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( t.a.v. registratieafdeling)
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Subject
Request for change in the product information following the PhVWP/CMDh decision
Antipsychotics – Risk of extrapyramidal effects and withdrawal symtoms in newborns after
exposure during the third trimester of pregnancy.
Following assessment of the available data relating to the risk on neonatal withdrawal syndrome and
extrapyramidal effects in newborns in association with antipsychotics and discussion at the
Pharmacovigilance Working Party and the Coordination Group for Mutual Recognition and
Decentralised Products – human (CMDh), all Marketing Authorisation (MA) holders for antipsychotics
are being requested to submit type 1B variations (variation number C.1.3.a) (or equivalent national
procedures – see below) for their relevant products to implement the final SmPC and PL wording
agreed by the PhVWP.
Link to the website with the published decision: http://www.hma.eu/222.html
You are requested to change the SmPC and Package Leaflet (PL) of
<product>
< RVG>
The agreed texts, together with the translation in Dutch, are attached to this letter.
These texts should be included literally in the SmPC and PL.. However, you are requested to check
the SmPC and PL carefully to make sure that there is no overlap with the current texts. If there is such
overlap, you should replace the current text with wording from the agreed texts. With regard to PL
wording, further user testing by individual MA holders will not be expected on this occasion.
For products registered via a MRP or DCP procedure, the RMS takes responsibility on behalf of CMS
to request the variation from the MA holder and initiate the procedure.
The applications do not require supporting information or expert statements and will be accepted by
Member States Competent Authorities without further assessment or amendment.
For nationally approved products there is no need to submit a Variation Application Form.
Applying for the type IB variation in a different way
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The MEB has already assigned you a case number for this variation. You should send your
application via e-mail to case@cbg-meb.nl, stating case number <XXXXX> in the subject field. Please
attach the adapted SmPC and PL (both clean and track-changes versions in Word format).
If the product was registered via MRP with NL = RMS, you are also asked to include a variation
application form and dispatch list with the submission dates in the CMSs. Please be informed that you
have to submit both the English texts and the national translations.
Please mention the following information in the ‘Subject’ field:
o Case number
o Procedure number (if applicable)
o Type IB on request of the MEB
o Name of the medicinal product
o RVG number of the lowest strength
And in the message:
o Implementation of PhVWP/CMDh decision
o The RVG numbers
o The MRP number (if applicable)
o Name, phone number and e-mail address of the representative
o Your reference (if applicable)
o When submitting the amended texts, please confirm that it concerns only the implementation
of agreed PhVWP/CMDh decision
o Please mention other variations concerning SmPC and/or PL changes that are currently
under consideration by the MEB (if applicable)
Timetable for implementation
You should submit variations no later than the 1st of January 2012.
You are obliged to start incorporating updated PLs into new production batches within a 6 month
timeframe after approval
On behalf of the Medicines Evaluation Board
in the Netherlands,
This notification has been produced centrally in an automated process and consequently does not
bear a signature.
Attachments:
Annex 1: agreed texts (English and Dutch versions)
Annex 2: Summary Assessment Report of the PhVWP on Antipsychotics and the risk of
extrapyramidal effects and withdrawal symptoms in newborns after exposure during pregnancy.
Note that not all active substances to which the class labelling is applicable are mentioned in
the conclusions of the report. The wording should however be implemented for all
antipsychotics (i.e. as stated in the AR ‘…these effects are likely to be a class effect and
considered that the wordings in the product information should be consistent for the whole
class of antipsychotics.’).
ANNEX 1
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Antipsychotics (conventional and atypical) and use during the third trimester of pregnancy
and risk of abnormal muscle movements and/or withdrawal symptoms in newborns.
PhVWP core SmPC wording section 4.6 for all antipsychotics
Neonates exposed to antipsychotics (including [NAME]) during the third trimester of pregnancy are at
risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in
severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia,
tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be
monitored carefully.
PhVWP core SmPC wording section 4.8 for all antipsychotics
System Organ Class: Pregnancy, puerperium and perinatal conditions.
Adverse Drug Reaction / Frequency: Drug withdrawal syndrome neonatal (see 4.6) / not known.
PhVWP core PIL wording for all antipsychotics (to be included in section 2 – subsection
pregnancy and breast feeding):
The following symptoms may occur in newborn babies, of mothers that have used [NAME] in the last
trimester (last three months of their pregnancy): shaking, muscle stiffness and/or weakness,
sleepiness, agitation, breathing problems, and difficulty in feeding. If your baby develops any of these
symptoms you may need to contact your doctor.
Dutch translation:
PhVWP core SmPC wording section 4.6 for all antipsychotics
Neonaten die tijdens het derde trimester van de zwangerschap zijn blootgesteld aan antipsychotica
(waaronder <productnaam>), lopen risico op bijwerkingen na de bevalling waaronder extrapiramidale
symptomen en/of onttrekkingsverschijnselen die kunnen variëren in ernst en in duur. Er zijn
meldingen van agitatie, hypertonie, hypotonie, tremor, slaperigheid, ademnood of voedingsstoornis.
Pasgeborenen moeten daarom nauwlettend worden gecontroleerd.
PhVWP core SmPC wording section 4.8 for all antipsychotics
Systeem/orgaanklasse: Zwangerschap, perinatale periode en puerperium
Bijwerking/frequentie: Niet bekend: neonataal onttrekkingssyndroom (zie rubriek 4.6).
PhVWP core PIL wording for all antipsychotics (to be included in section 2 – subsection
pregnancy and breast feeding):
De volgende symptomen kunnen optreden bij pasgeboren baby's van moeders die paliperidon in het
laatste trimester (laatste drie maanden van hun zwangerschap) hebben gebruikt: trillen, stijve en/of
zwakke spieren, slaperigheid, opwinding, ademhalingsproblemen en problemen met voeden. Als uw
baby last krijgt van een van deze symptomen, neem dan contact op met uw arts.
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ANNEX 2
Summary Assessment Report of the PhVWP July 2011
Antipsychotics – Risk of extrapyramidal effects and withdrawal symptoms in
newborns after exposure during pregnancy
Key message
Extrapyramidal effects and withdrawal symptoms may occur in newborns after exposure to
antipsychotics during the third trimester of pregnancy, and product information across the EU should
contain consistent information.
Safety concern and reason for current safety review
Following new data from worldwide spontaneous reporting and information made available to the
Agency by the US Food and Drug Administration (FDA) on neonatal withdrawal syndrome and
extrapyramidal effects in newborns in association with antipsychotics, the PhVWP agreed to review
the implications of this new information for the content of the summaries of product characteristics
(SmPCs) and package leaflets (PLs) of those products authorised in the EU.
The active substances included in the review were chlorpromazine, clotiapine, clozapine,
fluphenazine, haloperidol, loxapine, molindone, perphenazine, pimozide, prochlorperazine,
risperidone, thioridazine, thiothixene, trifluoperazine and ziprasidone.
Clinical setting
Antipsychotics are medicines used for some types of mental distress or disorder.
Information on the data assessed
The PhVWP reviewed data from worldwide spontaneous reporting and information made available to
the Agency by the US Food and Drug Administration (FDA) [1] on neonatal withdrawal syndrome and
extrapyramidal effects in newborns in association with antipsychotics.
A review of the SmPCs of the antipsychotics authorised in the EU showed inconsistencies between
the SmPCs in the information provided in section 4.6 on fertility, pregnancy and lactation about the
possible effects on the newborn following maternal use during the third trimester of pregnancy. In
many cases, this information was absent from the SmPCs.
At the same time, the marketing authorisation holder for the centrally authorised medicinal products
containing the antipsychotic paliperidone (INVEGA and XEPLION) had submitted a variation
application to update section 4.6 of the SmPC to include the risks of extrapyramidal effects and
withdrawal symptoms in response to the action taken in the US. The assessment of the application
concluded that there was a risk of extrapyramidal effects and of withdrawal symptoms in newborns
following maternal use of paliperidone during the third trimester of pregnancy and recommended
including these risks in SmPC section 4.6 and section 4.8 on undesirable effects and in the
corresponding sections of the PLs.
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Outcome of the assessment
Although the data was limited for some antipsychotics with regards to effects in newborns following
maternal use during pregnancy, the PhVWP agreed that these effects are likely to be a class effect
and considered that the wordings in the product information should be consistent for the whole class
of antipsychotics.
The PhVWP subsequently concluded that there was a risk of extrapyramidal effects and withdrawal
symptoms in newborns following maternal use of antipsychotics during the third trimester of
pregnancy and agreed core information to be included for the SmPCs and PLs for all antipsychotics in
the EU (i.e. chlorpromazine, clotiapine, clozapine, fluphenazine, haloperidol, loxapine, molindone,
perphenazine, pimozide, prochlorperazine, risperidone, thioridazine, thiothixene, trifluoperazine and
ziprasidone). The wordings of the core information are consistent with the wordings already agreed
for paliperidone and the FDA approved drug labels.
References
[1] U.S. Food and Drug Administration. FDA Drug Safety Communication: antipsychotic drug labels
updated on use during pregnancy and risk of abnormal muscle movements and withdrawal symptoms
in newborns. Silver Spring, MD: US FDA; 22 February 2011.