This information is intended for use by health professionals

1. Name of the medicinal product

Clopixol-Acuphase 50 mg/ml solution for injection

2. Qualitative and quantitative composition

Zuclopenthixol acetate 50 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

For the initial treatment of acute psychoses including mania and exacerbation of chronic psychoses, particularly where a duration of effect of 2-3 days is desirable.

4.2 Posology and method of administration

Posology

Adults

Dosage should be adjusted according to the severity of the patient's illness.

The usual dosage is 50-150 mg (1-3 ml), repeated if necessary after 2 or 3 days. Some patients may need an additional injection between 1 and 2 days after the first injection.

Clopixol-Acuphase is not intended for long-term use and duration of treatment should not be more than two weeks. The maximum accumulated dosage should not exceed 400 mg and the number of injections should not exceed four.

Older patients

The dosage may need to be reduced in older patients owing to reduced rates of metabolism and elimination. Maximum dosage per injection should be 100 mg.

Paediatric population

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

Patients with renal impairment

Clopixol-Acuphase 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 hepatic disease (see section 4.4). Patients with compromised hepatic function should receive half the recommended dosages. Serum-level monitoring is advised.

Maintenance Therapy

Clopixol-Acuphase is not intended for long-term use.

A single injection of Clopixol-Acuphase has an onset of sedative action shortly after injection and an antipsychotic action persisting for 2 to 3 days. In this period, maintenance treatment with tablets or a longer acting depot neuroleptic can be initiated. The possible side-effects of long-term maintenance treatment with a neuroleptic, including tardive dyskinesia, should be considered.

Maintenance treatment where required can be continued with Clopixol tablets, Clopixol Injection or Clopixol Conc. Injection, according to the following guidelines:

1. Introduce Clopixol tablets at a dosage of 20-60 mg/day in divided doses, 2 to 3 days after the last injection of Clopixol-Acuphase. If necessary increase the tablet dosage by 10-20 mg each day up to a maximum of 150 mg/day.

Or

2. Concomitantly with the last injection of Clopixol-Acuphase, administer 200-400 mg of Clopixol injection or Clopixol Conc. Injection by deep intramuscular injection and repeat the Clopixol injection or Clopixol Conc. injection at intervals of 2 to 4 weeks. Higher dosages or a shorter interval may be necessary.

Method of administration

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..

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 acetate should be used with caution in patients with organic brain syndrome, convulsions or advanced hepatic, renal or cardiovascular 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 acetate may cause QT prolongation. Persistently prolonged QT intervals may increase the risk of malignant arrhythmias. Therefore, zuclopenthixol acetate 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 acetate and preventive measures undertaken.

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

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

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 acetate 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 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.

Clopixol-Acuphase is 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.

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 acetate 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 acetate) 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 reproductive 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 acetate 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 clinically 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 was 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 dyskinesia and may aggravate it. 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

Zuclopenthixol is a potent neuroleptic of the thioxanthene series with a piperazine side-chain. The antipsychotic effect of neuroleptics is related to their dopamine receptor blocking effect. The thioxanthenes have a high affinity for both the adenylate cyclase coupled dopamine D1 receptors and for the dopamine D2 receptors; in the phenothiazine group the affinity for D1 receptors is much lower than that for D2 receptors, whereas butyrophenones, diphenylbutylpiperidines and benzamides only have affinity for D2 receptors.

In the traditional tests for antipsychotic effect, e.g. antagonism of stereotypic behaviour induced by dopamine agonists, the chemical groups of neuroleptics mentioned reveal equal but dosage dependent activity. However, the antistereotypic effect of phenothiazines, butyrophenones, diphenylbutylpiperidines, and benzamindes is strongly counteracted by the anticholinergic drug, scopolamine, while the antisteriotypic effect of the thioxanthenes, e.g. zuclopenthixol, is not, or only very slightly, influenced by concomitant treatment with anticholinergics.

5.2 Pharmacokinetic properties

By esterification of zuclopenthixol with acetic acid, zuclopenthixol has been converted to a more lipophilic substance, zuclopenthixol acetate. When dissolved in oil and injected intramuscularly this substance diffuses slowly into the surrounding body water, where enzymatic breakdown occurs releasing the active component zuclopenthixol.

Maximum serum concentrations of zuclopenthixol are usually reached 36 hours after an injection, after which the serum levels decline slowly. The average maximum serum level corresponding to the 100 mg dose is 41 ng/mL. Three days after the injection the serum level is about one third of the maximum.

Zuclopenthixol is distributed in the body in a similar way to other neuroleptics; with the higher concentrations of drug and metabolites in liver, lungs, intestines and kidneys and lower concentrations in heart, spleen, brain and blood. The apparent volume of distribution is about 20 L/kg and the protein binding about 98%.

Zuclopenthixol crosses the placental barrier in small amounts. Zuclopenthixol is excreted in small amounts with the milk - the ratio milk concentration/serum concentration in women is on average 0.3.

The metabolism of zuclopenthixol proceeds via three main routes - sulphoxidation, side chain N-dealkylation and glucuronic acid conjugation. The metabolites are devoid of psychopharmacological activity. The excretion proceeds mainly with the faeces but also to some degree with the urine. The systemic clearance is about 0.9 L/min.

The kinetics seem to be linear, since highly significant correlation exist between the dose and the area under the serum concentration curve.

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.

Mutagenicity and carcinogenicity

Zuclopenthixol has no mutagenic potential. In a rat oncogenicity study, 30 mg/kg/day resulted in slight non statistical increases in the incidence of mammary adenocarcinomas and pancreatic islet cell adenomas and carcinomas in females of thyroid parafollicular carcinomas. This is a common finding for D2 antagonists which increase prolactin secretion when administered to rats. The physiological differences between rats and humans suggest that these changes are not predictive of an oncogenic risk in patients.

Local toxicity

Local muscle damage is less pronounced with oily solutions of zuclopenthixol (including Clopixol-Acuphase) then with aqueous solutions of zuclopenthixol and other neuroleptics.

6. Pharmaceutical particulars
6.1 List of excipients

Thin vegetable oil (derived from coconuts).

6.2 Incompatibilities

This product may be mixed in the same syringe with other products in the Clopixol Injection range.

It should not be mixed with any other injection fluids.

6.3 Shelf life

2 years as packaged for sale.

6.4 Special precautions for storage

Store at or below 25°C. Protect from light.

6.5 Nature and contents of container

Clear glass ampoules containing 1 mL of zuclopenthixol acetate 5% w/v in thin vegetable oil.

The ampoules are packed in boxes of 5.

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)

PL 00458/0063

9. Date of first authorisation/renewal of the authorisation

Date of First Authorisation in the UK:

16 March 1990

Renewal of the Authorisation:

3 July 2008

10. Date of revision of the text

December 2016

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