Nozinan injection

1. Name Of The Medicinal Product

Nozinan 25mg/ml Injection.

2. Qualitative And Quantitative Composition

Levomepromazine hydrochloride 25mg per ml.

For excipients, see 6.1.

3. Pharmaceutical Form

Solution for injection.

Clear, colourless solution contained in a clear glass ampoule.

4. Clinical Particulars

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 12.5mg to 25mg (0.5ml to 1ml) 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 50mg (2ml) may be used, repeated every 6 to 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 (25mg to 200mg 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 tablets 25mg may be substituted for the injection if oral therapy is more convenient.

Children

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

4.3 Contraindications

Safety in pregnancy has not been established. There are no absolute contraindications to the use of Nozinan in terminal care.

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 Nozinan 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 neuroleptocs

• 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 trated with certain stypical 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.

Nozinan 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 Nozinan and preventive measures undertaken.

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).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Cytochrome P450 2D6 Metabolism: Levomepromazine and its nonhydroxylated metabolites are reported to be potent inhibitors of cytochrome P450 2D6. Co- administration of levomepromazine and drugs primarily metabolised by the cytochrome P450 2D6 enzyme system may result in increased plasma concentrations of the drugs that could increase or prolong both therapeutic or adverse effects of those drugs.

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, characterized by loss of consciousness for 48 to 72 hours. It is possible that this may occur with Nozinan, 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 Pregnancy And Lactation

Safety in pregnancy has not been established.

4.7 Effects On Ability To Drive And Use Machines

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

4.8 Undesirable Effects

Somnolence and asthenia are frequent side effects. Dry mouth is encountered occasionally. Hypotension may occur, especially in elderly patients. A raised ESR may occasionally be encountered. Agranulocytosis has been reported, as have photosensitivity and allergic skin reactions.

Parkinsonian-like reactions may occur in patients receiving prolonged high dosage. Jaundice is a rare side effect. Other adverse effects common to phenothiazine neuroleptics may be seen, such as heat stroke in hot and humid conditions, constipation that may become severe leading to paralytic ileus, neuroleptic malignant syndrome and rare cases of cardiac rhythm disturbances and prolongation of the QT interval.

In common with other antipsychotics, there is a potential risk of QT prolongation with Levomepromazine which may rarely result in precipitation of ventricular arrhythmias such as ventricular tachycardia or fibrillation, cardiac arrest. There have been isolated reports of sudden death, with possible causes of cardiac origin (see Section 4.4), as well as cases of unexplained sudden death, in patients receiving neuroleptic phenothiazines.

Very rarely cases of Torsades de Pointes have been reported, treatment of which should include discontinuation of levomepromazine and correction of hypoxia, electrolyte abnormalities and acid base disturbances.

Necrotizing enterocolitis which can be fatal, has been very rarely reported in patients treated with levomepromazine. Priapism has also been very rarely reported.

Cases of venous thromboembolism, including cases of pulmonary embolism, and cases of deep vein thrombosis have been reported with antipsychotic drugs – Frequency unknown

Intolerance to glucose, hyperglycaemia (see Section 4.4).

4.9 Overdose

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

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 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

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.

5.2 Pharmacokinetic Properties

Maximum serum concentrations are achieved in 2 to 3 hours depending on the route of administration. Excretion is slow, with a half-life of about 30 hours. It is eliminated via urine and faeces.

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. Pharmaceutical Particulars

6.1 List Of Excipients

Ascorbic acid

Sodium sulfite

Sodium chloride

Water for Injections

6.2 Incompatibilities

Incompatible with alkaline solutions.

6.3 Shelf Life

60 months.

6.4 Special Precautions For Storage

Protect from light.

6.5 Nature And Contents Of Container

Colourless type I glass ampoule. Each pack contains 10 ampoules.

6.6 Special Precautions For Disposal And Other Handling

Nozinan may be administered by intramuscular injection or intravenous injection after dilution with an equal volume of normal saline, or by continuous subcutaneous infusion with an appropriate volume of normal saline. Diamorphine hydrochloride is compatible with this solution.

7. Marketing Authorisation Holder

Sanofi-aventis

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

8. Marketing Authorisation Number(S)

PL 04425/0659

9. Date Of First Authorisation/Renewal Of The Authorisation

12th June 2009

10. Date Of Revision Of The Text

22 February 2010

LEGAL CLASSIFICATION

POM