October21, 2009
Mr. Akira Nagatuma, Minister of Health, Labour, and Welfare
Marc Dunoyer, President GlaxoSmithKline
Yakugai Ombudsperson
Medwatcher Japan
Toshihiro Suzuki, Representative
AM Bldg. 4th Floor, 1-14-4 Shinjuku,
Shinjuku-shu, Tokyo 〒162-0022
Tel.: 03(3350)0607
FAX 03(5363)7080
E-mail: yakugai@t3.rim.or.jp
URL: //www.yakugai.gr.jp

Demand Regarding Use of Antidepressant Paxil Tabletsin Pregnant Women
I. Purpose of the Demand
1.

Revision of Package Insert
Patient

and Need of Information leaflet for

We demand that the Warnings section of the package insert should be
revised to include at least following four issues and, that the information
leaflet for patient should be provided at medical practice in order to callsufficient attention to cardiac malformations, drug withdrawal syndrome
and persistent pulmonary hypertension in newborns as a result oftreatment with the antidepressant Paxil during pregnancy.
(1)

That there is a high risk of congenital anomalies, particularly
cardiovascular disorders (primarily ventricular septal defects and atrial
septal defects), drug withdrawal syndrome in newborns and persistentpulmonary hypertension of the newborn delivered by women treatedwith Paxil in pregnancy
-1-

(2)

That treatment should be discontinued or replaced with alternative
treatment when patients being treated with Paxil become pregnant
unless continuing treatment is clearly therapeutically justified(3)
That women who are pregnant or child-bearing age should not, as a
general rule, take this medication, and should not start treatment unlessno alternative treatment is available(4)
When Paxil is used, the patient's informed consent should beobtained after a full explanation of the dependency and the risk ofcongenital anomalies in newborns

2.

Establishment of Fact-Finding Research GroupWe demand the establishment of a research group to look into the facts
concerning the use of the antidepressant Paxil in pregnant women as wellas the facts concerning cardiac malformations in newborns when pregnant
women are treated with Paxil.

II. Reason for the Demand1.

Summary of Paxil Tablets

Paxil antidepressant tablets (generic name: paroxetine hydrochloride) area type of SSRI (selective serotonin reuptake inhibitor) which came out on
the market in November 2000 in Japan and are now widely used as anantidepressant. It became the top-earning antidepressant in the Japanesemarket (50 billion yen) in 2007.1 The dosage forms in Japan are the 10 mg
and 20 mg tablets, and are indicated for "depression, depressed state, panic
disorder, and obsessive compulsive disorder." 2

2.

Objective Evidence of Teratogenicity and Persistent Pulmonary
Hypertension
As noted below and shown in the research report by D.Healy and D.
-2-

Mangin (Attachment 1), and the report by R. Hama (Attachment 2), it is
now evident that the use of Paxil tablets (referred to below as "Paxil")
during pregnancy involves the risk of "teratogenicity," that is, congenital
anomalies in fetuses and persistent pulmonary hypertension of thenewborn (PPHN).
(1)

Results of Epidemiological Study

1) The FDA analyzed two unpublished epidemiological studies, andissued the following advisory concerning the teratogenicity of Paxil in
December 2005.3(i) In a study using Swedish national registry data, women who
received Paxil in early pregnancy had an approximately 2-foldincreased risk for having an infant with a cardiac defect compared tothe entire national registry population (the risk of a cardiac defect was
about 2% in Paxil-exposed infants vs. 1% among all registry infants).
(ii) In a separate study using a United States insurance claims database,infants of women who received Paxil in the first trimester ofpregnancy (up to the 14th week) had an approximately 1.5-foldincreased risk for cardiac malformations and an approximately
1.8-fold increased risk for congenital malformations overall compared
to infants of women who received other antidepressants. The risk of a
cardiac defect was 1.5% in Paxil-exposed infants vs. 1% among
infants exposed to other antidepressants.
(iii) Most of the cardiac defects were atrial or ventricular septal defects.
2)

A meta-analysis of epidemiological data on the risk of congenital
malformations during the use of Paxil in the first trimester ofpregnancy is available on the clinical study registry system of
GlaxoSmithKline, the manufacturer and distributor of Paxil.
According to the results, a total of 15 studies comprising 12 cohort
studies (two of which are (i) and (ii) above) and three case-control
studies indicated that the risk for congenital malformations is 1.3 times
greater and the risk for cardiac malformations is 1.5 times greater when
Paxil is used.4

3)

A retrospective case-control study in which 377 women whose
infants were born with PPHN and 836 women whose infants were-3-

born healthy indicated that risk of PPHN was increased ,approximately 6 times greater, in the infants delivered by women who
had administered SSRI after 20 th week of gestation.5(2)Matters Pointed Out in Japanese Review Report

The materials6 attached to the Review Report7 in Japan also include
results suggesting the effect of Paxil on fetuses. Specifically, rat
fertility and general reproductive studies conducted as part ofreproductive toxicity revealed effects such as increase in disability ofmating and fertility, increase in mortality of parent rat andpost-implantation, lower birth weight, and dose-dependent decrease in
4-days survival of newborns. Additional studies also revealed the male’s
lower fertility and injuries induced in male’s reproductive organs.
As noted in investigational report by R.Hama (Attachment 2), Paxil had
been found to result in reproductive toxicity at the approval review
stage.
However, the Review Report merely comments that "in view of the
reproductive toxicity profile (see Section II), the Precautions state that
'Paxil should not be given unless it is determined that the therapeutic
benefits outweigh risks (the safety of treatment during pregnancy has notbeen established)'," and the risks posed by Paxil to fetuses cannot be
said to have been adequately reviewed.

(3)

Case Reports of Adverse Drug Reactions in JapanNo epidemiological study such as those noted in section (1) has been
conducted in Japan, but 4 cases of atrial septal defects and 3 cases ofventricular septal defects were reported as adverse drug reactions ofPaxil to the MHLW from 2000 to 2008.8
The package insert for Paxil tablets state merely that the results ofoverseas epidemiological studies showed an increased risk forcongenital anomalies, especially cardiovascular abnormalities, innewborns, yet it is clear that cardiovascular abnormalities have also
occurred in Japanese newborns, as found in the above case reports ofadverse drug reactions to the MHLW(incidentally, MHLW has received
no reports of such ADR with Fluvoxamine (proprietary name: Luvox,
Depromel), which is another SSRI, or Milnacipran (proprietary name:-4-

Toledomin), which is an SNRI, or the like).

3.

Objective Evidence of Withdrawal Symptoms
It has also been pointed out that patients become dependent on SSRI's,
including Paxil tablets, and undergo withdrawal upon discontinuing
medication. This is an important point in reviewing the use of Paxil in
pregnant women as well as patients with child-bearing age.

(1)

Statements in the Review Report

The following is stated first on the issue of withdrawal in the section
entitled "2) Safety" in the "Overview of the Review by the Review
Center" of the Review Report7 detailing the results of the approval
review: " (v) Effects of Discontinuing Treatment: No data on the effects
of discontinuing treatment have been obtained in Japan, but abrupt
discontinuation of SSRI's, including Paxil, has been known in rare cases
to lead to withdrawal syndrome, including dizziness, head ache,insomnia, malaise, exacerbation of anxiety, agitation, queasiness, andsensation disorders (overseas references). As a result, the Precautions
describe symptoms and measures that should be taken when treatment is
discontinued."
The Review Report No2 also stated in "(g). Data on Clinical Study
Results" that the sponsor "was asked to compile data on the dependency
and withdrawal associated with Paxil, and responded that, based on
analysis of the preclinical and clinical safety database, the primary
symptom was dizziness, there was no difference in the types ofwithdrawal symptoms regardless of treatment period, severity was mild
to moderate, and problems could be prevented by gradually reducing thedose, etc."
The Review Report failed to point out any particular problems
concerning withdrawal other than the above.
(2)

Statements in Japanese Package Insert

Meanwhile, the Important Precautions on point 8 of the Japanese
package insert state the following: "Discontinuation of treatment(particularly sudden discontinuation) or dose reduction may result in-5-dizziness, perception disturbances (such as paresthesia, electric shock
sensation, and tinnitus), sleep disorders (including nightmares), anxiety,irritability, agitation, queasiness, tremors, confusion, diaphoresis, headache, diarrhea, and the like. Most symptoms appear within several daysof discontinuation, are mild to moderate, and resolve in about 2 weeks,
but may be severe in some individuals and may take 2 to 3 months ormore to resolve."
The package insert states that "based on the data thus far available,
these symptoms are not believed to be caused by drug dependency."
However, they are typical symptoms of withdrawal which occur
upon the discontinuation of drugs that can cause dependency.
It is stated that the following measures should be taken: "Take thefollowing precautions when reducing the dose or discontinuing Paxil. (1)Avoid abruptly discontinuing treatment. When discontinuing treatment,
gradually reduce the dose over a period of several weeks or several
months while monitoring patient condition. (2) In the event that
intolerable symptoms develop after dose reduction or discontinuation oftreatment, resume treatment at the dose prior to dose reduction or
discontinuation, and try reducing the dose more gradually. (3) Advise
patients not to stop taking the medication on their own. As symptoms
such as dizziness and perception disorders noted above may occur if thepatient forgets to take the medication, patients should be advised to be
sure to take their medication as directed."
These statements are more detailed than those on withdrawal in the
package inserts of other SSRI's (sertraline hydrochloride, fluvoxamine
maleate) (package insert for fluvoxamine maleate: "When discontinuing
treatment, take precautions such as gradually lowering the dose, as
sudden dose reductions and discontinuation have been reported to resultin head ache, queasiness, dizziness, anxiety, insomnia, decreased mental
concentration, etc."), and suggest that withdrawal may be a particular
problem with Paxil.
(3)

Reports in the Medical Literature

In a review of SSRI's by Motohashi, 9it is pointed out, in the section
on SSRI ADR, that "SSRI's are highly safe drugs, but that does not mean
there are no adverse drug reactions . The most frequent ones encounteredwith paroxetine are sedation, agitation, diaphoresis, sexual dysfunction,
and withdrawal."
Several overseas references reporting on Paxil withdrawal have also
-6-

been published, as mentioned in the Review Report7 and in the reportby D.Healy and D.Mangin (attachment 1), and by R.Hama (attachment
2).
A study using spontaneously reported data in France included many
reports of SSRI withdrawal and found a high risk in particular withvenlafaxine (not approved in Japan) and paroxetine (Paxil). 10
It is also pointed out that treatment with Paxil during pregnancy may
cause drug withdrawal syndrome in newborns.
(4)

Case Reports of Adverse Drug Reactions in Japan

In fact, from the FY 2000 to the FY 2008, the MHLW was notified of
21 ADR case reports involving drug withdrawal syndrome in newborns.
84.

Measures Needed to Prevent Congenital Anomalies in Newborns(1)

Generally Prohibited Use During Pregnancy

Since it is evident, as noted in 2 above, that there is a higher risk ofcongenital anomalies, particularly cardiovascular anomalies (primarily
ventral and atrial septal defects), in newborns when pregnant women aretreated with Paxil, its use in pregnant women should be prohibited as a
general rule, and should be limited to when no alternative therapy isavailable.
In this respect, the FDA pointed out, in December 2005, that analysisof the epidemiological studies noted in section 2(1) above, revealed anincreased risk of congenital malformations, particularly cardiac
malformations, when paroxetine was used in early pregnancy, and theclassification indicating the pharmaceutical risk posed to fetuses by theuse of Paxil in pregnant women was changed from category C to D
11
(Category D refers to when there is clear evidence indicating risk tofetuses based on post-marketing surveillance or studies on people, but
use in pregnant woman may be justified by the therapeutic benefits. In
contrast, category C means that animal experiments indicate adverse
drug reactions in fetuses, but use in pregnant women may be justified bytherapeutic benefits in the absence of well-controlled studies on-7-

pregnancy).
The FDA also asked for this to be stated in the Warnings section of
the package insert.

(2)

Limited Use in Patients with Child-bearing age

Paxil thus involves a high risk of teratogenicity, but it takes time forwomen to realize they have become pregnant. By the time that a woman
who has been using Paxil prior to pregnancy becomes aware that she has
become pregnant, a certain amount of time may already have passed
during the early stage of pregnancy which involves a high risk ofteratogenicity.
Another difficulty is that, even if treatment is discontinued tominimize the effects on the fetus, the medication cannot be discontinued
immediately in view of the symptoms of withdrawal associated with
Paxil, as outlined in section 3 above.
Therefore, in order to avoid congenital anomalies in newborns, notonly must treatment during pregnancy be limited, but the treatment ofpatients with child-bearing age must be similarly limited.
(3)

Patient Explanation and Consent

As noted above, the use of Paxil in women who are pregnant or childbearing age should be prohibited as a general rule, and should be limited
to when no alternative therapy is available, but even when Paxil must be
used, accurate information on Paxil dependency and the risk ofcongenital anomalies in newborns , drug withdrawal syndrome innewborns and their PPHN should be provided, and the informed consent
of the patient should be obtained when it is used (a decision issued by
the Tokyo High Court on January 27, 200512 also points out theimportance of informed consent for parents with regard to disease which
can occur in children when the parents want to have children).
(4)
In order to ensure the effectiveness of the measures in section (1)through (3) above, the following issues, section 5, are needed.
-8-5The Need to Revise the Package Insert(1)Statements in US Package Insert

As noted in section 4(1), in response to the FDA, the US package
insert for Paxil has now been revised as follows.
Specifically, the Warnings state that: (i)infants born of women who
used paroxetine during the first trimester of pregnancy have an
increased risk of cardiovascular anomalies, primarily ventricular septal
defects and atrial septal defects; (ii) if a patient becomes pregnant while
taking paroxetine, alternative therapy should be considered unlesscontinuing treatment is therapeutically justified; and (iii)when women
wish to become pregnant or are in their first trimester of pregnancy,
treatment should be started only after alternative treatment has been
considered. Use during pregnancy is classified as category D.13
(2)

Statements in Japanese Package Insert

In Japan, on the other hand, “the Important Precautions” section
states (this is section is not for most serious warnings in Japan) that "asthe risk of congenital anomalies is reportedly increased in newborns
delivered by women treated with Paxil, pregnant woman or women ofchild-bearing age should start treatment with Paxil only when thetherapeutic benefits outweigh risks (see Use During Pregnancy, Delivery,or Lactation)," while “the Use During Pregnancy, Delivery, or
Lactation” section states in brackets that "in overseas epidemiologicalstudies, there was an increased risk of congenital anomalies,
particularly cardiovascular anomalies (such as ventral or atrial septal
defects), in newborns delivered by women treated with Paxil in the firsttrimester of pregnancy," and provides the details of the studies. However,nothing is stated in the Warnings section.
Regarding the drug withdrawal syndrome and PPHN of newborns ,the section of “the Use During Pregnancy, Delivery, or Lactation”
states that “there are reports that such symptoms as respiratory distress,
cyanosis, apnea, higher ventilation ,epileptic-like seizure ,trembling,
hypotonia, hypertonia ,hyperliflexia, jitteriness, irritability, constantcrying, drawsiness, temperature instabiltiy, feeding difficulty, vomiting,and hypoglycemia are developed in newborns delivered by women-9-treated with Paxil in the late trimester of pregnancy. These symptoms
are observed just after birth or within 24 hrs, and are noted at times as
drug withdrawal symptom or apparent death. In overseas
epidemiological studies, there are reports of increased risk of PPHN innewborns delivered by women treated with SSRI after 20 th week ofgestation.”
However ,nothing is described in “the Warning” or “Important
Precautions” section.
(3)

Revision of Statement Details

As noted in section 4(1) and (3), the following are needed toprevent congenital anomalies in newborns ,drug withdrawal syndromein newborns and PPHN:(i)in view of serious effects on fetus andnewborns, the use of Paxil during pregnancy should be prohibited as a
general rule, and should be limited to when no alternative therapy isavailable; (ii) in view of the dependency and symptoms of withdrawal
when treatment is discontinued as well as the teratogenicity associatedwith Paxil, its use should be limited not only in pregnant and potentiallypregnant women, but also in patients with child-bearing age and(iii)adequate informed consent should be obtained even when treatment
is unavoidable. This should be explicitly stated in the package insert.
(4)

Revision of Section

The guidelines for package inserts, which were revised as a result ofa review14 by "study groups on the revision of pharmaceutical package
inserts" ("Guidelines on Precautions for Prescription Drugs,"
Notification No. 607 of the PAB, April 199715) in response to thedeath-incident caused by Sorivudine,16 require information to be written
conspicuously in red in the Warnings section at the beginning of
package inserts to draw attention to "cases in which fatal or extremely
serious and irreversible adverse drug reactions occur, or cases in which
the possibility that adverse drug reactions may lead to extremely serious
accidents necessitates particular precaution."
In light of the fact that the severity of the teratogenicity andespecially the cardiac malformations caused by Paxil necessitatedcardiac surgery in some cases, it is clear that the teratogenic risk of Paxil
and measures for avoiding that risk qualify as a case that should be- 10 -

noted in the Warnings section mandated by the above guidelines.
(5)

Conclusion
We therefore request the following to be stated in the Warnings:
1) that there is an increased risk of congenital anomalies, particularly
cardiovascular malformations (primarily ventricular septal defects andatrial septal defects), ,drug withdrawal syndrome and PPHN innewborns delivered by women treated with Paxil2) that treatment should be discontinued or replaced with alternative
treatment when patients being treated with Paxil become pregnant
unless continuing treatment is clearly therapeutically justified;3) that women who are pregnant or child-bearing age should not, as a
general rule, take this medication, and should start treatment only after
alternative treatment has been considered; and4) that when Paxil must be used, the patient's informed consent should
be obtained after a full explanation of the dependency and the risk ofcongenital anomalies in newborns.

6.

Raising Patients’ AwarenessCurrently, the MHLW recommends that pharmaceutical industries
draft Patients’ Information Guide (based on the administrative guidelines
on “Memorandum on Drafting Patients’ Information Guide,” and“Operation of Patients’ Information Guide”).
For Paxil, Patients’ Information Guide on aggravation of
impulsiveness has been drafted. However, nothing is stated in the Guideon congenital anomalies, PPHN and drug withdrawal syndrome innewborns. The GSK should at least provide Patients’ Information Guideon the congenital anomalies in newborns.
The present Patients’ Information Guide is not intended to answer
patients’ questions directly, thus the contents are not easy to understand.
(Regarding the congenital anomalies in newborns by Paxil, the difference
is obvious in comparison with the FDA or the EMEA). In addition, theaccess to the information is limited to internet.
Therefore, we request that the GSK provide pregnant women as wellas patients with child-bearing age with digestible type of information,such as those in “Frequently Asked Questions” format. The GSK should
also sufficiently raise patients’ awareness by improving contents andmethods, such as disseminating Patients’ Information Leaflet at- 11 -

pharmacies.

7.

The Need for a Fact-Finding Study
As noted previously, the results of overseas epidemiological studies
revealed the risk that fetuses may be affected by treatment during earlypregnancy, and Paxil-induced congenital anomalies, especially ventral andatrial septal defects, have been reported in the form of ADR case reports
to the MHLW.
However, the package insert fails to provide adequate warnings of that
risk, and the risks have not been fully publicized. It is therefore possiblethat the relationship between Paxil and congenital anomalies, PPHN andwithdrawal syndrome occurring in newborns as a result of such adverse
drug reactions has been overlooked and unreported, or that the drug is
being widely used by pregnant women or women with or child-bearingage.
Fact-finding studies and epidemiological studies on the use of Paxil in
pregnant women should therefore be promptly conducted to implement
appropriate safety measures, and the establishment of a research group forthat purpose is essential.

8.

Summary
In view of the above, as noted in the Purpose of the Demand, werequest the followings: (a) the package insert be revised; (b) sufficientawareness be raised using Patients’ Information Leaflet etc; and (c) afact-finding study be conducted.

Attachments
12David Healy, Derelie Mangin; Safety of Antidepressants in Pregnancy
With Particular Reference to Paroxetine (Paxil) ( July 21, 2009)
Hama R. On Reproductive Toxicity of Paroxetine (Paxil): Toxicities toFetus and Newborn--Focusing on the Neonatal Withdrawal toxicity andPersistent Pulmonary Hypertension of the Newborn,
Web-Kusuri-no-Check No 135 (Oct 21 2009). Digest version will be- 12 -

published on the October 2009 issue of “The Informed Prescriber”.
12
34

Pharmaceutical Affairs Handbook 2009
2 Package Insert for Paxil Tablets 10 mg and Paxil Tablets 20 mg, revised May 2009, (Ver. 16).
http://www.fda.gov/cder/drug/advisory/paroxetine200512.htm
GSK Clinical Study Register Study No. WEUSRTP2280; Paroxetine Use in First Trimester ofPregnancy and the Prevalence of Congenital, Specifically Cardiac, Malformations: Systematic
Review and Meta-Analysis of Epidemiological Data.

http://www.gsk-clinicalstudyregister.com/files/pdf/24089.pdf (accessed 22 July 2009).
Chambers CD, Hernandez-Diaz S, Van Marter LJ, Werler MM, Louik C, Jones KL, Mitchell
AA.Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of thenewborn. N Engl J Med. 2006 Feb 9;354(6):579-87.
6
GlaxoSmithKline "Data on paroxetine hydrochloride hydrate and Paxil tablets 10 mg and Paxil
tablets 20 mg
7
Director of National Institute of Health Sciences, "Review Report" (NIHS No. 2706) (July 19,
2007)
5

8

9

http://www.info.pmda.go.jp/fukusayou/menu_fukusayou_attention.html"Nobutaka Motohashi "Therapy: Antidepressant Types, Pharmacological Properties, and Clinical
Efficacy – Selective Serotonin Reuptake Inhibitors," (Japanese Journal of Clinical Medicine, Vol.
59, No. 8, page 1519) (August 2001)
10
Trenque T, Piednoir D, Frances C, Millart H, Germain ML. Reports of withdrawal syndrome withthe use of SSRIs: a case/non-case study in the French Pharmacovigilance database.
Pharmacoepidemiol Drug Saf. 2002; 11(4): 281-3.
11

12
13
14
15
16

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2005/ucm108527.htm

Tokyo High Court, Decision Issued January 21, 2005 (Reports of Precedents No. 1953, page 132)
PAXIL PRESCRIBING INFORMATION (©2009, GlaxoSmithKline.)
2005 Health Science "Study on Revisions of Pharmaceutical Package Inserts" Report (March 22,
1996)
Notification No. 607 of PAB "Guidelines for Precautions for Prescription Drugs (April 25, 1997)
PAB "Results of Study on Adverse Drug Reactions Caused by Sorivudine," (September 1994)- 13 -