SUMMARY OF PRODUCTS CHARACTERISTICS 1. NAME OF THE ...

1. NAME OF THE MEDICINAL
Neuleptil 4%, oral solution
Neuleptil 10 mg, capsule
SUMMARY OF PRODUCTS CHARACTERISTICS
2. QUALITATIVE AND QUANTITATIVE COMPOSTION
3. PHARMACEUTICAL FORM
4. CLINICAL PARTICULARS
4.1 Therapeutic Indications
Psychotic disorders
4.2 Posology and method of administration
1 drop contains 1 mg of periciazine
1 ml of solution contains 40 drops
ORAL ROUTE
Always seek the minimum effective dose. If the clinical condition of the patient allows it,
institute treatment at a low dose and gradually increase step-wise.
The daily dose should be divided into two or three intakes.
Adults :
The dose is 30 to 100 mg/day.
In certain exceptional cases, the dose may be increased to a maximum of 200 mg/day.
4.3 Contra-indications
This drug must not be used in the following cases :
- hypersensitivity to periciazine or to one of the other ingredients of this medicinal
product,
- risk of angle-closure glaucoma,
- risk of urinary retention linked to urethroprostatic disorders,
- history of agranulocytosis,
- combination with dopamine agonists (amantadine, apomorphine, bromocriptine,
cabergoline, entacapone, lisuride, pergolide, piribedil, pramiprexole, quinagolide,
ropinirole ) except in patients with Parkinson's disease
תואירבה דרשמ י"
ע עבקנ הז ןולע טמרופ
2007 רבמבונב
רשואו קדבנ ונכותו

AS GENERAL RULE, this drug SHOULD NOT BE USED in the following cases :
- lactation ( see. Pregnancy and lactation)
- combination with :
. alcohol
. levodopa
- . dopamine agonists (amantadine, apomorphine, bromocriptine, cabergoline,
entacapone, lisuride, pergolide, piribedil, pramiprexole, quinagolide, ropinirole ) in
patients with Parkinson's disease
- Breast cancer (potentially higher risk of disease progression and possible increased
resistance to endocrine and cytotoxic treatment, due to phenothiazine-induced
prolactin secretion
4.4 Warnings and special precautions for use
Warnings
• All patients must be advised that if they experience fever, sore throat or any other
infection, they should inform their physician immediately and undergo a complete
blood count.
Treatment will be discontinued if any marked changes (hyperleucocytosis,
granulocytopenia) are observed in the latter.
• Neuroleptic malignant syndrome : treatment must be interrupted in the event of
unexplained hyperpyrexia since this can be one of the signs of neuroleptic malignant
syndrome ( pallor, hyperthermia, disorders of autonomic function). Signs of
autonomic instability, such as sweating and irregular blood pressure, can precede the
onset of hyperthermia and as such constitue premonitory signs of this syndrome.
While this neurolepic-related effect can be od idiosyncratic origin, certain risk factors
such as dehydration and organic brain damage would seem to indicate a
predisposition.
• Prolonged QT interval : Neuroleptic phenothiazines may potentiate QT interval
prolongation which increase the risk of onset of serious ventricular arrhythmias of the
torsade de pointes type which is potentially fatal (sudden death). Periciazine prolongs
the QT interval in a dose-dependent fashion.
This effect, which is known to increase the risk of developing serious ventricular
arrhythmias of the torsades de pointes type, is exacerbated in the presence of
bradycardia, hypokalemia, and congenital or acquired long QT syndrome
(concomitant administration with a QT interval prolonging drug). Where clinically
possible, the absence of any factors favouring the onset of ventricular arrhythmias
should be ensured before administration :
- Bradycardia less than 55 beats per minute,
- Hypokalemia
- Congenital QT interval prolongation.
- Ongoing treatment with any drug that could induce marked bradycardia (

• With the exception of emergencies, it is recommended that the intitial work up of
patients receiving a neuroleptic should include an ECG.
• Except under exceptional circumstances, this drug must not be administered to
patients with Parkinson’s disease and in patients suffering from severe CNS
depression
• The onset of paralytic ileus with abdominal bloating and pain, must be treated as an
emergency.
• The solution contains sucrose and are therefore contraindicated in patients with
fructose intolerance, congenital galactosemia, glucose or galactose malabsorption
syndrome, and sucrase-isomalte deficiency
Special precautions for use
The following populations must be closely monitored afer administration of periciazine :
• epileptic patients, since periciazine may lower the seizure threshold. Treatment must
be discontinued if seizures occur,
• elderly patients presenting with :
- heightened susceptibility to postural hypotension, sedation and extrapyramidal effects,
- chronic constipation (risk of paralytic ileus),
- and potentially prostatic hypertrophy,
• patients presenting with certain forms of cardiovascular disease since this class of drug
has quinidine-like effects and can induce tachycardia and hypotension,
• patients with severe liver and/or renal failure because of the risk of accumulation.
•
Respiratory disorders, chronic, especially in children (may be potentiated due to CNS
depressant effect of phenothiazines . also, cough-suppressant effects of phenothiazines may be
especially problematic in these patients
Patients are strongly advised not to consume alcohol and alcohol-containing drugs throughout
treatment.
The alcohol content of the solution is 9 %, that is to say 90 mg of alcohol for 40 drops. His
presentation is inadvisable for patients suffering of liver disease, alcoholism, epilepsy,
medical and traumatic cerebral disorders.
Caution should also be used in geriatric, emaciated, and debilitated patients, who usually
require a lower initial dose . , and in patients who will be exposed to organophosphate or
carbamate pesticides , extreme heat , or extreme cold
When extended therapy is discontinued, a gradual reduction in phenothiazine dosage over
several weeks is recommended, since abrupt withdrawal may cause some patients on high or
long-term dosage to experience transient dyskinetic signs, nausea, vomiting, gastritis,
trembling, and/or dizziness .. The continuation of treatment with antidyskinetic medications
for several weeks after discontinuing the phenothiazine may reduce these symptoms . but can
precipitate psychosis .. Also, preliminary evidence suggests that gradual dosage reduction
may decrease the relapse risk associated with discontinuation .

Stroke:
In randomised clinical trials versus placebo performed in a population
of elderly patients with dementia and treated with certain atypical
antipsychotic drugs, a 3-fold increase of the risk of cerebrovascular events has
been observed. The mechanism of such risk increase is not known. An
increase in the risk with other antipsychotic drugs or other populations of
patients cannot be excluded. Nozinan should be used with caution in
patients with stroke risk factors.
4.5 Interaction with other medicinal products and other forms of interaction
Contraindicated association
Dopamine agonists (amantadine, apomorphine, bromocriptine, cabergoline, entacapone,
lisuride, pergolide, piribedil, pramiprexole, quinagolide, ropinirole) except in patients with
Parkinson's disease
Reciprocal antagonism of the dopamine agonist and neuroleptic drugs.
Neuroleptic-induced extrapyramidal syndrome should be treated with an anticholinergic
rather than a dopamine agonist.
Inadvisable associations
+ Alcohol :
Alcohol potentiates the sedative effects of neuroleptics. Impaired vigilance may make it
hazardous to drive motor vehicles or operate machinery.
Avoid consumption of alcoholic beverages and medications containing alcohol.
+ Levopoda :
Reciprocal interaction between levodopa and neuroleptic drugs.
In patients with Parkinson's disease, minimum effective doses of each medication should be
used.
+ Dopamine agonists (amantadine, apomorphine, bromocriptine, cabergoline, entacapone,
lisuride, pergolide, piribedil, pramiprexole, quinagolide, ropinirole) in patients with
Parkinson's disease
Reciprocal interaction between dopamine agonists and neuroleptic drugs. Dopamine agonists
may induce or aggravate psychotic disorders. If a Parkinsonian patient taking dopamine
agonists requires neuroleptic treatment, dopamine agonists should be gradually decreased
until discontinuation (sudden discontinuation of dopamine exposes the patient to risk of
«neuroleptic malignant syndrome»).
Associations requiring precautions for use
+ Topical gastrointestinal agents (magnesium, aluminium and calcium salts, oxides and
hydroxides) : decreased GI absorption of phenothiazine neuroleptics. Do not administer
phenothiazine neuroleptics simultaneously with topical GI agents (administer more than 2
hours apart if possible).

Associations to be taken into account
+ Antihypertensive agents : potentiation of the antihypertensive effect and risk of postural
hypotension (additive effects). (See below for guanethidine).
+ Guanethidine : inhibition of the antihypertensive effects of guanethidine (inhibition of
guanethidine uptake into sympathetic fibre, its site of action).
+ Atropine and other atropine derivatives : imipramine antidepressants, histamine H1receptor
antagonists, anticholinergic antiparkinsonism agents, atropinic antispasmodics,
disopyramide : build up of atropine-associated adverse effects such as urinary retention,
constipation and dry mouth, etc.
+ Other CNS depressants : morphine derivatives (analgesics, antitussives and substitution
treatments), barbiturates, benzodiazepines, anxiolytics other than benzodiapezines, carbamate,
captodiame, etifoxine, hypnotics, sedative antidepressants, histamine H1 receptor antagonists,
central antihypertensive agents, baclofen, thalidomide : increased central depression. Changes
in alertness can make it dangerous to drive motor vehicles or operate machinery.
4.6 Pregancy and lactation
Pregnancy
Animal studies have not evidenced teratogenicity.
In humans, the teratogenic risk of periciazine has not been evaluated. Different prospective
epidemiological studies conducted with other phenothiazines have yielded contradictory
results regarding teratogenic risk. No data exists regarding the impact of neuroleptics on the
foetal brain when administered throughout pregnancy.
Rare instances of the following have been observed in the neonates of mothers receiving long
term treatment with high doses of neuroleptics :
- signs related to the atropinic properties of phenothiazines (abdominal bloating,
meconium ileus, delayed meconium passage, initial feeding difficulties, tachycardia,
neurological disorders, etc.),
- extrapyramidal syndromes.
Consequently, the teratogenic risk, if it exists, appears to be low. Attempting to limit
treatment duration during pregnancy appears reasonable.
If possible, the dosages of both neuroleptic drugs and corrective antiparkinsonism agents
potentiating the atropinic effects of neuroleptics should be reduced near term. A period of
monitoring the neurological and gastrointestinal functions of the neonate appears warranted.
Lactation
In absence of data on excretion of the drug in breast milk, breast-feeding is not recommended
during treatment.

4.7 Effects on ability to drive and use machines
The attention of patients, particularly drivers and machine operators, should be drawn to the
risk of drowsiness with this medication especially at the start of treatment.
4.8 Undesirable effects
At low doses :
-Autonomic reactions :
. Postural hypotension.
. Anticholinergic effects such as dry mouth, accommodation disorders, risk of urinary
retention, constipation and even paralytic ileus (see Special warnings and special precautions
for use).
- Neuropsychaitric disorders :
. Sedation or drowsiness, particularly at the start of treatment.
. Lethargy, anxiety, mood disorders.
At higher doses :
. Early manifestations of dyskinesia (spasmodic torticolis, oculogyric crises, trismus, etc.).
. Tardive dyskinesia, particularly during long-term treatment.
Anticholinergic antiparkinsonism agents have no effect or aggravate the symptoms.
. Extrapyramidal syndrome :
- akinetic with or without hyertonia, partially resolving with anticholinergic
antiparkinsonism agents,
- hyperkinetohypertonic, excitomotor,
- akathisia
- Endocrine and metabolic reactions :
. Hyperprolactinemia : amenorrhoea, galactorrhoea, gynecomastia, impotence, frigidity.
. Weight gain.
. Thermoregulation disorders
. Hyperglycemia, changes in glucose tolerance.
Rarely, and in a dose dependent manner :
- Cardiac disorders :
. QT interval prolongation.
Very rarely and independent of dose :
- Skin reactions :
. Allergic skin reactions.
. Photosensitivity.
- Haematological disorders :
. Exceptionally agranulocytosis : regular blood counts are recommended.
. Leucocytopenia

- Ophthalmologic disorders :
.Brownish deposits in the anterior segment of the eye caused by accumulation of the
drug but generally without any impact on sight.
- Miscellaneous :
. Positive antinuclear antibodies wihtout clinical lupus erythematosus.
. Possible cholestatic jaundice.
. Neuroleptic malignant syndrome (see Warnings).
Cholestatic jaundice and liver injury, mainly of cholestatic or mixed type, are very rarely
reported in patients treated with periciazine. Priapism has been very rarely reported in patients
treated with periciazine.
There have been isolated reports of sudden death, with possible causes of cardiac origin ( see
Warnings ), as well as cases of unexplained sudden death, in patients receiving neuroleptic
phenothiazines.
4.9 Overdose
Extremely severe drug-induced parkinsonism, coma.
Symptomatic treatment, continuous respiratory and cardiac monitoring (risk of prolonged QT
interval) until the patient’s condition resolves.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
ANTIPSYCHOTIC – NEUROLEPTIC
PHENOTHIAZINE WITH PIPERIDINE STRUCTURE
(N: central nervous sysytem)
Neuroleptic antipsychotics have antidopaminergic properties to which are imputed :
• the antipsychotic effect sought in therapy,
• adverse effects (extrapyramidal syndrome, dyskinesias, hyperprolactinemia).
Periciazine has moderate antidopaminergic activity, its antipsychotic activity is moderated, it
has moderate extrapyramidal effects.
The molecule also has antihistamine properties ( causing sedation, a generally desired effect
In the clinic). It has marked adrenolytic and anticholinergic properties.
Neuleptil caps - Manufacturer: Haupt Pharma Livron, France
Neuleptil drops - Manufacturer: Aventis Pharma Ireland
License Holder : Sanofi-Aventis Israel ltd.