NOZINAN Tablets Ref.[7296] Active ingredients: Levomepromazine

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 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 with caution in epileptic patients.

Combinations requiring precaution

Cytochrome P450 2D6 Metabolism: 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 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.

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.

Nozinan 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).

Blood and lymphatic system disorders

Uncommon: Agranulocytosis

Not known: Raised ESR

Cardiac disorders

Common: QT prolongation

Rare: Ventricular arrhythmias such as ventricular tachycardia or fibrillation, Cardiac arrest, Cardiac rhythm disturbances

Not known: 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)

Gastrointestinal disorders

Very common: Dry mouth

Uncommon: Constipation

Not known: Ileus paralytic, Necrotizing enterocolitis (which can be fatal)

General disorders and administration site conditions

Common: Asthenia, Heat stroke (in hot and humid conditions)

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)

Nervous system disorders

Very common: Somnolence

Uncommon: Parkinsonism (with prolonged high dosage), Convulsions

Not known: Neuroleptic malignant syndrome, Confusional states, delirium

Pregnancy, puerperium and perinatal conditions

Not known: Drug withdrawal syndrome neonatal (see section 4.6)

Reproductive system and breast disorders

Not known: Priapism

Vascular disorders

Common: Hypotension (especially in elderly patients)

Uncommon: Venous thromboembolism

Not known: Deep vein thrombosis, Pulmonary embolism

Skin and subcutaneous tissue disorders

Not known: 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.

Not applicable.