This information is intended for use by health professionals

1. Name of the medicinal product

Lofepramine 70mg Tablets

2. Qualitative and quantitative composition

Each film-coated tablet contains lofepramine base 70mg (as 76.1mg of lofepramine hydrochloride).

Excipients with known effect: Each tablet contains 133mg Lactose, 0.01mg Sunset yellow and 1.22mg Carmoisine.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Tablet

Violet brown film coated tablet, approx 10mm diameter

4. Clinical particulars
4.1 Therapeutic indications

For the treatment of symptoms of depressive illness.

4.2 Posology and method of administration

Posology

Adults:

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

Elderly:

Elderly patients may respond to lower doses in some cases.

Paediatric population:

Not recommended

Method of administration

Lofepramine tablets are for oral administration only.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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 concurrently 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 shoud be avoided (see Section 4.5)

4.4 Special warnings and precautions for use

Suicide/suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.

Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.

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.

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.

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

Lofepramine should be used with caution in patients with cardiovascular disease, impaired liver function, impaired renal function, blood dyscrasias or porphyria.

Caution is called for where there is a history of prostatic hypertrophy, narrow angle glaucoma or increased intra-ocular pressure, because of lofepramine's anticholinergic properties.

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 antihypertensive 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 Section 4.5), therefore before local or general anaesthesia, the anaesthetist should be informed that the patient has been taking lofepramine.

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.

Abrupt withdrawal of lofepramine should be avoided if possible.

Excipient warning

Lactose

Patients with hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Sunset yellow and Carmoisine

Lofepramine tablets contain Sunset yellow FCF (E110) and Carmoisine (E122).

4.5 Interaction with other medicinal products and other forms of interaction

MAO Inhibitors:

Lofepramine should not be administered concurrently with or within 2 weeks of cessation of therapy with monoamine oxidase inhibitors (see Section 4.3). It should then be introduced cautiously using a low initial dosage.

SSRI Inhibitors:

Co-medication of lofepramine with SSRI inhibitors may lead to additive effects on the serotonergic system. Co-adiministration with fluvoxamine and fluoxetine may also increase plasma concentrations of lofepramine resulting in a lowered convulsion threshold and seizures.

Sympathomimetic drugs:

Lofepramine should not be given with sympathomimetic agents e.g. adrenalin, ephedin, isoprenaline, noradrenaline, phenylephedrine, phenylpropanolamine) since their cardiovascular effects may be potentiated.

CNS depressants:

Effects of lofepramine may be potentiated when administered with CNS depressant substances e.g. alcohol, general anaesthetics and barbiturates.

Thyroid hormone therapy:

Unwanted cardiac effects may be aggravated during concomitant treatment.

Anaesthetics:

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 (see Section 4.4).

Adrenergic neurone blockers:

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

Anti-arrhythmics:

There is an increased risk of ventricular arrhythmias if lofepramine is given with drugs which prolong the Q-T interval.

Tricyclic antidepressants should not be employed in combination with anti-arrhythmic agents including amiodarone (see Section 4.3), disopyramide, procainamide, propafenone and quinidine.

Anti-epileptics:

Co-medication of lofepramine with anti-epileptic agents may result in a lowered convulsion threshold and seizures. Plasma levels of some tricyclic antidepressants, and therefore the therapeutic effect, may be reduced.

Analgesics:

There is an increased risk of ventricular arrhythmias with lofepramine and analgesics. Increased side effects may result with nefopam. There is a possible risk of convulsions with tramadol and a possibility of increased sedation with opioid analgesics.

Anti-bacterials:

There is a possibility of plasma concentrations of some tricyclics being reduced by rifampicin.

Anti-cholinergic agents:

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

Anti-coagulants:

Lofepramine may change the anticoagulant effect by inhibiting hepatic metabolism. Careful monitoring of plasma prothrombin is advised.

Anti-malarials:

There is a possible risk of ventricular arrhythmias with halofantrine.

Antipsychotics:

There is an increased risk of ventricular arrhythmias with antipsychotics and lofepramine. Plasma levels of tricyclic antidepressant may increase and a lowered convulsion threshold and seizures may occur.

It is advised to avoid concomitant use with pimozide and sertindole. There have been incidences of increased plasma concentrations of tricyclic antidepressants and increased antimuscarinic side effects with phenothiazines and possibly clozapine.

Antivirals:

The plasma concentrations of some tricyclic antidepressants may be increased by ritonavir.

Anxiolytics and Hypnotics:

An enhanced sedative effect has been reported when taken with lofepramine.

Antihistamines:

When taken with lofepramine an increased antimuscarinic and sedative effect is observed. Avoid concomitant use with terfenadine due to increased risk of ventricular arrhythmias (see Section 4.3).

Clonidine:

The effect of antihypertensive agents of clonidine type may be weakened.

Digitalis glycosides:

Co-medication of lofepramine with digitalis glycosides increases risk of arrhythmias.

Dopaminergics:

CNS toxicity has been reported with selegiline. Avoid concomitant use of lofepramine with entacapone

Muscle relaxants:

An enhanced muscle relaxant effect occurs with baclofen when administered with lofepramine.

Nitrates:

There is a reduced effect of sublingual nitrates owing to dry mouth when taken with lofepramine

Others:

An increased risk of ventricular arrhythmias is associated with sotalol and cisapride. Postural hypotension is associated with lofepramine when administered with diuretics and altretamine. Cimetidine, diltiazem, verapamil, disulfiram, alprazolam and estrogens increase plasma concentrations of some tricyclic antidepressants, whose dosage should therefore be reduced.

4.6 Fertility, pregnancy and lactation

Pregnancy

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.

Breast-feeding

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.

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

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:

Haematological/biochemical: rarely, bone marrow depression including isolated reports of: agranulocytosis, eosinophilia, granulocytopenia, leucopenia, pancytopenia, thrombocytopenia.

Endocrine: rarely, an inappropriate secretion of antidiuretic hormone leading to hyponatraemia; interference with sexual function, changes of blood sugar level, gynaecomastia, galactorrhoea.

CNS and neuromuscular: dizziness, sleep disturbances, drowsiness, agitation, confusion, headache, malaise, paraesthesia and rarely tinnitus, hypomania, hallucinations and convulsions, 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 sense of taste.

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

Gastrointestinal: nausea, vomiting.

Urinogenital: testicular disorders eg pain.

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

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

Raised liver enzyme levels 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 clinical hepatitis and 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.

Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRs and TCAs. The mechanism leading to this risk is unknown.

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 website: www.mhra.gov.uk/yellowcard

4.9 Overdose

Overdosage: 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 to 6.72g, have shown no serious sequelae directly attributable to the drug.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antidepressant ATC code: NO6A A07

Lofepramine is a tricyclic antidepressant. Its mode of action in depression stems from the inhibition of re-uptake of monoamines in peripheral adrenergic nerves. When compared with imipramine, lofepramine had significantly reduced anticholinergic side effects. Whereas imipramine increases the intensity of delta, theta and beta frequencies of the EEG, lofepramine affects only the beta band. Lofepramine produces a lesser increase in heart rate than that produced by amitriptyline when administered to normal individuals.

5.2 Pharmacokinetic properties

a) General Characteristics of the Active Substance

Lofepramine is rapidly absorbed from the gastrointestinal tract and is extensively demethylated by first-pass metabolism in the liver to its primary metabolite, desipramine; thus the apparent bioavailability of oral lofepramine is below 10%. Peak plasma concentrations of lofepramine and desipramine are achieved within 1 hour and 4 hours, respectively. Lofepramine is mainly excreted in the urine, chiefly in the form of its metabolites. The plasma elimination half-life of lofepramine is relatively short, while that of desipramine is 12-24 hours. Lofepramine is highly bound to plasma proteins.

b) Characteristics in Patients

No correlation between plasma concentration and therapeutic effect has been found. Limited studies in the elderly have reported data consistent with those reported from younger subjects. The effects of renal and hepatic impairment on the pharmacokinetics of lofepramine have not been studied.

5.3 Preclinical safety data

Not applicable.

6. Pharmaceutical particulars
6.1 List of excipients

Citric acid anhydrous

Lactose

Maize starch

Povidone K25

Glycerol

Vegetable oil hydrogenated

Film Coat

Opadry Purple 03B25514

Hypromellose 6cP

Carmoisine (E122)

Indigo Carmine Aluminium Lake

Macrogol 400

Iron Oxide Red

Titanium Dioxide

Sunset Yellow FCF Aluminium Lake (E110)

6.2 Incompatibilities

Not applicable

6.3 Shelf life

2 years

6.4 Special precautions for storage

Blister: Store below 25°C. Store in the original package.

Container: Store below 25°C. Keep the bottle tightly closed.

6.5 Nature and contents of container

White opaque PVC/PE/PVDC blister pack with aluminium foil seal and contained in cardboard cartons. Pack sizes 28, 30, 56, 60 and 100 tablets.

HDPE Duma container with white LDPE Securipac cap. Pack size 250 tablets

HDPE container with induction inner seal and polypropylene closures. Pack size 250 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements

7. Marketing authorisation holder

Accord Healthcare Limited

Sage House

319 Pinner Road

North Harrow

Middlesex

HA1 4HF

United Kingdom

8. Marketing authorisation number(s)

PL 20075/0606

9. Date of first authorisation/renewal of the authorisation

11.11.2002

10. Date of revision of the text

04/12/2017