Moclobemide 150 Mg Film-Coated Tablet
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Moclobemide 150 mg film-coated tablet
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 150 mg moclobemide.
Excipients with known effect: Each tablet contains: 181 mg lactose (as lactose monohydrate)
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet
Beige, oblong film-coated tablet of length15.9-16.3mm, width 7.9-8.3mm and height of 5.0-5.4mm with score notch on both sides The tablet can be divided into equal halves.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Moclobemide is indicated for the treatment of major depressive episodes
4.2 Posology and method of administration
Posology
Adults:
Initial usual dose 300 mg, administered in divided doses after meals.
If necessary, the daily dose can be increased to 600 mg per day. However, the dose should not be increased during the 1st week of treatment, because the bioavailability increases during this time and a clinical effect may not be seen for 1-3 weeks. In individual cases, the therapeutic dose can be gradually reduced to 150 mg per day, depending on effect.
Duration of treatment:
Treatment with moclobemide should be continued for at least 4-6 weeks to be able to judge the efficacy of moclobemide. Treatment with moclobemide should preferably be continued for a symptom free period of 4-6 months. Then treatment can be gradually tapered off.
Antidepressants, particularly MAOIs, should be withdrawn gradually to reduce the risk of withdrawal symptoms.
Elderly:
No special dose adjustment is required Children and adolescents under the age of 18:
In view of the lack of clinical data available, moclobemide is not recommended for use in children and adolescents under the age of 18.
Renal/hepatic impairment:
Patients with reduced renal function do not require a special dose adjustment. In patients with impaired hepatic function, the daily dose of moclobemide should be reduced to a half or one third.
Method of administration
The tablets are for oral administration and should be taken with fluid.
4.3 Contraindications
• Hypersensitivity to active substance or to any of the excipients listed in section 6.1.
• Acute Confusional state.
• Patients with phaeochromocytoma.
• Moclobemide should not be used in pediatrics at present as clinical experience in this category is lacking.
• Concomitant treatment with selegeline, linezolid, bupropion, 5-HT re-uptake inhibitors (including those which are tricyclic antidepressants) or other antidepressants in order to prevent precipitation of serotonergic overactivity (see section 4.4 Special warnings and precautions for use, see 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 Moclobemide.
• Co-administration with dextromethorphan (contained in many proprietary cough medicines, as isolated cases of severe central nervous system adverse reactions have been reported after co-administration)., pethidine, tramadol and triptans (see 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.
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 to seek medical advice immediately if these symptoms present.
Depressive patients with excitation or agitation as the predominant clinical symptoms should either not be treated with moclobemide or only in combination with a sedative (e.g. a benzodiazepine) for not more than 2-3 weeks. If a depressive episode is treated in bipolar disorders, manic episodes may be provoked; in such cases treatment with moclobemide should be stopped.
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 Moclobemide (see 4.8 Undesirable effects), and should be considered in all patients who develop drowsiness, confusion or convulsions while taking an antidepressant.
Due to the lack of clinical data, patients with schizophrenia or schizoaffective disorders should not be treated with moclobemide without concomitant neuroleptic medication. As with other antidepressants, treatment may exacerbate the schizophrenic symptoms of depressive patients with schizophrenic or schizoaffective psychoses. If possible, therapy with long-acting neuroleptics should be continued in such patients.
Moclobemide is a reversible inhibitor of monoamine oxidase type A (RIMA). It causes less potentiation of tyramine than traditional irreversible MAOIs, and therefore Moclobemide 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 (e.g. mature cheese, yeast extracts and fermented soya bean products or red wine).
Concomitant ingestion of alcohol should be avoided, as with any psychotropic medication.
Patients with hypertension should be closely monitored when being treated with moclobemide. Theoretical considerations indicate that MAO inhibitors may also provoke a hypertensive reaction in patients with thyrotoxicosis or pheochromocytoma. Since there is a lack of experience in this patient group, caution should be exercised before prescribing moclobemide.
Patients should be advised to avoid sympathomimetic agents, such as ephedrine, pseudoephedrine, dextromethorphan and phenylpropanolamine (contained in many proprietary cough and cold medications) (see Section 4.5 Interaction with other medicinal products and other forms of interaction).
Patients should also be advised that if they require surgery they should inform the anaesthesiologist that they take moclobemide. In patients receiving moclobemide, particularly in multiple drug combinations caution should be exercised when co administering active substances that enhances serotonin in order to prevent precipitation of serotonergic syndrome, which may be fatal. This is particularly true for tricyclic antidepressants (e.g. clomipramine), selective serotonin (5-HT) re-uptake inhibitors (SSRI), other antidepressants or amphetamines (see section 4.3 and 4.5). A wash-out period is required between SSRIs and moclobemide therapy (see 4.5.).
Caution should be exercised in patients with congenital long QT syndrome or with a history of cardiac disorders (including disturbances of conduction, arrhythmia). Concomitant administration of QT prolonging medicinal products should be avoided.
These products contain lactose; therefore they should not be administered to patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
In the case of liver dysfunction, the dose should be reduced (see 4.2).
Insomnia or nervousness or jitteriness at the beginning of treatment with moclobemide can justify a dose reduction or temporary symptomatic treatment. In case of occurrence of mania or hypomania, or the onset of early symptoms of those reactions (grandiosity, hyperactivity (including increased speech), reckless impulsivity), treatment with moclobemide will be interrupted and alternative treatment will be initiated.
St. John’s wort (Hypericum)-containing phytotherapeutic products should be used with care in combination with moclobemide as this may increase the serotonin concentration.
4.5 Interaction with other medicinal products and other forms of interaction
Moclobemide potentiates the effects of opiates such as pethidine, dextromethorphan and tramadol (see 4.3.).The combination of moclobemide with these opiates is contraindicated due to the increased risk of onset of a serotonin syndrome.
Isolated cases of serotonin syndrome with severe central nervous system adverse reactions have been reported after co-administration with dextromethorphan. Since proprietary cough and cold medicinal products may contain dextromethorphan, they should not be taken without prior consultation with a physician and alternatives not containing dextromethorphan should be given.
In animals, moclobemide potentiates the effects of opiates. Opiate analgesics, such as, Morphine, fentanyl and codeine should be used with caution. An adjustment of the dose may therefore be necessary for these medicinal products.
Since the action of moclobemide is selective and reversible, its propensity to interact with tyramine is slight and short-lasting, as pharmacological studies in animals and man have shown (see section 4.4 Special warnings and precautions for use).
The potentiation of the pressor effect was even lower or did not occur when moclobemide was administered after a meal.
Concurrent administration of triptans and moclobemide is contraindicated due to the risk of hypertension or coronary artery vasoconstriction caused by combined serotonergic effects (see 4.3.) and triptans are potent serotonin receptor agonists and metabolized by monoamine oxidases (MAOs) and various cytrochrome P450 enzymes and the plasma concentrations of the triptans increases, e.g. sumatriptan, rizatriptan, zolmitriptan, almotriptan, naratriptan, frovatriptan and eletriptan,
Cimetidine inhibits the metabolism of moclobemide. The normal dose of moclobemide should therefore be reduced to half or a third in patients who are taking cimetidine.
Care should be taken with concomitant use of drugs that are metabolised by CYP2C19 as moclobemide is an inhibitor of this enzyme. The plasma concentration of these drugs (such as proton pump inhibitors (e.g. omeprazole), fluoxetine and fluvoxamine) may be increased when concomitantly used with moclobemide. Similarly, moclobemide inhibits the metabolism of omeprazole in CYP2C19 extensive metabolisers resulting in a doubling of the omeprazole exposure.
Care should be taken with concomitant use of trimipramine and maprotiline as the plasma concentration of these monoamine reuptake inhibitors increases upon concomitant administration with moclobemide.
The concomitant use of moclobemide and trycyclic antidepressants (e.g. clomipramine), SSRI antidepressants (e.g. fluoxetine and fluvoxamine) or other antidepressants is contraindicated. The combination treatment can cause the development of serotonin syndrome eventually leading to death.
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 anti-depressants such as venlafaxine, fluvoxamine, clomipramine, citalopram, escitalopram, paroxetine, sertraline, bupropion. Symptoms are: a rise in temperature (hyperthermia), confusion, hyperreflexia and myoclonus, rigidity, irritabiIity, tachycardia, rise in blood pressure, and tremors which are indicative of serotonergic overactivity (see 4.3. and 4.4 and section 4.8). Switching from another antidepressant agent to moclobemide: a wash-out period is recommended depending on the half-life of the antidepressant agent. Due to the generally long half-lives of SSRIs, a wash-out period of 4-5 half-lives of the active substance or any active metabolite is recommended after stopping treatment with the SSRI and starting treatment with moclobemide. Generally, an interval of 14 days is recommended for switching from an irreversible MAO inhibitor to moclobemide (e.g.
phenelzin, tranylcypromine). The starting dose of moclobemide should not exceed 300 mg daily during the first week. Treatment with a tricyclic or other antidepressant could be initiated the next day after withdrawal of moclobemide. Should such combined symptoms of serotonin syndrome occur, the patient should be closely observed by a physician (and if necessary hospitalised) and appropriate treatment given.
The pharmacological effect of systemically administered sympathomimetics (epinephrine and norepinephrine) may be potentiated and prolonged during treatment with moclobemide, a dosage adjustment may therefore be necessary for these active substances.
Combination treatment with selegiline is contraindicated (see 4.3).
At the present time, there is no experience of concomitant administration of moclobemide and buspirone in humans. However, cases of hypertensive crisis have been reported when other MAOIs were administered simultaneously with buspirone, therefore concurrent administration of buspirone and moclobemide is not
recommended.
The combination with millepertuis (Saint Johns Wort) may increase the risk of onset of a serotonin syndrome. A regular clinical monitoring is therefore recommended when moclobemide is concomitantly used.
Data from clinical studies suggests that no interactions exist between moclobemide and hydrochlorothiazide (HCT), in hypertensive patients, with oral contraceptives, digoxin, phenprocoumon, and alcohol.
As sibutramine is a norepinephrine-serotonin reuptake inhibitor, which would increase the effect of MAOIs, the concomitant use with moclobemide not
recommended.
Concomitant use of dextropropoxyphene is not advised as moclobemide may potentiate the effects of dextropropoxyphene.
The combination with other medicinal products that are known to prolong the QT interval should be avoided. Moclobemide should not be given with class Ia and III anti-arrhythmics, cisapride, macrolide antibiotics, anti-histaminics, medicinal
products, known to cause hypokalemia (e.g. certain diuretics) or can inhibit the
hepatic degradation of moclobemide (e.g. cimetidine, fluoxetine).
4.6 Fertility, pregnancy and lactation
Pregnancy
The safety of moclobemide in human pregnancy has not been established. There are no adequate data from the use of moclobemide in pregnant women. Animal studies do not indicate reproductive toxicity and have not revealed any risk to the foetus. However caution should be exercised when prescribing moclobemide during pregnancy. Therefore the benefits of drug therapy during pregnancy should be weighed against possible risk to the foetus.
Breast-feeding
Since only a small amount of moclobemide passes into breast milk (approx. 1/30 of the dose administered to the mother, corrected for bodyweight), the benefits of continued treatment during nursing should be carefully weighed against possible risks to the child.
4.7 Effects on ability to drive and use machines
No studies on the effect on the ability to drive and use machines have been performed.
Impairment of performance in activities requiring complete mental alertness (e.g. driving a motor vehicle) is generally not to be expected with moclobemide taking into consideration the adverse events profile. The reaction of the individual should however be monitored, especially during early treatment.
4.8 Undesirable effects
The undesirable effects observed during treatment with moclobemide are observed mainly during the first few weeks of treatment and regress subsequently, concomitantly with improvement of the depressive episode. This is particularly so for some of the undesirable effects that are related to the very nature of the depressive illness such as feelings of anxiety, agitation or irritability, mood switch with mania or delirium.
Frequency in compliance with MedDRA-convention:
Very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1000 to < 1/100); rare (> 1/10000 to < 1/1000); very rare (< 1/10000), not known (cannot be estimated from the available data).
Cardiac disorders
Moclobemide can cause QT interval prolongation. QT prolongation can lead to a torsade de pointes-type ventricular arrhythmia.
Nervous system disorders Very Common: headache, dizziness Common: paraesthesia Uncommon: Dysgeusia
Eye disorders
Uncommon: visual disturbances
Gastrointestinal disorders Very Common: nausea, dry mouth
Common: gastrointestinal disturbances (e.g. diarrhoea, constipation, vomiting)
General disorders and administration site conditions
Common: Irritability Uncommon: Asthenia
Skin and subcutaneous tissue disorders Common: Rash
Uncommon: Oedema, pruritus, urticaria Investigations
Rare: Serotonin syndrome* (co-administered with drugs that enhance serotonin, such as serotonin re-uptake inhibitors and many other antidepressants), Increased hepatic enzymes (without associated clinical sequel).
Reproductive system and breast disorders Very rare: galactorrhea
Psychiatric disorders
Very Common: Sleep disturbances / Sleep disorder Common: feelings of anxiety, agitation, restlessness
Uncommon: Cases of suicidal ideation, have been reported during moclobemide therapy or early after treatment discontinuation (see section 4.4).
Isolated cases of confusion have been seen; which disappeared quickly after discontinuation of treatment and restlessness has been reported.
Rare: Suicidal behabiours, delusions
Vascular disorders:
Common: Hypotension Uncommon: Flushing
Metabolism and nutrition disorders:
Hyponatraemia* has rarely been reported (see section 4.4 Special warnings and precautions for use).
Rare: Decreased appetite*
Symptoms of the serotonin syndrome may occur if Moclobemide 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).
*: Adverse reactions that were not reported in clinical studies but were only reported post-marketing are indicated by an asterix (*)
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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard.
4.9 Overdose
Experience of overdose in humans is so far limited. Overdoses of moclobemide alone induce generally mild and reversible signs of CNS and gastro-intestinal irritation. Signs of agitation, aggressiveness, and behavioural changes have been observed. Although moclobemide alone, even in high doses, seldom leads to fatal reactions, death due to overdose of moclobemide as the only drug has been reported. Treatment of overdose should be aimed primarily at maintenance of the vital functions. As with other antidepressants, mixed overdoses of moclobemide with other active substances (e.g. other CNS-acting active substances) could be life threatening.
Moclobemide prolongs the QT and QTc intervals in overdose and a 12-lead ECG should be done in the case of moclobemide overdose.
Therefore, patients should be hospitalised and closely monitored so that appropriate treatment may be given.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antidepressant ATC code: N06 AG 02
Moclobemide is an antidepressant that acts on the monoaminergic cerebral neurotransmitter system by reversibly inhibiting monoamine oxidase, primarily type A (RIMA). The metabolism of noradrenaline, dopamine and serotonin is thereby reduced, resulting in increased extracellular concentrations of these neurotransmitters.
5.2 Pharmacokinetic properties
After oral administration, moclobemide is absorbed completely from the gastrointestinal tract into the portal vein. A first-pass effect in the liver reduces the systemically available dose fraction (bioavailability F). This reduction is more pronounced after a single dose (F: 60%) than after multiple doses (F: 80%). Due to its lipophilic properties, moclobemide is distributed in the body with a volume of distribution (Vss) of approx. 1.2 l/kg. Binding to plasma proteins, mainly aIbumin, is relatively low (50%). Peak plasma concentrations are reached within 1 hour after administration. After multiple doses, the plasma concentrations of moclobemide increase over the first week of therapy, and thereafter remain stable. When the daily dose is increased, the increase in steady-state concentrations is more than proportional.
Moclobemide is almost entirely metabolised before it is eliminated: less than 1% of a dose is excreted unchanged via the kidneys. Metabolism occurs
mainly via oxidative reactions in the morpholine part of the molecule. The metabolites formed are excreted renally. Degradation products with pharmacological activity in vitro or in animal studies occur only in very low concentrations in humans.
Plasma clearance is approximately 20-50 l/hour, and the elimination half-life is 1 - 4 hours, this increases with higher doses due to saturation of the metabolic pathways.
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 the cytochrome P450 2C19 isozyme. The maximum plasma concentration (Cmax) and the area under the concentration time curve (AUC) have been found to be approximately 1.5 times greater in slow metabolisers compared with extensive metabolisers for the same dose of moclobemide.
5.3 Preclinical safety data
Preclinical data, based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction indicate there are no special hazards for humans associated with moclobemide.
6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients
Copovidone Lactose monohydrate Magnesium stearate Maize starch
Microcrystalline cellulose Sodium starch glycollate (type A) Silica colloidal anhydrous.
Coating:
Lactose monohydrate Hypromellose Macrogol 4000 Titanium dioxide (E171)
Ferric oxide yellow (E172)
6.2 Incompatibilities
Not applicable
6.3 Shelf life
3 years
6.4 Special precautions for storage
No special precautions for storage
6.5 Nature and contents of container
PVC/alu blister Packsizes:
150 mg: 20, 28, 30, 50, 60, 84, 100 film-coated tablets (For hospital use: 100 filmcoated tablets)
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements for disposal.
Any unused product or waste material should be disposed of in accordance with local requirements
MARKETING AUTHORISATION HOLDER
7
Tillomed Laboratories Ltd 3 Howard Road Eaton Socon St. Neots
Cambridgeshire PE19 8ET UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 11311/0493
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 17/06/2010
10 DATE OF REVISION OF THE TEXT
20/01/2015