Levomepromazine Maleate 50mg Tablets

Tablets. White to off white round shaped tablet with break line on one side and 'L2' debossing on another side. The tablet can be divided into equal halves.

4.1 Therapeutic indications Levomepromazine tablets is a neuroleptic with indications in psychiatry and general medicine, particularly in terminal illness. Clinically it is more sedative and more potent than chlorpromazine in the management of psychotic conditions and in the relief of severe chronic pain. Psychiatry As an alternative to chlorpromazine in schizophrenia especially when it is desirable to reduce psychomotor activity. General medicine – Terminal illness Adjunct therapy in the relief of pain and the accompanying distress.4.2 Posology and method of administration **Posology** Dosage varies with the condition under treatment and the individual response of the patient.

1. Terminal illness The dosage is 12.5mg to 50mg every 4 to 8 hours. Elderly No specific dosage recommendations.
2. Psychiatric conditions Adults Ambulant patients: initially the total daily oral dose should not exceed 25- 50mg usually divided into 3 doses; a larger portion of the dosage may be taken at bedtime to minimise diurnal sedation. The dosage is then gradually increased to the most effective level compatible with sedation and other side effects. Bed patients: initially the total daily oral dosage may be 100- 200mg, usually divided into 3 doses, gradually increased to 1g daily if necessary. When the patient is stable attempts should be made to reduce the dosage to an adequate maintenance level. Special populations *Paediatric population* Children are very susceptible to the hypotensive and soporific effects of levomepromazine. It is advised that a total daily oral dosage of 37.5mg should not be exceeded. The average effective daily intake for a ten year old is 12.5mg to 25mg. Elderly It is not advised to give levomepromazine to ambulant patients over 50 years of age unless the risk of a hypotensive reaction has been assessed. **Method of administration** For oral use only.4.3 Contraindications Hypersensitivity to levomepromazine or any of the other ingredients. In combination with: o citalopram, escitalopram o hydroxyzine o piperaquine o domperidone There are no absolute contraindications to the use of Levomepromazine in terminal care.4.4 Special warnings and precautions for use ****Special warnings**** **Blood disorders** In case of a persistent fever, sore throat or infection under levomepromazine use a complete blood count is advised. Treatment should be stopped in case of leucytosis, or leucopenia. **Neuroleptic malignant syndrome** levomepromazine has been associated with neuroleptic malignant syndrome, a rare idiosyncratic response characterised by hypothermia, generalised muscle rigidity, autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardia dysrhythmia), altered consciousness and increased serum creatine phosphokinase levels. Hyperthermia is often an early sign of this syndrome. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Antipsychotic treatment must be withdrawn immediately and appropriate supportive therapy and careful monitoring instituted. **Vascular disorders** The hypotensive effects of levomepromazine should be taken into account when it is administered to patients with cardiac disease and the elderly or debilitated. **Cardiac disorders** Except for in emergency situations, it is recommended that an ECG with measurement of serum calcium, magnesium and potassium levels is performed during the initial assessment of patients who require treatment with a neuroleptic. Periodic serum electrolyte levels should be monitored and corrected, if necessary, especially during long-term chronic usage. An ECG may be appropriate to assess the QT interval whenever dose escalation is proposed and when the maximum therapeutic dose is reached. As with other neuroleptics, cases of QT interval prolongation have been reported with levomepromazine, in a dose-dependent manner. This effect, which is known to potentiate the risk of onset of severe ventricular rhythm disorders, particularly torsades de pointes, is increased by the existence of bradycardia, hypokalaemia or a congenital or acquired long QT (through combination with a medicinal product which increases the QT interval) (see section 4.8).: It is therefore important to ensure the absence of factors which may promote the onset of this rhythm disorder prior to administration, if the clinical situation allows: • Bradycardia (<55 beats per minute) or 2nd or 3rd degree heart block. • Metabolic abnormalities such as hypokalaemia, hypocalcaemia or hypomagnesaemia. • Starvation or alcohol abuse. • A personal or family history of QT interval prolongation, ventricular arrhythmias or torsades de pointes. • Ongoing treatment with other medicinal product(s) liable to induce significant bradycardia (<55 beats per minute), electrolyte imbalance (including hypokalaemia), slowed intracardiac conduction or QT interval prolongation (see sections 4.3 and 4.5). Patients are strongly advised not to consume alcoholic beverages or to take medicines containing alcohol during treatment (see section 4.5). **Venous thromboembolism** Cases of venous thromboembolism (VTE) have been reported with antipsychotics. As patients treated with antipsychotics often have acquired risk factors for VTE, any potential risk factors for VTE should be identified before and during treatment with levomepromazine and preventive measures must be implemented (see section 4.8). **Hyperglycaemia** Hyperglycaemia or intolerance to glucose has been reported in patients treated with levomepromazine. Patients with an established diagnosis of diabetes mellitus or with risk factors for the development of diabetes who are started on levomepromazine, should get appropriate glycaemic monitoring during treatment (see section 4.8). **Special populations** The risk of onset of tardive dyskinesia, even at low doses, particularly in children and the elderly, should be taken into account, especially during prolonged treatments. Tardive dyskinesia sometimes occurs upon discontinuation of the neuroleptic and disappears when it is re-introduced, or the dosage is increased. Increased Mortality in Elderly people with Dementia: Data from two large observational studies showed that elderly people with dementia who are treated with conventional (typical) 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. Levomepromazine is not licensed for the treatment of dementia-related behavioural disturbances. Stroke: In randomized clinical trials versus placebo performed in a population of elderly patients with dementia and treated with certain atypical antipsychotic drugs, a 3-fold increase of the risk of cerebrovascular events has been observed. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other antipsychotics or other patient populations. Levomepromazine should be used with caution in patients with risk factors for stroke. ****Excipients**** Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine. ****Precautions for use**** This medicinal product should be used with caution in patients with: • hypothyroidism, • cardiac failure, • phaeochromocytoma, • myasthenia gravis, • prostate hypertrophy. • liver dysfunction Care must be taken with liver failure, due to the risk of overdose. At the start of treatment with Levomepromazine, liver function tests should be carried out. During chronic treatment, follow-up tests should be performed at least every 6 – 12 months. Except for in exceptional situations, this medicinal product should not be used in patients with Parkinson's disease. Levomepromazine may cause abdominal pain and distention mimicking of paralytic ileus which should be treated as an emergency. Monitoring of levomepromazine treatment should be reinforced: • in patients with epilepsy because of the possibility of lowering the seizure threshold (see section 4.8). The onset of seizures requires discontinuation of the treatment. • in subjects with certain cardiovascular conditions, due to the quinidine, tachycardia inducing, and hypotensive effects of this product class • in severe renal and /or hepatic failure, because of the risk of accumulation • in patients with agranulocytosis, regular blood count is recommended (see section 4.8) • in elderly patients with:

• greater susceptibility to orthostatic hypotension, sedation and extrapyramidal effects
• chronic constipation (risk of paralytic ileus)
• a possible prostatic hyperplasia4.5 Interaction with other medicinal products and other forms of interaction ****Contraindicated combinations (see section 4.3)**** Citalopram, escitalopram, hydroxyzine, piperaquine, domperidone Increased risk of ventricular rhythm disorders, particularly torsades de pointes. ****Combinations not recommended (see section 4.4)**** Adrenaline Adrenaline (epinephrine) must not be used in patients overdosed with neuroleptics (see section 4.9). Dopaminergics Mutual antagonism between dopaminergics and neuroleptics. Dopaminergics may cause or exacerbate psychotic disorders. If treatment with neuroleptics is required in patients with Parkinson's disease treated with dopaminergic, the latter should be tapered off gradually (sudden discontinuation of dopaminergic agents exposes the patient to a risk of “neuroleptic malignant syndrome”). Levodopa Reciprocal antagonism of the levodopa and the neuroleptics. In Parkinson's disease, use the minimum effective dose of each of the two medicinal products. Medicinal products likely to cause torsades de pointes: • class IA antiarrhythmics (e.g. quinidine, hydroquinidine, disopyramide, procainamide) • class III antiarrhythmics (e.g. amiodarone, dronedarone, sotalol, bretylium and dofetilide) • certain antimicrobials (such as sparfloxacin, moxifloxacin, IV spiramycin and IV erythromycin) and anti-parasitics (chloroquine, halofantrine, lumefantrine, pentamidine, quinine and mefloquine) • tricyclic antidepressants (e.g. amitriptyline) • tetracyclic antidepressants (e.g. maprotiline) • other neuroleptics (e.g. phenothiazines, pimozide and sertindole) • antihistamines (e.g. terfenadine, mizolastine, mequitazine) • other medicinal products such as arsenic trioxide, diphemanil, cisapride, IV dolasetron, prucalopride, toremifene, vandetanib, IV vincamine, methadone, hydroxychloroquine Increased risk of arrhythmias when antipsychotics are used with concomitant QT prolonging drugs (including certain antiarrhythmics, antidepressants and other antipsychotics) and drugs causing electrolyte imbalance. If possible, one of the two treatments should be discontinued. If the combination cannot be avoided, the QT interval should be checked before treatment and the ECG monitored (see section 4.4). ****Combinations which should be used with caution**** Beta blockers for heart failure (bisoprolol, carvedilol, metoprolol, nebivolol) Increased risk of ventricular rhythm disorders, particularly torsades de pointes. Vasodilator effect and risk of hypotension, particularly in orthostatic hypotension (additive effect). Clinical and ECG monitoring is required. Hypokalaemia-inducing medicinal products (potassium-depleting diuretics alone or in combination, stimulant laxatives, glucocorticoids, tetracosactide and intravenous amphotericin B) Diuretics, in particular those causing hypokalemia, should be avoided but, if necessary, potassium-sparing diuretics are preferred. Hypokalaemia should be corrected before administering the medicinal product and clinical, electrolyte, and electrocardiographic monitoring should be carried out. Other medicinal products which lower the seizure threshold The combined use of medicinal products which are pro-convulsant, or which lower the seizure threshold, should be carefully assessed due to the seriousness of the risk incurred. The main examples of such medicinal products are most of the antidepressants (imipramine-like, selective serotonin reuptake inhibitors), the neuroleptics (phenothiazines, butyrophenones), mefloquine, chloroquine, bupropion and tramadol. Cytochrome P450 2D6 Metabolism: There is a possible pharmacokinetic interaction between inhibitors of CYP2D6, such as phenothiazines and CYP2D6 substrates (mainly nortriptyline). Levomepromazine and its non-hydroxylated metabolites are reported to be potent inhibitors of cytochrome P450 2D6 (CYP2D6). Co-administration of levomepromazine and drugs primarily metabolised by the CYP2D6 enzyme system may result in increased plasma concentrations of these drugs. Monitor patients for dose-dependent adverse reactions associated with CYP2D6 substrates such as amitriptyline/amitriptylinoxide. Desferrioxamine Simultaneous administration of desferrioxamine and prochlorperazine has been observed to induce a transient metabolic encephalopathy, characterised by loss of consciousness for 48 to 72 hours. It is possible that this may occur with levomepromazine since it shares many of the pharmacological activities of prochlorperazine. ****Combinations to be considered**** Atropine-like medicinal products: The fact that the undesirable effects of atropine-like substances may be additive and more easily lead to urinary retention, an acute flare-up of glaucoma, constipation, dry mouth etc., must be considered. Examples of atropine-like medicinal products are imipramine-like antidepressants, most atropine-like H1 antihistamines, anticholinergic antiparkinsonian agents, atropine-like antispasmodics, disopyramide, phenothiazine neuroleptics and clozapine. Dapoxetine Risk of increased undesirable effects, particularly vertigo and syncope. Medicinal products that lower blood pressure Increased risk of hypotension, particularly orthostatic hypotension. As well as the antihypertensives, many medicinal products may lead to orthostatic hypotension. This is particularly the case of nitrate derivatives, phosphodiesterase type-5 inhibitors, alpha-blockers for urological purposes, imipramine antidepressants and neuroleptic phenothiazines, dopaminergic agonists, and levodopa. Using them in combination therefore risks increasing the frequency and intensity of this undesirable effect. Guanethidine Inhibition of the antihypertensive effect of guanethidine (inhibition of guanethidine uptake into sympathetic fibre, its site of action). Orlistat Risk of therapeutic failure in the case of concomitant treatment with orlistat. Lithium Risk of onset neuropsychiatric symptoms suggestive of a neuroleptic malignant syndrome or of lithium poisoning. Sedative medicinal products and barbiturates Increased CNS depression. Decreased alertness may make driving vehicles and using machines dangerous. Alcohol (beverage or excipient) Alcohol increases the sedative effect of these substances. Respiratory depression may occur. Decreased alertness may make driving vehicles and using machines dangerous. Avoid the consumption of alcoholic beverages and other medicinal products containing alcohol.4.6 Fertility, pregnancy and lactation **Pregnancy** Safety in pregnancy has not been established. Neonates exposed to antipsychotics (including levomepromazine) 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. The clinical data with levomepromazine are reassuring but still limited, and animal studies are insufficient for a conclusion to be reached regarding reproductive toxicity. In humans, the teratogenic risk of levomepromazine has not been evaluated. Different prospective epidemiological studies conducted with other phenothiazines have yielded contradictory results regarding teratogenic risk. Given these data, it is preferable to avoid using Levomepromazine during pregnancy as a precautionary measure and neonates must be closely monitored in the event of treatment at the end of pregnancy. **Breast-feeding** Levomepromazine is excreted in breast milk in low amounts in human milk. A risk to the breast-fed infant cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from levomepromazine therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. **Fertility** There are no fertility data in animals. In humans, because of the interaction with dopamine receptors, levomepromazine may cause hyperprolactinaemia which can be associated with impaired fertility in women. Some data suggest that levomepromazine treatment is associated with impaired fertility in men.4.7 Effects on ability to drive and use machines The attention of drivers of vehicles and users of machines, in particular, is drawn to the risks of drowsiness, disorientation, confusion or excessive hypotension related to this medicinal product, especially at the start of treatment.4.8 Undesirable effects Adverse effects have been ranked under headings of frequency using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). **Blood and lymphatic system disorders** Uncommon: Agranulocytosis Not known: Leukopenia **Endocrine disorders** Not known: Thermal dysregulation, hyperprolactinaemia (including galactorrhoea, gynaecomastia, amenorrhoea, impotence) **Cardiac disorders** Rare: Torsade de pointes, ECG changes include QT interval prolongation (as with other neuroleptics), ST depression, U-Wave and T-Wave changes. Cardiac arrhythmias, including ventricular arrhythmias and atrial arrhythmias, A-V block, ventricular tachycardia, which may result in ventricular fibrillation or cardiac arrest have been reported during neuroleptic phenothiazine therapy, possibly related to dosage. **Vascular disorders** Common: Postural hypotension (especially in elderly patients) Not known: Venous thromboembolism, deep vein thrombosis, pulmonary embolism (sometimes fatal) (see section 4.4). **Gastrointestinal disorders** Very common: Dry mouth Uncommon: Constipation Not known: Ileus paralytic, necrotising enterocolitis (which can be fatal) **Hepatobiliary disorders** Rare: Jaundice Not known: Hepatocellular, cholestatic and mixed liver injury **Metabolism and nutrition disorders** Not known: Glucose tolerance impaired, hyperglycaemia (see section 4.4), hyponatraemia, Syndrome of Inappropriate Antidiuretic Hormone secretion (SIADH) **Psychiatric disorders** Not known: Confusional states, delirium, indifference, anxiety, mood swings **Nervous system disorders** Very common: Sedation or somnolence, more pronounced early on in the treatment Uncommon: Parkinsonism (with prolonged high dosage), convulsions Not known: • Early dyskinesia (spasmodic torticollis, oculogyric crisis, trismus, etc.). • Extrapyramidal syndrome: o akinetic with or without hypertonia, and partially subsiding with anticholinergic antiparkinsonian agents; o hyperkinetic-hypertonic movements, motor-stimulant; o akathisia. • Tardive dyskinesia (anticholinergic antiparkinsonian agents have no effect or may cause the condition to worsen) • Neuroleptic malignant syndrome (see section 4.4). **Eye disorders** Not known: Brownish deposits in the anterior segment of the eye due to the accumulation of the product, generally with no impact on vision, accommodation disorders **Skin and subcutaneous tissue disorders** Not known: Photosensitivity reaction, dermatitis allergic **Reproductive system and breast disorders** Not known: Priapism **Pregnancy, puerperium and perinatal conditions** Not known: Drug withdrawal syndrome neonatal (see section 4.6) **Investigations** Not known: Weight gain, Antinuclear antibody positivity without clinical lupus erythematosus **General disorders and administration site conditions** Common: Asthenia, heat stroke (in hot and humid conditions) In addition, isolated cases of sudden death from cardiac origin have been reported in patients treated with antipsychotic neuroleptics with a phenothiazine, butyrophenone or benzamide structure (see section 4.4). **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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.4.9 Overdose **Symptoms** Symptoms of levomepromazine overdosage include drowsiness or loss of consciousness, hypotension, tachycardia, ECG changes, ventricular arrhythmias hypothermia and convulsions. Severe extrapyramidal dyskinesias may occur. **Management** If the patient is seen sufficiently soon (up to 6 hours) after ingestion of a toxic dose, gastric lavage may be attempted. Pharmacological induction of emesis is unlikely to be of any use. Activated charcoal should be given. There is no specific antidote. Treatment is supportive. Generalised vasodilatation may result in circulatory collapse; raising the patient's legs may suffice but, in severe cases, volume expansion by intravenous fluids may be needed; infusion fluids should be warmed before administration in order not to aggravate hypothermia. Positive inotropic agents such as dopamine may be tried if fluid replacement is insufficient to correct the circulatory collapse. Peripheral vasoconstrictor agents are not generally recommended; avoid use of adrenaline (epinephrine). Ventricular or supraventricular tachy-arrhythmias usually respond to restoration of normal body temperature and correction of circulatory or metabolic disturbances. If persistent or life-threatening, appropriate antiarrhythmic therapy may be considered. Avoid lidocaine (lignocaine) and, as far as possible, long acting anti-arrhythmic drugs. Pronounced central nervous system depression requires airway maintenance or, in extreme circumstances, assisted respiration. Severe dystonic reactions usually respond to procyclidine (5mg to 10mg) or orphenadrine (20mg to 40mg) administered intramuscularly or intravenously. Convulsions should be treated with intravenous diazepam. Neuroleptic malignant syndrome should be treated with cooling. Dantrolene sodium may be tried.

5.1 Pharmacodynamic properties ATC Code: NO5AA02 Pharmacotherapeutic group: Antipsychotics The mechanisms of action of levomepromazine involve blocking of D2, αl- and α2-adrenergic, and Ml cholinergic receptors thereby exerting multiple therapeutic effects. It is utilized for the treatment of psychotic disturbances such as acute and chronic schizophrenias, senile psychoses, and manic-depressive syndromes. The antipsychotic effect of levomepromazine is mediated by blocking of central dopamine receptors, while the side effects are mediated by antagonism of peripheral α-adrenoceptors. Other common side effects such as dry mouth and urine retention are mediated by antagonism of muscarinic cholinergic receptors. Levomepromazine has the histamine-antagonist properties of the antihistamines together with central nervous system effects resembling those of chlorpromazine. A relationship has been demonstrated between the sedative effects of psychotropic drugs and their ability to antagonize histamine Hl receptors in mouse and rat brain, and it seems likely that the sedative effects of some neuroleptics may be related to their histamine receptor-blocking properties. Levomepromazine as an analgesic is also effective for the treatment of pain due to cancer, trigeminal neuralgia, and neurocostal neuralgia.5.2 Pharmacokinetic properties Maximum serum concentrations are achieved in 2 to 3 hours depending on the route of administration. On average 50% of orally administered drug reached the general circulation as unchanged levomepromazine. The apparent volume of distribution was 23 to 42 L/kg, and the biologic half-life, 15 to 30 hr. The metabolism of levomepromazine was studied in man after oral administration. The study demonstrated glucuronides, sulfoxide and possibly non-oxidized drug in the urine and non-oxidized drug in the faeces. Cytochrome P450 isoenzymes involved in the 5-sulfoxidation and N-demethylation of the aliphatic-type phenothiazine neuroleptic levomepromazine were identified in human liver. CYP3A4 is the main isoform responsible for levomepromazine 5-sulfoxidation (72%) and N-demethylation (78%) at a therapeutic concentration of the drug (10 μM). CYP1A2 contributes to a lesser degree to levomepromazine 5-sulfoxidation (20%). Excretion is slow, with a half-life of about 30 hours. It is eliminated via urine and faeces. The elimination of levomepromazine metabolites occurs mainly in the urine with only smaller amounts of unchanged drug or demethylated products in the faeces. An average 10% of the daily dose was eliminated in the urine as levomepromazine sulfoxide.5.3 Preclinical safety data No data on the mutagenicity or carcinogenicity of levomepromazine are available.

6.1 List of excipients Lactose monohydrate Pregelatinized maize starch Povidone K-29/32 Silica, colloidal anhydrous Magnesium stearate6.2 Incompatibilities Not applicable.6.3 Shelf life 3 years6.4 Special precautions for storage This medicinal product does not require any special temperature storage conditions. Store in the original package in order to protect from light.6.5 Nature and contents of container PVC/PVdC-Alu blisters containing 7, 10, 14, 20, 24, 28, 30, 56, 60, 84, 90, 100 and 112 tablets. Not all pack sizes may be marketed.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.