4.1. Therapeutic indications

Management of the terminally ill patient. Levomepromazine resembles chlorpromazine and promethazine in the pattern of its pharmacology. It possesses anti-emetic, antihistamine and anti-adrenaline activity and exhibits a strong sedative effect.

Nozinan potentiates the action of other central nervous system depressants but may be given in conjunction with appropriately modified doses of narcotic analgesics in the management of severe pain. Nozinan does not significantly depress respiration and is particularly useful where pulmonary reserve is low.

Nozinan is indicated in the management of pain and accompanying restlessness or distress in the terminally ill patient.

4.2. Posology and method of administration

Intramuscular and intravenous injection

Dosage varies with the condition and individual response of the patient. Nozinan injection may be administered by intramuscular injection or intravenous injection after dilution with an equal volume of normal saline.

The usual dose for adults and the elderly is 12.5 – 25 mg (0.5 – 1 ml) by intramuscular injection, or by the intravenous route after dilution with an equal volume of normal saline immediately before use. In cases of severe agitation, up to 50 mg (2 ml) may be used, repeated every 6 – 8 hours.

Continuous subcutaneous infusion

Nozinan injection may be administered over a 24-hour period via a syringe driver. The required dose of Nozinan injection (25 – 200 mg per day) should be diluted with the calculated volume of normal saline. Diamorphine hydrochloride is compatible with this solution and may be added if greater analgesia is required.

Nozinan 25 mg Tablets may be substituted for the injection if oral therapy is more convenient.

Paediatric population

Clinical experience with parenteral levomepromazine in children is limited. Where indicated, doses of 0.35 – 3.0 mg/kg/day are recommended.

4.3. Contraindications

• Hypersensitivity to levomepromazine or to any of the other ingredients (see section 6.1).

• In combination with:

o citalopram, escitalopram,

o hydroxyzine

o piperaquine

o domperidone.

There are no absolute contraindications to the use of Nozinan 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

Nozinan 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 Nozinan should be taken into account when it is administered to patients with cardiac disease and the elderly or debilitated. Phenothiazine treated patients who experience postural hypotension should be cautioned to not get up quickly and to obtain assistance when necessary.

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 very rarely 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, slowed intracardiac conduction or QT interval prolongation (see sections 4.3 and 4.5)

Patients are also 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 Nozinan and preventive measures must be implemented (see section 4.8).

Hyperglycaemia

Hyperglycaemia or intolerance to glucose has been reported in patients treated with Nozinan.

Patients with an established diagnosis of diabetes mellitus or with risk factors for the development of diabetes who are started on Nozinan, 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.

Nozinan 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.

Excipient(s) with known effect

Sulphites: May rarely cause severe hypersensitivity reactions and bronchospasm.

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

Precautions for use

This medicinal product should be used with caution in patients with:

• hypothyroidism

• cardiac failure

• phaeochromocytoma

• myasthenia gravis

• prostate hypertrophy

• liver dysfunction

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 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 subjects with:

- greater susceptibility to orthostatic hypotension, sedation and extrapyramidal effects

- chronic constipation (risk of paralytic ileus)

- a possible prostatic hyperplasia

4.5. 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 hypokalaemia, should be avoided but, if necessary, potassium-sparing diuretics are preferred. Hypokalaemia should be corrected before administering the medicinal product and clinical, electrolyte, and ECG monitoring should be carried out.

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 – 72 hours. It is possible that this may occur with Nozinan, 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 which 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 of 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 Nozinan) 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 Nozinan during pregnancy as a precautionary measure and neonates must be closely monitored in the event of treatment at the end of pregnancy.

The injectable neuroleptics used in emergency situations can trigger maternal hypotension.

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 Nozinan 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 the 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

General 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 anti-arrhythmic 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 – 10 mg) or orphenadrine (20 – 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.