Manerix 300mg Film Coated Tablets

1 film-coated 300mg tablet contains 300mg moclobemide.

300mg of moclobemide.

Major depression.

Treatment of social phobia.

Manerix tablets are for oral administration.

The tablets should be taken at the end of a meal.

Adults

Major depression

The recommended initial dose is 300mg daily, usually administered in divided doses. The dose may be increased up to 600mg/day depending on the severity of the depression.

The individual response may allow a reduction of the daily dose to 150mg.

Treatment of social phobia

The recommended dose of moclobemide is 600mg/day, given in 2 divided doses. The moclobemide dose should be started at 300mg/day and should be increased to 600mg/day on day 4. Continuing the 300mg/day dose for longer than 3 days is not recommended, as the efficacious dose is 600mg/day. Treatment with 600mg/day should continue for 8 - 12 weeks in order to assess the efficacy of the drug. Social phobia may be a chronic condition and it is reasonable to consider continuation of treatment for a responding patient. Patients should be periodically re-evaluated to determine need for further treatment.

Elderly

Elderly patients do not require a special dose adjustment of Manerix.

Children

In view of the lack of clinical data available, Manerix is not recommended for use in children.

Renal/hepatic impairment

Patients with reduced renal function do not require a special dose adjustment of Manerix. When hepatic metabolism is severely impaired by hepatic disease or a drug that inhibits microsomal mono-oxygenase activity (e.g. cimetidine), normal plasma levels are achieved by reducing the daily dose of Manerix to half or one third (see section 5.2 Pharmacokinetics in special populations).

Manerix is contra-indicated in patients with known hypersensitivity to the drug or to any component of the product, in acute confusional states and in patients with phaeochromocytoma.

Manerix should not be co-administered with pethidine or selegiline (see section 4.5 Interaction with other medicinal products and other forms of interaction).

Manerix should not be co-administered with 5-HT re-uptake inhibitors (including those which are tricyclic antidepressants) in order to prevent precipitation of serotonergic overactivity (see section 4.4 Special warnings and precautions for use, section 4.5 Interaction with other medicinal products and other forms of interaction and section 4.8 Undesirable effects). After stopping treatment with 5-HT re-uptake inhibitors a time period equal to 4 - 5 half lives of the drug or any active metabolite should elapse between stopping therapy and starting therapy with Manerix.

Manerix should not be co-administered with dextromethorphan, contained in many proprietary cough medicines, as isolated cases of severe central nervous system adverse reactions have been reported after co-administration.

Manerix should not be administered to children for the time being as clinical experience in this category is lacking.

Manerix is a reversible inhibitor of monoamine oxidase type A (RIMA). It causes less potentiation of tyramine than traditional irreversible MAOIs, and therefore Manerix does not generally necessitate the special dietary restrictions required for these irreversible MAOIs. However, as a few patients may be especially sensitive to tyramine, all patients should be advised to avoid the consumption of large amounts of tyramine rich food (mature cheese, yeast extracts and fermented soya bean products).

Patients should be advised to avoid sympathomimetic agents such as ephedrine, pseudoephedrine and phenylpropanolamine (contained in many proprietary cough and cold medications) (see section 4.5 Interaction with other medicinal products and other forms of interaction).

Depressive patients with excitation or agitation as the predominant clinical feature should either not be treated with Manerix or only in combination with a sedative (e.g. a benzodiazepine). The sedative should only be used for a maximum of 2 to 3 weeks.

If a depressive episode is treated in bipolar disorders, manic episodes can be provoked.

Due to the lack of clinical data, patients with concomitant schizophrenia or schizo-affective organic disorders should not be treated with Manerix.

Theoretical pharmacological considerations indicate that MAO inhibitors may precipitate a hypertensive reaction in patients with thyrotoxicosis. As experience with Manerix in this population group is lacking, caution should be exercised before prescribing Manerix.

In patients receiving Manerix, caution should be exercised when co-administering drugs that enhance serotonin in order to prevent precipitation of serotoninergic syndrome (see section 4.3 Contraindications and section 4.5 Interaction with other medicinal products and other forms of interaction).

Hypersensitivity may occur in susceptible individuals. Symptoms may include rash and oedema.

Hyponatraemia, (usually in the elderly and possibly due to inappropriate secretion of antidiuretic hormone) has been associated with all types of antidepressants, although very rarely with Manerix (see 4.8 Undesirable effects), and should be considered in all patients who develop drowsiness, confusion or convulsions while taking an antidepressant.

Suicide/suicidal thoughts or clinical worsening

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

Other psychiatric conditions for which Manerix is prescribed can also be associated with an increased risk of suiciderelated events. In addition, these conditions may be comorbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.

Patients with a history of suiciderelated 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 metaanalysis of placebocontrolled 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.

Owing to the presence of lactose, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Co-administration of Manerix with pethidine or selegiline is contraindicated (see section 4.3 Contraindications).

In animals, Manerix potentiates the effects of opiates. Opiate analgesics, such as, Morphine and fentanyl should be used with caution. A dosage adjustment may be necessary for these drugs.

Cimetidine prolongs the metabolism of Manerix. The normal dose of Manerix should therefore be reduced to half the dose in patients taking cimetidine.

In patients receiving Manerix, additional drugs that enhance serotonin, such as many other antidepressants, particularly in multiple-drug combinations, should be given with caution. In isolated cases there have been combinations of serious symptoms and signs, including hyperthermia, confusion, hyperreflexia and myoclonus, which are indicative of serotonergic overactivity (see section 4.3 Contraindications, section 4.4 Special warnings and precautions for use and section 4.8 Undesirable effects). Should such combined symptoms occur, the patient should be closely observed by a physician (and if necessary hospitalised) and appropriate treatment given.

The pharmacologic action of systemic regimens of sympathomimetic agents may possibly be intensified and prolonged by concurrent treatment with moclobemide.

Reproduction studies in animals have not revealed any risk to the foetus, but the safety of Manerix in human pregnancy has not been established. Therefore the benefits of drug therapy during pregnancy should be weighed against possible risk to the foetus.

Since only a small amount of Manerix passes into breast milk (approximately ¹/₃₀ of the maternal dose), the benefits of continuing drug therapy during nursing should be weighed against possible risks to the child.

Impairment of performance in activities requiring complete mental alertness (e.g. driving a motor vehicle) is generally not to be expected with Manerix. The individual reaction should however be monitored during early treatment.

The following undesirable effects have been observed:

Metabolism and nutrition disorders:

Hyponatraemia has very rarely been reported (see section 4.4 Special warnings and precautions for use).

Psychiatric disorders:

Sleep disturbances, agitation, anxiety, restlessness. Isolated cases of confusional state have been seen; these have resolved quickly on discontinuation of therapy. Cases of suicidal ideation and suicidal behaviours have been reported during antidepressant therapy or early after treatment discontinuation (see section 4.4 Special warnings and precautions for use).

Nervous system disorders:

Dizziness, headache, paraesthesia.

Eye disorders:

Visual disturbances.

Vascular disorders:

Flushing.

Gastrointestinal disorders:

Dry mouth, nausea, vomiting, diarrhoea, constipation.

Skin and subcutaneous tissue disorders:

Oedema, rash, pruritus, urticaria.

General disorders and administration site conditions:

Irritability.

Investigations:

There appears to be a low incidence of increased hepatic enzymes without associated clinical sequelae.

Symptoms of the serotonin syndrome may occur if Manerix is co-administered with drugs that enhance serotonin, such as 5-HT re-uptake inhibitors and many other antidepressants (see section 4.3 Contraindications and section 4.5 Interaction with other medicinal products and other forms of interaction).

Overdoses of moclobemide alone induce generally mild and reversible signs of CNS and gastro-intestinal irritation.

Treatment of overdose should be aimed primarily at maintenance of the vital functions.

As with other antidepressants, mixed overdoses of moclobemide with other drugs (e.g. other CNS acting drugs) could be life-threatening. Therefore, patients should be hospitalised and closely monitored so that appropriate treatment may be given.

Manerix is an antidepressant which affects the monoaminergic cerebral neurotransmitter system by means of a reversible inhibition of monoamine oxidase preferentially of type A (RIMA). The metabolism of noradrenaline, dopamine and serotonin (5-HT) is decreased by this effect, and this leads to increased extracellular concentrations of these neuronal transmitters.

Absorption

After oral administration, moclobemide is completely absorbed from the gastrointestinal tract into the portal blood. Peak plasma concentrations of the drug are usually reached within one hour of dosage. A hepatic first-pass effect reduces the systemically available dose fraction (bioavailability F). This reduction is more pronounced after single (F: 60%) than after multiple (F: 80%) doses. After multiple dosing, plasma concentrations of moclobemide increase over the first week of therapy and remain stable thereafter. When the daily dose is increased, there is a more than proportional increase in steady-state concentrations.

Distribution

Due to its lipophilic nature, moclobemide is extensively distributed in the body. The volume of distribution (V_ss) is about 1.0 l/kg. Binding of the drug to plasma proteins, mainly albumin, is low (50%).

Metabolism

The drug is almost entirely metabolised before its elimination from the body. Metabolism occurs largely via oxidative reactions on the morpholine moiety of the molecule. Degradation products with pharmacological activity are present in the systemic circulation in man at very low concentrations only. The major metabolites present in plasma are a lactam derivative and an N-oxide derivative. Moclobemide has been shown to be metabolised in part by the polymorphic isoenzymes CYP2C19 and CYP2D6. Thus, in genetically or drug-induced (via metabolic inhibitors) poor metabolisers, metabolism of the drug may be affected. Two studies conducted to investigate the magnitude of these effects suggested that, due to the presence of multiple alternative metabolic pathways, they are of no clinical significance and should not necessitate dosage modification.

Elimination

Moclobemide is rapidly eliminated by metabolic processes. Total clearance is approximately 20 - 50 1/hour. The mean elimination half-life during multiple dosing (300mg b.i.d) is approximately 3 hours and generally ranges from 2 - 4 hours in most patients. Less than 1% of a dose is excreted renally in unchanged form. The metabolites formed are eliminated renally. Insignificant amounts are excreted in human breast milk.

Pharmacokinetics in special populations

Elderly

Absorption and disposition parameters are unchanged in the elderly.

Patients with renal impairment

Renal disease does not alter the elimination characteristics of moclobemide.

patients with hepatic impairment

In advanced liver insufficiency, the metabolism of moclobemide is reduced (see section 4.2 Posology and method of administration).

Not applicable.

Lactose, maize starch, povidone K30, sodium starch glycollate, magnesium stearate, hydroxypropyl methylcellulose, ethylcellulose, polyethylene glycol 6000, talc and titanium dioxide (E171).

Not applicable.

5 years.

No special precautions for storage.

Blister packing.

Pack sizes: 30 and 60 tablets (300mg tablets)

Not applicable.

Meda Pharmaceuticals Ltd

249 West George St

Glasgow

G2 4RB

Trading as:

Meda Pharmaceuticals Ltd

Skyway House

Parsonage Road

Takeley

Bishop's Stortford

CM22 6PU

PL 15142/0104

First approved 5 June 1994