It is recommended that you also refer to http://www.medicines.ie as the Summary of Product Characteristics may have been updated since this copy was printed.

SANOFI

SANOFI

Summary of Product Characteristics last updated on medicines.ie: 11/5/2015

Molipaxin 100mg Capsules

1. NAME OF THE MEDICINAL PRODUCT

Molipaxin 100mg Capsules.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 100mg trazodone hydrochloride.

Excipient: Contains 159mg lactose monohydrate.

For a full list of excipients, see section 6.1

3. PHARMACEUTICAL FORM

Capsule, hard.

Size No. 2 opaque violet/fawn hard gelatin capsules having the code 'R365C' imprinted on one piece, the Roussel logo on the other piece and containing a white powder.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

For oral administration

Indications for use

Relief of symptoms in all types of depression including depression accompanied by anxiety.

4.2 Posology and method of administration

Recommended Dosage

Adults Only:

According to severity, treatment should be initiated at 75 to 150mg per day as a single evening dose and then increased to 200 or 300mg per day, respectively, at the end of the first week. In hospitalised patients with exceptionally severe depression, dosage may be further increased to a maximum of 600mg per day in divided doses.

The Elderly:

For very elderly or frail patients, the recommended initial dose is reduced to 100 mg a day, administered in divided doses or as a single night time dose (See section 4.4). This may be incrementally increased, as described under Adults, under supervision, according to tolerance and efficacy. In general, single doses above 100 mg should be avoided in these patients. It is unlikely that a dose of 300 mg per day will be exceeded.

Children:

Trazodone is not recommended for use in children below the age of 18 years due to a lack of data on safety.

Decrease of the side-effects (increase of the resorption and decrease of the peak plasma concentration) can be reached by taking trazodone hydrochloride after a meal.

Hepatic Impairment:

Trazodone undergoes extensive hepatic metabolism, see section 5.2, and has also been associated with hepatotoxicity, see sections 4.4 and 4.8. Therefore caution should be exercised when prescribing for patients with hepatic impairment, particularly in cases of severe hepatic impairment. Periodic monitoring of liver function may be considered.

Renal Impairment:

No dosage adjustment is usually necessary, but caution should be exercised when prescribing for patients with severe renal impairment (see also section 4.4 and 5.2).

4.3 Contraindications

Known sensitivity to Trazodone or any of the excipients

Alcohol intoxication and intoxication with hypnotics.

Acute myocardial infarction.

4.4 Special warnings and precautions for use

Use in children and adolescents under the age of 18

Trazodone should not be used in the treatment of depression in children and adolescents under the age of 18 years. Studies with other classes of antidepressants have shown a risk of suicidality, self-harm and hostility to be related to the compounds. This risk cannot be excluded in Trazodone. Furthermore, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are not available.

Elderly

Elderly patients may more often experience orthostatic hypotension, somnolence and other anticholinergic effects of trazodone. Careful consideration should be given to the potential for additive effects with concomitant medication use such as with other psychotropics or antihypertensives or in the presence of risk factors such as comorbid disease, which may exacerbate these reactions. It is recommended that the patient/carer is informed of the potential for these reactions and monitored closely for such effects following initiation of therapy, prior to and following upward dose titration.

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 Molipaxin 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 close 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.

To minimise the potential risk of suicide attempts, particularly at therapy initiation, only restricted quantities of trazodone should be prescribed at each occasion.

It is recommended that careful dosing and regular monitoring is adopted in patients with the following conditions:

• Epilepsy, specifically abrupt increases or decreases of dosage should be avoided

• Patients with hepatic or renal impairment, particularly if severe

• Patients with cardiac disease, such as angina pectoris, conduction disorders or AV blocks of different degree, recent myocardial infarction

• Hyperthyroidism

• Micturition disorders, such as prostate hypertrophy, although problems would not be anticipated as the anticholinergic effect of trazodone is only minor

• Acute narrow angle glaucoma, raised intra-ocular pressure, although major changes would not be anticipated due to the minor anticholinergic effect of trazodone .

Administration of antidepressants in patients with schizophrenia or other psychotic disorders may result in a possible worsening of psychotic symptoms. Paranoid thoughts may be intensified. During therapy with trazodone a depressive phase can change from a manic – depressive psychosis into a manic phase. In that case trazodone must be stopped.

Interactions in terms of serotonine syndrome/malignant neuroleptic syndrome have been described in case of concomitant use of other serotonergically acting substances like other antidepressants (e.g. tricyclic antidepressants, SSRI's, SNRI's and MAO-inhibitors) and neuroleptics. Malignant neuroleptic syndromes with fatal outcome have been reported in cases of coadministration with neuroleptics, for which this syndrome is a known possible adverse drug reaction. See Sections 4.5 and 4.8 for further information.

Severe hepatic disorders with potential fatal outcome have been reported with trazodone use (see adverse reaction section). Patients should be instructed to report immediately signs such as asthenia, anorexia, nausea, vomiting, abdominal pain or icterus to a physician. Investigations including clinical examination and biological assessment of liver function should be undertaken immediately and withdrawal of trazodone therapy be considered.

Should jaundice occur in a patient, trazodone therapy must be withdrawn.

Since agranulocytosis may clinically reveal itself with influenza-like symptoms, sore throat, and fever, in these cases it is recommended to check haematology.

Hypotension, including orthostatic hypotension and syncope, has been reported to occur in patients receiving trazodone. Concomitant administration of antihypertensive therapy with trazodone may require a reduction in the dose of the antihypertensive drug.

Following therapy with trazodone, particularly for a prolonged period, an incremental dosage reduction to withdrawal is recommended, to minimise the occurrence of withdrawal symptoms, characterised by nausea, headache, and malaise.

There is no evidence that trazodone hydrochloride possesses any addictive properties.

As with other antidepressant drugs, cases of QT interval prolongation have been reported with trazodone very rarely. Caution is advised when prescribing trazodone with medicinal products known to prolong QT interval. Trazodone should be used with caution in patients with known cardiovascular disease including those associated with prolongation of the QT interval.

Potent CYP3A4 inhibitors may lead to increases in trazodone serum levels. See Section 4.5 for further information.

As with other drugs with alpha-adrenolytic activity, trazodone has very rarely been associated with priapism. This may be treated with an intracavernosum injection of an alpha-adrenergic agent such as adrenaline or metaraminol. However there are reports of trazodone-induced priapism which have required surgical intervention or led to permanent sexual dysfunction. Patients developing this suspected adverse reaction should cease trazodone immediately.

Undesirable effects may be more common during concomitant use of trazodone and herbal preparations containing St. John's wort (Hypericum perforatum).

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

General: The sedative effects of antipsychotics, hypnotics, sedatives, anxiolytics, and antihistaminic drugs may be intensified; dosage reduction is recommended in such instances.

The metabolism of antidepressants is accelerated due to hepatic effects by oral contraceptives, phenytoin, carbamazepine and barbiturates. The metabolism of antidepressants is inhibited by cimetidine and some other antipsychotics.

CYP3A4 inhibitors: Drug metabolism studies in vitro are indicative that there is a potential for drug interactions when trazodone is given with potent CYP3A4 inhibitors such as erythromycin, ketoconazole, itraconazole, ritonavir, indinavir, and nefazodone. It is likely that potent CYP3A4 inhibitors may lead to substantial increases in trazodone plasma concentrations. It has been confirmed in in- vivo-studies in healthy volunteers, that a ritonavir dose of 200 mg BID increased the plasma levels of trazodone by greater than twofold, leading to nausea, syncope and hypotension. If trazodone is used with a potent CYP3A4 inhibitor, a lower dose of trazodone should be considered. However, co-administration of trazodone and potent CYP3A4 inhibitors should be avoided where possible.

Carbamazepine: Co-administration results in reduced plasma concentrations of trazodone. Concomitant use of carbamazepine 400 mg daily led to a decrease of plasma concentrations of trazadone and its active metabolite m-chlorophenylpiperazine of 76 % and 60 %, respectively. Patients should be closely monitored to ascertain if an increased trazodone dosage is required.

Tricyclic antidepressants: concurrent administration should be avoided due to the risk of interaction. Serotonine syndrome and cardiovascular side effects should be bewared.

Fluoxetine: rare cases have been reported of elevated trazodone plasma levels and adverse effects when trazodone had been combined with fluoxetine, a CYP1A2/2D6 inhibitor. The mechanism underlying a pharmacokinetic interaction is not fully understood. A pharmacodynamic interaction (serotonine syndrome) could not be excluded.

Monoamine oxidase inhibitors: Possible interactions with monoamine oxidase inhibitors have occasionally been reported. Although some clinicians do give both concurrently, use of trazodone concomitantly with MAOIs, or within two weeks from discontinuation of these substances, is not recommended. The administration of MAOIs within one week since discontinuation of trazodone treatment is not recommended either.

Phenothiazines: Severe orthostatic hypotension has been observed in case of concomitant use of phenothiazines, like e.g. chlorpromazine, fluphenazine, levomepromazine, perphenazine.

Anaesthetics/muscle relaxants: Trazodone hydrochloride may enhance the effects of muscle relaxants and volatile anaesthetics, and caution should be exercised in such instances.

Alcohol: Trazodone intensifies the sedative effects of alcohol. Alcohol should be avoided during trazodone therapy.

Levodopa: Antidepressants can accelerate the metabolism of levodopa.

Other

Concomitant use of Trazodone with drugs known to prolong the QT interval may increase the risk of ventricular arrhythmias, including torsade de pointes. Caution should be used when these drugs are coadministered with trazodone.

Since trazodone is only a very weak inhibitor of noradrenaline re-uptake and does not modify the blood pressure response to tyramine, interference with the hypotensive action of guanethidine-like compounds is unlikely. However, studies in laboratory animals suggest that trazodone may inhibit most of the acute actions of clonidine. In the case of other types of antihypertensive drug, although no clinical interactions have been reported, the possibility of potentiation should be considered.

Undesirable effects may be more frequent when trazodone is administered together with preparations containing Hypericum perforatum.

There have been reports of changes in prothrombin time in patients concomitantly receiving trazodone and warfarin.

Concurrent use with trazodone may result in elevated serum levels of digoxin or phenytoin.

Monitoring of serum levels should be considered in these patients.

4.6 Fertility, pregnancy and lactation

Trazodone should only be administered during pregnancy or lactation if considered essential by the physician.

Pregnancy:

Data on a limited number (< 200) of exposed pregnancies indicate no adverse effects of trazodone on pregnancy or on the health of the foetus/newborn child. To date, no other relevant epidemiological data area available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development at therapeutic doses (see section 5.3).

Caution should be exercised when prescribing to pregnant women. When trazodone is used until delivery, newborns should be monitored for the occurrence of withdrawal symptoms.

Lactation:

Limited data indicate that excretion of trazodone in human breast milk is low, but levels of the active metabolite are not known. Due to the paucity of data, a decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with trazodone should be made taking into account the benefit of breast-feeding to the child and the benefit of trazodone therapy to the woman.

4.7 Effects on ability to drive and use machines

Trazodone has minor or moderate influence on the ability to drive and use machines.

Patients should be cautioned against the risks of driving or operating machinery until they are sure they are not affected by drowsiness, sedation, dizziness, confusional states, or blurred vision.

4.8 Undesirable effects

Cases of suicidal ideation and suicidal behaviours have been reported during trazodone therapy or early after treatment discontinuation (see Section 4.4).

The following symptoms, some of which are commonly reported in cases of untreated depression, have also been recorded in patients receiving trazodone therapy.

MedDRA System Organ Class

Frequency not known (cannot be estimated from the available data)

Blood and the lymphatic system disorders

Blood dyscrasias (including agranulocytosis, thrombocytopenia, eosinophilia, leucopenia and anaemia)

Immune system disorders

Allergic reactions

Endocrine disorders

Syndrome of Inappropriate Antidiuretic Hormone Secretion

Metabolism and nutrition disorders

Hyponatraemia4, weight loss, anorexia, increased appetite,

Psychiatric disorders

Suicidal ideation or suicidal behaviours5, confusional state, insomnia, disorientation, mania, anxiety, nervousness, agitation

(very occasionally exacerbating to delirium), delusion, aggressive reaction, hallucinations, nightmares, libido decreased, withdrawal syndrome

Nervous system disorders

Serotonin syndrome, convulsion, neuroleptic malignant syndrome, dizziness, vertigo, headache, drowsiness6, restlessness, decreased alertness, tremor, blurred vision, memory disturbance, myoclonus, expressive aphasia, paraesthesia, dystonia, taste altered

Cardiac disorders

Cardiac arrhythmias7 (including Torsade de Pointes, palpitations, premature ventricular contractions, ventricular couplets, ventricular tachycardia), bradycardia, tachycardia, ECG abnormalities (QT prolongation)2

Vascular disorders

Ortostatic hypotension, hypertension, syncope

Respiratory, thoracic and mediastinal disorders

Nasal congestion, dyspnoea

Gastrointestinal disorders

Nausea, vomiting, dry mouth, constipation, diarrhoea, dyspepsia, stomach pain, gastroenteritis, increased salivation, paralytic ileus

Hepato-biliary disorders

Severe hepatic disorders such as hepatitis/fulminant hepatitis, hepatic failure with potential fatal outcome.

Hepatic function abnormalities (including jaundice and hepatocellular damage)8 , cholestasis intrahepatic

Skin and subcutaneous tissue disorders

Skin rash, pruritus, hyperhidrosis

Musculoskeletal and connective tissue disorders

Pain in limb, back pain, myalgia, arthralgia

Renal and urinary disorders

Micturition disorders

Reproductive system and breast disorders

Priapism9

General disorders and administration site conditions

Weakness, oedema, influenza-like symptoms, fatigue, chest pain, fever

Investigations

Elevated liver enzymes

4 Fluid and electrolyte status should be monitored in symptomatic patients.

5 See also Section 4.4.

6 Trazodone is a sedative antidepressant and drowsiness, sometimes experienced during the first days of treatment, usually disappears on continued therapy.

7 Studies in animals have shown that trazodone is less cardiotoxic than the tricyclic antidepressants, and clinical studies suggest that the drug may be less likely to cause cardiac arrhythmias in man. Clinical studies in patients with pre-existing cardiac disease indicate that trazodone may be arrhythmogenic in some patients in that population.

8 Adverse effects on hepatic function, sometimes severe, have been rarely reported. Should such effects occur, trazodone should be immediately discontinued.

9 See also Section 4.4

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

4.9 Overdose

Features of toxicity

The most frequently reported reaction to overdose have included drowsiness, dizziness, nausea and vomiting. In more serious cases coma, tachycardia, hypotension, hyponatraemia, convulsions and respiratory failure have been reported. Cardiac features may include bradycardia, QT prolongation and torsade de pointes. Symptoms may appear 24 hours or more after overdose.

Overdoses of Trazodone in combination with other antidepressants may cause serotonin syndrome.

Management

There is no specific antidote to trazodone. Activated charcoal should be considered in adults who have ingested more than 1 g trazodone, or in children who have ingested more than 150 mg trazodone within 1 hour of presentation. Alternatively, in adults, gastric lavage may be considered within 1 hour of ingestion of a potentially life-threatening overdose.

Observe for at least 6 hours after ingestion (or 12 hours if a sustained release preparation has been taken). Monitor BP, pulse and GCS. Monitor oxygen saturation if GCS is reduced. Cardiac monitoring is appropriate in symptomatic patients.

Single brief convulsions do not require treatment. Control frequent or prolonged convulsions with intravenous diazepam (0.1 – 0.3mg/kg/bodyweight) or lorazepam (4mg in an adult and 0.5mg/kg in a child). If these measures do not control the fits, an intravenous infusion of phenytoin may be useful. Give oxygen and correct acid base and metabolic disturbances as required.

Treatment should be symptomatic and supportive in the case of hypotension and excessive sedation. If severe hypotension persists consider use of inotropes, e.g. dopamine or dobutamine

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Molipaxin is a potent antidepressant. It also has anxiety reducing activity. Molipaxin is a triazolopyridine derivative chemically unrelated to known tricyclic, tetracyclic and other anti-depressant agents. It has negligible effect on noradrenaline re-uptake mechanisms. Whilst the mode of action of Molipaxin is not known precisely, its antidepressant activity may concern noradrenergic potentiation by mechanisms other than uptake blockade. A central anti-serotonin effect may account for the drug's anxiety reducing properties.

5.2 Pharmacokinetic properties

Trazodone is rapidly absorbed from the gastro-intestinal tract and extensively metabolised. Paths of metabolism of Trazodone include n-oxidation and hydroxylation. The metabolic m-chlorophenylpiperazine is active. Trazodone is excreted in the urine almost entirely in the form of its metabolites, either in free or in conjugated form. The elimination of Trazodone is biphasic, with a terminal elimination half-life of 5-13 hours. Trazodone is excreted in breast milk.

There was an approximate two-fold increase in terminal phase half-life and significantly higher plasma concentrations of Trazodone in 10 subjects aged 65 to 74 years compared with 12 subjects aged 23 to 30 years following a 100mg dose of Trazodone. It was suggested that there is an age-related reduction in the hepatic metabolism of Trazodone.

In vitro studies in human liver microsomes show that trazodone is mainly metabolised by cytochrome P4503A4 (CYP3A4).

5.3 Preclinical safety data

Not applicable.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose Monohydrate

Magnesium Stearate

Gelatin

Titanium dioxide (E171)

Erythrosine (E127)

Indigo carmine (E132)

Red Iron Oxide (E172)

Yellow Iron Oxide (E172)

Printing Ink

Shellac

Propylene glycol

Black Iron Oxide (E172)

Ammonium Hydroxide Or Potassium Hydroxide and Ammonia Solution

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 25°C. Store in the original package.

6.5 Nature and contents of container

Amber glass bottle with jay-cap closure containing 100 capsules.

PVdC coated 250 µm PVC blister pack sealed with 20µm aluminium foil containing 56 or 100 capsules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. MARKETING AUTHORISATION HOLDER

sanofi-aventis Ireland Ltd., T/A SANOFI

Citywest Business Campus,

Dublin 24.

8. MARKETING AUTHORISATION NUMBER(S)

PA 540/56/2

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

2 February 1977/2 February 2007

10. DATE OF REVISION OF THE TEXT

21 April 2015.

It is recommended that you also refer to http://www.medicines.ie as the Summary of Product Characteristics may have been updated since this copy was printed.