12 years

old weighing < 35 kg, the recommended dose is 0.25 mg/

kg orally up to three times daily. For rectal administration,

these patients may also be given 0.75 mg/kg twice daily as

suppositories.

HSA is working with the product registrants to update the local

PIs of products containing domperidone. These include new

recommendations on the dosing regimen, treatment duration and

relevant safety information and contraindications.

Healthcare professionals are encouraged to take into

consideration the above recommendations when prescribing

domperidone. They are also encouraged to report any suspected

serious adverse reactions related to domperidone to the Vigilance

and Compliance Branch of HSA.

Liver

Hepatitis virus

Adverse Drug Reaction News • May 2017 • Vol.19 • No.1

References

1. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/

news/2016/12/news_detail_002669.jsp&mid=WC0b01ac058004d5c1

2. http://www.fda.gov/Drugs/DrugSafety/ucm522932.

htm?source=govdelivery&utm_medium=email&utm_source=govdelivery

3. http://www.medsafe.govt.nz/profs/adverse/Minutes167.htm#3.2.4

4. https://www.tga.gov.au/alert/direct-acting-antiviral-medicines

5. http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2016/61274a-eng.php

receiving treatment with DAAs for HCV infection. FDA’s review

of the FDA Adverse Event Reporting System (FAERS) database

and the medical literature for cases reported or published between

22 November 2013 and 18 July 2016 had identied 24 cases

of HBV reactivation in patients receiving DAAs for the treatment

of HCV. The cases of HBV reactivation had generally occurred

within four to eight weeks of starting HCV treatment, and were

heterogeneous in terms of the HCV genotype and status of

baseline HBV disease. Of the 24 cases with HBV reactivation,

two had a fatal outcome, while one patient had required a liver

transplant.

The US FDA has since recommended for the package inserts

(PIs) of DAAs to be updated with warnings about the risk of

HBV reactivation. Healthcare professionals were also advised

to screen patients for evidence of current or prior HBV infection

before starting treatment with DAAs, and to monitor patients for

hepatitis are or HBV reactivation during DAA treatment and

post-treatment follow-up.

c) Other international regulatory agencies

3-5

Besides the EMA and US FDA, several other international

regulatory agencies had similarly conducted safety reviews to

assess the risk of HBV reactivation associated with the use of

DAAs for the treatment of HCV infection. In September 2016, the

New Zealand Medicines Adverse Reactions Committee (MARC)

concluded from its review that there was insufcient evidence

to conrm a causal association. However, considering that HBV

reactivation could lead to potentially life-threatening events,

the MARC recommended that the risk of HBV reactivation and

the need for screening and monitoring for HBV in patients who

are prescribed DAAs be updated in the PIs of DAA-containing

products.

In December 2016, both the Australian Therapeutic Goods

Administration (TGA) and Health Canada concluded from their

safety reviews that there is a potential risk of HBV reactivation

in patients co-infected with HBV and HCV who were receiving

treatment with DAAs for HCV infection. Consequentially, both

agencies have also requested for additional safety information

regarding the risk for HBV reactivation to be updated to the PIs of

DAA-containing products.

Local situation and HSA’s advisory

To date, HSA has not received any local adverse reaction

report of HBV reactivation in patients receiving treatment with

DAAs for HCV infection. The Singapore PIs for DAA-containing

products that are approved for the treatment of HCV infection in

interferon-free regimens are in the process of being updated to

include safety information regarding the risk of HBV reactivation.

Healthcare professionals are encouraged to be vigilant for HBV

reactivation in patients who have a past or current HBV infection,

and who have been prescribed DAA-containing products for the

treatment of HCV infection.

Key Points

In 2016, NSAIDs and antibiotics were the two highest

reported pharmacotherapeutic groups of western drugs

suspected to cause AEs. The two major classes of AEs

were skin-related disorders and those affecting the body

as a whole

The most commonly reported vaccine AE in children

under 12 years was seizure (febrile and afebrile) with the

measles, mumps and rubella (MMR), MMR and varicella,

varicella, 5-in-1 and pneumococcal conjugate vaccines

No reports of vaccine-associated anaphylaxis were

received in the paediatric population, consistent with the

trend in the last preceding seven years

Healthcare professionals are encouraged to stay vigilant

for AEs from adulterated complementary health products

as the average number of detected cases has been 15

per year in the past ve years

This review provides an analysis of the adverse events (AEs)

associated with health products (namely western drugs, vaccines

and complementary health products) that were reported to HSA

in 2016.

Report analysis for 2016

(a) Volume of reports

In 2016, HSA reviewed 21,637 valid

local AE reports suspected

to be associated with health products, an increase of 4.9% over

preceding year. The breakdown of the number of valid reports

captured in the national AE database for the past 10 years based

on the date of receipt is illustrated in Figure 1.

ANALYSIS OF ADVERSE EVENT

(AE) REPORTS FOR YEAR 2016

Figure 1. Number of valid reports captured in the AE database from year

2007 to 2016 based on date of receipt

30,000

2007 2008 2009 2010 2011 2012 2013 2014 2015 2016

25,000

20,000

15,000

10,000

5,000

Number of AE Reports Captured

Year

+ Reports lacking important details such as names of suspected

drugs and AE descriptions were regarded as invalid reports and

were not captured into the national AE database as they could not

be assessed for causality.

Adverse Drug Reaction News • May 2017 • Vol.19 • No.1

(e) Adverse events

The top System Organ Classes (SOC*) reported were skin-

related disorders, followed by those affecting the body as a

whole and respiratory system as shown in Table 1, a consistent

trend observed in the past 5 years.

* The System Organ Class refers to the adverse reaction terminology developed

by the World Health Organisation (WHO). (N.B: More than one AE term may be

described in an AE report)

(f) Serious AEs of interest

The drugs suspected to cause serious skin, body as a whole,

renal and hepatic adverse reactions are listed in Table 2.

Vaccine adverse event (VAE) reports

There were 315 AE reports suspected to be associated with

vaccines, of which 273 reports (86.7%) involved children aged

12 years and below, which corresponded to the age group of

vaccinees under the National Childhood Immunisation Schedule.

Of these, 87.5% of the reports (n=239) were captured by KK

Women’s and Children’s Hospital (KKH) active surveillance

sentinel site, which screens all paediatric hospital admissions for

possible relationship to vaccination.

The most commonly reported AE in children aged 12 years

and below was seizures (febrile and afebrile seizures) with

the measles, mumps and rubella (MMR), MMR and varicella,

varicella, 5-in-1** and pneumococcal conjugate vaccines. Other

more commonly reported AEs included rash, fever, Kawasaki

disease and thrombocytopenia involving a variety of vaccines,

injection-site reactions with 5-in-1 and Bacillus Calmette-Guérin

(BCG) vaccines, lymphadenitis with the BCG vaccine and

gastrointestinal events with the rotavirus vaccine.

Based on yearly trend analysis, there were more reports of febrile

seizures with the 5-in-1 vaccine and aseptic or viral meningitis

with the hepatitis B vaccine received in 2016. All patients

recovered without sequelae. Overall, the number of AE reports

received remained consistent with the expected frequencies of

AE occurrence listed in the package inserts of the vaccines or in

literature.

Figure 2. Top 20 drugs (by active ingredients) suspected of causing AEs

lohexol

Amlodipine

Enalapril

Atorvastatin

Lisinopril

Simvastatin

0 1 2 3 4 5 6 7 8 9 10

Tramadol

Erythromycin

Etoricoxib

Mefenamic Acid

Aspirin

Naproxen

Diclofenac

Ibuprofen

Clarithromycin

Ciprooxacin

Cotrimoxazole

Amoxicillin

Coamoxiclav

Paracetamol

Contrast

Agent

Cardiac

therapy

agents

Analgesics,

Antipyretics

Antibiotics

NSAIDS

1.7%

8.5%

9.0%

20.1%

21.1%

% of total no. of reports

Pharmacotherapeutic Group

Table 1. Top AEs by System Organ Class*

Ranking System Organ Class

No. of

reports

% of

reports

1 Skin And Appendages Disorders

e.g., angioedema, rash, urticaria

11,949 48.6

2 Body As A Whole - General Disorders

e.g., anaphylactic reaction, fever, oedema,

pain

4,399 17.9

3 Respiratory System Disorders

e.g., coughing, shortness of breath,

wheezing

1,473 6.0

4 Central & Peripheral Nervous System

Disorders

e.g., convulsions, giddiness, headache,

oculogyric crisis

1,292 5.3

5 Gastro-Intestinal System Disorders

e.g., abdominal pain, diarrhoea, vomiting

1,289 5.2

6 Urinary System Disorders

e.g., abnormal renal function, interstitial

nephritis, urinary retention

826 3.4

7 Vascular Disorders

e.g., ushing, stroke, vasculitis

412 1.7

8 Musculo-Skeletal System Disorders

e.g., arthralgia, myalgia, rhabdomyolysis

377 1.5

9 Heart Rate And Rhythm Disorders

e.g., bradycardia, chest pain, palpitation

321 1.3

10 Psychiatric Disorders

e.g., agitation, confusion, hallucination

220 0.9

** 5-in-1 refers to Diphtheria, Pertussis, Tetanus, Inactivated Polio and

Haemophilus inuenza type B vaccine

(b) Source and types of reports

As in previous years, the majority of the reports analysed were

associated with pharmaceutical drugs (96.6%). The other reports

were associated with vaccines (1.6%), biologics (1.1%), and

complementary health products (CHPs) (0.7%), which included

Chinese Proprietary Medicines (CPM), health supplements,

traditional medicines, and cosmetics. Most of the reports were

contributed by the public hospitals/healthcare organisations

(57.3%) and polyclinics (39.6%), while the rest were from private

hospitals/clinics, retail pharmacies (1.2%) and pharmaceutical

companies (1.9%). Doctors (83.2%) contributed most to the

number of reports in 2016, followed by pharmacists (12.2%). The

other contributors were dentists, nurses, research coordinators

and drug companies (4.6%).

Chinese patients constituted the highest proportion (59.0%) of AE

reports, followed by Malays (11.0%) and Indians (7.5%). There

were more reports of AEs occurring in females (57.0%) than in

males. The age range of the patients with the highest frequency

reported was 50 to 59 years of age (15.6%), followed by 60 to 69

years (14.8%).

(d) Suspected drugs

The top 20 suspected drugs commonly reported to cause AEs

were from the following pharmacotherapeutic groups: nonsteroidal

anti-inammatory agents (NSAIDs) (21.1%), antibiotics (20.1%),

analgesics and antipyretics (9.0%), cardiac therapy agents

(8.5%), and contrast agent (1.7%) (Figure 2). This constituted

more than half of the total volume of reports received. The most

commonly reported AEs were related to allergic reactions such

as rash, angioedema and face oedema.

Adverse Drug Reaction News • May 2017 • Vol.19 • No.1

Table 2. Drugs suspected of causing serious AEs

Description WHO preferred

terms

Suspected active ingredient(s) (2016)

(number in bracket denotes the number of times the drug has

been implicated

)

Top 10 suspected active ingredient(s) (2011 to 2015)

(number in bracket denotes the cumulative number of times the drug has been

implicated

)

Skin disorders Stevens Johnson Syndrome

(SJS) / Toxic Epidermal

Necrolysis (TEN) / SJS-TEN

Cotrimoxazole (7), Allopurinol (4), Omeprazole (4),

Pembrolizumab (3), Carbamazepine (2), Diclofenac (2),

Etoricoxib (2)

Carbamazepine (35), Omeprazole (27), Allopurinol (25), Coamoxiclav

(25), Cotrimoxazole (23), Phenytoin (22), Lamotrigine (16), Amoxicillin (15),

Ceftriaxone (15), Etoricoxib (15)

Body as a whole Anaphylactic reaction/

Anaphylaxis

Diclofenac (17), Paracetamol (12), Ibuprofen (10), Ceftriaxone

(8), Naproxen (8), Aspirin (7), Coamoxiclav (7), Amoxicillin (4),

Benzylpenicillin/ Penicillin G (4), Cefazolin (4), Atracurium (3),

Etoricoxib (3), Fentanyl (3), Omeprazole (3)

Diclofenac (64), Ibuprofen (52), Paracetamol (42), Aspirin (37), Coamoxiclav

(35), Naproxen (34), Ceftriaxone (31), Amoxicillin (27), Ciprooxacin (23),

Iohexol (18)

Renal disorders Acute renal failure/Interstitial

nephritis/Renal impairment

Cotrimoxazole (4), Omeprazole (4), Ciprooxacin (3),

Coamoxiclav (3), Naproxen (3), Lisinopril (2)

Ciprooxacin (14), Diclofenac (11), Enalapril (7), Cotrimoxazole (6), Losartan

(5), Omeprazole (5), Coamoxiclav (4), Mefenamic Acid (4), Vancomycin (4),

Metformin (3), Sitagliptin (3), Sulfadiazine (3)

Hepatic disorders Hepatic failure/ Hepatitis/

Hepatitis cholestatic/

Hepatoxicity/ Jaundice

Coamoxiclav (3), Efavirenz (2), Regorafenib (2) Cotrimoxazole (8), Coamoxiclav (5), Carbimazole (5), Amiodarone (4),

Regorafenib (4), Ketoconazole (4), Simvastatin (4), Allopurinol (3), Azathioprine

(3), Fenobrate (3), Gabapentin (3), Piperacillin-Tazobactam (3)

# More than one suspected drug may be implicated in a single AE report. Only active ingredients implicated more than once are listed here.

^ Based on onset date of the AE

The commonly reported vaccines suspected to cause AEs

in adults and children above 12 years of age were the human

papillomavirus (HPV), pneumococcal, seasonal inuenza and

tetanus toxoid vaccines. The commonly reported AEs included

rash, angioedema and injection-site reactions associated with a

variety of vaccines. Serious AEs included an isolated report of

Guillain-Barré syndrome with the inuenza vaccine (with another

suspected drug, pembrolizumab) and reports of tonic-clonic

movements with the HPV vaccine and vaccine failure with the

inuenza vaccine.

VAE of interest: anaphylaxis

Anaphylaxis is a potentially life-threatening allergic reaction

which can occur after different exposures to substances e.g.,

food, venom, drugs or vaccines. A study in the US using data

collected on more than nine million subjects found the risk of

anaphylaxis following vaccination to be rare, with a rate of 1.3 per

million vaccine doses administered.

The incidence did not vary

signicantly by age.

Analysis of the local VAE reports for the past ten years found

six cases of anaphylaxis, three associated with the tetanus

toxoid vaccine, two with the inuenza vaccine and one with the

typhoid vaccine. The age of the patients ranged between 34 to

43 years old.

There have been no cases of anaphylaxis in children reported to

HSA related to vaccines. KKH’s active surveillance of VAEs at the

inpatient setting for close to seven years did not report any cases

of anaphylaxis following vaccination. This observation was also

noted by a study of anaphylaxis in children seen at the paediatric

emergency department in the same hospital from 2007 to 2014.

Based on more than one million patient attendances where 485

episodes of anaphylaxis were picked up, none was associated

with vaccines.

Despite its rarity, anaphylaxis is a potentially life-threatening

medical emergency that healthcare professionals should be

prepared to treat. It is also important to recognise anaphylaxis

and distinguish it from a vasovagal reaction for the purpose of

clinical management. HSA had developed a guide for recognising

anaphylaxis, in consultation with Prof Chng Hiok Hee, Clinical

Professor in Rheumatology, Allergy and Immunology. Healthcare

professionals may wish to refer to the guide which contains a

questionnaire to aid reporting of anaphylaxis as an AE.

Complementary health products (CHP) AE

reports

In 2016, there were 161 suspected AE reports involving CHPs,

an increase of 15% over the preceding year. Of these, 99 reports

(61%) were associated with glucosamine-containing products,

describing mostly non-serious hypersensitivity reactions (e.g.,

rash, pruritus and periorbital oedema).

There were ten reports (6.2%) of hepatic reactions (e.g.,

transaminitis and jaundice) associated with CHPs, of which

seven patients were hospitalised. One of the implicated products,

‘Snake Powder Capsules’, was found to be adulterated with

western medicines, namely, chloramphenicol, chlorpheniramine,

dexamethasone, ibuprofen and tetracycline.

With the help of astute clinicians, HSA detected 11 adulterated

CHPs and issued ve press releases.

Common adulterants

included corticosteroids (e.g., dexamethasone), antihistamines

(e.g., chlorpheniramine) and analgesics (e.g., ibuprofen, diclofenac).

Acknowledgement

The Vigilance and Compliance Branch would like to take this

opportunity to thank you, our healthcare professionals for your

active participation in the reporting of AEs. This has helped HSA

in the early detection of potential safety signals and enabled the

relevant regulatory actions to be taken to safeguard public health.

With your vigilance in reporting AEs to HSA, Singapore has

retained its rst position globally in 2016 in terms of the number of

valid ADR reports per million inhabitants submitted to the World

Health Organisation global pharmacovigilance database for ve

consecutive years since 2011.

References

1. Vaccine 2014; 32(39): 5000-5005

2. The J Allergy Clin Immunol 2016; 137 (3): 868-878

3. Ann Acad Med Singapore. 2016; 45: 542-8

4. http://www.hsa.gov.sg/content/dam/HSA/HPRG/Safety_Alerts_Product_

Recalls_Enforcement/Anaphylaxis_guide.pdf

5. http://www.hsa.gov.sg/press_releases

Adverse Drug Reaction News • May 2017 • Vol.19 • No.1

HIGHLIGHTS ON LOCAL SAFETY

SIGNALS FOR THE YEAR 2016

The Health Sciences Authority (HSA) conducts regular individual

and aggregated reviews of all adverse event (AE) reports. This

is to identify serious, unexpected AEs that were not included in

the drug’s package insert (PI) or higher than expected reporting

frequency of established AEs from clinical trials or global post-

marketing experience. Any local safety signals and signicant

drug-AE pair of interest relevant to the local context will be

published in this bulletin to raise the awareness of our healthcare

professionals.

In 2016, the following local safety signals were identied by HSA:

Gemeprost and uterine rupture

Gemeprost (Cervagem®, Sano-Aventis Singapore Pte Ltd)

is a prostaglandin analogue indicated for the softening and

dilatation of the uterine cervix prior to transcervical intrauterine

operative procedures in pregnant patients in the rst trimester of

gestation, therapeutic termination of pregnancy in patients in the

second trimester of gestation and induction of abortion of second

trimester pregnancies complicated by intrauterine foetal death.

HSA was alerted by one healthcare institution which observed a

cluster of seven reports over a period of nine months of uterine

rupture associated with gemeprost indicated for the termination

of mid-trimester pregnancy. Patients’ age ranged from 25 to 38

years old and gemeprost was the only suspected drug listed in

the reports. The diagnosis of uterine rupture was conrmed in all

the patients through scans and repair of the uterus was done in

which all patients recovered. Six out of the seven patients had

past history of uterine surgery where lower segment caesarean

section was performed.

HSA investigated this issue and the product quality report by the

company did not show any product quality issues for the affected

batch. Further investigations carried out by the healthcare

institution identied a group of patients at risk for uterine rupture

(e.g., two or more previous uterine scars) and a risk mitigation

protocol for gemeprost was implemented. Following this, no

further cases of uterine rupture associated with gemeprost were

reported to-date.

Uterine rupture is a rare AE reported with gemeprost, most

commonly in multiparous women and in those women with a

history of uterine surgery.

Healthcare professionals are advised

to monitor patients’ cervical dilatation and uterine contractions

when using this drug in the termination of pregnancy especially

in patients at higher risk of uterine rupture or during the second

trimester or the second course of the therapy.

Dinoprostone Vaginal Delivery System

10mg and placental abruption

Dinoprostone Vaginal Delivery System (VDS) 10mg (Cervidil®,

Ferring Pharmaceuticals Pte Ltd) is indicated for the initiation

of cervical ripening in patients, at- or near-term, who have

favourable induction features and in whom there is a medical or

obstetrical indication for induction of labour.

In 2016, HSA received two reports of placental abruption with

dinoprostone VDS 10mg. The patients were reported to experience

severe vaginal bleeding and one neonate died in connection with

placental abruption during labour. Cardiotocography monitoring

was done before and after dinoprostone VDS 10mg insertion. The

company’s review of the manufacturing records and analyses of

samples from the implicated batch did not show any deviations.

Placental abruption is a complication of pregnancy, with a

background incidence of between 0.2 to 1% of pregnancies.

2,3

Risk factors for placental abruption include chronic hypertension,

eclampsia, premature rupture of membranes, previous abruption,

maternal age and smoking during pregnancy.

Placental abruption as an AE is currently not listed in the PI of

Cervidil®.

The company recently submitted an application to

update the PI to reect the uncommon occurrence of placental

abruption, based on observations from clinical studies. Healthcare

professionals are advised to take into consideration the reports of

placental abruption following the use of dinoprostone-containing

preparation in the routine monitoring of patients for the induction

of labour.

Pembrolizumab and Stevens Johnson

Syndrome (SJS)/Toxic Epidermal

Necrolysis (TEN)

Pembrolizumab (Keytruda®, MSD Pharma (Singapore) Pte

Ltd) is indicated for the treatment of patients with unresectable

or metastatic melanoma, and those with locally advanced or

metastatic non-small cell lung carcinoma whose tumours express

PD-L1 as determined by a validated test and who have received

platinum-containing chemotherapy.

From June 2016 to November 2016, HSA received three reports

of SJS/TEN associated with pembrolizumab. The patients’ ages

ranged from 45 to 81 years old. In one case, SJS developed

after 19 weeks of therapy, given once every three weeks. The

second and third patient developed SJS and TEN, 10 and 14

days, respectively after their rst dose. Pembrolizumab was the

only suspected drug in all three cases. Two patients recovered

and one died.

At least one case of pembrolizumab-associated SJS has been

described in published literature, with onset of rash beginning

one week after the rst dose. The patient rst developed

maculopapular rash and diagnosis of SJS was made following

four skin biopsies as the reaction progressed.

In the WHO global

pharmacovigilance database (as of 31 March 2017), three other

cases of pembrolizumab-associated SJS/TEN were reported in

the United States and France. Two of them had co-suspected

drugs, and in one case the patient died.

The company will be issuing a Dear Healthcare Professional

Letter (DHCPL) and HSA is currently working with them to update

the local PI to reect this new safety information, and will continue

to monitor this signal closely.

References

1. Singapore package insert for Cervagem®. Approved June 2016

2. PLoS One 2015; 10:e0125246

3. Am J Obstet Gynecol 2015; 213:573.e1

4. http://www.uptodate.com/contents/placental-abruption-clinical-features-and-

diagnosis

5. Singapore package insert for Cervidil®. Approved July 2013

6. Reactions Weekly 2016; 1621:203

For details of the DHCPL, please log on to MOHAlert via your

professional board’s website.

Medical devices

8 Nov 2016*

SynchroMed® II Implantable Drug Infusion Pump

Updated information on the issue of overinfusion

10 Nov 2016*

8840 N'Vision® Clinician Programmer and

SynchroMed® II Infusion System

Update of the Model 8870 software application card to

mitigate the potential for clinical effects of drug over-

delivery during the SynchroMed® II full system priming

bolus procedure

Therapeutic products

22 Sep 2016*

Technescan DTPA for Injection

Change of representation of active ingredient in the

labelling

12 Dec 2016

Dilantin® (phenytoin sodium) 20mg and 100mg

capsules

Potential non-engagement/securing of the Child

Resistant Closure for certain batches

3 Jan 2017

Mirena® (levonorgestrel) Intrauterine Delivery

System

Affected product may have an incorrectly mounted

insertion tube which may result in the inversion of the

insertion depth scale

25 Jan 2017

Bayer Aspirin 500mg tablets

Notication of drug shortage and advisory to switch

patients taking affected product to alternative therapies/

treatments

2 Feb 2017

Zelboraf® (vemurafenib)

Potential risk of Dupuytren’s contracture and plantar

fascial bromatosis associated with use

20 Mar 2017

Solu-Medrol® 500 mg/8ml injection

(methylprednisolone)

Selected batches do not contain Singapore Approved

Packaging

5 Apr 2017

Cotellic™ (cobimetinib)

Risk of severe haemorrhage associated with use of

cobimetinib

LIST OF DEAR HEALTHCARE

PROFESSIONAL LETTERS ON

SAFETY CONCERNS ISSUED BY HSA,

PHARMACEUTICAL AND MEDICAL

DEVICE COMPANIES

(1 DECEMBER 2016 TO 30 APRIL 2017)

Healthcare professionals are encouraged to report any suspected

serious AEs related to health products to the Vigilance and

Compliance Branch of HSA. With your continuous vigilance in

identifying these serious AEs, regulatory or clinical actions may

be taken to mitigate the risks and help protect public health.

* DHCPLs not published in Dec 2016 issue

Doctors, dentists and pharmacists can claim continuing

education points for reading each issue of the HSA

ADR News Bulletin. Doctors can apply for one non-core

Continuing Medical Education (CME) point under category

3A, dentists can apply for one Continuing Professional

Education (CPE) point under category 3A and pharmacists

can apply for one patient-care Continuing Professional

Education (CPE) point under category 3A per issue of the

bulletin.

Useful Information

Adverse Drug Reaction News • May 2017 • Vol.19 • No.1

6 Dec 2016

Exactech Equinoxe Reverse Shoulder Fixed Angle

Torque Dening Screwdriver

Potential non-retention of screw head in the affected

device

15 Dec 2016

Claria MRI™ CRT-D SureScan™ and Amplia MRI™

CRT-D SureScan™ devices

Loss of LV pacing that may occur for all models

10 Jan 2017

Synthes Radial Head Prosthesis

Voluntary recall due to possible loosening post-operatively

at the stem bone interface for the radial stem

21 Feb 2017

Medtronic Strata™ II/Strata™ NSC Valves

Update to the Instruction For Use due to possible reverse

polarity of the valve magnet that can lead to inaccurate

pressure level reading on the Strata™ Indicator Tool or

StrataVarius™ system

24 Feb 2017

Starclose SE Vascular Closure System

Voluntary recall of selected lots due to difculty or failure in

deploying the StarClose SE Clips

27 Feb 2017

MiniMed™ 640G Insulin Infusion Pump

Software issue that could prevent the internal battery of

the pump from charging

1 Mar 2017

Endurant™/Endurant II™ 23mm and 25mm Bifurcated

Stent Graft Systems

Voluntary recall of specic lots due to greater susceptibility

to fabric permeability variations that may be associated

with endoleaks observed during the initial implant

procedure

3 Mar 2017

Cordis® S.M.A.R.T® Flex Vascular Stent System sizes

5x200mm and 6x200mm

Voluntary recall of all unexpired lots due to higher

frequency of deployment issues compared to other sizes

22 Mar 2017

Medtronic StrataMR™ Adjustable Valves & Shunts

Voluntary recall of all unused units due to the potential for

underdrainage of cerebrospinal uid

31 Mar 2017

Lotus™ Valve System

Voluntary recall of all units due to a higher than anticipated

number of reports of early pin release prior to locking the

valve in its nal position

11 Apr 2017

Zenith Alpha™ Thoracic Endovascular Graft

Update to the Instructions for Use due to new information

including recommendations on patient selection, device

planning and sizing, and patient monitoring for blunt

thoracic aortic injury

Adverse Drug Reaction News • May 2017 • Vol.19 • No.1

Editor-in-Chief

A/Prof. Chan Cheng Leng, BSc (Pharm) Hons

Executive Editor

Valerie Wee, BSc (Pharm)

Editorial Board

Clinical Prof. Goh Chee Leok

Prof. Edmund Lee Joo Deoon

Clinical Prof. Chng Hiok Hee

Clinical A/Prof. Gilbert Lau Kwang Fatt

Asst Prof. Tan Tze Lee

Contributing Authors

Belinda Foo, BSc (Pharm) Hons

Lee Pui Ling, BSc (Pharm) Hons

Adena Lim, BSc (Pharm) Hons, MPharm

Anna Lim, BSc (Pharm)

Patricia Ng, BSc (Pharm)

Jalene Poh, BSc (Pharm)

Dr Anuradha Poonepalli, MBBS, PhD

Sally Soh, BSc (Pharm) Hons

Liesbet Tan, BSc (Pharm) Hons

Tham Mun Yee, BSc (Pharm) Hons, MPH

Dr Dorothy Toh, BSc (Pharm) Hons, MPH, PhD

Editorial Assistant

Saw Huiping

Please send your enquiries,

comments and suggestions to:

Vigilance and Compliance Branch

Health Products Regulation Group

Health Sciences Authority

11 Biopolis Way, #11-01,

Helios, Singapore 138667

Tel : (65) 6866 3538

Fax : (65) 6478 9069

Website: http://www.hsa.gov.sg

Email: [email protected].sg

The contents are not to be reproduced in part

or in whole, without prior written approval

from the editor. Whilst every effort is made

in compiling the content of this publication,

the publishers, editors and authors accept no

liability whatsoever for the consequences of

any inaccurate or misleading data, opinions

or statements. The mention of any product

by the authors does not imply any ofcial

endorsement of the product by the Health

Sciences Authority.

RISK OF FALSELY ELEVATED OESTRADIOL LEVELS DUE TO CROSS-REACTIVITY

OF FULVESTRANT WITH OESTRADIOL IMMUNOASSAYS

Key Points

Medical and scientic literature as well as rare international post-

marketing reports suggest that fulvestrant can cross-react with

oestradiol (E2) immunoassays due to its structural similarity with

E2. This can result in falsely elevated E2 levels, which may in turn

lead to misinterpretation of the menopausal status of women

Healthcare professionals are advised to indicate if their patient is

on fulvestrant when requesting for blood tests that include E2, and

to consider the need to review the previously reported test results

Healthcare professionals may wish to consider alternative

methods for E2 measurements (e.g., liquid chromatography-mass

spectrometry) in patients on fulvestrant

HSA would like to highlight to healthcare professionals about the risk of

falsely elevated oestradiol (E2) levels due to cross-reactivity of fulvestrant

with E2 immunoassays, which can result in unnecessary therapy

modication.

Fulvestrant (Faslodex®, AstraZeneca Singapore Pte Ltd) has been

registered in Singapore since 2006. It is indicated for the treatment of

post-menopausal women with oestrogen receptor (ER)-positive, locally

advanced or metastatic breast cancer for disease relapse on or after

adjuvant anti-oestrogen therapy, or disease progression on therapy with

an anti-oestrogen. Fulvestrant is a competitive ER antagonist with an

afnity comparable to E2. Its mechanism of action is associated with down-

regulation of ER protein levels.

Background

Medical and scientic literature as well as rare international post-marketing

reports suggest that fulvestrant can cross-react with E2 immunoassays

due to its structural similarity with E2. This can result in falsely elevated E2

levels, which could potentially lead to unnecessary surgery or endocrine

therapy modication due to misinterpretation of menopausal women as

being premenopausal.

Case report on falsely elevated E2 levels in a

postmenopausal patient

A 36-year-old woman with ER-positive breast cancer underwent bilateral

oophorectomy, followed by treatment with letrozole and fulvestrant. The

patient was later found to have an unexpected increase in E2 level which

was inconsistent with the menopausal symptoms she experienced, such as

hot ushes. A pelvic ultrasound revealed a possible small soft tissue density

in the left adnexal region that was suspected to be residual ovarian tissue

persisting after oophorectomy (a rare condition known as ovarian remnant

syndrome). The patient subsequently underwent additional imaging and

surgical intervention with diagnostic laparoscopy to remove the possible

remnant. Pathology however, revealed no ovarian tissue, thus ruling out

ovarian remnant syndrome as the cause of her increased E2 levels.

Testing of the patient’s serum E2 levels using a more sensitive and

specic liquid chromatography-tandem mass spectrometry (LC-MS/MS)

method showed the patient’s serum E2 levels to be undetectable, hence

conrming that an exogenous agent was likely to be cross-reacting with

the immunoassay and producing falsely elevated serum E2 readings.

Fulvestrant possesses the basic structure of E2 with the exception of an

aliphatic chain of 14 carbons at position 7α (Figure 1). This allows the drug

to bind anti-E2 antibodies in the immunoassay and cause false positive

results. Based on this structural similarity, fulvestrant was deemed the most

likely culprit that led to the falsely elevated E2 reading in this patient.

Actions by other regulatory agencies

Health Canada has published an advisory regarding the risk of unnecessary

therapy modication due to falsely elevated E2 levels in patients taking

fulvestrant.

Apart from issuing a Dear Healthcare Professional Letter in

Canada, AstraZeneca has also updated the Faslodex® product monograph

to include warnings about this safety issue.

The Australian Therapeutic Goods Administration (TGA),

European

Medicines Agency (EMA)

and United States Food and Drug Administration

(US FDA)

have also updated the product labelling of Faslodex®

with warnings that fulvestrant can interfere with E2 measurement by

immunoassays, resulting in falsely elevated E2 levels.

Local situation

To date, HSA has not received any local ADR reports of falsely elevated

E2 levels associated with the use of fulvestrant. HSA is working with

AstraZeneca to update the local Faslodex® package insert to reect

information on the drug-mediated cross-reactivity of fulvestrant with E2

immunoassays.

HSA’s advisory

Healthcare professionals are advised to indicate if their patient is on

fulvestrant when requesting blood tests that include E2 levels and to consider

alternative methods such as liquid chromatography-mass spectrometry

instead of immunoassays to detect E2. Healthcare professionals may also

consider the need to carry out a review of the previously reported E2 test

results in patients on fulvestrant.

Figure 1. Chemical structure of oestradiol and fulvestrant

References

1. http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2016/60590a-eng.php

2. Clin Breast Cancer 2016; 16: e11-3

3. Faslodex® Australian Product information, updated on 8 August 2016

4. Faslodex® Summary of Product Characteristics, updated on 9 November 2016

5. Faslodex® US Product label, updated on 7 December 2016

Oestradiol Fulvestrant