Levorol

Levorol 6.25 mg Tablets

Each tablet contains 6.25 mg of levomepromazine maleate.

For the full list of excipients, see section 6.1.

Tablets.

White, flat, round tablets of approximately 6 mm diameter scored on one side.

The tablet can be divided into equal doses.

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.

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.

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

Safety in pregnancy has not been established.

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 2^nd or 3^rd 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'.

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.

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.

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

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).

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.

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.

Pharmacotherapeutic group: Antipsychotics, ATC code: N05AA02

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 α₁/α₂ adrenergic and 5-hydroxytryptamine-2 (5HT₂) binding sites.

Levomepromazine also binds to muscarinic (M₁) cholinergic receptors and to histamine H₁ receptors.

Pharmacodynamic effects

Levomepromazine antagonizes dopamine receptors in the central nervous system, depressing the cerebral cortex, hypothalamus and limbic system. The clinical effects produced by this action include: a depressant action on conditioned responses and emotional responsiveness; a sedative action useful for the treatment of restlessness and confusion; an anti-emetic effect through blockade of the chemoreceptor trigger zone (CTZ), which is useful to treat vomiting; and antihistamine activity.

Clinical efficacy and safety

The clinical efficacy of levomepromazine for the suppression of psychomotor activity has been established in comparison to placebo or other neuroleptics. The results of clinical studies support also the use of levomepromazine in combination with other medications for the treatment of serious or chronic pain in terminal illness. With regards to extrapyramidal side effects, levomepromazine has a significant advantage over typical antipsychotics.

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 1 g 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

The efficacy and safety of levomepromazine has been established in children for its antipsychotic effects. Lower doses are recommended due to its hypotensive and soporific effects.

Absorption

On average 50 % of orally administered drug reaches the general circulation as unchanged levomepromazine.

The apparent volume of distribution (V_β) 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.

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 non-oxidized 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 μM). 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

More than proportional increase in AUC and maximum plasma concentrations has been shown for levomepromazine maleate.

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.

Starch, pregelatinised

Calcium hydrogen phosphate (E341)

Sodium laurilsulfate (E487)

Magnesium stearate (E572)

Not applicable

3 years

Store in the original package in order to protect from light.

This medicinal product does not require any special temperature storage conditions.

PVC/PVDC/aluminium blisters.

Pack size: 28 tablets.

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

Galvany Pharma Limited

Business & Technology Centre

Bessemer Drive, Stevenage

SG1 2DX, UK

PL 56809/0015

10/07/2023

08/2023