Lomont 70mg / 5ml Oral Suspension

1. Name Of The Medicinal Product

Lomont 70mg/5ml Oral Suspension

2. Qualitative And Quantitative Composition

Active Ingredient	Per 5ml
Lofepramine Hydrochloride,	76.1mg
(equivalent to Lofepramine base)	70mg

3. Pharmaceutical Form

A white to pale yellow/orange suspension with odour of Cherry.

4. Clinical Particulars

4.1 Therapeutic Indications

For the treatment of symptoms of depressive illness.

4.2 Posology And Method Of Administration

Adults: The usual dose 70mg twice daily (140mg) or three times daily (210mg) depending upon patient response.

Elderly: Elderly patients may respond to lower doses in some cases.

Children: Not recommended

4.3 Contraindications

Lofepramine should not be used in patients hypersensitive to dibenzazepines, in mania, severe liver impairment and/or severe renal impairment, heart block, cardiac arrhythmias, or during the recovery phase following a myocardial infarction.

Lofepramine should not be administered with or within 2 weeks of cessation of therapy with monoamine oxidase inhibitors (see Section 4.5).

Use of lofepramine with amiodarone should be avoided (see Section 4.5).

Use of lofepramine with terfenadine should be avoided (see Section 4.5).

4.4 Special Warnings And Precautions For Use

It should be remembered that severely depressed patients are at risk of suicide. An improvement in depression may not occur immediately upon initiation of treatment, therefore the patient should be closely monitored until symptoms improve.

Lofepramine may lower the convulsion threshold, therefore it should be used with extreme caution in patients with a history of epilepsy or recent convulsions or other predisposing factors, or during withdrawal from alcohol or other drugs with anticonvulsant properties.

Concurrent electroconvulsive therapy should only be undertaken with careful supervision.

Lofepramine should be used with caution where there is a history of mania. Psychotic symptoms may be aggravated. There have also been reports of hypomanic or manic episodes during a depressive phase in patients with cyclic affective disorders receiving tricyclic antidepressants.

Lofepramine should be used with caution in patients with cardiovascular disease, impaired liver or renal function, narrow angle glaucoma, symptoms suggestive of prostatic hypertrophy, blood dyscrasias or porphyria.

Caution is needed in patients with hyperthyroidism, or during concomitant treatment with thyroid preparations, since aggravation of unwanted cardiac effects may occur.

In chronic constipation, tricyclic antidepressants may cause paralytic ileus, particularly in elderly and bedridden patients.

Care should be exercised in patients with tumours of the adrenal medulla (eg phaeochromocytoma, neuroblastoma) in whom tricyclic antidepressants may provoke hypertensive crises.

Blood pressure should be checked before initiating treatment because individuals with hypertension, or an unstable circulation, may react to lofepramine with a fall in blood pressure.

Anaesthetics may increase the risks of arrhythmias and hypotension (see Interactions), therefore before local or general anaesthesia, the anaesthetist should be informed that the patient has been taking lofepramine.

Hyponatraemia (usually in the elderly and possibly due to inappropriate secretion of antidiuretic hormone) has been associated with all types of antidepressants and should be considered in all patients who develop drowsiness, confusion or convulsions while taking lofepramine.

Abrupt withdrawal of lofepramine should be avoided if possible.

Suicide/suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide

Patients with a history of suicide

Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

Excipient Warnings

This product contains 10%v/v ethanol, i.e. up to 395mg per dose equivalent to 10ml of beer or 4ml of wine per dose. It is harmful for those suffering from alcoholism. It should be taken into account in pregnant or lactating women, children and high-risk groups such as patients with liver disease or epilepsy. It may modify or increase the effect of other medicines. The amount of alcohol in this product may impair the ability to drive or use machines.

This product also contains liquid maltitol and sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

Methyl and propyl hydroxybenzoates are contained in this product which may cause allergic reactions (possibly delayed).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Lofepramine should not be administered concurrently with or within 2 weeks of cessation of therapy of monamine oxidase inhibitors. It should then be introduced cautiously using a low initial dosage.

SSRI Inhibitors: co-medication may lead to additive effects on the serotonergic system. Fluvoxamine and fluoxetine may also increase plasma concentrations of lofepramine resulting in a lowered convulsion threshold and seizures.

Anti-arrhythmic drugs: There is an increased risk of ventricular arrhythmias if lofepramine is given with drugs which prolong the Q-T interval e.g. disopyramide, procainamide, propafenone, quinidine and amiodarone. Concomitant use with amiodarone should be avoided (See Section 4.3)

Neuroleptics: There is an increased risk of arrhythmias; there may be an increased plasma level of the tricyclic antidepressant, a lowered convulsion threshold and seizures.

Lofepramine should not be given with sympathomimetic agents (cardiovascular effects may be potentiated), central nervous depressants including alcohol or thyroid hormone therapy since its effects may be potentiated.

Lofepramine may decrease the antihypertensive effect of adrenergic neurone-blocking drugs; it is therefore advisable to review this form of antihypertensive therapy during treatment.

Anaesthetics given during tricyclic antidepressant therapy may increase the risk of arrhythmias and hypotension. If surgery is necessary, the anaesthetist should be informed that a patient is being so treated. Barbiturates may increase the rate of metabolism.

Possible interactions between lofepramine and warfarin, leading to an enhancement of anticoagulant effect, have been reported rarely. Careful monitoring of plasma prothrombin is advised.

Anti-cholinergic agents: Lofepramine may potentiate the effects of these drugs (e.g. phenothiazine, antiparkinson agents, antihistamines, atropine, beperiden) on the central nervous system, eye, bowel and bladder.

Analgesics: There is an increased risk of ventricular arrhythmias.

Anti-epileptics: Antagonism can lead to a lowering of the convulsive threshold. Plasma levels of some tricyclic antidepressants, and therefore the therapeutic effect, may be reduced.

Calcium channel blockers: diltiazem and verapamil increase the plasma concentration of lofepramine.

Diuretics: There is an increased risk of postural hypotension.

Terfenadine: There is an increased risk of ventricular arrhythmias therefore concomitant use should be avoided.

Rifampicin: The metabolism of lofepramine is accelerated by rifampicin leading to a reduced plasma concentration

Digitalis glycosides: With digitalis glycosides there is a higher risk of arrhythmias.

Sotalol: The risk of ventricular arrhythmias associated with sotalol is increased.

Cimetidine: Cimetidine can increase the plasma concentration of lofepramine.

Clonidine: The effect of antihypertensive agents of the clonidine type can be weakened.

Altretamine: There is a risk of severe postural hypotension when co-administered with tricyclic antidepressants

Disulfiram and alprazolam: Co-medication with either disulfiram or alprazolam may require a reduction in the dose of lofepramine.

Nitrates: The effectiveness of sublingual nitrates may be reduced where the tricyclic antidepressant's anticholinergic effect has lead to dryness of the mouth.

Ritonavir: There may be an increased plasma concentration of lofepramine.

Oral contraceptives: Oestrogens and progestogens may antagonise the therapeutic effect of tricyclic antidepressants whilst the latter's side effects may be exacerbated due to an increased plasma concentration.

4.6 Pregnancy And Lactation

The safety of Lofepramine for use during pregnancy has not been established and there is evidence of harmful effects in pregnancy in animals when high doses are given. Lofepramine has been shown to be excreted in breast milk. The administration of Lofepramine in pregnancy and during breast feeding therefore, is not advised unless there are compelling medical reasons.

Adverse effects such as withdrawal symptoms, respiratory depression and agitation have been reported in neonates whose mothers have taken tricyclic antidepressants during the last trimester of pregnancy.

4.7 Effects On Ability To Drive And Use Machines

Ability to drive a car and operate machinery may be affected. Therefore caution should be exercised initially until the individual reaction to treatment is known.

4.8 Undesirable Effects

Lofepramine has been shown to be well tolerated and side-effects, when they occur, tend to be mild. Comparative clinical trials have shown that Lofepramine is associated with a low incidence of anticholinergic side effects. The following side effects have been reported with Lofepramine:

Cardiovascular: Hypotension, tachycardia, cardiac conduction disorders, increase in cardiac insufficiency, arrhythmias.

CNS and Neuromuscular: Dizziness, sleep disturbances, agitation, confusion, headache, malaise, paraesthesia; rarely, drowsiness, hypomania and convulsions (See section 4.4 Special Warnings and Precautions for Use); very rarely, uncoordinated movement.

Anticholinergic: Dryness of mouth, constipation, disturbances of accommodation, urinary hesitancy, urinary retention, sweating and tremor, induction of glaucoma; rarely, impairment of the sense of taste; very rarely, tinnitus.

Urinogenital: Testicular disorders e.g. pain.

Allergic: Skin rash, allergic skin reactions, photosensitivity reactions, facial oedema; rarely, cutaneous bleeding, inflammation of mucosal membranes.

Gastro-intestinal: Nausea, vomiting

Endocrine: Rarely, hyponatraemia (inappropriate secretion of antidiuretic hormone), interference with sexual function, changes of blood sugar level, gynaecomastia, galactorrhoea.

Haematological/ biochemical: Rarely, bone marrow depression including isolated report of: agranulocytosis, eosinophilia, granuloctyopenia, leucopenia, pancytopenia, thrombocytopenia. Increases in liver enzymes, sometimes progressing to clinical hepatitis and jaundice, have been observed in some patients, usually occurring within the first three months of starting therapy. There have been a small number of reports of jaundice. These reactions are reversible on cessation of therapy.

The following adverse effects have been encountered in patients under treatment with tricyclic antidepressants and should therefore be considered as theoretical hazards of Lofepramine even in the absence of substantiation: psychotic manifestations including mania and paranoid delusions may be exacerbated during treatment with tricyclic antidepressants; withdrawal symptoms may occur on abrupt cessation of therapy and include insomnia, irritability and excessive perspiration; adverse effects such as withdrawal symptoms, respiratory depression and agitation have been reported in neonates whose mothers have taken tricyclic antidepressants during the last trimester of pregnancy.

Cases of suicidal ideation and suicidal behaviours have been reported during lofepramine therapy or early after treatment discontinuation (see section 4.4).

4.9 Overdose

Treatment of overdosage is symptomatic and supportive. It should include immediate gastric lavage and routine close monitoring of cardiac function. Reports of overdosage with Lofepramine, with quantities ranging from 0.7g up to 6.72g, have shown no serious sequelae directly attributable to the drug.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Lofepramine inhibits the re-uptake of monoamines in peripheral adrenergic nerves. Lofepramine produces a lesser increase in heart rate than that produced by Amitriptyline when administered to normal individuals.

5.2 Pharmacokinetic Properties

Lofepramine is rapidly absorbed with peak plasma concentration being reached within 1 hour and having a plasma half-life of 5 hours. In common with Imipramine, Lofepramine appears to undergo significant presystemic metabolism.

Plasma protein binding is approximately 99%. After oral administration higher concentrations of Lofepramine and its metabolites can be found in blood, lungs, liver, kidney and brain.

Almost all of the drug is metabolized before excretion, which is mainly in the urine and in faeces. Lofepramine is metabolized by N-dealkylation, hydroxylation and glucuronidation. It is extensively metabolized to its principal metabolite, desmethylimipramine, on first pass through the liver. During chronic administration, the plasma level of desmethylimipramine is typically three times greater than that of lofepramine, except in the first few hours following administration of each dose, during which time the plasma level of the parent drug can exceed that of its metabolite. Desipramine, which is also an antidepressant is converted to 2-hydroxydesipramine in the liver. Both compounds are excreted mainly in the urine as glucuronides, but also by biliary excretion in the faeces. Less than 5% is excreted unchanged in the urine over 24 hours.

Neither renal disease or old age has any appreciable effect on the kinetics of desipramine. Elimination may be reduced and bioavailability increased in hepatic disease.

5.3 Preclinical Safety Data

Lofepramine Hydrochloride is a well established active substance.

Lofepramine, like other tricyclic antidepressants, has been shown to inhibit the neuronal uptake of noradrenaline and to potentiate serotonergic transmission.

The safety of Lofepramine for use during pregnancy has not been established and there is evidence of harmful effects in pregnancy in animals when high doses are given. Lofepramine has been shown to be excreted in breast milk. The administration of Lofepramine in pregnancy and breast feeding therefore, is not advised unless there are compelling medical reasons.

Adverse effects such as withdrawal symptoms, respiratory depression and agitation have been reported in neonates whose mothers have taken tricyclic antidepressants during the last trimester of pregnancy.

The toxological data available in the published literature on lofepramine have not revealed any hazards, which are likely to occur at the usual oral therapeutic dosage. The excipients in the formulation would not be anticipated to influence the pharmacology or toxicology of the drug.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Purified water, sodium ascorbate, sorbitol solution 70% (non-crystallising), liquid maltitol, methyl hydroxybenzoate, propyl hydroxybenzoate, propylene glycol, ethanol (absolute), colloidal silicon dioxide (aerosil) and cherry flavour 28T7704.

6.2 Incompatibilities

None known

6.3 Shelf Life

24 months

6.4 Special Precautions For Storage

Store between 4°C and 25°C. Protect from light.

6.5 Nature And Contents Of Container

150ml, 200ml or 300ml amber (type III) glass bottles

Closures: - 1) Aluminium, EPE wadded, roll-on, pilfer-proof, or 2) HDPE, EPE wadded, tamper evident or 3) HDPE EPE wadded, tamper evident child resistant.

6.6 Special Precautions For Disposal And Other Handling

Keep out of the reach of children. Shake before use.

Administrative Data

7. Marketing Authorisation Holder

Rosemont Pharmaceuticals Ltd

Rosemont House

Yorkdale Industrial Park

Braithwaite Street

Leeds

LS11 9XE

8. Marketing Authorisation Number(S)

0427/0094

9. Date Of First Authorisation/Renewal Of The Authorisation

1 February 1996

10. Date Of Revision Of The Text

02 February 2009