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 2-3 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. The dose should not be raised until after the first week, as bioavailability increases during this period. Treatment should continue for at least 4-6 weeks in order to assess the efficacy of the drug.

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.

Special populations 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 Impairment Patients with reduced renal function do not require a special dose adjustment of Manerix.

g. 2 Pharmacological properties).

). 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. 4. Special warnings and precautions for use 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. 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). 5 Interaction with other medicinal products and other forms of interaction).

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.

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.

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.

5 Interaction with other medicinal products and other forms of interaction). 5). If concomitant treatment with buprenorphine is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

Symptoms of serotonin syndrome may include mental-status changes, autonomic instability, neuromuscular abnormalities, and/or gastrointestinal symptoms. If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy should be considered depending on the severity of the symptoms.

Hypersensitivity may occur in susceptible individuals. Symptoms may include rash and oedema. 8 Undesirable effects), and should be considered in all patients who develop drowsiness, confusion or convulsions while taking an antidepressant.

St John’s Wort (Hypericum) – containing phytotherapeutic products should be used with care in combination with moclobemide as this may increase the serotonin concentration. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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 Manerix 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 […]

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 the following drugs (see section

MANERIX (moclobemide) is indicated for the treatment of major depressive disorder (MDD) in adults. 1 Pediatrics  The safety and efficacy of MANERIX has not been studied in pediatric population (<18 years of age). Therefore, its use is not indicated in this population.

2 Geriatrics  No dosage adjustments are necessary in elderly patients (see 10 CLINICAL PHARMACOLOGY, Special Populations, Single and Multiple Dose).

1 Drug-Drug Interactions).  Patients with hepatic disease. 1 Drug-Drug Interactions). In patients receiving MANERIX concomitantly with cimetidine, a 50% reduction in the dosage of MANERIX may be necessary. 2 Recommended Dose and Dosage Adjustment Usual Adult Dosage The administration of MANERIX should be initiated at 300 mg daily dose (in two divided doses) and increased gradually to a maximum of 600 mg/day if needed, noting carefully the clinical response and any evidence of intolerance.

Individual patient response may allow for a reduction of the daily dose. As with other antidepressants, it should be kept in mind that there may be a lag time in therapeutic response. There is no evidence that increasing the dosage rapidly shortens this latent period and may, in fact, increase the incidence of side -effects.

3 Pharmacokinetics), the initial daily dose of 300 mg should not be increased until after this first week of therapy. g. cimetidine), the daily dose of MANERIX should be reduced to one third or one half of the standard dose. Renal Impairment Single dose pharmacokinetic data suggest that no dosage adjustment may be required in patients with impaired renal function.

However, multiple dose studies with MANERIX have not been performed in patients with renal dysfunction, therefore, MANERIX should be used with caution in this patient population. In normal volunteers, the absolute bioavailability almost doubles following multiple dosing as compared to a single dose.

Geriatrics No dosage adjustments are necessary in elderly patients. PrMANERIX® Product Monograph Page 6 of 35

2 Clinical Trial Adverse Reactions Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug .

Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use. The following table lists the adverse events reported during clinical trials in which 1,922 patients were treated with 50 to 600 mg/day MANERIX (moclobemide) for depressive illness.

Limited experience in 60 patients treated with 601 to 750 mg/day of MANERIX suggests that the incidence of adverse events may increase at higher doses. 3 Less Common Clinical Trial Adverse Reactions Other clinical adverse events with an incidence of < 1% in clinical studies, or reported in post - marketing surveillance, are as follows: PrMANERIX® Product Monograph Page 11 of 35  Psychiatric: Difficulty falling asleep, nightmares/dreams, hallucinations, memory disturbances, confusion, disorientation, delusions, increased depression, excitation/irritability, hypomanic symptoms, aggressive behaviour, apathy, tension.

Cases of suicidal ideation and suicidal behaviour have been reported during antidepressant therapy or early after treatment discontinuation (see 7 WARNINGS AND PRECAUTIONS).  Cardiovascular: Hypertension, bradycardia, extrasystoles, angina/chest pain, phlebitic symptoms, flushing.

 Central and Peripheral Nervous System: Migraine, extrapyramidal effects, tinnitus, paresthesia, dysarthria.  Dermatological/Mucocutaneous: Exanthema/rash, allergic skin reaction, itching, gingivitis, stomatitis, dry skin, conjunctivitis, pruritus, urticaria.

 Gastrointestinal: Heartburn, gastritis, meteorism, indigestion.  Genito-Urinary: Disturbances of micturition (dysuria, polyuria, tenesmus) metrorrhagia, prolonged menstruation.  Miscellaneous: General malaise, skeletal/muscular pain, altered taste sensations, hot flushes/cold sensation, photopsia, dyspnea, visual disturbances.

4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data Clinical Trial Findings Laboratory examinations were performed in a total of 1,401 patients during clinical trials with MANERIX. Reductions were observed in leucocyte, SGOT and SGPT values, however, these reductions were attributed to raised baseline values returning to normal and were not considered clinically relevant.

No other laboratory abnormalities were noted during clinical trials. 5 Post-Market Findings In post-market surveillance, there appeared to be a low incidence of raised liver enzymes, without associated clinical sequelae PrMANERIX® Product Monograph Page 12 of 35

MANERIX (moclobemide) is contraindicated:  In patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or the component of the container. For a complete listing see 6 DOSAGE FORMAS, STRENGTHS, COMPOSITION AND PACKAGING.

 In patients in an acute confusional state. 1 Drug-Drug Interactions). 1 Drug-Drug Interactions). 1 Drug-Drug Interactions).  In combination with meperidine. Although there is limited experience with the concomitant use of MANERIX and narcotics, death has occurred in patients receiving a conventional MAO inhibitor and meperidine (pethidine) given concomitantly.

1 Drug-Drug Interactions).  Concomitantly with dextromethorphan (contained in many proprietary cough medicines).  In combination with trimipramine/maprotiline.  In combination with bupropion.  In combination with triptans.  In combination with tramadol.

PrMANERIX® Product Monograph Page 5 of 35