Notes
Distributed by Medsurge Healthcare Pty Ltd.
1 Name of Medicine
Tranylcypromine (as sulfate).
2 Qualitative and Quantitative Composition
Each tablet contains 10 mg of tranylcypromine (as sulfate).
For the full list of excipients, see Section 6.1 List of Excipients.
3 Pharmaceutical Form
Tranylmed tablets are red, round, biconvex film coated tablets debossed "10" on one side.
4.1 Therapeutic Indications
Tranylmed is indicated for the treatment of symptoms of depressive illness especially where treatment with other types of antidepressants has failed. It is not recommended for use in mild depressive states resulting from temporary situational difficulties.
4.2 Dose and Method of Administration
Tranylmed tablets are for oral administration only.
Adults.
Begin with 20 mg a day - given as 10 mg in the morning and 10 mg in the afternoon.
If there is no satisfactory response after two weeks, add one more tablet at midday. Continue this dosage for at least a week. A dosage of 3 tablets a day should only be exceeded with caution, and the maximum dose should not exceed 30 mg/day. When a satisfactory response is established, dosage may be reduced to a maintenance level. Some patients will be maintained on 20 mg per day, some will need only 10 mg daily. If no improvement occurs, continued administration is unlikely to be beneficial.
When given together with a tranquilliser, the dosage of tranylcypromine sulfate is not affected. When the medicine is given concurrently with electroconvulsive therapy, the recommended dosage is 10 mg twice a day during the series and 10 mg a day afterwards as maintenance therapy.
Elderly.
See Section 4.3 Contraindications.
Paediatric population.
Tranylmed is not indicated for children under 18 years of age.4.3 Contraindications
Because the effect of many antidepressant medicines may persist for several days, do not commence tranylcypromine therapy within less than the time periods specified below, then use half the normal dosage for the first week. Similarly, allow at least a week (or longer as specified below) to elapse between the discontinuance of tranylcypromine and the administration of any other medicine that is contraindicated with tranylcypromine.
Tranylmed is contraindicated:
In patients with a known hypersensitivity to tranylcypromine or to any of the excipients.
In combination with other MAOIs.
Such as phenelzine and moclobemide, furazolidone, iproniazid, isocarboxazid, nialamide, pargyline, and procarbazine hydrochloride. Avoid for at least 2 weeks after stopping previous MAOI and then start at a reduced dose. Similarly, at least a week should elapse between the discontinuance of tranylcypromine and the administration of another MAOI, or the re-administration of tranylcypromine. Hypertensive crises or severe convulsive seizures may occur in patients receiving such combinations.
In combination with, or within 3 weeks of, clomipramine or imipramine.
Clomipramine, in combination with a MAOI, has been reported to result in hyperpyrexia, diffuse intravascular coagulation, and status epilepticus.
In combination with other dibenzazepine (tricyclic) antidepressants.
Such as amitriptyline, desipramine, dosulepin (dothiepin), nortriptyline, trimipramine and doxepin, or in combination with carbamazepine, as these combinations may induce hypertensive crises or severe convulsive seizures. Reports of hyperactivity, hypertonicity, hyperpyrexia, coma and death have been associated with the use of tranylcypromine in combination with tricyclic antidepressants. Tetracyclic antidepressants should also be avoided. After stopping tranylcypromine, do not start tricyclic-related antidepressants for 2 weeks, also MAOIs should not be started until at least 1-2 weeks (3 weeks in case of clomipramine or imipramine) after stopping tricyclic antidepressants.
In combination with sympathomimetics.
Including amphetamines, fenfluramine or similar anti-obesity agents, ephedrine, phenylpropanolamine and over-the-counter (OTC) medicines such as cold, hayfever and weight-reducing preparations that contain vasoconstrictors, as severe hypertensive reactions may result. Also, methyldopa, dopamine, levodopa and tryptophan as they may result in potentiation, precipitating hypertension, severe headache and hyperpyrexia; cerebral haemorrhage may occur. MAOIs in combination with tryptophan have been reported to cause behavioural and neurologic syndromes including disorientation, confusion, amnesia, delirium, agitation, hypomanic signs, ataxia, myoclonus, hyperreflexia, shivering, ocular oscillations and Babinski's signs. Patients must be warned against self-medication with proprietary medicines such as cold, hayfever or weight-reducing medicines that contain pressor agents.
With pethidine, closely related narcotic analgesics and nefopam.
As CNS excitation or depression, respiratory depression, hypotension or hypertension, restlessness and coma may ensue. Wait until two weeks after stopping MAOIs before starting treatment with opioid analgesics.
In combination with dextromethorphan.
The combination of MAOIs and dextromethorphan has been reported to cause brief episodes of psychosis or bizarre behaviour.
In combination with fluoxetine and other selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs).
There have been reports of serious and sometimes fatal reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation leading to delirium and coma) in patients receiving fluoxetine in combination with MAOIs and in patients who have recently discontinued fluoxetine prior to the commencement of MAOI therapy. There also have been cases presented with features resembling neuroleptic malignant syndrome. Use of MAOIs with or after fluvoxamine has been reported to produce a serotonin syndrome, sometimes fatal.
Therefore, tranylcypromine should not be used in combination with fluoxetine, or its congeners. Allow at least five weeks between discontinuation of fluoxetine and initiation with tranylcypromine, as fluoxetine and its major metabolite have very long half lives. Fluoxetine should not be given within two weeks of tranylcypromine discontinuation. Tranylcypromine should not be given together with or within two weeks of treatment with other SSRIs (e.g. paroxetine, sertraline) and SNRIs (e.g. venlafaxine).
In combination with bupropion.
The concurrent administration of bupropion and a MAOI is contraindicated. At least two weeks should elapse between discontinuation of a MAOI and initiation of treatment with bupropion.
In combination with buspirone hydrochloride.
Tranylcypromine should not be used in combination with buspirone hydrochloride since several cases of elevated blood pressure have been reported in patients taking MAOIs who were then given buspirone hydrochloride. At least 10 days should elapse between the discontinuation of tranylcypromine and the institution of buspirone HCl.
In combination with cheese or other foods with a high tyramine content.
Hypertensive crises have sometimes occurred during tranylcypromine therapy after ingestion of foods with a high tyramine content. It is therefore important that patients be told to avoid matured cheese and protein extracts such as Marmite, Vegemite, Bonox, Bovril etc. In general, the patient should avoid protein foods in which ageing or protein breakdown is used to increase flavour. Other foods to be avoided are the pods of broad beans which contain levodopa, sauerkraut, pickled herring, sour cream, soy sauce, avocado pears, yeast extracts and banana skins. Alcoholic drinks, which may contain significant amounts of tyramine, especially red wine such as Chianti, should also be avoided.
In patients with cerebrovascular or cardiovascular disease, a history of recurrent or frequent headaches, blood dyscrasias or porphyria.
Tranylcypromine should not be administered to any patient with a confirmed or suspected cerebrovascular defect or to any patient with cardiovascular disease or hypertension. Tranylcypromine should not be used in patients with known, blood dyscrasia or porphyria.
In patients with phaeochromocytoma.
Tranylcypromine should not be used in the presence of phaeochromocytoma, or if it is suspected, as such tumours secrete pressor substances.
In patients with hyperthyroidism.
These patients have increased sensitivity to pressor amines.
In the elderly.
Tranylcypromine should not be administered to any patient beyond 60 years of age because of the possibility of existing cerebral sclerosis with damaged blood vessels.
In patients with impaired hepatic function.
Tranylcypromine should not be used in patients with a history of liver disease or in those with abnormal liver function tests.4.4 Special Warnings and Precautions for Use
Like all powerful medicines tranylcypromine may occasionally provoke serious adverse effects. If patients are kept under regular and frequent observation, the medicine can be stopped should any adverse effects occur. It is important for the physician to be fully aware of the adverse effects, contraindications and precautions described in the prescribing information.
Identified precautions.
Clinical worsening and suicide risk.
The risk of suicide attempt is inherent in depression and may persist until significant remission occurs. Patients with depression may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviour (suicidality), whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs.
The risk is increased in patients less than 25 years old. As improvement may not occur during the first few weeks or more of treatment, all patients should be closely monitored for clinical worsening of suicidality, especially at the beginning of a course of treatment, or at the time of dose changes, either increases or decreases. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistent or whose emergent suicidality is severe, abrupt in onset or was not part of the patient's presenting symptoms.
Patients (and caregivers of patients) should be alerted about the need to monitor for any worsening of their condition and/or the emergence of suicidal ideation/behaviour or thoughts of harming themselves, and to seek medical advice immediately if these symptoms present. Patients with co-morbid depression associated with other psychiatric disorders being treated with antidepressants should be similarly observed for clinical worsening and suicidality. Pooled analyses of 24 short-term (4 - 16 weeks), placebo-controlled trials of nine antidepressant medicines (SSRIs and others) in 4,400 children and adolescents with major depressive disorders (16 trials), obsessive compulsive disorder (4 trials), or other psychiatric disorders (4 trials) have revealed a greater risk of adverse events representing suicidal behaviour or thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients treated with an antidepressant was 4%, compared with 2% of patients given placebo. There was considerable variation in risk among the antidepressants, but there was a tendency towards an increase for almost all antidepressants studied. The risk of suicidality was most consistently observed in the major depressive disorder trials, but there were signals of risk arising from trials in other psychiatric indications (obsessive compulsive disorders and social anxiety disorder) as well. No suicides occurred in these trials. It is unknown whether the suicidality risk in children and adolescent patients extends to use beyond several months. The nine antidepressant medicines in the pooled analyses included five SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) and four non-SSRIs (bupropion, mirtazapine, nefazodone, venlafaxine).
Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond the age of 24 years, and there was a reduction with antidepressants compared to placebo in adults aged 65 years and older. Symptoms of anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adults, adolescents and children being treated with antidepressants for major depressive disorders as well as for other indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such symptoms and either worsening of depression and/or emergence of suicidal impulses has not been established, there is concern that such symptoms may be precursors of emerging suicidality.
Families and caregivers of patients being treated with antidepressants for major depressive disorders or for any other condition (psychiatric or non-psychiatric) should be informed about the need to monitor these patients for the emergence of agitation, irritability, unusual changes in behaviour, and other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. It is particularly important that monitoring be undertaken during the initial few months of antidepressant treatment or at times of dose increase or decrease.
Prescriptions for tranylcypromine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Mania and bipolar disorder.
A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with any antidepressant alone may increase the likelihood of a mixed/manic episode in patients at risk for bipolar disorder. Prior to initiating treatment with an antidepressant, patients should be adequately screened to determine if they are at risk for bipolar disorder. It should be noted that tranylcypromine is not approved for use in treating bipolar depression.
Caution is required when giving tranylcypromine in the following conditions:
Diabetes.
Some MAOIs have contributed to hypoglycaemic episodes in diabetic patients receiving insulin or oral hypoglycaemic agents. Tranylcypromine should therefore be used with caution in diabetics under treatment with these medicines.
Epileptic patients.
Because the influence of tranylcypromine on the convulsive threshold is variable in animal experiments, suitable precautions should be taken if epileptic patients are treated with tranylcypromine.
Surgery.
Although excretion of tranylcypromine is rapid, it is advisable wherever possible to discontinue tranylcypromine therapy at least two weeks before surgery, because of possible interference with the action of certain anaesthetics and analgesics. Patients taking MAOIs should not be given cocaine or local anaesthesia containing vasoconstrictors. The possible combined hypotensive effects of MAOIs and spinal anaesthesia should be kept in mind.
Patients with angina.
MAOIs have the capacity to suppress anginal pain that would otherwise serve as a warning of myocardial ischaemia.
Patients with a history of drug or alcohol dependence.
Angle-closure glaucoma.
Antidepressants including tranylcypromine may have an effect on pupil size resulting in mydriasis. This mydriatic effect has the potential to narrow the eye angle resulting in increased intraocular pressure and angle-closure glaucoma, especially in pre-disposed patients. Tranylcypromine should therefore be used with caution in patients with raised intraocular pressure and in those at risk of angle-closure glaucoma.
Stopping treatment.
Tranylcypromine therapy should be withdrawn gradually to reduce the risk of withdrawal symptoms (see Section 4.8 Adverse Effects (Undesirable Effects)).
Use in hepatic impairment.
See Section 4.3 Contraindications.
Use in renal impairment.
There is a possibility of cumulative effects in patients with impaired renal function.
Use in the elderly.
See Section 4.3 Contraindications.
Paediatric use.
The safety and efficacy of tranylcypromine for the treatment of depression or other psychiatric disorders in children and adolescents aged less than 18 years has not been satisfactorily established. Tranylcypromine should not be used in this age group for the treatment of depression or other psychiatric disorders.
Effects on laboratory tests.
No data available.4.5 Interactions with Other Medicines and Other Forms of Interactions
Patients should be specifically asked if they are taking any other medication because of the possibility of drug interactions.
See Section 4.3 Contraindications for medicines that should not be taken with tranylcypromine. Exercise caution when giving tranylcypromine with the following medicines:
Guanethidine.
As its action may be antagonised.
Reserpine.
As hyperactivity may occur.
Other hypotensive agents.
Because of the possibility of additive hypotensive effects.
Barbiturates, and possibly other hypnotics, and antimuscarinic agents.
As their action may be prolonged or potentiated.
Anti-parkinsonism agents.
As the combination may result in potentiation, with profuse sweating, tremulousness, and rise in body temperature.
Anticoagulants.
As some animal studies have suggested that the effect of anticoagulants may be potentiated if a MAOI is given concurrently. One suspected case of potentiation has been reported in man.
Oral hypoglycaemic agents or insulin.
As their action may be potentiated.
Metrizamide.
Should be avoided since it may lower the seizure threshold.
Antiepileptics.
Since MAOIs possibly antagonise anticonvulsant effects of antiepileptics (convulsive threshold lowered).
Antihistamines.
Since antimuscarinic and sedative effects of antihistamines are increased by MAOIs.
Patients should be advised not to consume excessive amounts of caffeine in any form. See Section 4.3 Contraindications for other foods and drinks to avoid while taking tranylcypromine.4.6 Fertility, Pregnancy and Lactation
Effects on fertility.
No data available.
(Category B2)
Adequate human data on use during pregnancy and adequate animal reproduction data are not available. Tranylcypromine should not be used in pregnancy unless considered essential by the physician.
Use of any medicine in pregnancy requires that the potential benefits of the medicine be weighed against its possible hazards to mother and child. Animal reproductive studies show that tranylcypromine passes through the placental barrier into the foetus of the rat. Epidemiological studies have suggested an increased risk of congenital abnormalities associated with use of antidepressants in pregnancy.
Neonates exposed to antidepressants late in the third trimester have shown drug withdrawal symptoms such as dyspnoea, lethargy, colic irritability, hypotension or hypertension and tremor or spasms.
Epidemiological data suggests that the use of antidepressants in pregnancy may be associated with an increase in pre-term delivery.
Adequate human data on use during lactation and adequate animal reproduction data are not available. Tranylcypromine is secreted into breast milk of lactating mothers but the clinical significance of this has not been fully evaluated.
Therefore, tranylcypromine should be used in lactating women only if clearly needed and if the potential benefits justify the potential risk.4.7 Effects on Ability to Drive and Use Machines
Tranylcypromine may affect the ability to drive or operate machinery.
Tranylcypromine may cause dizziness and drowsiness. Patients should be advised not to drive a vehicle or operate machinery if they are affected. Avoid alcohol, see Section 4.3 Contraindications.
4.8 Adverse Effects (Undesirable Effects)
The most important adverse effect associated with tranylcypromine is the occurrence of hypertensive crises which have sometimes been fatal.
Cases of sudden paroxysmal rise in blood pressure have occurred, notably in association with foods containing tyramine. These crises are characterised by some or all of the following symptoms: occipital headache which may radiate frontally, palpitation, neck stiffness or soreness, multiple extrasystoles, often with substernal pain, nausea or vomiting, sweating with early pallor, sometimes followed later by flushing. Either tachycardia or bradycardia may be present; and associated mydriasis, angle-closure glaucoma and photophobia may also occur. Throbbing headache may be an early warning of hypertensive crisis. This headache, together with pain and stiffness in the cervical muscles, may mimic subarachnoid haemorrhage, but can equally be associated with actual intracranial bleeding, as in other conditions where a sudden rise in blood pressure occurs. Cases of such bleeding have been reported, some of which have been fatal.
Therapy should be discontinued immediately upon the occurrence of palpitation or frequent headache during tranylcypromine therapy. These signs may be prodromal of a hypertensive reaction. Patients should be instructed to report promptly the occurrence of headache or other symptoms.
Recommended treatment in hypertensive reactions.
If a hypertensive reaction occurs, tranylcypromine should be discontinued and therapy to lower blood pressure should be instituted immediately, if indicated. Headache tends to abate as blood pressure falls. On the basis of present evidence, phentolamine is recommended (the dosage reported for phentolamine is 5 mg i.v.). Reserpine should not be used. Care should be taken to administer phentolamine slowly in order to avoid producing an excessive hypotensive effect. Fever should be managed by means of external cooling. Other symptomatic and supportive measures may be desirable in particular cases. Acute symptoms generally subside within 24 hours.
Other side effects.
The most frequently seen side effect is insomnia, which can usually be overcome by giving the last dose of the day not later than 3 pm, by reducing the dose, or by prescribing a mild hypnotic. Occasional cases of dizziness, palpitation, weakness, fatigue, dry mouth and drowsiness have been reported, as have nausea, vomiting, diarrhoea, abdominal pain, constipation, sleep disturbances and skin rash. Most of these effects can be relieved by lowering the dosage or by giving suitable concomitant medication.
Palpitations or unusually frequent headaches, unaccompanied by paroxysmal hypertension, may possibly be dose-related in some patients. Such symptoms may respond to reduction of dosage. If improvement is not rapid, the medicine should be discontinued.
Hypotension, which may be postural, has been observed during tranylcypromine therapy. Syncope has been rarely seen. Dosage should not be increased in the presence of hypotension. This adverse effect is usually temporary, but if it persists, the medicine should be discontinued. The blood pressure will then return rapidly to pre-treatment level.
Tachycardia, significant anorexia, oedema, blurred vision, chills and impotence have each been reported.
Impaired water excretion compatible with the syndrome of inappropriate antidiuretic hormone (ADH) secretion (SIADH) has been reported.
Overstimulation, which may include increased anxiety and agitation, and manic symptoms, may sometimes occur with normal dosage but is more commonly associated with overdosage. Reduction of the dose is indicated. In certain instances it may be helpful to administer a sedative phenothiazine tranquilliser, such as chlorpromazine, concomitantly.
There is a risk of dependency development, with tolerance to high doses, which can occur in patients without past history of drug dependence. This should be distinguished from the return of features of the original illness on cessation of treatment. Withdrawal symptoms may be anticipated.
Rare instances of hepatitis, hepatocellular damage, jaundice, hallucinations and blood dyscrasias have been reported.
Tinnitus, muscle spasm, tremors, myoclonic jerks, numbness, paraesthesia, urinary retention and retarded ejaculation have been reported.
Haematological disorders including anaemia, leukopenia, agranulocytosis and thrombocytopenia have been reported.
Cases of suicidal ideation and suicidal behaviours have been reported during tranylcypromine therapy or early after treatment discontinuation (see Section 4.4 Special Warnings and Precautions for Use).
Reporting suspected adverse effects.
Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.4.9 Overdose
Symptoms.
The characteristic symptoms that may be caused by overdosage are usually those described under Section 4.8 Adverse Effects (Undesirable Effects). Tachycardia, sweating and hyperpyrexia with restlessness and excitement are usually produced. Tremor, convulsions, depression, stupor or coma may however be present or develop. Blood pressure may be raised, but hypotension may supervene.
Treatment.
Treatment should normally consist of general supportive measures, close observation of vital signs and steps to counteract specific symptoms as they occur since MAO inhibition may persist. The management of hypertensive reactions is described under Section 4.8 Adverse Effects (Undesirable Effects).
External cooling is recommended if hyperpyrexia occurs. Barbiturates have been reported to help myoclonic reactions, but frequency of administration should be controlled carefully because tranylcypromine may prolong barbiturate activity. When hypotension requires treatment, the standard measures for managing circulatory shock should be initiated. If pressor agents are required, noradrenaline is the most suitable; however, its action may be potentiated, and the rate of infusion should be regulated by careful observation of the patient. Metaraminol may be required if marked refractory hypotension occurs (left ventricular failure should be excluded).
A successful recovery following haemodialysis after a self-administered overdosage of 350 mg of tranylcypromine has been reported.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).5 Pharmacological Properties
5.1 Pharmacodynamic Properties
Mechanism of action.
Tranylcypromine is a non-hydrazine monoamine oxidase inhibitor (MAOI) with a rapid onset of activity. It increases the concentration of adrenaline (epinephrine), noradrenaline (norepinephrine), and serotonin in storage sites throughout the nervous system, and in theory, this increased concentration of monoamines in the brainstem is the basis for its antidepressant activity. When tranylcypromine is withdrawn, monoamine oxidase activity is recovered in 3 to 5 days, although the drug is excreted in 24 hours.
Clinical trials.
No data available.
5.2 Pharmacokinetic Properties
No data available.
5.3 Preclinical Safety Data
Genotoxicity.
No data available.
Carcinogenicity.
No data available.6 Pharmaceutical Particulars
6.1 List of Excipients
Tranylmed tablets contain: microcrystalline cellulose, pregelatinised maize starch, colloidal anhydrous silica, magnesium stearate, Opadry II complete film coating system 85F250100 red (polyvinyl alcohol, macrogol 4000, purified talc, allura red AC aluminium lake, titanium dioxide, carmine).
6.2 Incompatibilities
Incompatibilities were either not assessed or not identified as part of the registration of this medicine. See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions for details.
6.3 Shelf Life
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
6.4 Special Precautions for Storage
Store below 25°C.
6.5 Nature and Contents of Container
PA/Al/PVC/Al - polyamide-aluminium foil-polyvinylchloride/aluminium foil blister packs of 50 tablets.
6.6 Special Precautions for Disposal
In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.
6.7 Physicochemical Properties
Chemical structure.
Name: (1RS,2SR)-2-phenyl-cyclopropylamine sulfate.
Molecular formula: (C9H11N)2.H2SO4.
Molecular weight: 364.5.
Tranylcypromine sulfate is a white or almost white, crystalline powder, soluble in water, very slightly soluble in ethanol (96%) and in ether.
CAS number.
13492-01-8.7 Medicine Schedule (Poisons Standard)
Schedule 4 Prescription Only Medicine.
Summary Table of Changes
