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.

Levorol 5 mg/ml Oral Solution is indicated:

For the suppression of psychomotor restlessness and agitation within the context of psychotic disorders.

For acute agitation states in manic episodes.

General medicine – Palliative care

As an adjunct therapy for the treatment of severe and/or chronic pain.

As 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. The daily dose is usually split into three to four individual doses.

Adults

Ambulant patients: 15-30 mg levomepromazine/day (3-6 ml of Levorol oral solution) up to 75 – 150 mg levomepromazine/day (15-30 ml of Levorol oral solution).

Bed Patients with psychosis: Initially the total daily oral dosage is 75-100 mg (5 ml, 3 to 4 times), increased to 150 mg/day (10 ml, 3 times) up to 300 mg/day (20 ml, 3 times) and for severe psychoses up to 600 mg levomepromazine/day.

For doses higher than 300 mg Levomepromazine should be taken in the form of Tablets.

Bed Patients with severe pain:

Initially the total daily oral dosage is 25-50-75 mg/day (5-10-15 ml), gradually increased, if necessary, up to 300 mg/day (60 ml).

Note: If therapy with analgesics has been initiated before levomepromazine treatment, the dose of levomepromazine can be reduced. If hypnotic drugs are used concomitantly, the dose of levomepromazine should be reduced at least by half.

For treatment of nausea:

1.2 mL (6 mg) once daily, taken at bedtime, increased if necessary to 2.5 mL – 5 mL (12.5-25 mg) twice daily.

Elderly and patients with renal or hepatic impairment

In elderly patients and patients with hepatic and renal impairment the dose must be adjusted with special caution, as there is an increased incidence of side effects.

Paediatric population

The use of Levorol oral solution in children and adolescents under 16 years is not recommended (see Section 4.3).

Method of administration

Levorol 5 mg/ml oral solution is for oral use only.

A 5 ml graduated oral syringe with intermediate graduations of 0.1 ml and a “Press- In” Bottle Adapter (PIBA) are provided with the product.

1. Open the bottle and insert the “Press-In” Bottle Adapter (PIBA) when first use.

2. Insert the syringe into the PIBA and draw out the required volume from the inverted bottle.

3. Remove the filled syringe from the bottle in the upright position.

4. Discharge the syringe contents into the mouth. Repeat steps 2 to 4 as needed to achieve the required dose.

5. Rinse the syringe and replace the cap on the bottle (PIBA remains in place).

4.3. Contraindications

Hypersensitivity to the active substance, levomepromazine hydrochloride, thioxanthenes and phenothiazines or to any of the excipients listed in Section 6.1.

Levorol oral solution should not be used in:

• acute alcohol-, sleeping medication-, analgesic- and psychopharmaceutical- intoxication

• shock (circulatory failure)

• coma

• impairment of the hematopoietic system

The use of Levorol oral solution in children and adolescents under 16 years is not recommended.

4.4. Special warnings and precautions for use

Levorol oral solution should be avoided or used with caution in the following conditions:

- hepatic failure and end stage renal disease

- previous cardiac disease

- prolactin-dependent tumours, such as breast tumours

- severe hypotension or hypertension, postural hypotension

- history of brain disease or epileptic seizures

- non-drug induced Parkinson's disease

- atherosclerotic cerebrovascular disease

- history of Malignant Neuroleptic Syndrome

- glaucoma

- micturition disorder

- pyloric stenosis

- benign prostatic hyperplasia

- congenital long QT syndrome or other clinically significant cardiac disorders (especially coronary artery disease, conduction disorders, arrhythmias)

- concomitant treatment with drugs that prolong the QT interval in the ECG or cause hypokalaemia (See Section 4.5)

Blood count (including platelet and differential count) should be checked before treatment with tricyclic neuroleptics agents. If blood values are outside the normal range, levomepromazine should not be used.

Blood count (leukocyte count and differential count) should be performed regularly during levomepromazine therapy. Blood monitoring should be performed weekly within the first four months of treatment initiation and if values are within the normal ranges, a monthly blood monitoring is sufficient. Treatment with levomepromazine should be discontinued if values of leucocytes below 3000/mm3or other changes in blood count occur. If required, intensive care measures should be given.

Patients should be advised not to self-medicate in case of fever, mouth and gum inflammation, sore throat or purulent angina, and flu-like symptoms, especially if these occur within the first three months of drug treatment, but to seek medical advice immediately.

Initiation of treatment with levomepromazine should be followed by ECG monitoring. Whilst on therapy, liver function should be monitored every 6-12 months.

Levomepromazine may prolong the QT interval leading (rarely) to fatal arrhythmias, and Torsade de Pointes (see Section 4.8). In these cases, levomepromazine must be discontinued.

Blood pressure lowering effects may occur within 10-20 minutes after intramuscular injection of levomepromazine, lasting 4-6 hours (rarely up to 12 hours). As a rule, the blood pressure-reducing effect of levomepromazine is reduced over longer treatment periods. If the treatment is interrupted for several days, further administration of levomepromazine might again lead to a blood pressure reduction. After parenteral administration as well as at the initiation of administration of higher doses, the patient needs bed rest for 5-6 hours. Hospitalization is recommended for daily doses over 150 mg.

If high fever and muscle stiffness occur, the possibility of a malignant neuroleptic syndrome (increase in myoglobin and creatine kinase activity [CK] in the blood) should be considered, which is often misdiagnosed as catatonia. Since the re- administration of neuroleptics can have life-threatening consequences, the differentiation from catatonia is decisive in the differential diagnosis (medical history, examination for rigor, fever, as well as an increase in CK and myoglobin in the blood or urine. The following treatment options are recommended:

- Immediate drug withdrawal

- Cooling employed for hyperthermia

- Treatment for fluid and electrolyte imbalance, cardiovascular manifestations, infections, respiratory and renal complications

- Treatment with dantrolene infusions (3 to 10 mg/kg/day) in combination with bromocriptine (7.5 to 30 mg/day orally)

Increased mortality in elderly people with dementia

Data from two clinical studies indicated that elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of mortality. The extent to which this association is attributable to the medicinal product, as opposed to being confounded by patient characteristics, has not yet been elucidated.

Levorol oral solution is not indicated for the treatment of dementia-related behavioural disturbances.

Increased risk of adverse cerebrovascular events

In randomised, placebo-controlled clinical studies in the dementia population, there was an approximately 3-fold increased risk of cerebrovascular adverse events with some atypical antipsychotics. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other patient populations.

Levorol oral solution must be used with caution in patients with risk factors for stroke.

Venous thromboembolism risk

Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with levomepromazine solution and preventive measures should be undertaken.

Note: Because of the risk of photosensitisation, patients should be advised to avoid exposure to direct sunlight (see Section 4.8).

Propylene glycol

This medicine contains 150.95 mg propylene glycol in each 1 ml of oral solution.

Medical monitoring is required in patients with impaired renal or hepatic functions because various adverse events attributed to propylene glycol have been reported such as renal dysfunction (acute tubular necrosis), acute renal failure and liver dysfunction.

While propylene glycol has not been shown to cause reproductive or developmental toxicity in animals or humans, it may reach the foetus and was found in milk. As a consequence, administration of propylene glycol to pregnant or lactating patients should be considered on a case by case basis.

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per 40 ml of oral solution, that is to say essentially 'sodium-free'.

Sodium benzoate

This medicine contains 0.3 mg sodium benzoate in each 1 ml of oral solution.

Benzyl alcohol

This medicine contains 0.03 mg benzyl alcohol in each 1 ml of oral solution.

Benzyl alcohol may cause allergic reactions.

High volumes should be used with caution and only if necessary, especially in subjects with liver or kidney impairment because of the risk of accumulation and toxicity (metabolic acidosis).

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

Effects of other medicinal products on levomepromazine

Concomitant administration of carbamazepine and barbiturates can induce the CYP enzyme activity resulting in decreased levomepromazine plasma concentrations.

The effects of levomepromazine can be inhibited by anticholinergic medicinal products, such as biperiden.

The moderate anticholinergic effects of levomepromazine can be enhanced by other anticholinergic agents or other medicinal products with anticholinergic effects.

Concomitant administration of drugs known to inhibit hepatic metabolism of levomepromazine, might lead to enhanced therapeutic effects of levomepromazine.

Effects of levomepromazine on other medicinal products

The concomitant use of levomepromazine with analgesics, hypnotic agents, sedatives or other Central Nervous System antidepressants can lead to increased sedation and respiratory depression.

Levomepromazine is an inhibitor 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 (risperidone, haloperidol, amitriptyline, captopril, ondansetron, codeine, celecoxib, flecainide and amphetamine derivatives).

Concomitant use of levomepromazine may affect the metabolism of phenytoin, resulting in toxic plasma concentrations of phenytoin.

Levomepromazine can enhance the respiratory depression after concomitant administration with polypeptide antibiotics (Capreomycin, Colistin, Polymyxin B).

Levomepromazine can affect the hepatic metabolism of tricyclic antidepressants (TCAs) resulting in increased plasma levels of TCAs. Caution should be exercised if levomepromazine is combined with MAO inhibitors.

Patients undergoing surgical repair should be carefully monitored for potential hypotension. The dose of anaesthetics may need to be reduced.

The effects of antihypertensive drugs can be enhanced with the concomitant use of levomepromazine. The hypotensive effects of guanethidine, clonidine and alpha- methyldopa can, however, be depressed.

The combined use of levomepromazine with dopamine agonists (e.g. levodopa) may result in diminished effects of dopamine agonists. The alpha-adrenergic effects of adrenaline are also diminished.

The response to gonadorelin can be diminished by phenothiazines due to the enhanced levels of prolactin.

Other drug interactions

The combined use of levomepromazine and propranolol may result to increased levels of both drugs.

The concomitant use of levomepromazine and piperazine anthelmintics and metoclopramide can result to an increased risk of extrapyramidal symptoms.

The absorption of other drug substances can be affected by the inhibition of gastrointestinal motility.

Treatment with levomepromazine may affect the PKU Test for Phenylketonuria (false-positive result).

The concomitant use of medicinal products that prolong the QT interval (class IA or III antiarrhythmics, cisapride, certain antibiotics, antimalarials, antihistamines, antidepressants) or lead to hypokalaemia (e.g. certain diuretics) should be avoided.

4.6. Fertility, pregnancy and lactation

Pregnancy

There have been isolated case reports and one controlled study of different congenital malformations with the use of phenothiazines. Any correlation could not be confirmed by clinical studies. There are insufficient data on the effects of levomepromazine on human embryo or foetus and animal studies are insufficient with respect to reproductive toxicity (see Section 5.3).

Levorol oral solution should not be used in the first trimester of pregnancy. Levomepromazine should be avoided in the second and third trimesters, unless considered essential by the physician. The lowest effective dose should be used.

Neonates exposed to antipsychotics (including Levorol oral solution) 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 carefully monitored.

Levorol oral solution should not be used during the last 10 days of pregnancy to prevent extrapyramidal and/or withdrawal symptoms in the neonate.

Levorol oral solution is not recommended during pregnancy. If Levorol is prescribed to a female patient of child-bearing age, she should be advised to contact her doctor immediately if she would like to become pregnant or suspects that she is pregnant.

Breast-feeding

Levomepromazine and its metabolites are excreted to human milk. If treatment cannot be avoided, breast-feeding should be discontinued.

Fertility

There are no human data available on fertility.

4.7. Effects on ability to drive and use machines

Levomepromazine may cause tiredness, dizziness and fatigue which may affect the patient's ability to drive or operate machinery. Patients should avoid the performance of potentially dangerous tasks, which require alertness and good concentration, such as driving a motor vehicle or operating machinery, at any time when affected.

Simultaneous intake of alcohol may further affect the ability to drive and use machines.

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)

Very Rare (<1/10,000)

Not known (cannot be estimated from available data)

Blood and lymphatic system disorders

Blood dyscrasias

Immune system disorder

Anaphylactic reaction

Metabolism and nutrition disorders

Weight gain

Nervous system disorders

Fatigue

Extrapyramidal symptoms such as dyskinesia, Parkinson's disease, akathisia

Restlessness, agitation, drowsiness, depressed mood, lethargy, dizziness, headache, exacerbation of psychotic symptoms, confusion, seizures, disturbance of temperature regulation

Malignant neuroleptic syndrome

Delirium

Pregnancy, puerperium and perinatal conditions

Withdrawal syndrome

Eye disorders

Eye dystonia, blurred vision, ocular hypertension

Anterior corneal pigmentations

Cardiovascular disorders

Orthostatic hypotension, Tachycardia, ECG changes

Torsade de Pointes

Thromboembolism

Respiratory, thoracic and mediastinal disorders

Nasal congestion

Gastrointestinal disorders

Constipation, nausea, vomiting, diarrhoea, loss of appetite, xerostomia

Paralytic ileus

Ulcerative colitis

Hepatobiliary disorders

Liver dysfunction, bile drainage problems, jaundice

Skin and subcutaneous tissue disorders

Skin hypersensitivety reactions, photosensitivity

Renal and urinary disorders

Micturition disorder

Reproductive system and breast disorders

Gynecomastia, menstrual disorders, galactorrhoea, sexual dysfunction

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 the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

4.9. Overdose

Signs and symptoms

Somnolence to coma, confusion and agitation, cardiac failure, arrhythmia, hypotension, tachyarrhythmia, dry mucous membranes, constipation, paralytic ileus, urinary retention, mydriasis, convulsions, hypo- or hyperthermia, parkinsonism.

Management and treatment

Initial treatment consists of induction of emesis. Gastric lavage can be attempted many hours after ingestion of a toxic dose by using high amounts of lubricant due to the existing dry mucous membranes. Activated charcoal and Glauber's salt should be administered repeatedly to inhibit the absorption and accelerate the elimination of levomepromazine. Dialysis does not offer significant benefits.

The antidote for the anticholinergic symptoms is physostigmine. The risk with physostigmine treatment should be weighed against its benefit on the management of levomepromazine overdose.

Due to the enterohepatic circulation of tricyclic substances, treatment with cholestyramine may be attempted (3 × 4 g daily).

Symptomatic treatment such as controlled ventilation and intubation may be considered, as well as general intensive medical care for restoring electrolyte balance, serum tonicity, through intravenous infusion of positive inotropic agents, ECG and intraocular pressure monitoring.

Infusion of alpha sympathomimetics such as norfenefrine or noradrenaline may be considered.

Do not use adrenaline.

Severe dystonic reactions usually respond to biperiden (adults: 2.5-5 mg IM or slow IV) or diphenhydramine (50 mg orally every 6 hours) or diazepam (3-10 mg slow IV).