1. Name Of The Medicinal Product
Moclobemide 150mg Tablets
2. Qualitative And Quantitative Composition
Each tablet contains 150mg of Moclobemide
For excipients see 6.1
3. Pharmaceutical Form
Film-coated Tablets
Yellow, round, biconvex, plain on one side, and “MOC” breakline “150” on the other side. Diameter 10mm
4. Clinical Particulars
4.1 Therapeutic Indications
Moclobemide Tablets are reversible inhibitors of monoamine oxidase Type A (RIMA) and are indicated for the treatment of major depression and social phobia.
4.2 Posology And Method Of Administration
Adults
Major Depression: To begin treatment, 300mg of Moclobemide should be given daily, usually as 2 divided doses. Depending on the severity of the depressive symptomology and the individual's response, the dose can be increased to a maximum of 600mg daily or decreased to 150mg daily. It may take up to 2 weeks before the therapeutic benefit of these tablets will be observed. Treatment should then be maintained at the appropriate level for at least another 2 months before any reduction in dose is considered.
Social Phobia: The initial recommended starting dose is 300mg per day, which should be increased to 600mg per day (in 2 divided doses), on the fourth day of treatment. 600mg should be given daily in 2 divided doses for at least 8 to 12 weeks which will allow adequate assessment of the effect of treatment. As social phobia may be a long term problem, consideration should be given to continuing treatment in those patients who show a response. However the patient should be re-evaluated at regular intervals to assess the need for further treatment.
Elderly
As for adults
Children
Not recommended for use in children
Renal and hepatic impairment
Patients with renal impairment do not need dosage adjustment.
Patients with severe hepatic impairment, as a result of liver disease or drugs that inhibit microsomal mono-oxygenase activity, such as Cimetidine, may need to reduce their dose of Moclobemide to half or a third of that of adults.
In all individuals, upon cessation of treatment, the drug should be withdrawn gradually to prevent relapse and decrease the chance of withdrawal symptoms.
Route of Administration
Oral. Tablets should be taken after food.
4.3 Contraindications
Moclobemide Tablets are contraindicated if the patient
- Is sensitive to moclobemide or any of the excipients of the tablet
- Is in an acute confusional state
- Has phaeochromocytoma
- Is a child
Moclobemide Tablets should not be used when the patient is being treated with the following
- Pethidine or selegiline
- 5-HT reuptake inhibitors or tricyclic antidepressants, as there is a risk of dangerously high levels of serotonin being produced. After ceasing treatment with other anti-depressants an interval of at least 4 to 5 half lives of the drug or active metabolites should elapse before using Moclobemide Tablets (see also interaction section)
- Dextromethorphan which is contained in many proprietary cough medicines (See section 4.5 Interaction with other medicaments and other forms of interaction)
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.
Other psychiatric conditions for which moclobemide is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid 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 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 seek medical advice immediately if these symptoms present.
The dietary restrictions that are needed when being treated by irreversible MAOI's are not generally required with reversible inhibitors of Monoamine Oxidase Type A (RIMA). However as a small number of patients may be sensitive to tyramine it is advised that all patients avoid eating large amounts of tyramine rich food such as mature cheese, yeast extracts and fermented soya bean products.
Patients should avoid using cough and cold medicines as many of them contain sympathomimetic agents such as pseudoephedrine, ephedrine and phenylpropanolamine.
Patients who are depressed but are frequently expressing excitation or agitation should not be treated with moclobemide. However treatment is possible, in such cases, if Moclobemide Tablets are administered concurrently with a sedative such as a benzodiazepine. The use of the sedative should be limited to a period of 2 to 3 weeks.
Treating the depression of a bipolar disorder can generate a manic episode.
Patients with schizophrenia or schizo-affective disorders should not be treated with Moclobemide Tablets due to lack of clinical data to support its use in this area.
Patients with thyrotoxicosis are theoretically at risk of having a hypertensive reaction if MAOIs are given, therefore, Moclobemide should be given with care.
In patients receiving Moclobemide, 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 medicaments and other forms of interaction). This is especially true for clomipramine.
As with all antidepressants, the suicidal ideation and tendencies of the patient should be closely monitored at the beginning of treatment with Moclobemide Tablets.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Moclobemide Tablets potentiate the effect of opiates. Morphine and fentanyl should be used with caution. An adjustment in the dosage may be necessary for these drugs.
Cimetidine prolongs the metabolism of moclobemide and therefore the normal daily dose of moclobemide should be halved when co-administering cimetidine.
In patients receiving Moclobemide, additional drugs that enhance serotonin, such as many other antidepressants, particularly in multiple-drug combinations should be given with caution. This is particularly true for clomipramine. 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 and Section 4.4 Special warnings for use). Should such combined symptoms occur, the patient should be closely observed by a physician (and if necessary hospitalised) and appropriate treatment given. Treatment with a tricyclic or other antidepressant could be initiated immediately after withdrawal of Moclobemide (i.e. without a wash out period), provided similar caution is observed.
Hypertension has been reported when buspirone is given with MAOIs but there is no data on the co-administration of buspirone with moclobemide.
Isolated cases of severe central nervous system adverse reactions have been reported after co-administration of Moclobemide and dextromethorphan. Since proprietary cough and cold medicines may contain dextromethorphan, they should not be taken without prior consultation with a physician and, if possible, alternatives not containing dextromethorphan should be given (See Section 4.3 Contraindications).
The pharmacologic action of systemic regimens of sympathomimetic agents may possibly be intensified and prolonged by concurrent treatment with Moclobemide.
4.6 Pregnancy And Lactation
Reproduction studies in animals have not revealed any risk to the foetus, but the safety of Moclobemide in human pregnancy has not been established. Therefore the benefits of drug therapy during pregnancy should be weighed against the possible risk to the foetus.
Only a small amount of Moclobemide 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.
4.7 Effects On Ability To Drive And Use Machines
It is not thought that moclobemide will affect performance in activities requiring complete mental alertness. However reactions should be monitored at the beginning of treatment.
4.8 Undesirable Effects
Undesirable effects that have been reported include dry mouth, nausea, diarrhoea, constipation, vomiting and oedema.
Skin reactions such as flushing, rash, urticaria and pruritus have also been documented.
Sleep disturbances, agitation, anxiety, restlessness, irritability, dizziness, paraesthesia, visual disturbances and headache have been observed. Occasionally patients on moclobemide have become confused but this resolves rapidly on discontinuation of therapy.
There have been a few reports of raised liver enzymes without any apparent clinical consequences.
Cases of suicidal ideation and suicidal behaviors have been reported during moclobemide therapy or early after treatment discontinuation (see section 4.4).
4.9 Overdose
When moclobemide is the sole drug taken in overdose, there are fairly mild and reversible central or gastrointestinal symptoms. Those that have been reported include agitation, aggression and behavioural changes. The main aim of treatment in overdose is to maintain vital functioning.
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 give.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
ATC code: N06A G02 Monoamine oxidase type A inhibitors.
Moclobemide is an antidepressant as it is a reversible inhibitor of Monoamine Oxidase Type A (RIMA) which affects the monoaminergic neurotransmitter system in the brain. Inhibition of monoamine oxidase reduces the breakdown of noradrenaline, dopamine and serotonin, thereby increasing the extracellular concentration of these neurotransmitters in the brain.
5.2 Pharmacokinetic Properties
Moclobemide is absorbed quickly and almost completely (>95%) from the gastrointestinal tract. As a result of first pass metabolism in the liver, the bioavailability of the drug is reduced to 60% after a single dose and to 80% after repeated doses.
Moclobemide is widely distributed throughout the body due to its lipophilic nature. Binding of the drug to plasma proteins, mainly albumin, is relatively low (50%). Peak plasma concentrations are achieved within one hour of dosage. 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 the steady-state concentrations.
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 in in vitro or animal experiments are present in the systemic circulation in man at very low concentrations only. Approximately 2% of the Caucasian population and 15% of the Asian population have been shown to be slow metabolisers with respect to oxidative hepatic metabolism via cytochrome P4502C19. It was found that the maximum plasma concentration (Cmax) and area under the concentration time curve (AUC) was approximately 1.5 times greater in slow metabolisers than in extensive metabolisers who were taking the same dosage of moclobemide.
Moclobemide is quickly eliminated from the body. Blood clearance is approximately 20-50 1/hour, the elimination half-life one to four hours. Less than 1% of a dose is excreted renally in unchanged form. The metabolites that are formed are eliminated renally.
5.3 Preclinical Safety Data
Moclobemide, in contrast to iproniazid, was not hepatotoxic in rats pretreated with phenobarbitone. There are no other preclinical data of relevance to the prescriber.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Lactose Monohydrate
Pregelatinised Maize Starch
Polyvidone
Sodium Starch Glycollate
Magnesium Stearate
Hypromellose
Polyoxyl-8-Stearate
Microcrystalline Cellulose
Propylene Glycol
Titanium Dioxide (E171)
Iron Oxides (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
3 years.
6.4 Special Precautions For Storage
No special storage precautions.
6.5 Nature And Contents Of Container
Blister packs (Al/PVC)
HDPE containers with LDPE cap
Pack size: 12, 24, 28, 30, 56, 84, or 100.
6.6 Special Precautions For Disposal And Other Handling
None
7. Marketing Authorisation Holder
Sandoz Ltd
Woolmer Way
Bordon
Hampshire GU35 9QE
8. Marketing Authorisation Number(S)
PL 4416/0371
9. Date Of First Authorisation/Renewal Of The Authorisation
26 September 2001
10. Date Of Revision Of The Text
23rd January 2009
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