4.1. Therapeutic indications

a) In adults with schizophrenia or other psychoses, for the treatment of symptoms or prevention of relapse.

b) In anxiety, psychomotor agitation, violent or dangerously impulsive behaviour. Pericyazine is used as an adjunct to the short-term management of these conditions.

4.2. Posology and method of administration

Posology

Severe conditions

Indication (a) Adults: Initially 75 mg per day in divided doses. Dosage should be increased by 25 mg per day at weekly intervals until the optimum effect is achieved. Maintenance therapy would not normally be expected to exceed 300 mg per day. Elderly: Initially 15-30 mg per day in divided doses. If this is well tolerated the dosage may be increased if necessary for optimum control of behaviour.

Mild or moderate conditions

Indication (b) Adults: Initially 15-30 mg daily, divided into two portions with a larger dose being given in the evening. Elderly: 5-10 mg per day is suggested as a starting dose. It may be divided so that a larger portion is given in the evening. Half or quarter the normal adult dose may be sufficient for maintenance therapy.Pericyazine tablets are not recommended for children.

Method of administration

Oral.

Dosage requirement varies with the individual and the severity of the condition being treated. Initial dosage should be low with progressive increases until the desired response is obtained, after which dosage should be adjusted to maintain control of the symptoms.

4.3. Contraindications

See use in pregnancy below. Known hypersensitivity to pericyazine or to any of the other excipients listed in section 6.1.

Risk of urinary retention due to urethroprostatic disorders.

Dopaminergic antiparkinsonism agents (see section 4.5).

Do not use in children younger than 1 year, due to a possible link between use of phenothiazine-containing products and Sudden Infant Death Syndrome (SIDS).

Risk of angle-closure glaucoma.

History of agranulocytosis.

Hypersensitivity or intolerance to gluten, because the medicinal product contains wheat starch (gluten).

4.4. Special warnings and precautions for use

Neuroleptics should be avoided in patients with liver or renal dysfunction, Parkinson's disease, hypothyroidism, cardiac failure, phaeochromocytoma, myasthenia gravis, prostrate hypertrophy. It should be avoided in patients known to be hypersensitive to phenothiazines or with a history of narrow angle glaucoma or agranulocytosis. It should be used with caution in the elderly, particularly during very hot or very cold weather (risk of hyper-hypothermia).

Close monitoring is required in patients with epilepsy or a history of seizures, as phenothiazines may lower the seizure threshold. The occurrence of convulsive seizures necessitates the discontinuation of treatment.

As agranulocytosis may occur rarely, regular monitoring of the complete blood count is recommended.

It is imperative that treatment be discontinued in the event of unexplained fever, as this may be a sign of neuroleptic malignant syndrome (pallor, hyperthermia, autonomic dysfunction, altered consciousness, muscle rigidity). Signs of autonomic dysfunction, such as sweating and arterial instability, may precede the onset of hyperthermia and serve as early warning signs. Although neuroleptic malignant syndrome may be idiosyncratic in origin, dehydration and organic brain disease are predisposing factors.

The occurrence of unexplained infections or fever may be evidence of blood dyscrasia (see section 4.8 below), and requires immediate haematological investigation.

All patients should be informed that, should fever, sore throat or another infection occur, the consulting physician must be notified immediately and the blood count monitored. If there is a marked change in the latter (hyperleucocytosis, granulopenia), administration of Pericyazine 2.5mg Tablets should be stopped.

Acute withdrawal symptoms, including nausea, vomiting and insomnia, have very rarely been reported following the abrupt cessation of high doses of neuroleptics. Relapse may also occur, and the emergence of extrapyramidal reactions has been reported. Therefore, gradual withdrawal is advisable.

In schizophrenia, the response to neuroleptic treatment may be delayed. If treatment is withdrawn, the recurrence of symptoms may not become apparent for some time.

Neuroleptic phenothiazines may potentiate QT interval prolongation which increases the risk of onset of serious ventricular arrhythmias of the torsade de pointes type, which is potentially fatal (sudden death). QT prolongation is exacerbated, in particular, in the presence of bradycardia, hypokalaemia, and congenital or acquired (i.e. drug induced) QT prolongation. The risk-benefit should be fully assessed before pericyazine treatment is commenced. If the clinical situation permits, medical and laboratory evaluations (e.g. biochemical status and ECG) should be performed to rule out possible risk factors (e.g. cardiac disease; family history of QT prolongation; metabolic abnormalities such as hypokalaemia, hypocalcaemia or hypomagnesaemia; starvation; alcohol abuse; concomitant therapy with other drugs known to prolong the QT interval) before initiating treatment with pericyazine and during the initial phase of treatment, or as deemed necessary during the treatment (see also sections 4.5 and 4.8).

Use with caution in patients with certain cardiovascular conditions, because of the quinidine-like, tachycardia-inducing and hypotensive effects of this class of products.

Avoid concomitant treatment with other neuroleptics (see section 4.5).

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. Pericyazine should be used with caution in patients with stroke risk factors.

As with all antipsychotic drugs, pericyazine should not be used alone where depression is predominant. However, it may be combined with antidepressant therapy to treat those conditions in which depression and psychosis coexist.

Because of the risk of photosensitisation, patients should be advised to avoid exposure to direct sunlight.

In those frequently handling preparations of phenothiazines, the greatest care must be taken to avoid contact of the drug with the skin, since contact skin sensitisation occurs rarely.

Cases of venous thromboembolism (VTE), sometimes fatal, have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with pericyazine and preventive measures undertaken.

Hyperglycaemia or intolerance to glucose has been reported in patients with pericyazine.

Patients with an established diagnosis of diabetes mellitus or with risk factors for the development of diabetes who are started on pericyazine, should get appropriate glycaemic monitoring during treatment (see section 4.8).

Careful monitoring of treatment with Pericyazine 2.5mg Tablets is required in patients with severe hepatic impairment and/or renal impairment, due to the risk of accumulation.

The consumption of alcohol and of any medication containing alcohol is highly inadvisable during treatment.

The onset of paralytic ileus, which can manifest itself as abdominal bloating and pain, requires emergency treatment.

Careful monitoring of treatment with Pericyazine 2.5mg Tablets is required in elderly patients exhibiting greater susceptibility to orthostatic hypotension, sedation and extrapyramidal effects; chronic constipation (risk of paralytic ileus); possible prostatic hypertrophy.

Elderly Patients with Dementia:

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death in clinical trials with atypical antipsychotics were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.

Increased Mortality in Elderly people with Dementia

Data from two large observational studies showed that elderly people with dementia who are treated with conventional (Typical) antipyschotics 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.

Pericyazine is not licensed for the treatment of dementia-related behavioural disturbances.

Methyl hydroxybenzoate:

Each 2.5mg tablet contains 0.001 mg benzoate salt.

Lactose:

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose galactose malabsorption should not take this medicine.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Contra-indicated drug combinations:

Antiparkinsonism dopaminergic agonists agents (amantadine, apomorphine, bromocriptine, cabergoline, entacapone, lisuride, pergolide, piribedil, pramiprexole, quinagolide, ropinirole): Reciprocal antagonism between the dopaminergic agonist and neuroleptics. Neuroleptic-induced extrapyramidal syndrome should be treated with an anticholinergic rather than a dopaminergic antiparkinsonism agent (dopaminergic receptors blocked by neuroleptics).

Patients being treated for Parkinson's disease with a dopaminergic antiparkinsonism agent and requiring a neuroleptic, should cease antiparkinsonism therapy since such agents exacerbate psychotic disorders and cannot act on receptors blocked by neuroleptics.

Drug combinations not recommended:

Sultopride: Increased risk of ventricular arrhythmias, particularly of the torsades de pointes type, by addition of electrophysiological effects.

Alcohol: Intensification of the sedative effects of neuroleptics. Impaired vigilance may make it dangerous to drive or use machines. Avoid consumption of alcoholic beverages and medications containing alcohol.

Levodopa: Reciprocal antagonism between levodopa and neuroleptics. In parkinsonian patients, use the minimum effective doses of both medications.

Drug combinations requiring precautions:

Topical gastro-intestinal agents (magnesium, aluminium and calcium salts, oxides and hydroxides): Reduced gastro-intestinal absorption of phenothiazine neuroleptics. Antacids should not be taken at the same time as phenothiazine neuroleptics (at least 2 hours apart, if possible).

Lithium (high doses of neuroleptics): Concomitant use might increase the risk of QT prolongation and the risk of the appearance of neuropsychiatric signs suggestive of neuroleptic malignant syndrome or lithium poisoning. Regular clinical and biological monitoring of serum (lithium), especially when the combination is initiated.

Drug combinations to be taken into consideration:

Atropine and other atropine-like substances: Imipramine antidepressants, sedative H1 antihistamines, anticholinergic antiparkinsonian agents, atropine-like antispasmodics, disopyramide: cumulative atropine-like side effects such as urinary retention, constipation, dry mouth.

Antihypertensives: Increased antihypertensive effect and risk of orthostatic hypotension (cumulative effect).

Guanethidine: Inhibition of the antihypertensive effect of guanethidine (inhibition of guanethidine uptake by sympathetic nerve fibres, the site of action).

Other central nervous system depressants: Morphine derivatives (analgesics, antitussives and replacement therapies), barbiturates , benzodiazepines, anxiolytics other than benzodiazepines (carbamates, captodiame, etifoxine), hypnotics, sedative antidepressants, sedative H1 antihistamines, central antihypertensives, baclofen, thalidomide: enhanced central depression. Impaired vigilance may have serious consequences when driving or using machines.

Interactions of phenothiazine neuroleptics:

The CNS depressant actions of neuroleptic agents may be intensified (additively) by alcohol, barbiturates and other sedatives. Respiratory depression may occur.

The hypotensive effect of most antihypertensive drugs, especially alpha adrenoceptor blocking agents may be exaggerated by neuroleptics.

There is an increased risk of arrhythmias when neuroleptics are used with concomitant QT prolonging drugs (including certain antiarrhythmics, antidepressants, and other antipsychotics) and drugs causing electrolyte imbalance (see sections 4.4 and 4.8).

The mild anticholinergic effect of neuroleptics may be enhanced by other anticholinergic drugs, possibly leading to constipation, heat stroke, etc.

The action of some drugs may be opposed by neuroleptics; these include amphetamine, levodopa, clonidine, guanethidine, adrenaline.

Where treatment for neuroleptic-induced extrapyramidal symptoms is required, anticholinergic antiparkinsonian agents should be used in preference to levodopa, since neuroleptics antagonise the antiparkinsonian action of dopaminergics.

Anticholinergic agents may reduce the antipsychotic effect of neuroleptics.

Some drugs interfere with absorption of neuroleptic agents: antacids, anti-Parkinson drugs, lithium. Increases or decreases in the plasma concentrations of a number of drugs, e.g: propranolol, phenobarbital have been observed but were not of clinical significance. High doses of neuroleptics may reduce the response to hypoglycaemic agents the dosage of which might have to be raised.

In patients treated concurrently with neuroleptics and lithium, there have been rare reports of neurotoxicity.

Adrenaline must not be used in patients overdosed with neuroleptics.

Simultaneous administration of desferrioxamine and prochlorperazine has been observed to induce a transient metabolic encephalopathy characterised by loss of consciousness for 48-72 hours. It is possible this may occur with pericyazine since it shares many of the pharmacological properties of prochlorperazine.

There is an increased risk of agranulocytosis when neuroleptics are used concurrently with drugs with myelosuppressive potential, such as carbamazepine or certain antibiotics and cytotoxics.

Phenothiazines are potent inhibitors of CYP2D6. There is a possible pharmacokinetic interaction between inhibitors of CYP2D6, such as phenothiazines, and CYP2D6 substrates. Co-administration of phenothiazines with amitriptyline/amitriptylinoxide, a CYP2D6 substrate, may lead to an increase in the plasma levels of amitriptyline/amitriptylinoxide. Monitor patients for dose-dependent adverse reactions associated with amitriptyline/amitriptylinoxide.

4.6. Fertility, pregnancy and lactation

Pregnancy

Available data from studies in animals have shown no evidence of a teratogenic effect. Available human data are insufficient to exclude a risk of congenital malformation in children exposed in utero to Pericyazine 2.5mg Tablets. As a precautionary measure, the use of periciazine should be avoided during pregnancy unless the potential benefits outweigh the potential risks.

If possible, it is preferable to taper the dosage of both neuroleptics and antiparkinsonians, which potentiate the atropine-like effects of neuroleptics, at the end of pregnancy.

A period of monitoring of the neurological and gastro-intestinal functions of the neonate appears warranted.

There is inadequate evidence of the safety of pericyazine in humans. There is evidence with some neuroleptics of harmful effects in animals. Like other drugs pericyazine should be avoided in pregnancy unless the physician considers it essential. It may occasionally prolong labour and at such a time should be withheld until the cervix is dilated 3-4 cm. Possible adverse effects on the foetus include lethargy or paradoxical hyperexcitability, tremor and low Apgar score.

The following effects have been reported (in postmarketing surveillance) in neonates exposed to phenothiazines during the third trimester of pregnancy:

- Various degrees of respiratory disorders ranging from tachypnea to respiratory distress, bradycardia and hypotonia, most often when other drugs such as psychotropic or antimuscarinic drugs were coadministered.

- Signs related to the atropinic properties of phenothiazines such as meconium ileus, delayed meconium passage, initial feeding difficulties, abdominal bloating, tachycardia;

- Neurological disorders such as extrapyramidal symptoms including tremor and hypertonia, somnolence, agitation. Appropriate monitoring and treatment of neonate born to mother receiving Pericyazine 2.5mg Tablets are recommended.

Neonates exposed to antipsychotics (including pericyazine) 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.

Lactation

In the absence of data on excretion in breast milk, breastfeeding is not recommended during treatment.

4.7. Effects on ability to drive and use machines

Patients should be warned about drowsiness during early days of treatment, and advised not to drive or operate machinery. The elderly are particularly susceptible to postural hypotension.

4.8. Undesirable effects

The following CIOMS frequency rating is used, when applicable: Very common ≥ 10 %; Common ≥ 1 and <10 %; Uncommon ≥ 0.1 and < 1 %; Rare ≥ 0.01 and < 0.1 %; Very rare < 0.01 %; Not known (frequency cannot be estimated from available data).

Endocrine disorders:

Liver function: jaundice, occurs in a very small percentage of patients taking neuroleptics. A premonitory sign may be a sudden onset of fever after one to three weeks of treatment followed by the development of jaundice. Neuroleptic jaundice has the biochemical and other characteristics of obstructive (cholestatic) jaundice and is associated with obstruction of the canaliculi by bile thrombi; the frequent presence of an accompanying eosinophilia indicates the allergic nature of this phenomenon. Liver injury has been reported very rarely in patients treated with pericyazine. Treatment should be withheld on the development of jaundice.

Cardiac Disorders:

Cardiorespiratory: hypotension, usually postural, commonly occurs. Elderly or volume depleted subjects are particularly susceptible.

ECG changes, include QT prolongation (as with other neuroleptics), ST depression, U-Wave and T-Wave changes. Cardiac arrhythmias, including ventricular arrhythmias and atrial arrhythmias, a-v block, ventricular tachycardia, which may result in ventricular fibrillation or cardiac arrest have been reported during neuroleptic phenothiazine therapy, possibly related to dosage. Pre-existing cardiac disease, old age, hypokalaemia and concurrent tricyclic antidepressants may predispose.

There have been isolated reports of sudden death, with possible cases of cardiac origin (see section 4.4, above), as well as cases of unexplained sudden death, in patients receiving neuroleptic phenothiazines.

Respiratory, thoracic and mediastinal disorders:

Respiratory depression is possible in susceptible patients.

Blood and lymphatic system disorders:

A mild leukopenia occurs in up to 30% of patients on prolonged high dosage of neuroleptics; agranulocytosis may occur rarely; it is not dose-related. Regular monitoring of the complete blood count is recommended.

Nervous system disorders:

Not known: Sedation or somnolence, which is more marked at the beginning of treatment, neuroleptic malignant syndrome (see section 4.4), anticholinergic effects such as dry mouth, constipation, paralytic ileus (see section 4.4), accommodation disorders, risk of urinary retention.

Extrapyramidal: acute dystonias or dyskinesias, usually transitory are commoner in children and young adults, and usually occur within the first four days of treatment or after dosage increases.

• Akathisia characteristically occurs after large initial doses.

• Parkinsonism is commoner in adults and the elderly. It usually develops after weeks or months of treatment. One or more of the following may be seen: tremor, rigidity, akinesia, or other features of Parkinsonism. Commonly just tremor.

• Not known: Tardive dyskinesia: if this occurs it is usually, but not necessarily after prolonged or high dosage. It can even occur after treatment has been stopped. Dosage should therefore be kept low whenever possible. Anticholinergic antiparkinsonian agents have no effect and may cause exacerbation.

• Akinesia with or without hypertonia, partially relieved by anticholinergic antiparkinsonian agents.

• Hyperkinetic -hypertonic movements, motor excitation.

At higher doses:

Not known: Early dyskinesia (spasmodic torticollis, oculogyric crises, trismus, etc.)

Skin and subcutaneous tissue disorders:

Contact skin sensitisation may occur rarely in those frequently handling preparations of phenothiazines (see section 4.4, above. Skin rashes of various kinds may also be seen in patients treated with the drug. Patients on high dosage should be warned that they may develop photosensitivity in sunny weather and should avoid exposure to direct sunlight.

Unknown: Allergic skin reactions, photosensitivity reaction

Eye disorders:

Not known: Brownish deposits in the anterior segment of the eye, due to accumulation of the product, generally without effects on vision.

Endocrine disorders:

Hyperprolactinaemia which may result in galactorrhoea, gynaecomastia, amenorrhoea; impotence, frigidity.

Not known: Weight gain, temperature dysregulation

Priapism has very rarely been reported in patients treated with pericyazine.

Neuroleptic malignant syndrome (hyperthermia, rigidity autonomic dysfunction and altered consciousness) may occur with any neuroleptic.

Minor side effects are nasal stuffiness, dry mouth, insomnia, agitation

Vascular disorders:

Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs (see also section 4.4).

Orthostatic hypotension, elderly or volume depleted patients are particularly susceptible.

Metabolism and nutrition disorders:

Not known: Intolerance to glucose, hyperglycaemia (see section 4.4).

Pregnancy, puerperium and perinatal conditions:

rug withdrawal syndrome neonatal (see section 4.6) – Frequency not known.

Psychiatric disorders:

Not known: Indifference, anxiety reactions, mood variations, agitation.

Investigations:

Unknown: Positive serology for antinuclear antibodies without clinical lupus erythematosus

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Toxicity and treatment of overdosage:

Symptoms of neuroleptic overdosage include drowsiness or loss of consciousness, hypotension, tachycardia, ECG changes, ventricular arrhythmias and hypothermia. Severe extrapyramidal dyskinesias may occur.

If the patient is seen sufficiently soon (up to 6 hours) after ingestion of a toxic dose, gastric lavage may be attempted. Pharmacological induction of emesis is unlikely to be of any use. Activated charcoal should be given. There is no specific antidote. Treatment is supportive.

Generalised vasodilatation may result in circulatory collapse; raising the patient's legs may suffice; in severe cases, volume expansion by intravenous fluids may be needed; infusion fluids should be warmed before administration in order not to aggravate hypothermia.

Positive inotropic agents such as dopamine may be tried if fluid replacement is insufficient to correct the circulatory collapse. Peripheral vasoconstrictor agents are not generally recommended; avoid the use of adrenaline.

Ventricular or supraventricular tachy-arrhythmias usually respond to restoration of normal body temperature and correction of circulatory or metabolic disturbances. If persistent or life threatening, appropriate anti-arrhythmic therapy may be considered. Avoid lidocaine, and as far as possible long acting, anti-arrhythmic drugs.

Pronounced central nervous system depression requires airway maintenance or, in extreme circumstances, assisted respiration. Severe dystonic reactions usually respond to procyclidine (5-10 mg) or orphenedrine (20-40 mg) administered intramuscularly or intravenously. Convulsions should be treated with intravenous diazepam.

Neuroleptic malignant syndrome should be treated with cooling. Dantrolene sodium may be tried.