This information is intended for use by health professionals

1. Name of the medicinal product

Clopixol 200 mg/ml solution for injection.

Clopixol Conc. 500 mg/ml solution for injection.

2. Qualitative and quantitative composition

Clopixol Injection:

Zuclopenthixol decanoate 200 mg/ml.

Clopixol Conc. Injection:

Zuclopenthixol decanoate 500 mg/ml.

For the full list of excipients, see section 6.1

3. Pharmaceutical form

Solution for injection.

Clear, yellowish oil, practically free from particles.

4. Clinical particulars
4.1 Therapeutic indications

The maintenance treatment of schizophrenia and paranoid psychoses.

4.2 Posology and method of administration

Posology

Adults

Dosage and dosage interval should be adjusted according to the patient's symptoms and response to treatment.

The usual dosage range of zuclopenthixol decanoate is 200 - 500 mg every one to four weeks, depending on response, but some patients may require up to 600 mg per week. The maximum single dose at any one time is 600 mg. For example, 1200 mg every 2 weeks should not be given. In patients who have not previously received depot antipsychotics, treatment is usually started with a small dose (e.g. 100 mg) to assess tolerance. An interval, of at least one week should be allowed before the second injection is given at a dose consistent with the patient's condition.

Adequate control of severe psychotic symptoms may take up to 4 to 6 months at high enough dosage. Once stabilised lower maintenance doses may be considered, but must be sufficient to prevent relapse.

Injection volumes of greater than 2 ml should be distributed between two injection sites.

Older patients

In accordance with standard medical practice initial dosage may need to be reduced to a quarter or half the normal starting dose in the frail or older patients.

Paediatric population

Clopixol is not recommended for use in children due to lack of clinical experience.

Patients with renal impairment

Clopixol can be given in usual doses to patients with reduced renal function. Where there is renal failure dosage should be reduced to half the normal dosage.

Patients with hepatic impairment

Use with caution in patients with liver disease (see section 4.4). Patients with compromised hepatic function should receive half the recommended dosages. Serum-level monitoring is advised.

Method of administration

By deep intramuscular injection into the upper outer buttock or lateral thigh.

Note

As with all oil-based injections it is important to ensure, by aspiration before injection, that inadvertent intravascular entry does not occur.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Circulatory collapse, depressed level of consciousness due to any cause (e.g. intoxication with alcohol, barbiturates or opiates), coma.

4.4 Special warnings and precautions for use

Caution should be exercised in patients having: liver disease; cardiac disease, or arrhythmias; severe respiratory disease; renal failure; epilepsy (and conditions predisposing to epilepsy, e.g. alcohol withdrawal or brain damage); Parkinson's disease; narrow angle glaucoma; prostatic hypertrophy; hypothyroidism; hyperthyroidism; myasthenia gravis; phaeochromocytoma and patients who have shown hypersensitivity to thioxanthenes or other antipsychotics.

Acute withdrawal symptoms, including nausea, vomiting, sweating and insomnia have been described after abrupt cessation of antipsychotic drugs. Recurrence of psychotic symptoms may also occur, and the emergence of involuntary movement disorders (such as akathisia, dystonia and dyskinesia) has been reported. The plasma concentrations of zuclopenthixol decanoate gradually decrease over several weeks which make gradual dosage tapering unnecessary.

When transferring patients from oral to depot antipsychotic treatment, the oral medication should not be discontinued immediately, but gradually withdrawn over a period of several days after administering the first injection.

The possibility of development of neuroleptic malignant syndrome (hyperthermia, muscle rigidity, fluctuating consciousness, instability of the autonomous nervous system) exists with any neuroleptic. The risk is possibly greater with the more potent agents. Patients with pre-existing organic brain syndrome, mental retardation and opiate and alcohol abuse are over-represented among fatal cases.

Treatment:

Discontinuation of the neuroleptic. Symptomatic treatment and use of general supportive measures. Dantrolene and bromocriptine may be helpful. Symptoms may persist for more than a week after oral neuroleptics are discontinued and somewhat longer when associated with the depot forms of the drugs.

Like other neuroleptics, zuclopenthixol decanoate should be used with caution in patients with organic brain syndrome, convulsions or advanced hepatic disease.

Blood dyscrasias have been reported rarely. Blood counts should be carried out if a patient develops signs of persistent infection.

As with other drugs belonging to the therapeutic class of antipsychotics, zuclopenthixol decanoate may cause QT prolongation. Persistently prolonged QT intervals may increase the risk of malignant arrhythmias. Therefore, zuclopenthixol decanoate should be used with caution in susceptible individuals (with hypokalaemia, hypomagnesaemia or genetic predisposition) and in patients with a history of cardiovascular disorders, e.g. QT prolongation, significant bradycardia (<50 beats per minute), a recent acute myocardial infarction, uncompensated heart failure, or cardiac arrhythmia.

Cases of venous thromboembolism (VTE) 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 zuclopenthixol decanoate and preventive measures undertaken.

Concomitant treatment with other antipsychotics should be avoided (see section 4.5).

As described for other psychotropics, zuclopenthixol decanoate may modify insulin and glucose responses calling for adjustment of the antidiabetic therapy in diabetic patients.

Leukopenia, neutropenia and agranulocytosis have been reported with antipsychotics, including zuclopenthixol decanoate.

Long-acting depot antipsychotics should be used with caution in combination with other medicines known to have a myelosuppressive potential, as these cannot rapidly be removed from the body in conditions where this may be required.

Older people

Older people require close supervision because they are especially prone to experience such adverse effects as sedation, hypotension, confusion and temperature changes.

Cerebrovascular

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.

Zuclopenthixol should be used with caution in patients with risk factors for stroke.

Increased Mortality in Older People with Dementia

Data from two large observational studies showed that older 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.

Clopixol Conc. Injection and Clopixol Conc. Injection are not licensed for the treatment of dementia-related behavioural disturbances.

4.5 Interaction with other medicinal products and other forms of interaction

In common with other antipsychotics, zuclopenthixol enhances the response to alcohol, the effects of barbiturates and other CNS depressants.

Zuclopenthixol may potentiate the effects of general anaesthetics and anticoagulants and prolong the action of neuromuscular blocking agents.

The anticholinergic effects of atropine or other drugs with anticholinergic properties may be increased.

Concomitant use of drugs such as metoclopramide, piperazine or antiparkinson drugs may increase the risk of extrapyramidal effects such as tardive dyskinesia.

Combined use of antipsychotics and lithium or sibutramine has been associated with an increased risk of neurotoxicity.

Antipsychotics may enhance the cardiac depressant effects of quinidine; the absorption of corticosteroids and digoxin.

The hypotensive effect of vasodilator antihypertensive agents such as hydralazine and α blockers (e.g. doxazosin), or methyl-dopa may be enhanced.

Concomitant use of zuclopenthixol and drugs known to cause QT prolongation or cardiac arrhythmias, such as tricyclic antidepressants or other antipsychotics should be avoided.

Increases in the QT interval related to antipsychotic treatment may be exacerbated by the co administration of other drugs known to significantly increase the QT interval. Co-administration of such drugs should be avoided.

Relevant classes include:

• class Ia and III antiarrhythmics (e.g. quinidine, amiodarone, sotalol, dofetilide)

• some antipsychotics (e.g. thioridazine)

• some macrolides (e.g. erythromycin)

• some antihistamines

• some quinolone antibiotics (e.g. moxifloxacin)

The above list is not exhaustive and other individual drugs known to significantly increase QT interval (e.g. cisapride, lithium) should be avoided. Drugs known to cause electrolyte disturbances such as thiazide diuretics (hypokalemia) and drugs known to increase the plasma concentration of zuclopenthixol should also be used with caution as they may increase the risk of QT prolongation and malignant arrhythmias (see section 4.4).

Antipsychotics may antagonise the effects of adrenaline and other sympathomimetic agents, and reverse the antihypertensive effects of guanethidine and similar adrenergic-blocking agents.

Antipsychotics may also impair the effect of levodopa, adrenergic drugs and anticonvulsants.

The metabolism of tricyclic antidepressants may be inhibited and the control of diabetes may be impaired.

Since zuclopenthixol is partly metabolised by CYP2D6 concomitant use of drugs known to inhibit this enzyme may lead to higher than expected plasma concentrations of zuclopenthixol, increasing the risk of adverse effects and cardiotoxicity.

4.6 Fertility, pregnancy and lactation

Pregnancy

Zuclopenthixol decanoate should not be administered during pregnancy unless the expected benefit to the patient outweighs the theoretical risk to the foetus.

Neonates exposed to antipsychotics (including zuclopenthixol decanoate) 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.

Animal studies have shown reproduction toxicity (see section 5.3).

Breast-feeding

As zuclopenthixol is found in breast milk in low concentrations it is not likely to affect the infant when therapeutic doses are used. The dose ingested by the infant is less than 1% of the weight related maternal dose (in mg/kg). Breast-feeding can be continued during zuclopenthixol decanoate therapy if considered of clinical importance, but observation of the infant is recommended, particularly in the first 4 weeks after giving birth.

Fertility

In humans, adverse events such as hyperprolactinaemia, galactorrhoea, amenorrhoea, erectile dysfunction and ejaculation failure have been reported (see section 4.8). These events may have a negative impact on female and/or male sexual function and fertility.

If clinical significant hyperprolactinaemia, galactorrhoea, amenorrhoea or sexual dysfunctions occur, a dose reduction (if possible) or discontinuation should be considered. The effects are reversible on discontinuation.

Administration of zuclopenthixol to male and female rats was associated with a slight delay in mating. In an experiment where zuclopenthixol was administered via the diet, impaired mating performance and reduced conception rate were noted.

4.7 Effects on ability to drive and use machines

Zuclopenthixol is a sedative drug.

Alertness may be impaired, especially at the start of treatment, or following the consumption of alcohol; patients should be warned of this risk and advised not to drive or operate machinery until their susceptibility is known.

Patients should not drive if they have blurred vision.

4.8 Undesirable effects

The majority of undesirable effects are dose dependent. The frequency and severity are most pronounced in the early phase of treatment and decline during continued treatment.

Extrapyramidal reactions may occur, especially in the early phase of treatment. In most cases these side effects can be satisfactorily controlled by reduction of dosage and/or use of antiparkinsonian drugs. The routine prophylactic use of antiparkinsonian drugs is not recommended.

Antiparkinsonian drugs do not alleviate tardive dyskinsea and may aggravate them. Reduction in dosage or, if possible, discontinuation of zuclopenthixol therapy is recommended. In persistent akathisia a benzodiazepine or propranolol may be useful.

Blood and lymphatic system disorders

Thrombocytopenia, neutropenia, leukopenia, agranulocytosis.

Immune system disorders

Hypersensitivity, anaphylactic reaction.

Endocrine disorders

Hyperprolactinaemia.

Metabolism and nutrition disorders

Increased appetite, weight increased .

Decreased appetite, weight decreased.

Hyperglycaemia, glucose tolerance impaired, hyperlipidaemia.

Psychiatric disorders

Insomnia, depression, anxiety, nervousness, abnormal dreams, agitation, libido decreased.

Apathy, nightmare, libido increased, confusional state.

Nervous system disorders

Somnolence, akathisia, hyperkinesia, hypokinesia.

Tremor, dystonia, hypertonia, dizziness, headache, paraesthesia, disturbance in attention, amnesia, gait abnormal.

Tardive dyskinesia, hyperreflexia, dyskinesia, parkinsonism, syncope, ataxia, speech disorder, hypotonia, convulsion, migraine.

Neuroleptic malignant syndrome.

Eye disorders

Accommodation disorder, vision abnormal.

Oculogyration, mydriasis.

Ear and labyrinth disorders

Vertigo.

Hyperacusis, tinnitus.

Cardiac disorders

Tachycardia, palpitations.

Electrocardiogram QT prolonged.

Vascular disorders

Hypotension, hot flush.

Venous thromboembolism

Respiratory, thoracic and medistianal disorders

Nasal congestion, dyspnoea.

Gastrointestinal disorders

Dry mouth.

Salivary hypersecretion, constipation, vomiting, dyspepsia, diarrhoea.

Abdominal pain, nausea, flatulence.

Hepato-biliary disorders

Liver function test abnormal.

Cholestatic hepatitis, jaundice.

Skin and subcutaneous tissue disorders

Hyperhidrosis, pruritus.

Rash, photosensitivity reaction, pigmentation disorder, seborrhoea, dermatitis, purpura.

Musculoskeletal and connective tissue disorder

Myalgia.

Muscle rigidity, trismus, torticollis.

Renal and urinary disorders

Micturition disorder, urinary retention, polyuria.

Pregnancy, puerperium and perinatal conditions

Drug withdrawal syndrome neonatal (see 4.6)

Reproductive system and breast disorders

Ejaculation failure, erectile dysfunction, female orgasmic disorder, vulvovaginal dryness.

Gynaecomastia, galactorrhoea, amenorrhoea, priapism.

General disorders and administration site conditions

Asthenia, fatigue, malaise, pain.

Thirst, injection site reaction, hypothermia, pyrexia.

As with other drugs belonging to the therapeutic class of antipsychotics, rare cases of QT prolongation, ventricular arrhythmias - ventricular fibrillation, ventricular tachycardia, Torsade de Pointes and sudden unexplained death have been reported for zuclopenthixol (see section 4.4).

Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs – Frequency unknown.

Abrupt discontinuation of zuclopenthixol may be accompanied by withdrawal symptoms. The most common symptoms are nausea, vomiting, anorexia, diarrhoea, rhinorrhoea, sweating, myalgias, paraesthesias, insomnia, restlessness, anxiety, and agitation. Patients may also experience vertigo, alternate feelings of warmth and coldness, and tremor. Symptoms generally begin within 1 to 4 days of withdrawal and abate within 7 to 14 days.

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

4.9 Overdose

Symptoms: somnolence, coma, extrapyramidal symptoms, convulsions, hypotension, shock, hyper or hypothermia. ECG changes, QT prolongation, Torsade de Pointes, cardiac arrest and ventricular arrhythmias have been reported when administered in overdose together with drugs known to affect the heart.

Treatment: treatment is symptomatic and supportive. Measures aimed at supporting the respiratory and cardiovascular systems should be instituted.

Adrenaline (epinephrine) must not be used in these patients. There is no specific antidote.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Neuropleptics (antipsychotics), ATC Code: N05AF05

Mechanism of action

The action of zuclopenthixol, as with other antipsychotics is mediated through dopamine receptor blockade. Zuclopenthixol has a high affinity for D1 and D2 receptors and activity has been demonstrated in standard animal models used to assess antipsychotic action. Serotonergic blocking properties, a high affinity for alpha-adrenoreceptors and slight antihistamine properties have been observed.

5.2 Pharmacokinetic properties

After deep intramuscular injection of Clopixol, serum levels of zuclopenthixol increase during the first week and decline slowly thereafter. A linear relationship has been observed between Clopixol dosage and serum level. Metabolism proceeds by sulphoxidation, dealkylation and glucuronic acid conjugation. Sulphoxide metabolites are mainly excreted in the urine while unchanged drug and the dealkylated form tend to be excreted in the faeces.

5.3 Preclinical safety data

Reproductive toxicity

Impaired mating performance and reduced conception rates were observed in rats treated with zuclopenthixol at doses equal to the maximum recommend human dose of 50 mg on a mg/m2 basis.

There was no evidence of embryotoxicity or teratogenic effects in rats treated with zuclopenthixol, however adverse effects on pre-and postnatal development (i.e. increased stillbirths, reduced pup survival and delayed development of pups) was observed. The clinical significance of these findings is unclear and it is possible that the effect on pups was due to neglect from the dams that were exposed to doses of zuclopenthixol producing maternal toxicity.

6. Pharmaceutical particulars
6.1 List of excipients

Thin vegetable oil

6.2 Incompatibilities

This product may be mixed in the same syringe with other products in the Clopixol Injection range, including Clopixol-Acuphase Injection (zuclopenthixol acetate 50 mg/ml).

It should not be mixed with any other injection fluids.

6.3 Shelf life

Clopixol Injection:

1 ml ampoules: 36 months.

10 ml vials: 36 months (unopened), shelf life after opening vials: 1 day

Clopixol Conc. Injection:

48 months.

6.4 Special precautions for storage

Keep the ampoules in the outer carton in order to protect from light.

6.5 Nature and contents of container

Clopixol Injection:

Ampoules containing 1 ml of 200 mg/ml zuclopenthixol decanoate in thin vegetable oil. Pack size : 10 ampoules per box.

10 ml clear glass vials with a rubber stopper secured with an aluminium collar having a fliptop cap. Pack size: 1 vial per box.

Clopixol Conc. Injection:

Ampoules containing 1 ml of 500 mg/ml zuclopenthixol decanoate in thin vegetable oil. Pack size : 5 ampoules per box.

6.6 Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Lundbeck Limited

2nd Floor

Building 3, Abbey View

Everard Close

St Albans

AL1 2PS

United Kingdom

8. Marketing authorisation number(s)

Clopixol Injection

Clopixol Conc. Injection

PL 0458/0017

PL 0458/0060

9. Date of first authorisation/renewal of the authorisation

Date of First Authorisation in the UK:

Clopixol Injection

Clopixol Conc. Injection

15 May 1978

21 November 1988

Renewal of the Authorisation:

Clopixol Injection

Clopixol Conc. Injection

3 July 2008

3 July 2008

10. Date of revision of the text

December 2016

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