Explanation of changes product info ztas 290312

NEW ANNOUNCEMENT
IMPORTANT CHANGES TO ZAPONEX PRODUCT INFORMATION

PLEASE READ THE FOLLOWING INFORMATION BEFORE LOGGING ON TO ZTAS!
At the request of the UK Medicines and Healthcare products Regulatory Agency (MHRA), all
manufacturers of antipsychotic drugs were asked to update fragments of the Summary of Product
Characteristics (SmPC) with warnings regarding the use of antipsychotics (conventional and atypical)
during pregnancy and risk of abnormal muscle movements and/or withdrawal symptoms in newborns.
The wording has been dictated on a European level by the so-called ‘European Committee for Human
Medicinal Products’ Pharmacovigilance Working Party (PhVWP)’, in June 2011.
In addition to these European level changes, the MHRA has requested Leyden Delta BV (the
Marketing Authorisation Holder of Zaponex®) harmonise the SmPC and PIL with those of the brand
leader in the United Kingdom. As a result several undesirable effects have now been added as
listed adverse events.
The updates to the SmPC are highlighted in yellow below. The Patient Information Leaflet (PIL) has
been updated accordingly.
The changes were approved in January 2012. As a consequence, as of 1 May 2012 a completely
updated PIL will be introduced in all newly-packaged Zaponex boxes and pots.
As the total amount of information provided in the PIL has increased the new leaflet is larger than the
previous version.
It could take a few months for this new stock to be delivered to your hospital or retail pharmacies.
However, the updated product information is available on the ZTAS websites (under ‘Download forms’
on the public site and under ‘Information’ on the secured site) and can be printed from there.
Changes to the SUMMARY OF PRODUCT CHARACTERISTICS
Warnings regarding the use during pregnancy and risk in newborns:

Section 4.6 ‘Fertility, pregnancy and lactation’,

• Under ‘Pregnancy’ a second paragraph has been added, reading:
Neonates exposed to antipsychotics (including Zaponex) during the first 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.

Section 4.8 ‘Undesirable effects’,

• A System Organ Class has been added: Pregnancy, puerperium and perinatal conditions
which lists the following Adverse Drug Reaction / Frequency: Drug withdrawal syndrome neonatal (see
4.6) – Not known
Changes resulting from harmonisation with the brand leader:
General

The wording ‘drug’ / ‘drugs’ has been replaced by ‘substance’ / ‘substances’.
Section 1 ‘Name of the medicinal product’,

• The information in this section has been re-ordered, re-worded and partly extended.
• The following information has been added: “When a monitoring service is not used, evidence suggests a mortality rate from agranulocytosis of 0.3%[1]. This is compared to a mortality rate from agranulocytosis when Zaponex is used in conjunction with the Zaponex Treatment Access System, of 0.01%[2].” • It is now mentioned clearly that “Monitoring must continue throughout treatment and for at least 4 • References [1] and [2] are added.
• In the boxed warning ‘should’ has been replaced by ‘must’.
Section 2 ‘Qualitative and quantitative composition’,

A sentence has been added:
Zaponex 25 mg Tablets: “Excipients: also includes lactose monohydrate 48 mg per tablet.”
Zaponex 100 mg Tablets: “Excipients: also includes lactose monohydrate 192 mg per tablet.”
Section 4.2 ‘Posology and method of administration’,

• The subsection ‘Use in children’ has been changed to ‘Use in children and adolescents’.
• The first sentence of this subsection has been reworded to: “Zaponex is not recommended for use in children or in adolescents under the age of 16 due to lack of data on safety and efficacy.”
Section 4.3 ‘Contraindications’,

The last mentioned contraindication from this section has been removed and is now mentioned in
section 4.4 ‘Special warnings and precautions for use’ under the subsection ‘Other precautions’.
Section 4.4 ‘Special warnings and precautions for use’,

All throughout the boxed warning ‘should’ has been replaced by ‘must’. The final sentence has been
tightened and now reads: “Patients who have low WBC counts because of benign ethnic neutropenia
should be given special consideration and may only be started on clozapine with the agreement of a
haematologist.”
The subsection ‘Other precautions’ has been extended with the following information:
This medicinal product contains lactose monohydrate.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose
galactose malabsorption should not take this medicine. (Previously listed as a contraindication.)
Acute withdrawal reactions have been reported following abrupt cessation of clozapine therefore
gradual withdrawal is recommended. If abrupt discontinuation is necessary (e.g. because of
leukopenia), the patient should be carefully observed for the recurrence of psychotic symptoms and
symptoms related to cholinergic rebound, such as profuse sweating, headache, nausea, vomiting and
diarrhoea. (In sections 4.2 and 4.8 reference is made to this information.)

An approximately 3-fold increased risk of cerebrovascular adverse events has been seen in
randomised placebo controlled clinical trials in the dementia population with some atypical
antipsychotics. The mechanism for this increased risk is not known. An increased risk cannot be
excluded for other antipsychotics or other patient populations. Clozapine should be used with caution
in patients with risk factors for stroke.
As with other antipsychotics, caution is advised in patients with known cardiovascular disease or
family history of QT prolongation.
As with other antipsychotics, caution should be exercised when clozapine is prescribed with medicines
known to increase QTc interval.

At the end of section 4.4 a subsection has been added, ‘Increased mortality in elderly people with
dementia’, stating the following information:
Data from two large observational studies showed that elderly people with dementia who are treated
with antipsychotics are at a small increased risk of death compared with those who are not treated.
There are insufficient data to give a firm estimate of the precise magnitude of the risk and the cause of
the increased risk is not known.
Zaponex is not approved for the treatment of dementia-related behavioural disturbances.
Section 4.5 ‘Interaction with other medicinal products and other forms of interaction’,

In the subsection ‘Precautions including dose adjustment’ the information on SSRIs has been changed
with regard to the position of paroxetine.
The text in the previous SmPC (March 2010) was: “Concomitant administration of drugs known to
inhibit the activity of some cytochrome P450 isozymes may increase the levels of clozapine, and the
dose of clozapine may need to be reduced to prevent undesirable effects. This is more important for
CYP 1A2 inhibitors such as caffeine (see below) and the selective serotonin reuptake inhibitors
fluvoxamine and (more controversial) paroxetine. Some of the other serotonin reuptake
inhibitors such as fluoxetine and sertraline are CYP 2D6 inhibitors and, as a consequence, major
pharmacokinetic interactions with clozapine are less likely.”
The bold section has now been changed to read: “This is more important for CYP 1A2 inhibitors such
as caffeine (see below) and the selective serotonin reuptake inhibitor fluvoxamine. Some of the other
serotonin reuptake inhibitors such as fluoxetine, paroxetine and, to a lesser degree, sertraline, are
CYP 2D6 inhibitors and, as a consequence, major pharmacokinetic interactions with clozapine are
less likely.”
The subsection ‘Precautions including dose adjustment’ has been extended with the following
information:
Cases have been reported of an interaction between citalopram and clozapine, which may increase
the risk of adverse events associated with clozapine. The nature of this interaction has not been fully
elucidated.
Known inducers of CYP1A2, such as omeprazole, may lead to decreased clozapine levels. The
potential for reduced efficacy of clozapine should be considered when it is used in combination with
these substances.
The subsection ‘Other’ has been extended with the following information:
As with other antipsychotics, caution should be exercised when clozapine is prescribed with medicines known to increase QTc interval, or causing electrolyte imbalance. An outline of drug interactions believed to be most important with clozapine is given in Table 2. It is added that “The list is not exhaustive.” Table 2 has been extended with two categories of substances: Potential for reduced efficacy of clozapine Potential for increase in adverse effects. medications as there will be a decrease in clozapine levels
Section 4.8 ‘Undesirable effects’,
• There is a new order in presenting the System Organ Classes and a new System Organ Class
has been added (see above, yellow marking). • Anaemia and Thrombocythaemia have been added to the SmPC as listed undesirable effects,
under ‘Blood and lymphatic system disorders’, with respective frequencies ‘Rare’ and ‘Very rare’. • Obsessive compulsive symptoms has been added to the SmPC as listed undesirable effect,
under ‘Nervous system disorders’, with frequency ‘Very rare’. • Pneumonia and lower respiratory tract infection which may be fatal have been added to the
SmPC as listed undesirable effect, under ‘Respiratory, thoracic and mediastinal disorders’, with frequency ‘Rare’. • Hypercholesterolaemia has been added to the SmPC as listed undesirable effect, under
‘Metabolism and nutrition disorders’, with frequency ‘Very rare’. • Dysarthria and Dysphemia have been added to the SmPC as listed undesirable effects, under
‘Psychiatric disorders’, with respective frequencies ‘Common’ and ‘Uncommon’.
At the end of the section a new paragraph is added: “Very rare events of ventricular tachycardia and
QT prolongation which may be associated with Torsades De Pointes have been observed although
there is no conclusive causal relationship to the use of this medicine.”
Section 4.9 ‘Overdose’,

• Subsection ‘Treatment’: The third sentence was incomplete and has been rewritten and extended
to read “Symptomatic treatment under continuous cardiac monitoring, surveillance of respiration, monitoring of electrolytes and acid-base balance. The use of epinephrine should be avoided in the treatment of hypertension because of the possibility of a ‘reverse epinephrine’ effect.
Sections 6.2 ‘Incompatibilities’ and 6.6 ‘Special precautions for disposal and other handling’,

• The content has been changed/shortened to read “Not applicable” and “No special requirements”,
N.B.: In order to keep this message as concise as possible only the clinically relevant changes are described above. If you are interested to know all changes, please send an email to info@ztas.co.uk with a request for a marked copy of the SmPC, showing all changes.

Source: http://www.ztas.co.uk/pdf/Explanation_of_changes_to_Zaponex_product_information_290312.pdf