Moclobemide 300mg Film-Coated Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Teva Moclobemide 300 mg Film-coated Tablets.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 300 mg moclobemide.
Excipients: 20 mg of lactose-monohydrate/film-coated tablet For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet.
White to off-white, oval shaped, bevelled edged, film coated tablet, on one side deep
MCL
break line, on the other side engraved “ ”.
300
The tablet can be divided into equal doses.
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 is dose 300 mg,.
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 jugde the efficacy of moclobemide. Treatment with moclobemide should preferably be continued for a symptom free period of 4-6 months. Then treatment can be radualy tapered off.
Antidepressants, particularly MAOIs, should be withdrawn gradually to reduce the risk of withdrawal symptoms.
Older people
No special dose adjustment is required.
Paediatric population
In view of the lack of clinical data available, moclobemide is not recommended for use in children and adolescents.
Renal or 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 half or one third.
Method of administration
Initial usual dose 300 mg, administered in divided doses after meals. The tablets are for oral administration and should be taken with fluid.
4.3 Contraindications
- Patients with known hypersensitivity to moclobemide or to any component of the product.
- Acute confusional states.
- Moclobemide should not be used in paediatrics at present, as clinical experience of the drug's action in children is lacking.
- Patients with phaeochromocytoma.
- Co-administration of moclobemide with the following drugs is contraindicated (see also section 4.5. “Interaction with other medicinal products and other forms of interaction”).
- Selegiline
- 5 HT re-uptake inhibitors and other antidepressants (including tricyclic antidepressants)
- Linezolid
- Triptans (e.g. sumatriptan, rizatriptan, zolmitriptan, almotriptan, naratriptan, frovatriptan and eletriptan)
- Pethidine
- Tramadol
- Bupropion
- Dextromethorphan
4.4 Special warnings and precautions for use
Warning
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.
Generally during therapy with moclobemide, special dietary restrictions are not necessary. Since hypersensitivity to tyramine may exist in some patients, all patients should be advised to avoid the consumption of large amounts of tyramine-rich food.
Although no interaction with alcohol has been demonstrated, it is recommended to avoid alcohol, as with any psychotropic medication.
Hypersensitivity may occur in susceptible individuals. Symptoms may include rash and edema.
Patients with hypertension should be closely monitored when being treated with moclobemide. Theoretical pharmacological considerations indicate that MAO inhibitors may precipitate a hypertensive reaction in patients with thyrotoxicosis or pheochromocytoma. As experience with moclobemide in this population group is lacking, caution should be exercised with regard to prescribing moclobemide.
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 tricyclic antidepressants (e.g. clomipramine) and selective serotonin (5-HT) reuptake inhibitors (SSRI) antidepressants (see section 4.5 Interaction with other medicinal products and other forms of interaction).
St. John’s wort (Hypericum)-containing phytotherapeutic products should be used with care in combination with moclobemide as this may increase the serotonin concentration.
As in treatment with other antidepressants, there is a risk of attempted suicide in patients suffering from depression at the start of treatment, since the compensation of the psychomotor inhibition effect may precede the anti-depression action of this medication, and patients should be closely monitored initially.
Patients should be advised to avoid sympathomimetic agents, such as ephedrine, pseudoephedrine and phenylpropanolamine (contained in many proprietary cough medicinal products).
Patients should also be advised that if they require surgery they should inform the anaesthesiologist that they take moclobemide.
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 tricyclic antidepressants (e.g. clomipramine) and selective serotonin (5-HT) reuptake inhibitors (SSRI) antidepressants (see section 4.5 Interaction with other medicinal products and other forms of interaction).
Co-administration of moclobemide and dextromethorphan, which may be contained in cough cold medicines, is not recommended (see section 4.5 Interaction with other medicinal products and other forms of interaction).
This products contains lactose, therefore it 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 Posology and method of administration).
Precautions
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.
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.
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 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.
Specific product-related information
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
Co-administration of moclobemide with selegiline (Deprenyl®) or with linezolid is contraindicated.
Co-administration of moclobemide with triptans is contraindicated, because they are potent receptor agonists and metabolised by monoamine oxidases (MAOs) and various cytochrome p450 enzymes and the plasma concentrations of the triptans increases, e.g. sumatriptan, rizatriptan, zolmitriptan, almotriptan, naratriptan, frovatriptan and eletriptan - due to the risk of hypertension or coronary artery vasoconstriction caused by combined serotonergic effects (see 4.3 Contraindications).
Moclobemide potentiates the effects of opiates such as, dextromethorphan and tramadol (see section 4.3 “Contraindications”). The combination of moclobemide with these opiates is contraindicated due to the risk of onset of a serotonin syndrome.
In animals, moclobemide potentiates the effects of opiates. Morphine, fentanyl and codeine should be used with caution. A dosage adjustment may therefore be necessary for these medicinal products.
The combination with pethidine is contra-indicated because of the increased risk of serotonergic syndrome (confusion, fever, convulsions, ataxia, hyperreflexia, myoclonus, diarrhoea).
Isolated cases of severe central nervous system adverse reactions have been reported after co-administration of Moclobemide and with dextromethorphan. Since 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 4.4. “Special warnings and precautions for use”).
Cimetidine prolongs the metabolism of moclobemide moclobemide (see section 4.2 “Posology and method of administration”). The normal dose of moclobemide should therefore be reduced to half or a third in patients taking 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 anti-depressants such as clomipramine, venlafaxine, fluvoxamine, citalopram, escitalopram, paroxetine, sertraline, bupropion. This is because in isolated cases there has been a combination of serious symptoms and signs, including hyperthermia, confusion, hyperreflexia and myoclonus, which are indicative of serotonergic overactivity. Should such combined symptoms occur, the patient should be closely observed by a physician (and if necessary hospitalized) and appropriate treatment given. Treatment with a tricyclic or other antidepressant could be initiated the next day after withdrawal of Moclobemide (i.e. without a wash-out period) and vice versa, provided similar caution is observed. When switching from a serotonin reuptake inhibitor to Moclobemide, the half-life of the former should be taken into account (see section 4.4. Special warnings and precautions for use). Generally, an interval of 14 days is recommended for switching from an irreversible MAO inhibitor to moclobemide (e.g. phenelzin, tranylcypromine) and the dose should not exceed 300 mg/day during the first week (see section 4.4. Special warnings and precautions for use).
The pharmacologic action of systemic regimens of sympathomimetic agents (epinephrine and norepinephrine) may possibly be intensified and prolonged by concurrent treatment with moclobemide, a dosage adjustment may therefore be necessary for these active substances.
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.
The daily dose of moclobemide should be reduced to half or one-third in patients whose hepatic metabolism is severely inhibited by a drug that blocks microsomal mixed function oxidase activity, such as cimetidine (see section 4.2 Posology and method of administration).
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.
At 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 hypericum perforatum (St. John’s 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 suggess 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.
4.6 Fertility, pregnancy and lactation
Pregnancy
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 possible risk to the foetus.
Breast-feeding
Since only a small amount of moclobemide passes into breast milk (approx.
1/30 of the maternal dose), the benefits of continuing drug therapyduring nursing should be 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. The individual reaction should however be monitored, especially during early treatment.
4.8 Undesirable effects
The undesirable effects during treatment with moclobemide are observed mainly during the first few weeks of treatment and regress concomitantly with improvement of the depressive episode. This is particularly true 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, restlessness, mood switches with mania or delirium.
The frequencies of adverse events are ranked according to the following: very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).
Metabolism and nutrition disorders
Rare: Decreased appetite *
Hyponatraemia
Psychiatric disorders
Very common Sleep disorder
Common: Anxiety, agitation, restlessness
Uncommon: Suicidal ideation and suicidal behaviours, Confusional
state (these have resolved quickly on discontinuation of therapy)
Rare Suicidal behaviors, delusion *
Nervous system disorders Very common: Dizziness, headache Common: Paraesthesia
Uncommon: Dysgeusia
Eye disorders
Uncommon: Visual disturbances
Vascular disorders Common: Hypotension
Uncommon: Flushing
Gastrointestinal disorders
Very common: Nausea, dry mouth
Common: Vomiting, diarrhoea, constipation
Skin and sub-cutaneous disorders Common: Rash
Uncommon: Oedema, pruritus, urticaria
Reproductive system and breast disorders Very rare: Galactorrhea
General disorders and administration site conditions Common: Irritability
Uncommon: Asthenia
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 sequelae)
* 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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9 Overdose
Signs
Experience of overdose in humans is so far limited. Generally mild and reversible sings of CNS (agitation, aggressiveness and behavioural changes) and gastro-intestinal irritation have been observed.
Management
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.
5. PHARMACOLOGICAL PROPERTIES
5.1. Pharmacodynamic Properties
Pharmacotherapeutic group. Antidepressant. ATC code: N06 AG 02
Moclobemide is an antidepressant which 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
Absorption
After oral administration, moclobemide is absorbed completely from the gastrointestinal tract into the portal blood. A first-pass effect in the liver reduces the systemically available dose fraction (bioavailability F). This reduction is more pronounced after single (F: 60%) than after multiple doses (F: 80%).
Distribution
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 albumin,
is relatively low (50%). Peak plasma concentrations are reached within one hour after administration. After multiple dosing, 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.
Biotransformation
Moclobemide is almost entirely metabolised before its 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 in vitro or animal studies occur only in very low concentrations in humans.
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 2Cl 9 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.
Elimination
Plasma clearance is approximately 20-50 1/hour, and the elimination half-life is 1-4 hours, this increases with higher doses due to saturation of the metabolic pathways.
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 that there are no special hazards for humans associated with moclobemide.
6.1 List of excipients
Lactose monohydrate
Maize starch
Sodium starch glycolate (type A)
Povidone
Magnesium stearate
Coating Macrogol Hypromellose Titanium dioxide (E171)
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 Content of Container
White opaque PVC/PVdC/Aluminium blisters.
Pack sizes: 15, 16, 20 (including samples) 28, 30, 50, 60 and 100 film-coated tablets.
Not all pack sizes may be marketed.
6.6.
Special precautions for disposal and other handlings
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Teva Pharma B.V.
Swensweg 5 2031 GA Haarlem The Netherlands
8. MARKETING AUTHORISATION NUMBER(S)
PL 14776/0061
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
11/11/2006
10 DATE OF REVISION OF THE TEXT
28/07/2015