Nozinan 25mg/Ml Solution For Injection Or Infusion
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Nozinan 25 mg/ml Solution for Injection/Infusion
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Levomepromazine hydrochloride 25mg per ml.
For excipients, see 6.1.
3 PHARMACEUTICAL FORM
Solution for injection/infusion.
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:
nd rd
Bradycardia or 2 or 3 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 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 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.
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).
Convulsions:
Levomepromazine may lower epileptic threshold (see section 4.8) and should be used in caution with epileptic patients.
4.5 Interaction with other medicinal products and other forms of interaction
Cytochrome P450 2D6 Metabolism: Levomepromazine and its non-hydroxylated 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 anti-arrhythmics (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, characterised 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 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. 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. Nozinan 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 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
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
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 |
Very |
Common |
Uncommon |
Rare |
Not known (cannot |
|
class |
common |
( 1/100 to |
( 1/1,000 to |
(>1/10,000 to |
be estimated from |
|
( 1/10) |
<1/10 ) |
<1/100) |
<1/1,000) |
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) | ||
|
Gastrointestina l 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 |
|
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) |
|
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 thromboembolis m |
Deep vein thrombosis Pulmonary embolism | ||
|
Skin and subcutaneous tissue disorders |
Photosensitivity reaction Dermatitis allergic |
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
Symptoms of levomepromazine overdosage include drowsiness or loss of consciousness, hypotension, tachycardia, ECG changes, ventricular arrhythmias, hypothermia and convulsions. 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 antiadrenaline 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
36 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
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
Aventis Pharma Limited
One Onslow Street
Guildford
Surrey
GU1 4YS
Or trading as:
Sanofi-aventis or Sanofi
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 May 1999 / 11 May 2004
10 DATE OF REVISION OF THE TEXT
25/02/2015