Clopixol Injection 200mg/Ml
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Clopixol 200 mg/ml solution for injection.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Zuclopenthixol decanoate 200 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 Clopixol Injection 200 mg/ml 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 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 may cause QT prolongation. Persistently prolonged QT intervals may increase the risk of malignant arrhythmias. Therefore, zuclopenthixol should be used with caution in susceptible individuals (with hypokalemia, hypomagnesia 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 Clopixol and preventive measures undertaken.
Concomitant treatment with other antipsychotics should be avoided (see section 4.5).
As described for other psychotropics zuclopenthixol 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 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 a 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 thiazidediuretics (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 to higher than expected plasma concentrations of zuclopenthixol, increasing the risk of adverse effects and cardiotoxicity.
4.6 Fertility, pregnancy and lactation
Pregnancy
Zuclopenthixol 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 Clopixol) 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 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
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Blood and lymphatic system disorders |
Thrombocytopenia, neutropenia, leukopenia, agranulocytosis. |
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Immune system disorders |
Hypersensitivity, anaphylactic reaction. |
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Endocrine disorders |
Hyperprolactinaemia. |
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Metabolism and nutrition disorders |
Increased appetite, weight increased . Decreased appetite, weight decreased. Hyperglycaemia, glucose tolerance impaired, hyperlipidaemia. |
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Psychiatric disorders |
Insomnia, depression, anxiety, nervousness, abnormal dreams, agitation, libido decreased. Apathy, nightmare, libido increased, confusional state. |
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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. |
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Eye disorders |
Accommodation disorder, vision abnormal. Oculogyration, mydriasis. |
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Ear and labyrinth disorders |
Vertigo. Hyperacusis, tinnitus. |
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Cardiac disorders |
Tachycardia, palpitations. Electrocardiogram QT prolonged. |
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Vascular disorders |
Hypotension, hot flush. Venous thromboembolism |
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Respiratory, thoracic and medistianal disorders |
Nasal congestion, dyspnoea. |
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Gastrointestinal disorders |
Dry mouth. |
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Salivary hypersecretion, constipation, vomiting, dyspepsia, diarrhoea. | |
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Abdominal pain, nausea, flatulence. | |
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Hepato-biliary disorders |
Liver function test abnormal. |
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Cholestatic hepatitis, jaundice. | |
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Skin and subcutaneous tissue disorders |
Hyperhidrosis, pruritus. |
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Rash, photosensitivity reaction, pigmentation disorder, seborrhoea, dermatitis, purpura. | |
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Musculoskeletal and connective tissue disorder |
Myalgia. |
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Muscle rigidity, trismus, torticollis. | |
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Renal and urinary disorders |
Micturition disorder, urinary retention, polyuria. |
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Pregnancy, puerperium and perinatal conditions |
Drug withdrawal syndrome neonatal (see 4.6) |
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Reproductive system and breast disorders |
Ejaculation failure, erectile dysfunction, female orgasmic disorder, vulvovaginal dryness. |
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Gynaecomastia, galactorrhoea, amenorrhoea, priapism. | |
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General disorders and administration site conditions |
Asthenia, fatigue, malaise, pain. |
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Thirst, 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
Overdose
4.9
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
1 ml ampoules: 36 months.
10 ml vials: 36 months (unopened), shelf life after opening vials: 1 day
6.4 Special precautions for storage
Store below 25°C.
Keep the ampoules and vial in the outer carton in order to protect from light.
6.5.
Nature and Contents of Container
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 flip-top cap. Pack size: 1 vial per box.
6.6 Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Lundbeck Limited Building K1 Timbold Drive Kents Hill Milton Keynes MK7 6BZ United Kingdom
8. MARKETING AUTHORISATION NUMBER
PL 0458/0017
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
03/07/2008
10 DATE OF REVISION OF THE TEXT
22/10/2015