Novartis Pharmaceuticals UK Ltd

Neonates exposed to antipsychotics (including Clozaril) 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.

Section 4.8 the following wording has been added:

Pregnancy, puerperium and perinatal conditions

Not known               Drug withdrawal syndrome neonatal (see 4.6)

The tablet can be divided into equal halves.

Section 4.8 -  The text shown in italics has been added to Section 4.8 as shown below:

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.

Increased mortality in elderly people with dementia:

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.

Clozaril is not approved for the treatment of dementia-related behavioural disturbances.

Section 4.2

The following text has been added:

For doses not realisable/practicable with one strength, other strengths of this medicinal product are available.

Section 4.4:

The following text has been added:

This medicinal product contains lactose monohydrate.

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.  Use of Clozaril has not been studied in patients with dementia and is therefore not recommended in this patient population.

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.

Section 4.5:

The following text has been added:

As with other antipsychotics, caution should be exercised when clozapine is prescribed with medicines known to increase QTc interval, or causing electrolyte imbalance.

The following information has been added to Table 2: Reference to the most common drug interactions with Clozaril.

Section 4.8:

Table 4: Treatment-emergent adverse experience frequency estimate from spontaneous and clinical trial reports has been reformatted.

Additionally, the following text has been added:

Very rare events of 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.