4.1. Therapeutic indications

Levomepromazine 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 and possesses anti-emetic effects.

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.

• Second or third line treatment of adults with refractory nausea unassociated with chemotherapy, where other agents have failed to give adequate control.

4.2. Posology and method of administration

Posology

Dosage varies with the condition under treatment and the individual response of the patient.

Adults

Psychiatric Conditions

Ambulant patients: initially the total daily oral dose should not exceed 25 mg to 50 mg 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 mg to 200 mg, usually divided into 3 doses, gradually increased to 1 g daily if necessary.

When the patient is stable attempts should be made to reduce the dosage to an adequate maintenance level.

Terminal illness

Relief of pain and the accompanying distress: 12.5 mg to 50 mg every 4 to 8 hours.

Treatment of refractory nausea: 6.25 mg once daily, taken at bedtime, increased -if necessary- to 12.5-25 mg twice daily.

Paediatric population

Psychiatric Conditions

Children are very susceptible to the hypotensive and soporific effects of levomepromazine. It is advised that a total daily oral dosage of 37.5 mg (6 tablets of Levorol 6.25 mg Tablets) should not be exceeded. The average effective daily intake for a ten-year-old is 12.5 mg to 25 mg (2 to 4 tablets of Levorol 6.25 mg Tablets).

Terminal illness

The use of levomepromazine in paediatric population has not been established.

Elderly

Psychiatric Conditions

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.

Terminal illness

No specific dosage recommendations.

Renal impairment

No dosage adjustment is required in patients with GFR >10 ml/min. In patients with end-stage renal disease (GFR< 10 ml/min) initial smaller doses are recommended.

Hepatic impairment

There is no experience regarding the use of Levomepromazine tablets in patients with hepatic impairment.

Method of administration

For oral use only.

The tablets can be divided into equal doses.

4.3. Contraindications

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

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 other 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.

Levorol 6.25 mg Tablets contains sodium.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Combinations requiring precaution

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.

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 hypokalaemia, 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

Adverse effects have been ranked under headings of frequency using the following convention: very common (≥1/10); common (≥1/100; <1/10); uncommon (≥1/1,000; <1/100); rare (≥1/10,000; <1/1,000); very rare (<1/10,000); frequency not known (cannot be estimated from the available data).

System organ class

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)

Not known (cannot be estimated from available data)

Blood and lymphatic system disorders

Agranulocytosis

Raised ESR

Cardiac disorders

QT prolongation

Ventricular arrhythmias such as ventricular tachycardia or fibrillation

Cardiac arrest Cardiac rhythm disturbances

Sudden death/sudden cardiac death (see Section 4.4) Torsades de Pointes (treatment of which should include discontinuation of levomepromazine and correction of hypoxia, electrolyte abnormalities and acid base disturbances)

Gastrointestinal disorders

Dry mouth

Constipation

Ileus paralytic

Necrotizing enterocolitis (which can be fatal)

General disorders and administration site conditions

Asthenia

Heat stroke (in hot and humid conditions)

Hepatobiliary disorders

Jaundice

Hepatocellular, cholestatic and mixed liver injury

Metabolism and nutrition disorders

Glucose tolerance impaired Hyperglycaemia (see Section 4.4). Hyponatraemia Syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Nervous system disorders

Somnolence

Parkinsonism (with prolonged high dosage) Convulsions

Neuroleptic malignant syndrome

Confusional states, delirium

Pregnancy, puerperium and perinatal conditions

Drug withdrawal syndrome neonatal (see section 4.6)

Reproductive system and breast disorders

Priapism

Vascular disorders

Hypotension (especially in elderly patients)

Venous thromboembolism

Deep vein thrombosis

Pulmonary embolism

Skin and subcutaneous tissue disorders

Photosensitivity reaction

Dermatitis allergic

Most available data on adverse effects are related to application of higher doses, i.e., ≥ 25 mg.

No formal reporting has been made about the undesirable effects of low dose levomepromazine formulations; therefore, adverse effects cannot be ranked by frequency.

In the only double blind, randomised, controlled trial of low dose levomepromazine (6.25 mg 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 (5 mg to 10 mg) or orphenadrine (20 mg to 40 mg) administered intramuscularly or intravenously.

Convulsions should be treated with intravenous diazepam.

Neuroleptic malignant syndrome should be treated with cooling. Dantrolene sodium may be tried.