LEVOMEPROMAZINE MALEATE 6 MG TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Levomepromazine Maleate 6mg Tablets.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 6mg levomepromazine maleate.

Excipient with known effect:

Each tablet contains 85.74 mg lactose (as lactose monohydrate).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablets.

White to off white round shaped tablet with break line on one side and ‚L4‘ debossing on another side.

The tablet can be divided into equal halves.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Levomepromazine is a phenothiazine used in palliative care and indicated for second or third line-treatment of adults with refractory nausea unassociated with chemotherapy, where other agents have failed to give adequate control (CCC System – B62.1 Nausea Care).

4.2 Posology and method of administration

Posology

Adults

Nausea in palliative care.

Patients will require daily physician review.

Paediatric population

No data is available. Levomepromazine tablets should not be used in children aged under 18 years.

Method of administration

For oral use only.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Levomepromazine tablets is contraindicated in children aged under 18 years.

Safety in pregnancy has not been established.

4.4 Special warnings and precautions for use

The drug should be avoided, or used with caution, in patients with liver dysfunction or cardiac disease.

The hypotensive effects of levomepromazine should be taken into account when it is administered to patients with cardiac disease and the elderly or debilitated. Patients receiving large initial doses should be kept in bed.

As with other neuroleptics, cases of QT interval prolongation have been reported with levomepromazine very rarely.

Consequently, and if the clinical situation permits, absence of the following risk factors for onset of this type of arrhythmia should be verified prior to administration:

Bradycardia or 2nd or 3rd degree heart block.

Metabolic abnormalities such as hypokalaemia, hypocalcaemia or hypomagnesaemia.

Starvation or alcohol abuse.

A history of QT interval prolongation, ventricular arrhythmias or Torsades de Pointes.

A family history of QT interval prolongation.

Concomitant neuroleptics

Ongoing treatment with another drug(s) liable to induce marked bradycardia, electrolyte imbalance, slowed intracardiac conduction or prolonged QT interval.

Prior to initiation of treatment with levomepromazine, it may be appropriate to consider an ECG with measurement of serum calcium, magnesium and potassium levels. 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.

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.

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.

Venous thromboembolism:

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 levomepromazine and preventive measures undertaken.

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).

Convulsions:

Levomepromazine may lower epileptic threshold (see section 4.8) and should be used with caution in epileptic patients.

Excipients

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Combinations requiring precaution:

Cytochrome P450 2D6 Metabolism: Levomepromazine and its nonhydroxylated 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.

There is an increased risk of arrhythmias when neuroleptics are used with drugs that prolong the QT interval such as certain class 1A and III antiarrhythmics (such as quinidine, disopyramide, procainamide, amiodarone, sotalol and dofetilide), certain antimicrobials (such as sparfloxacin, moxifloxacin and erythromycin IV), tricyclic antidepressants (e.g. amitriptyline), tetracyclic antidepressants (e.g. maprotiline), other neuroleptics (e.g. phenothiazines, pimozide and sertindole), antihistamines (e.g. terfenadine), cisapride, bretylium and antimalarials (e.g. quinine and mefloquine).

The anticholinergic effect of neuroleptics may be enhanced by other anticholinergic drug­s.

Avoid concomitant neuroleptics and any other drugs that may cause electrolyte imbalance. Diuretics, in particular those causing hypokalemia, should be avoided but, if necessary, potassium-sparing diuretics are preferred. 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. Adrenaline (epinephrine) must not be used in patients overdosed with neuroleptics. Alcohol should be avoided.

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. Consequently, newborns should be monitored carefully.

Animal studies are insufficient with respect to 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. Levomepromazine is not recommended during pregnancy and in women of childbearing potential not using contraception.

Lactation

Levomepromazine is excreted in breast milk in low amounts in human milk. A risk to the suckling child 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

Levomepromazine can cause drowsiness, disorientation, confusion or excessive hypotension, which may affect the patient's ability to drive or operate machinery.

4.8 Undesirable effects

No formal reporting has been made about the undesirable effects of low-dose levomepromazine formulations; therefore, adverse effects cannot be ranked by frequency. Most available data on adverse effects are related to application of higher doses, i.e., > 25 mg. Adverse effects that are more frequent and indicate the need for medical attention are as follows:

Dystonic extrapyramidal effects (spasms of eye, face, neck and back muscles)

Akathisia (motor restlessness)

Hypotension

Ocular changes including deposition of opaque material in lens and cornea, epithelial keratopathy or pigmentary retinopathy (blurred vision; defective colour vision; difficulty seeing at night)

Parkinsonism-like extrapyramidal effects (rigidity and tremor)

Tardive dyskinesia (unusual facial expressions or body positions, increased blinking or spasms of eyelid, uncontrolled twisting movements of neck, trunk, arms, or legs).

Hypotension is more frequent in the elderly and at the beginning of treatment, especially if high doses are used. Parkinsonian effects and tardive dyskinesia also occur more frequently in the elderly, whereas dystonia occurs more often in younger patients. Extrapyramidal effects may be dose-related and may decrease with a decrease in dosage. Ocular changes occur more frequently with high-dose or longterm use of phenothiazines.

Less frequent AEs include difficulty in urinating, photosensitivity (may cause severe sunburn), skin rash associated with contact dermatitis or cholestatic jaundice.

With rare incidence the following AEs may occur:

Blood dyscrasias including agranulocytosis leukocytopenia or thrombocytopenia (Agranulocytosis can develop within the first 3 months of treatment, with recovery within 1 to 2 weeks after medication is discontinued; it may recur upon rechallenge in recovered patients.)

Melanosis (Skin pigmentation changes in melanosis occur on exposed areas of the body and may fade after discontinuation of the drug.)

Neuroleptic malignant syndrome (NMS may occur at any time during neuroleptic therapy and is potentially fatal. It is most commonly seen within the first month of therapy, after the patient has switched from one neuroleptic to another, or after a dosage increase.)

Obstipation or paralytic ileus

QT prolongation and torsades de pointes

Seizures

Dark urine (Dark urine usually is caused by the presence of phenothiazine metabolites in the urine.)

Significant fever, and temperature regulation dysfunction (Significant fever not attributable to any other cause may represent an idiosyncratic reaction.

Levomepromazine may cause hypothermia in cold weather, since the disruption of the thermoregulatory mechanisms results in a poikilothermic sta­te.

Heatstroke caused by phenothiazine-induced suppression of temperature regulation in the hypothalamus may occur in environmental conditions of high heat and high humidity).

Jaundice may appear about 2 weeks after severe pruritus and may progress to chronic active hepatitis.)

In the only double blind, randomised, controlled trial of low-dose levomepromazine (6.25mg once or twice daily), the most frequent side effects were

Drowsiness (20.4%)

Fatigue (16.3%)

Constipation (12.2%)

Headache, hypotension, and dry mouth (each 8.2%).

Additional side effects included dyspepsia, hypertension, diarrhoea, bruising (each 6.1%), dizziness, bowel colic, blurred vision (each 4.1%), confusion, sensitivity to light, palpitations, and jaundice (each 2.0%). Side effects worse than baseline were minimal, specifically those relating to extrapyramidal reactions.

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 of levomepromazine overdosage include drowsiness or loss of consciousness, hypotension, tachycardia, ECG changes, ventricular arrhythmias hypothermia and convulsions. Severe extrapyramidal dyskinesias may occur.

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 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC Code: NO5AA02

Pharmacotherapeutic group: Antipsychotics

Mechanism of action

The therapeutic effects of levomepromazine as an antipsychotic are largely due to its dopamine-2 receptor (D2) blocking ability. The drug has affinity to other receptors as well including al / a2 adrenergic and 5-hydroxytryptamine-2 (5HT2) binding sites. Levomepromazine also binds to muscarinic (M1) cholinergic receptors and to histamine Hl receptors.

Pharmacodynamic effects

Vomiting is caused by noxious stimulation of one or more of four sites, the gastrointestinal tract, the vestibular system, the chemoreceptor trigger zone (CTZ) in the area postrema of the floor of the fourth ventricle, and higher centres in the central nervous system. The activation of the CTZ is mediated by D2 receptors. Efferent stimuli from the CTZ then activate the vomiting center via H1 or M1 receptors, and the result is vomiting. H1 and M1 receptors are thought to exist on vestibular afferents. By blocking the dopaminergic, muscarinic and histamine receptors, levomepromazine may also reduce activity along these pathways.

Clinical efficacy and safety

Clinical efficacy and safety of low-dose dose levomepromazine maleate (6.25 mg, QD or BID) have been demonstrated in a double blind, randomised, controlled trial. Supportive evidence has been collected in open trials and case studies. Its safety is further supported by the fact that in clinical practice, the recommended daily dose of levomepromazine maleate is 25 – 200 mg. For the treatment of psychiatric conditions, the dose can be gradually increased to 1g daily if necessary. This medicinal product is a low-dose preparation not intended for long-term use; consequently, the potential incidence of AEs is expected to be lower than that with currently marketed higher dose products.

Paediatric population

No data are available. Levomepromazine tablets should not be used in children aged under 18 years.

5.2 Pharmacokinetic properties

Absorption

On average 50% of orally administered drug reaches the general circulation as unchanged levomepromazine. The apparent volume of distribution (Vb) was 23 to 42 L/kg, and the biologic half-life, 15 to 30 hr. The plasma concentration curves for levomepromazine have a deflection and become apparently linear 8 to 12 h after administration of the last maintenance dose. A possible explanation is that distribution equilibrium between plasma and the various tissues first was attained after 8 to 12 h, due to enterohepatic recycling. The apparent volume of distribution (Vb) shows the ratio of the total amount of levomepromazine in the body and the plasma concentration, in the post distribution phase. The values for Vb /FIM indicate that only a small fraction of the dose remains in plasma after the distribution phase.

Distribution

Levomepromazine and desmethyl-levomepromazine, one of its metabolites, appear to accumulate in human brain tissue relative to blood. Mean concentrations differed largely between individual brains, in part due to differences in dose of drug, duration of treatment and drug-free time before death. There was an apparent region-specific difference in levomepromazine concentrations with highest values in the basal ganglia and lowest values in the cortex cerebri. The elimination half-life from brain tissue is longer than from blood and was calculated to be about one week. Similar results were obtained with desmethyl-levomepromazine. Its protein binding is very high (> 90%) in the plasma.

Biotransformation

Following oral administration in human, glucuronides, sulfoxide and possibly nonoxidized drug could be detected in the urine and non-oxidized drug in the faeces. At least 10 polar metabolites are present in the urine from patients treated with levomepromazine. These metabolites were mainly glucuronides hydrolysable with 8-glucuronidase or hydrochloric acid, but it is also possible that sulfuric acid conjugation occurs. Cytochrome P450 isoenzymes (CYPs) involved in the 5-sulfoxidation and N-demethylation of the aliphatic-type phenothiazine neuroleptic levomepromazine were identified in human liver. CYP2D6 has been shown to be involved in the metabolism. CYP3A4 is the main isoform responsible for levomepromazine 5-sulfoxidation (72%) and N-demethylation (78%) at a therapeutic concentration of the drug (10 jiM). CYP1A2 contributes to a lesser degree to levomepromazine 5-sulfoxidation (20%).

Elimination

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. No sulfoxide was found in the faeces. Only small amounts (about 1% of the dose) of non-oxidized drug appeared in the urine, but in the faeces, somewhat larger but varying amounts were excreted. Glucuronic acid conjugates were eliminated in the urine, but not in the faeces.

Linearity/non-linearity

Levomepromazine maleate indicates a non-linear kinetic with more than proportional increase in AUC and maximum plasma concentration with the increasing dose.

5.3 Preclinical safety data

There are no pre-clinical safety data of relevance to the prescriber which are additional to those already included in other sections of the Summary of Product Characteristics.

6.1 List of excipients

Lactose monohydrate

Pregelatinized maize starch

Povidone K-29/32

Silica, colloidal anhydrous

Magnesium stearate

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

6.4 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

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.