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CLOPIXOLŽ CLOPIXOL-ACUPHASEŽ CLOPIXOLŽ DEPOT
Lundbeck
Zuclopenthixol Dihydrochloride
Zuclopenthixol Acetate
Zuclopenthixol Decanoate
Antipsychotic
 
Action And Clinical Pharmacology: Zuclopenthixol, a thioxanthene derivative, has high affinity for both dopamine D1 receptors and dopamine D2 receptors. Zuclopenthixol also has high affinity for a1-adrenergic and 5-HT2 receptors. It has weaker histamine H1 receptor blocking activity, and even lower affinity for muscarinic cholinergic and a2-adrenergic receptors.

Pharmacokinetics: The pharmacokinetics of zuclopenthixol appear to be linear over the dosage range studied. A strong correlation exists between dose and steady-state serum level, and between dose and area under the serum concentration time curve. The apparent volume of distribution is 20 L/kg. Protein binding is approximately 98%.

The metabolism of zuclopenthixol is mainly by sulfoxidation, side chain N-dealkylation and glucuronic acid conjugation. The metabolites are devoid of pharmacological activity. Zuclopenthixol is excreted mainly in feces with about 10% excreted in the urine. Approximately 0.1% of a dose is excreted unchanged in the urine. The systemic clearance is approximately 0.9 L/min.

Zuclopenthixol acetate and zuclopenthixol decanoate are long-acting forms of zuclopenthixol that have been made more lipophilic by esterification with acetic and decanoic acid, respectively. Both esters of zuclopenthixol are dissolved in fractionated coconut oil and when injected i.m., diffuse slowly from the oil depot to the body water phase where they are rapidly hydrolyzed to the active substance, zuclopenthixol. Once hydrolyzed, zuclopenthixol is distributed, metabolized and excreted as described.

Clopixol: Maximum serum concentrations of zuclopenthixol are reached in approximately 4 hours (range 2 to 12 hours) following administration. The elimination half-life is approximately 20 hours (range 12 to 28 hours). The mean steady-state serum level of zuclopenthixol corresponding to a daily 20 mg dose of zuclopenthixol dihydrochloride is about 13 ng/mL (33 nmol/L).

Clopixol-Acuphase: Maximum serum concentrations of zuclopenthixol are reached, on average, 24 to 48 hours after i.m. injection, followed by a gradual decline. Average maximum serum concentration of zuclopenthixol corresponding to a 100 mg i.m. dose of zuclopenthixol acetate is 41 ng/mL (102 nmol/L). Three days after injection, serum levels are approximately one-third the maximum.

Clopixol Depot: Maximum serum concentrations of zuclopenthixol are reached 3 to 7 days following i.m. injection. The serum concentration time curve declines exponentially with a half-life of 19 days, reflecting the rate of release from the oil depot. Zuclopenthixol decanoate, when given at a dose of 200 mg every 2 weeks, results, on average, in a steady-state zuclopenthixol serum concentration of approximately 10 ng/mL (25 nmol/L), when measured immediately prior to the next injection.

Indications And Clinical Uses: For the management of the manifestations of schizophrenia.

Clopixol-Acuphase is intended for the initial treatment of acute psychotic episodes or exacerbation of psychosis associated with schizophrenia. Clopixol Depot is intended for maintenance treatment. Clopixol tablets may be used during either phase.

Contra-Indications: Patients with: acute alcohol, barbiturate or opiate intoxication; CNS depression due to any cause, comatose states, suspected or established subcortical brain damage, circulatory collapse, blood dyscrasias or pheochromocytoma; known hypersensitivity to the thioxanthenes, zuclopenthixol or any of the excipients of the product. tag_WarningWarnings

Manufacturers' Warnings In Clinical States: Neuroleptic Malignant Syndrome: Neuroleptic malignant syndrome (NMS) is a rare, sometimes fatal, neurological disorder that has been reported in association with antipsychotic drugs including zuclopenthixol (see Adverse Effects). NMS is characterized by hyperthermia, muscle rigidity, altered consciousness, and signs of autonomic instability including irregular blood pressure, tachycardia, cardiac arrhythmias and diaphoresis. Additional signs may include greatly elevated creatine phosphokinase, myoglobinuria and acute renal failure.

The management of NMS should include immediate discontinuation of all antipsychotic drugs including zuclopenthixol, intensive monitoring of symptoms, and treatment of any associated medical problems. There is no general agreement about specific pharmacological treatment for NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the reintroduction of therapy should be carefully considered, since recurrence of NMS has been reported.

Tardive Dyskinesia: Tardive dyskinesia is a potentially irreversible neurological syndrome associated with the use of antipsychotic drugs, including zuclopenthixol (see Adverse Effects). It is characterized by stereotypical, repetitive, involuntary movements of the jaw, tongue and in some cases, the extremities. Tardive dyskinesia occurs more frequently in elderly patients. However, patients of any age can be affected. The risk of developing tardive dyskinesia, and the chance of it becoming irreversible, are believed to increase as the duration of treatment and the cumulative dose of antipsychotic drugs increase. However, the syndrome can develop, although less commonly, after relatively brief periods of treatment at low doses. Tardive dyskinesia may remit, partially or completely, if antipsychotic drug treatment is withdrawn. Antipsychotic drug treatment itself, however, may suppress the signs and symptoms of tardive dyskinesia, thereby masking the underlying process.

In view of these considerations, zuclopenthixol should be prescribed in a manner that is most likely to minimize the risk of tardive dyskinesia. The lowest effective dose and the shortest duration of treatment should be used, and treatment should be discontinued at the earliest opportunity, or if a satisfactory response cannot be obtained. If the signs and symptoms of tardive dyskinesia appear during treatment, discontinuation of zuclopenthixol should be considered.

Precautions: Occupational Hazards: Since sedation is known to occur with zuclopenthixol, patients should be cautioned against performing activities requiring a high degree of mental alertness and physical coordination (such as driving a car or operating machinery) until the effect of the drug is determined.

Anticholinergic Effects: Although its anticholinergic effects are weak, zuclopenthixol use should be avoided in patients who are known to have, or suspected of having narrow angle glaucoma. Zuclopenthixol may potentiate anticholinergic effects of concurrent medications.

Endocrine Effects: Antipsychotic drugs elevate prolactin levels with the effect persisting during chronic administration. Since tissue culture experiments indicate that approximately one third of human breast cancers are prolactin dependent, in vitro, zuclopenthixol should only be administered to patients with previously detected breast cancer if the benefits outweigh the potential risks. Caution should also be exercised when considering zuclopenthixol treatment in patients with pituitary tumors. Possible manifestations associated with elevated prolactin levels are amenorrhea, galactorrhea and menorrhagia (see Adverse Effects).

Chronic administration of zuclopenthixol (30 mg/kg/day for 2 years) in rats resulted in small, but significant, increases in the incidence of thyroid parafollicular carcinomas and, in females, of mammary adenocarcinomas and of pancreatic islet cell adenomas and carcinomas. An increase in the incidence of mammary adenocarcinomas is a common finding for D2 antagonists which increase prolactin secretion when administered to rats. An increase in the incidence of pancreatic islet cell tumors has been observed for some other D2 antagonists. The physiological differences between rats and humans with regard to prolactin make the clinical significance of these findings unclear.

Antiemetic Effects: An antiemetic effect of zuclopenthixol has been observed in animals. Since this effect may also occur in man, zuclopenthixol may mask signs of toxicity due to overdosage of other drugs, or may mask symptoms of disease such as brain tumor or intestinal obstruction.

Photosensitivity Reactions: Photosensitivity reactions, pigmentary retinopathy and lenticular and corneal deposits have been reported with related drugs. Lens opacity has been reported rarely with zuclopenthixol.

Seizures: Zuclopenthixol should be used with caution in patients with a history of convulsive disorders, as drugs of this class are known to lower seizure threshold.

Cardiovascular Disease: Caution should be used when using zuclopenthixol in patients with advanced cardiovascular disease or in those at risk of developing conduction abnormalities.

Pregnancy: The safe use of zuclopenthixol during pregnancy has not been established. Zuclopenthixol was not teratogenic in either rats or rabbits, however, increases in the number of stillbirths, reduced pup survival and delayed development of pups were seen in rats. The clinical significance of these findings is unclear. It has been shown that zuclopenthixol crosses the placenta of mice. Zuclopenthixol should not be administered during pregnancy unless the expected benefit to the patient outweighs the potential risk to the fetus.

Lactation: Zuclopenthixol is excreted in human milk with an average milk/serum concentration ratio of approximately 0.3. Because the safe use of zuclopenthixol during lactation has not been established, it is recommended that breast-feeding should not be undertaken in women receiving zuclopenthixol.

Children: The safety and efficacy of zuclopenthixol in children under the age of 18 years has not been established; therefore, its use is not recommended.

Geriatrics: The pharmacokinetics, safety, and efficacy of zuclopenthixol in elderly patients with schizophrenia has not been systematically evaluated in clinical trials. Caution should thus be exercised in dose selection for an elderly patient, recognizing the more frequent hepatic, renal and cardiac dysfunction in this population.

Impaired Liver Function: The use of zuclopenthixol in patients with impaired liver function has not been studied. As zuclopenthixol is extensively metabolized by the liver and primarily excreted in the bile (see Pharmacology, Pharmacokinetics), caution should be exercised in dose selection for patients with this condition.

Impaired Renal Function: The use of zuclopenthixol in patients with impaired renal function has not been studied. Caution should thus be exercised in dose selection for patients with this condition.

Drug Interactions: Zuclopenthixol enhances the sedative response to alcohol and the effects of barbiturates and other CNS depressants. It should not be administered with high doses of hypnotics due to the possibility of potentiation.

Zuclopenthixol should not be given concomitantly with guanethidine or similar acting compounds, since antipsychotic drugs such as zuclopenthixol may block the antihypertensive effect of these compounds.

Many antipsychotic and antidepressant drugs may mutually inhibit the metabolism of each other.

Concomitant use of metoclopramide or piperazine increases the risk of extrapyramidal symptoms.

Zuclopenthixol may antagonize the effects of levodopa and dopamine agonists.

Patients with Parkinson's Disease: Zuclopenthixol should be used with caution in patients with Parkinsonism, as it is known that dopamine antagonists such as zuclopenthixol, can cause a deterioration of the disease.

Adverse Reactions: Adverse events were recorded in controlled and uncontrolled European and Canadian clinical trials in which 1 922 patients were treated with either zuclopenthixol dihydrochloride, zuclopenthixol acetate or zuclopenthixol decanoate.

The most common adverse events reported were drowsiness, fatigue, dizziness and extrapyramidal symptoms.

All adverse events reported in clinical trials at an incidence of greater than 1% are listed in Table I by formulation.

Adverse events reported in clinical trials, occurring at rates of 1% or less are summarized below for all three formulations together: Body as a Whole: allergic reaction, application site disorder, arthritis, back pain, chest pain, precordial chest pain, conjunctivitis, faintness, fever, hot flushes and toothache.

Psychiatric: drug dependence, excitability, irritability, increased libido, melancholia and paroniria.

Neurological: acute dyskinesia, ataxia, convulsions, hyperreflexia, hypotonia, migraine, oculogyric crisis, and speech disorder.

Gastrointestinal: abdominal pain, dysphagia, gastric ulcer, glossitis and meteorism.

Cardiovascular: hypotension.

Respiratory: dyspnea, nasal congestion, pharyngitis and rhinitis.

Hematological: purpura.

Special Senses: mydriasis, hyperacusis and tinnitus.

Skin and Appendages: dermatitis, photosensitivity reaction, abnormal pigmentation, rash, erythematous rash and psoriasiform rash.

Urinary: polyuria, urinary incontinence, urinary infection and urinary retention.

Reproductive: erectile dysfunction, galactorrhea, gynecomastia and dry vagina.

In the worldwide postmarketing surveillance database (1964 to 1993; >1 000 000 treated; >80% of the database from Scandinavia, Netherlands, Switzerland and the UK) the following additional serious adverse events have been rarely reported: Neuroleptic Malignant Syndrome (57 cases) (see Warnings); apnea and respiratory depression (13 cases); sudden death (5 cases), agranulocytosis (5 cases).

Alterations in liver function, particularly increased bilirubin levels have occasionally been reported. Transient increases in ALT and ALP values may also occur. Transient, benign leukopenia has been reported rarely. Peripheral edema has occasionally been reported.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Although there have not been any cases of overdosage reported, the symptoms are likely to be somnolence, coma, extrapyramidal symptoms, convulsions, hypotension, shock, or hyper- or hypothermia.

There is no specific antidote for zuclopenthixol. Treatment should be symptomatic and supportive. Gastric lavage (after intubation, if the patient is unconscious) and administration of activated charcoal should be considered. Measures aimed at supporting the respiratory and cardiovascular systems should be instituted. Hypotension and circulatory collapse may be counteracted by use of i.v fluids. Epinephrine must not be used as a further lowering of blood pressure may result. In cases of severe extrapyramidal reactions, antiparkinsonian medication should be administered. Close monitoring and medical supervision should continue until the patient recovers.

In managing overdose, the physician should consider the possibility of multiple drug involvement.

Dosage And Administration: Clopixol: Dosage should be individualized according to the patient's condition. In general, small doses should be used initially and increased until an optimal response is obtained.

When initiating treatment with zuclopenthixol tablets, it is recommended that the drug be given in divided doses (b.i.d. or t.i.d.). During the maintenance phase of treatment, tablets may be given as a single nighttime dose.

For acute psychosis, the usual starting dose is 10 to 50 mg/day, which may be increased by 10 to 20 mg every 2 to 3 days, according to the patient's response. The usual therapeutic range is 20 to 60 mg daily. However, as with other antipsychotic drugs, some patients may require lower, while others may require higher dosage in order to obtain optimal benefit. Daily dosage higher than 100 mg is not recommended. For maintenance therapy, dosage should be reduced to the lowest level compatible with symptom control. The usual maintenance dose is 20 to 40 mg/day.

Clopixol-Acuphase: Zuclopenthixol acetate is intended for use during acute psychotic episodes or exacerbation of psychosis associated with schizophrenia, when compliance with oral medication may be unreliable. Zuclopenthixol acetate has an onset of action within 2 to 4 hours, and a duration of action of 2 to 3 days following a single i.m. injection. Significant dose-dependent sedation occurs within 2 hours of injection, usually reaching a maximum after 8 hours. Tolerance to the sedative effect may develop with repeated injection. Maximum serum concentration of zuclopenthixol are reached, on average, 24 to 36 hours after injection.

Dosage should be individually adjusted according to the patient's condition. The usual dose is 50 to 150 mg (1 to 3 mL) administered i.m. and repeated if necessary, at intervals of 2 to 3 days. Some patients may need an additional injection 1 or 2 days after the first injection.

Due to the delay in reaching peak zuclopenthixol blood levels and maximum pharmacologic effect, close supervision is required in order to minimize the risk of over-medication or insufficient suppression of psychotic symptoms.

Zuclopenthixol acetate is not intended for long-term use, and the duration of treatment should not exceed 2 weeks. The maximum cumulative dosage should not exceed 400 mg, and the number of injections should not exceed 4.

Following treatment with zuclopenthixol acetate, antipsychotic therapy, when indicated, should be continued with either oral or long-acting injectable antipsychotic medications such as zuclopenthixol dihydrochloride or zuclopenthixol decanoate, respectively. Tables II and III provide guidelines for dosage form conversion. The tablets should usually be started 2 to 3 days after the last injection of Clopixol-Acuphase. If Clopixol Depot is used for maintenance, it can be given concomitantly with the last injection of Clopixol-Acuphase (see Co-injection of Clopixol-Acuphase and Clopixol Depot).

Clopixol Depot: Zuclopenthixol decanoate is intended for maintenance treatment of chronic schizophrenia in patients who have been stabilized with oral or other short-acting medication, and who might benefit from transfer to longer-acting injectable therapy.

Close supervision is required during the period following initiation of Depot treatment, in order to minimize the risk of over-medication or insufficient suppression of psychotic symptoms. Supplemental oral antipsychotic medication may be required in diminishing dosage during this period.

The usual maintenance dose is 150 to 300 mg i.m., every 2 to 4 weeks. Some patients may require higher or lower doses, or shorter intervals between doses.

During treatment with zuclopenthixol decanoate, the patient should be maintained at the lowest dose level compatible with adequate symptom control.

Co-injection of Clopixol-Acuphase and Clopixol Depot: For patients with exacerbation of chronic psychoses, Clopixol-Acuphase and Clopixol Depot can be mixed in a syringe and given as one injection (co-injection). Since Clopixol-Acuphase and Clopixol Depot are dissolved in the same vehicle, mixing will not affect the pharmacokinetics of either formulation and will allow the administration of an acute and maintenance dose with one injection. Subsequent doses of Clopixol Depot and the interval between injections should be adjusted according to the patient's response. Clopixol-Acuphase cannot be mixed with other antipsychotic depot formulations.

Geriatrics: The use of zuclopenthixol in elderly patients with schizophrenia has not been systematically evaluated. Caution should thus be exercised in dose selection for an elderly patient, recognizing the more frequent hepatic, renal and cardiac dysfunctions in this population.

Impaired Liver Function: The use of zuclopenthixol in patients with impaired liver function has not been studied. As zuclopenthixol is extensively metabolized by the liver and primarily excreted in the bile (see Pharmacology, Pharmacokinetics), caution should be exercised in dose selection for patients with this condition.

Impaired Renal Function: The use of zuclopenthixol in patients with impaired renal function has not been studied. Caution should be exercised in dose selection for patients with this condition.



Availability And Storage: Clopixol: 10 mg: Each light red-brown, round, biconvex, film-coated tablet contains: zuclopenthixol 10 mg as zuclopenthixol dihydrochloride. Nonmedicinal ingredients: castor oil, ferric oxide, glycerol, hydroxypropyl methylcellulose, lactose, Macrogol 6 000, magnesium stearate, microcrystalline cellulose, polyvidone acetate, potato starch, talc and titanium dioxide. Amber glass bottles of 100. Store between 15 and 25°C.

25 mg: Each red-brown, round, biconvex, film-coated tablet contains: zuclopenthixol 25 mg as zuclopenthixol dihydrochloride. Nonmedicinal ingredients: castor oil, ferric oxide, glycerol, hydroxypropyl methylcellulose, lactose, Macrogol 6 000, magnesium stearate, microcrystalline cellulose, polyvidone acetate, potato starch, talc and titanium dioxide. Amber glass bottles of 100. Store between 15 and 25°C.

40 mg: Each dark red-brown, round, biconvex, film-coated tablet contains: zuclopenthixol 40 mg as zuclopenthixol dihydrochloride. Nonmedicinal ingredients: castor oil, ferric oxide, glycerol, hydroxypropyl methylcellulose, lactose, Macrogol 6 000, magnesium stearate, microcrystalline cellulose, polyvidone acetate, potato starch, talc and titanium dioxide. Amber glass bottles of 100. Store between 15 and 25°C.

Clopixol-Acuphase: Each mL contains: zuclopenthixol acetate 50 mg (equivalent to zuclopenthixol 45.25 mg/mL) in fractionated coconut oil. Colorless glass ampuls of 1 and 2 mL. Packages of 5. Store between 15 and 25°C. Protect from light.

Clopixol Depot: Each mL contains: zuclopenthixol decanoate 200 mg (equivalent to zuclopenthixol 144.4 mg/mL) in fractionated coconut oil. Colorless vials of 10 mL. Store between 15 and 25°C. Protect from light.