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Information for Healthcare Professionals
NAME OF THE MEDICINAL PRODUCT
Haldol-Janssen solution for injection 5 mg/mL QUALITATIVE AND QUANTITATIVE COMPOSITION
1 mL solution for injection contains 5 mg haloperidol. For a full list of excipients, see section 6.1. PHARMACEUTICAL FORM
Solution for injection Clear, colourless solution. CLINICAL PARTICULARS
Therapeutic indications
For acute intervention or when oral therapy is not possible in - acute and chronic schizophrenic syndromes - states of psychomotor agitation of psychotic origin Posology and method of administration
Haldol-Janssen solution for injection 5 mg/mL is recommended for intramuscular injection only. The dosage, pharmaceutical form and duration of use must be adjusted to the individual response, indication and the severity of the disorder. In general, the lowest effective dose should be given. For outpatient therapy, treatment initiation with a slowly increasing dose is recommended, whereby the effect and adverse reactions should be weighed against each other. Inpatient treatment can also be started at higher doses in order to achieve a rapid effect. Abrupt marked changes in dose increase the risk of adverse reactions. After prolonged therapy, the dose must be tapered off in very small decrements over a long period of time. The daily doses listed below are for guideline purposes. The daily dose can be divided into 1 to 3 single doses, or even more frequent single doses at high dosages. Unless otherwise prescribed, for acute and chronic schizophrenic syndromes and states of psychomotor agitation: Start with 5 mg haloperidol intramuscularly; if necessary, every hour until sufficient control of symptoms is achieved. A daily dose of 20 mg haloperidol should not be exceeded. After acute pathological signs subside, treatment should be continued with oral formulations. Posology in elderly patients: In elderly patients, particularly those with cognitive impairment, an effect can generally be achieved at lower doses. Start with single doses of 0.5-1.5 mg haloperidol. Elderly patients may develop extrapyramidal adverse reactions even at low dosages. The frequency of tardive dyskinesias is increased. In addition, the sedative effect and anticholinergic effect are more pronounced in elderly patients. Hypotension may occur more frequently. Daily doses not exceeding 5 mg haloperidol are recommended. In the case of anticoagulant treatment, haloperidol must not be injected intramuscularly. The duration of treatment depends on the clinical picture and individual progression, whereby the lowest maintenance dose necessary should be sought. The need for continued treatment should be decided on the basis of an ongoing, critical assessment. Paediatric population: The safety and efficacy of Haldol-Janssen solution for injection 5 mg/mL in children and adolescents have not been established. Haldol-Janssen must not be used in the following cases: - hypersensitivity to the active substance, other butyrophenones or to any of the excipients - Parkinson's disease - known history of neuroleptic malignant syndrome after haloperidol - children and adolescents Special warnings and precautions for use
Haldol-Janssen must be used with particular caution in the following cases: - acute intoxication with alcohol, opioids, hypnotics or psychotropic agents that depress the central nervous system - hepatic or renal insufficiency - hypokalaemia/electrolyte imbalances - severe hypotension or orthostatic dysregulation - risk factors for prolonged QT interval, such as congenital long QT syndrome or other clinically significant cardiac disorders (especially conduction disturbances, arrhythmias), a family history of QT prolongation, concomitant treatment with medicinal products that can also prolong the QT interval in the ECG or can cause hypokalaemia/electrolyte imbalances (see section 4.5) - prolactin-dependent tumours, e.g. mammary tumours - depressive illness - haematopoietic system disorders - known history of neuroleptic malignant syndrome after use of other neuroleptics - organic brain disease or epilepsy - hyperthyroidism (see below) Increased mortality in elderly people with dementia
Data from two large observational studies have shown that elderly people with dementia treated with conventional (typical) antipsychotics are exposed to a slightly increased risk of mortality compared to those not treated with antipsychotics. Based on the study data available, it is not possible to specify the exact level of this risk and the cause of this increase in risk is not known. On account of these risks, the attending physician must assess in each individual case whether Haldol-Janssen is to be used for treating behavioural disorders associated with dementia. Increased risk for the occurrence of adverse cerebrovascular events
In randomised, placebo-controlled clinical studies in patients with dementia treated with some atypical antipsychotics, an approximately three-fold increased risk of adverse cerebrovascular events was observed. The mechanism leading to this increase in risk is unknown. It cannot be excluded that this effect might also occur with the use of other antipsychotics or in other patient groups. Haldol-Janssen should therefore be used with caution in patients with an increased risk of stroke. Patients/caregivers should be urged to report signs of a possible cerebrovascular event, such as sudden flaccidity, numbness in the face, arms or legs, as well as speech or visual disturbances, immediately to the attending physician. All therapeutic options or discontinuation of treatment with Haldol-Janssen must be considered without delay. Thromboembolic risk
In association with the use of antipsychotics, cases of venous thromboembolism (VTE) have been reported. As patients treated with antipsychotics often have acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Haldol-Janssen and preventive measures taken. Patients with phaeochromocytoma, renal insufficiency, heart failure or cerebral insufficiency exhibit hypotensive reactions more frequently after administration of haloperidol and should therefore be carefully monitored. Before treatment with Haldol-Janssen, blood counts must be checked (including differential blood count and platelet count). If blood counts are abnormal, treatment with Haldol-Janssen may be administered only when strictly indicated, together with frequent blood count monitoring. Existing hypokalaemia must be corrected before the start of treatment. Renal and hepatic function, as well as circulatory status (including ECG tracings), must be monitored at regular intervals during therapy. A baseline ECG and EEG should be available for subsequent follow-ups. Cardiovascular effects Hypotension and orthostatic dysregulation - as well as a reflex rise in the heart rate - frequently occur, particularly at the start of treatment. Tachycardia has been reported in some patients. Very rarely, prolongation of the QT interval in the ECG and/or ventricular arrhythmia/torsade de pointes have been reported during the use of haloperidol, as well as rare cases of sudden death. This may occur more frequently with administration of high doses and in predisposed patients. In the event of these ECG findings, treatment with haloperidol must be discontinued. Caution must be exercised in patients with risk factors for QT prolongation (long QT syndrome, hypokalaemia, electrolyte disturbances, cardiovascular disease, a family history of QT prolongation) or during concomitant treatment with medicinal products that also prolong the QT interval in the ECG, especially when Haldol-Janssen is administered parenterally. The risk of QT prolongation and/or ventricular arrhythmias may be increased at higher doses (see sections 4.5, 4.8 and 4.9) or with parenteral administration, particularly when administered intravenously. If Haldol-Janssen is administered intravenously, continuous ECG monitoring should be performed to detect QT interval prolongation and severe cardiac arrhythmias. Haldol-Janssen solution for injection 5 mg/mL is recommended for intramuscular injection only. Neuroleptic malignant syndrome During treatment with neuroleptics, life-threatening neuroleptic malignant syndrome (fever over 40°C, muscular rigidity, autonomic crisis with tachycardia and hypertension, impaired consciousness and even coma) may occur, which requires immediate discontinuation of the medication. The frequency of this syndrome is reported to be 0.07-2.2%. In such cases, intensive care procedures are required. At the onset of high fever and muscle rigidity, neuroleptic malignant syndrome must be considered, which is not infrequently misdiagnosed as catatonia. As re-administration of neuroleptics may have life-threatening consequences in such cases, differential diagnosis is of crucial importance (history of medications, testing for rigors, fever, as well as CK elevation in blood and urine). At the onset of fever, inflammation of the gums and oral mucosa, sore throat or purulent angina and flu-like symptoms, especially if these symptoms occur within the first 3 months after initiation of haloperidol treatment, patients should be urged not to self-medicate with analgesics etc., but rather consult their attending physician immediately. Tardive dyskinesias Mostly after prolonged therapy with high doses or upon discontinuation of therapy, tardive dyskinesias may manifest (persistent, often irreversible hyperkinetic syndromes with abnormal involuntary movements, especially in the maxillofacial muscles, but also athetoid and ballistic movements of the extremities). At present, there is no known reliable treatment of these symptoms. Extreme vigilance is required for initial dyskinetic signs, mainly in the glossal and digital region, and termination of neuroleptic therapy should be considered. During longer-term treatment with Haldol-Janssen, tardive dyskinesias can be masked and may not manifest until after cessation of treatment. Although the prevalence of tardive dyskinesias has not yet been adequately researched, it appears that elderly patients, especially older women, are particularly predisposed. The risk of tardive dyskinesias and particularly that of irreversibility is thought to increase with the duration of therapy and neuroleptic dosage level. However, tardive dyskinesia can also develop even after a short duration of treatment and low dosage. The neuroleptic treatment itself can initially mask the symptoms of incipient tardive dyskinesia. Upon discontinuation of the medication, this then becomes manifest. Extrapyramidal symptoms As with all neuroleptics, extrapyramidal symptoms may occur, e.g. tremor, rigidity, hypersalivation, bradykinesia, akathisia, acute dystonia. Early dyskinesias are very common during treatment with Haldol-Janssen, especially in the first few days and weeks. Parkinson's syndrome and akathisia generally occur at a later stage. At the onset of early dyskinesias or Parkinson's syndromes, a dose reduction or treatment with an anticholinergic antiparkinson agent is required. However, this medication should be administered only when needed and not on a routine basis. If an antiparkinson medication is required, the excretion of which is more rapid than that of haloperidol, it may be necessary to continue this antiparkinson medication even after discontinuation of Haldol-Janssen, in order to avoid the onset or exacerbation of extrapyramidal motor symptoms. Vigilance is required for a possible increase in intraocular pressure when co-administering Haldol-Janssen and anticholinergic medications, including antiparkinson medications (see section 4.5). Treatment of akathisia is difficult. Initially, a dose reduction can be attempted; if unsuccessful, trial treatment with sedatives, hypnotics or beta-receptor blockers can be performed. Particular caution should be exercised in patients with organic brain damage, atherosclerotic cerebrovascular disease and susceptibility to seizures (a history thereof, e.g. in alcohol withdrawal), as haloperidol lowers the threshold for the onset of seizures and grand mal seizures may occur. Patients with epilepsy should only be treated whilst maintaining anticonvulsant therapy with Haldol-Janssen. Hepatobiliary tract As haloperidol is metabolised by the liver, caution should be exercised in patients with hepatic disease. Isolated cases of liver dysfunction or hepatitis, mostly cholestatic, have been reported. Endocrine system Thyroxine can increase the rate of adverse reactions to Haldol-Janssen. Antipsychotic therapy in patients with hyperthyroidism should only be performed with extreme caution and must be supported therapeutically to achieve a euthyroid state. Hormonal effects of antipsychotic neuroleptics include hyperprolactinaemia, which may cause galactorrhoea, gynaecomastia and oligo- or amenorrhoea. Experiments on tissue cultures suggest that about one-third of human breast tumours are prolactin-dependent in vitro. Although meaningful clinical or epidemiological studies are not yet available, caution is advisable in patients with a relevant history. Very rarely, cases of hypoglycaemia and syndrome of inappropriate antidiuretic hormone secretion have been reported. Additional circumstances to be considered In schizophrenia, the onset of response to treatment with antipsychotic agents may be delayed. Similarly, symptoms may not be visible for several weeks or months after discontinuation of medication. Following abrupt withdrawal of high-dose antipsychotic agents, very rare cases of acute withdrawal symptoms, such as nausea, vomiting and insomnia, have been reported. Relapse may occur and gradual discontinuation is recommended. As with all antipsychotic agents, Haldol-Janssen should not be used alone in severe depressive disorders. In cases of concomitant depression and psychosis, Haldol-Janssen can be combined with an antidepressant (see section 4.5). Paediatric population: Available data on safety in children and adolescents indicate a risk for extrapyramidal symptoms, including tardive dyskinesias, and sedation. There are no long-term safety data. Interaction with other medicinal products and other forms of interaction
Concomitant use of medicinal products that also the prolong QT interval (e.g. Class IA or III antiarrhythmic agents, macrolide antibiotics, antihistamines), which lead to electrolyte disturbances (e.g. certain diuretics) or can inhibit the hepatic breakdown of haloperidol (e.g. cimetidine, fluoxetine) is to be avoided. Haloperidol is metabolised via several pathways, including glucuronidation and the cytochrome P450 enzyme system (especially CYP 3A4 and CYP 2D6). Inhibition of these metabolic pathways by other medicines may lead to increased haloperidol concentrations and an increased risk of adverse drug reactions, including prolonged QT interval. In pharmacokinetic studies, mild to moderately elevated haloperidol concentrations were reported when haloperidol was administered together with medicines which are substrates or inhibitors of CYP 3A4 or CYP 2D6 isoenzymes, such as itraconazole, nefazodone, buspirone, venlafaxine, alprazolam, fluvoxamine, quinidine, fluoxetine, sertraline, chlorpromazine and promethazine. A decrease in CYP2D6 enzyme activity may lead to elevated haloperidol concentrations. Prolongation of the QTc interval has been observed with combined use of haloperidol and the metabolic inhibitors ketoconazole (400 mg/day) and paroxetine (20 mg/day). It may be necessary to reduce the haloperidol dose. Effect of haloperidol on other medicinal products During combined use with CNS depressants (hypnotics, analgesics, other psychotropic agents, antihistamines), increased sedation or respiratory depression may occur. Respiratory depression induced by polypeptide antibiotics (e.g. capreomycin, colistin, polymyxin B) may be enhanced by haloperidol. Haloperidol is an inhibitor of the CYP2D6 enzyme. Concomitant administration of tricyclic antidepressants and haloperidol leads to an increase in antidepressant plasma levels - increased toxicity of both active substances (anticholinergic effect, lowering of the seizure threshold and, in particular, cardiac effects [QT interval prolongation]) must be anticipated. For this reason, this combination is not recommended. The following interactions result from the effect of haloperidol on alpha-adrenoreceptors: Amphetamine-type stimulants: The stimulating effect of amphetamine is reduced; the antipsychotic effect of haloperidol may be reduced by activity on the dopamine receptors. Epinephrine: Paradoxical hypotension, tachycardia. Dopamine: Peripheral vasodilation (e.g. renal artery) or, at high doses, vasoconstriction may be antagonised by haloperidol. The effect of antihypertensive agents may be potentiated if haloperidol is co-administered. In combination with methyldopa, enhanced central nervous effects may result. Haloperidol can antagonise the action of adrenaline and other sympathomimetic agents and thus reverse the hypotensive action of adrenergic-blocking agents such as guanethidine. During concomitant treatment with levodopa or dopamine agonists, their effect may be attenuated. If haloperidol is co-administered with medicinal products with an anticholinergic effect (e.g. atropine, biperiden), this effect may be potentiated. This may manifest as visual disturbances, increased intraocular pressure, dry mouth, rapid heartbeat, constipation, micturition disorders, impaired salivation, speech block, memory impairment or reduced sweating. During treatment with haloperidol, the effect of disulfiram is attenuated by concomitant alcohol consumption. Due to interactions with anticoagulants, regular monitoring of the coagulation status at relatively short intervals is indicated during concomitant anticoagulant therapy. There have been reports of an antagonistic effect on the anticoagulant phenindione. Due to the increase in prolactin induced by haloperidol, the response to gonadorelin administration may be attenuated. Effect of other medicinal products on haloperidol When co-administered with carbamazepine, rifampicin, phenobarbital or phenytoin, or as a result of smoking, blood levels of haloperidol may be significantly reduced due to enzyme induction, thus leading to an attenuated effect of haloperidol. During combined treatment, the Haldol-Janssen dose should therefore be adjusted as necessary. Once administration of these medicines has ceased, a reduction in the Haldol-Janssen dosage may be necessary. Sodium valproate, an inhibitor of glucuronidation, does not affect the plasma concentration of haloperidol. Other interactions Concomitant intake of alcohol and haloperidol may lead to potentiation of the alcohol effect and to a decrease in blood pressure. In rare cases, neurotoxic symptoms may occur with co-administration of lithium, with impaired consciousness and increased body temperature. Furthermore, concomitant ingestion of lithium may lead to EEG changes, increased extrapyramidal motor disorders, as well as fatigue, tremor and dry mouth. It remains unclear whether this is one single pathology or whether the symptoms are due to neuroleptic malignant syndrome and/or lithium neurotoxicity. Nevertheless, in patients concomitantly treated with lithium and haloperidol, the medication should be terminated immediately at any signs of neurotoxicity. In combined use of neuroleptics and other dopamine antagonists (e.g. metoclopramide), the extrapyramidal motor effects may be potentiated. When treating cocaine-intoxicated drug addicts with Haldol-Janssen, the extrapyramidal motor effects may be potentiated. Fertility, pregnancy and lactation
Pregnancy Onset of pregnancy during treatment with Haldol-Janssen should be avoided wherever possible. A pregnancy test should therefore be performed before the start of treatment. During treatment, appropriate contraceptive measures must be taken. Should treatment during pregnancy be required, the benefits and risks must be carefully weighed against each other, as no adequate studies are available on the safety of haloperidol during pregnancy. Animal studies have produced indications of embryofoetal damage (see section 5.3). Newborn infants exposed to antipsychotics (including haloperidol) during the third trimester of pregnancy are at risk from adverse reactions, including extrapyramidal symptoms and/or withdrawal phenomena, the severity and duration of which may vary post-partum. There have been reports of agitation, increased or decreased muscle tone, tremor, somnolence, dyspnoea or poor sucking reflex. Consequently, newborn infants should be carefully monitored. Breastfeeding Haloperidol is excreted in human milk. Extrapyramidal symptoms have been observed in breast-fed infants whose mothers had been receiving haloperidol. Women should therefore not breast-feed during haloperidol treatment. Effects on ability to drive and use machines
Even when used as directed, this medicinal product may alter responsiveness to such an extent that the ability to drive, use machines or work without suitable safeguards is impaired. This applies particularly at the start of treatment and in combination with alcohol. Patients should therefore refrain completely from driving, using machines or performing other hazardous activities - at least during the initial phase of treatment. The decision should be made by the attending physician in each individual case, taking into account the individual response and the respective dosage. Undesirable effects
In the lower dosage range (1-2 mg daily) adverse reactions to haloperidol are comparatively rare, mild and transient. At higher doses, some adverse reactions are more common. Neurological symptoms are predominant. The following categories are used for expressing the frequency of undesirable effects: ( 1/100 to < 1/10) ( 1/1,000 to < 1/100) ( 1/10,000 to < 1/1,000) (cannot be estimated from the available data) The following is a list of adverse reactions that have been reported in clinical trials and post-marketing experience. Adverse reactions by system organ class and frequency

Blood and lymphatic system disorders
Uncommon:
Very rare: Agranulocytosis, pancytopenia, thrombocytopenia, neutropenia Not known:
Immune system disorders
Uncommon:
Hypersensitivity Very rare: Anaphylactic reaction
Endocrine disorders
Very rare:
Inappropriate antidiuretic hormone secretion Not known: Hyperprolactinaemia
Metabolism and nutrition disorders
Very rare:

Psychiatric disorders
Very common:
Agitation, insomnia Psychotic disorder, depression Uncommon: Not known: Decreased libido
Nervous system disorders
Very common:
Extrapyramidal disorders Tardive dyskinesia Uncommon: Not known: Motor dysfunction Involuntary muscle contractions Neuroleptic malignant syndrome
Eye disorders
Common:
Visual disturbances Oculogyric crisis Not known:
Cardiac disorders
Very rare:
Torsade de pointes, ventricular fibrillation, ventricular tachycardia, extrasystoles Not known:
Vascular disorders
Common:
Orthostatic hypotension Not known: Cases of thromboembolic events (including cases of pulmonary embolism and cases of deep vein thrombosis)
Respiratory, thoracic and mediastinal disorders
Uncommon:
Very rare: Laryngospasm, laryngeal oedema
Gastrointestinal disorders
Common:
Uncommon: Diarrhoea, loss of appetite, heartburn, dyspepsia Very rare:
Hepatobiliary disorders
Common:
Abnormal liver function test Uncommon: Hepatitis, jaundice Very rare: Acute hepatic failure, cholestasis
Skin and subcutaneous tissue disorders
Common:
Uncommon: Photosensitive reaction, urticaria, pruritus, hyperhidrosis, allergic skin reactions Very rare: Leukocytoclastic vasculitis, exfoliative dermatitis
Musculoskeletal and connective tissue disorders
Very rare:
Not known: Muscle stiffness Musculoskeletal stiffness Muscle twitching
Renal and urinary disorders
Common:
Urinary retention
Pregnancy, puerperium and perinatal conditions
Not known:
Drug withdrawal syndrome in the newborn (see section 4.6)
Reproductive system and breast disorders
Common:
Erectile dysfunction Very rare: Priapism, gynaecomastia Not known: Chest complaints Sexual dysfunction Menstrual complaints
General disorders and administration site conditions
Uncommon:
Oedema, hyperthermia Very rare: Sudden death, facial oedema, hypothermia Not known:
Investigations
Common:
Weight gain, weight loss Prolongation of the QT interval in the electrocardiogram Other CNS effects: Fatigue may occur especially at the start of treatment, as well as restlessness, agitation, light-headedness, depressive mood (especially in long-term therapy), lethargy, dizziness, headache, delirium symptoms (especially in combination with anticholinergic substances) or cerebral seizures, dysregulation of body temperature as well as speech, memory and sleep disorders. Autonomic nervous system: Uncommonly, autonomic symptoms may occur at high doses, such as accommodation disturbances, feeling of nasal congestion, increased intraocular pressure, micturition disorders. Peripheral oedema, hyponatraemia, alopecia, respiratory rhythm disorders, bronchopneumonia and pigment deposits in the cornea and lens. Overdose
Due to the relatively large therapeutic index, intoxication generally occurs only in the event of a larger overdose. Symptoms of overdose In the event of an overdose, those adverse reactions described in section 4.8 in particular may increasingly occur, depending on the dose taken: - extrapyramidal disorders: acute dyskinetic or dystonic symptoms, tongue protrusion spastic involuntary, oculogyric crisis, laryngeal or pharyngeal spasms - somnolence to the point of coma, sometimes agitation and delirious confusion - cerebral seizures - hyperthermia or hypothermia - cardiovascular: hypotension, as well as hypertension, tachycardia or bradycardia, ECG changes such as PQ-, QT-interval prolongation, torsade de pointes, cardiovascular failure - anticholinergic effects: blurred vision, increased intraocular pressure, reduced bowel motility, urinary retention - respiratory complications: respiratory depression, apnoea, aspiration, cyanosis, pneumonia Measures in the event of overdose Intensive care treatment must be initiated as quickly as possible. Treatment is symptomatic: volume replacement, anticonvulsants, vasoconstrictor agents (NB: not adrenalin) and possibly antiarrhythmics can be used, as well as sodium bicarbonate or lactate in some cases for cardiac complications. ECG and vital signs must be monitored until the ECG has returned to normal. Analeptics are contraindicated, as there is a tendency for cerebral seizures due to the reduction in the seizure threshold caused by haloperidol. Beta-blockers should also be avoided because they increase vasodilation. Antiparkinson agents for severe extrapyramidal symptoms, e.g. biperiden IV; in some cases, it may be necessary to administer the antiparkinson medication over several weeks. High fever should be treated with antipyretics, possibly with ice baths, hypothermia by slow warming. If an anticholinergic syndrome occurs, physostigmine salicylate is available for use under intensive care conditions (important: ECG monitoring). Due to the large volume of distribution and high plasma protein binding, forced diuresis or haemodialysis is of little assistance in cases of pure haloperidol intoxication. PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties
Pharmacotherapeutic group: antipsychotics, butyrophenone derivatives ATC code: N05AD01 Haloperidol is a potent neuroleptic from the butyrophenone series. In particular, haloperidol induces dopamine receptor blockade, thereby reducing the effect of dopamine as a transmitter substance. Haloperidol has a high affinity for D2 receptors. With chronic administration, dopamine receptors may become hypersensitive in certain regions ("supersensitivity", "up-regulation"). Less pronounced than the dopamine antagonistic effect is the effect on the serotonin (5-HT1A- and 5HT2-), (sigma) opioid receptors and the α-adrenoreceptors (1 > 2). Haloperidol also has an anticholinergic and a H1 antihistamine effect but only at very high doses. The clinical effect profile is characterised by antipsychotic effects (reduction of delusions, hallucinations, ego- and thought disorders, suppression of psychomotor and catatonic excitement, affective tension, as well as manic depression and increased drive). In addition, haloperidol has a sedative effect (but not hypnotic), is therapeutically beneficial in certain hyper- and dyskinetic syndromes and has an antiemetic effect. Pharmacokinetic properties
Following oral administration, haloperidol is rapidly and almost completely absorbed from the gastrointestinal tract; absorption is complete after 3 hours. Due to the high first-pass effect, absolute bioavailability after oral administration is 60-70%. Peak plasma concentrations have been measured after 2-6 hours when administered orally and after 20 minutes following intramuscular administration. Due to its high lipophilicity, haloperidol is distributed throughout the entire body. The volume of distribution at steady state is 7.9±2.5 L/kg BW. Haloperidol is excreted in human milk and crosses the blood-brain barrier. Plasma protein binding is 92%. Haloperidol is almost completely metabolised in the liver by several routes, including glucuronidation and the cytochrome P450 system (mainly CYP3A4 or CYP2D6). The main degradation pathway is cleavage of the N-side chain by oxidative dealkylation (CYP3A4) and subsequent ß-oxidation of the carboxylated side chain. Thus, 4-fluorobenzoylpropionic acid and 4-fluorophenylacetic acid are found in the urine as pharmacologically inactive metabolites. Haloperidol reduced at the keto group, with a weak antipsychotic effect, has also been found in the urine and serum. Metabolism of haloperidol is accelerated by enzyme-inducing agents (phenobarbital, phenytoin, carbamazepine). The plasma elimination half-life is 24 hours (12-38 hours) following oral ingestion and 21 hours (13-36 hours) after intramuscular administration. 60% of the substance is excreted in the faeces and 40% in the urine. Only about 1% of the active substance is excreted unchanged via the kidneys. The course of plasma levels suggests a multiphasic elimination of the substance. The elimination rate is reduced at night. Therapeutic plasma levels Therapeutic plasma levels are thought to be between 4 and 20-25 µg/L. Pathophysiological variations Dialysis patients: Due to its high volume of distribution and its low plasma level, only very small amounts are removed by dialysis. An additional dose or a modified haloperidol dosage regimen is therefore not usually necessary. Preclinical safety data
Acute toxicological effects of haloperidol primarily concern the central nervous system and cardiovascular system (see section 4.9). Chronic toxicity studies on rats and dogs produced no indications of clinically significant toxic effects. Several in vitro and in vivo tests to investigate the mutagenicity of haloperidol gave no relevant indications of a mutagenic effect. Long-term studies on the tumorigenic potential of haloperidol showed no indications of carcinogenicity in rats. In mice, an increase in the number of mammary tumours and pituitary tumours, as well as the total number of neoplasms, was observed in the high dose group. Mammary tumours may be the result of increased prolactin concentrations in the blood. Numerous neuroleptics also induce hyperprolactinaemia in humans. Haloperidol crosses the placenta and is excreted in breast milk. Haloperidol proved to be teratogenic in mice and hamsters; in rats, it showed embryo- and foetotoxic effects. Treatment with haloperidol during the peri/postnatal phase led to behavioural changes in rats. After haloperidol administration, the fertility of female mice and rats, as well as the fertility of male dogs and rats, was impaired. In vitro, haloperidol blocks expressed hERG channels in the upper nanomolar concentration range that can be achieved in plasma under therapeutic conditions. These channels are responsible for repolarisation in the heart. Thus, haloperidol has the potential to trigger certain forms of ventricular arrhythmias (torsade de pointes). As part of in vivo studies, intravenous haloperidol administration caused significant QTc prolongation in some animal models. The dosages were approximately 0.3 mg/kg BW IV, which resulted in peak plasma concentrations (Cmax) which were 3- to 7-fold higher than therapeutic plasma levels of 4 to 20 μg/L in humans. These intravenously administered dosages, at which prolongation of the QTc interval was observed, caused no arrhythmias. In some studies, higher intravenous haloperidol doses of 1 to 5 mg/kg BW induced QTc prolongation and/or ventricular arrhythmias. In this case, peak plasma concentrations (Cmax) were 19 to 68-fold higher than the therapeutic plasma levels in humans. PHARMACEUTICAL PARTICULARS
List of excipients
Lactic acid, water for injections. There are no known incompatibilities. Shelf life
After opening, discard any remaining solution. This medicinal product should not be used after the expiry date. Special precautions for storage
Store Haldol-Janssen solution for injection 5 mg/mL between 15°C and 25°C. Nature and contents of container
Original pack with 5 ampoules, each containing 1 mL solution for injection Hospital pack with 50 (10x5) ampoules, each containing 1 mL solution for injection Special precautions for disposal and other handling
No special requirements. MARKETING AUTHORISATION HOLDER
JANSSEN-CILAG GmbH Tel: +49 (0)2137 955-955 MARKETING AUTHORISATION NUMBER
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
12/05/1999 / 29/08/2007 DATE OF REVISION OF THE TEXT
GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription

Source: https://health.gov.mt/en/poyc/Documents/Haldol%205mg-ml%20injekt.(D)%20SPC_uk2.pdf