Parnate Product Monograph

Recent Major Label Changes

Table of Contents

Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

Recent Major Label Changes ................................................................................................... 2

Table of Contents ................................................................................................................... 2

Part 1: Healthcare Professional Information ........................................................................... 5

1. 1.

   Indications ....................................................................................................................... 5

   1.1. Pediatrics .................................................................................................................. 5

   1.2. Geriatrics .................................................................................................................. 5

2. 2. Contraindications ............................................................................................................ 5
3. 3. Serious Warnings and Precautions Box ............................................................................ 6
4. 4.

   Dosage and Administration ............................................................................................. 6

   4.1. Dosing Considerations .............................................................................................. 6

   4.2. Recommended Dose and Dosage Adjustment ......................................................... 6

   4.2.1. Discontinuing Treatment ................................................................................. 7

   4.4. Administration .......................................................................................................... 7

   4.5. Missed Dose ............................................................................................................. 7

5. 5. Overdose ......................................................................................................................... 7
6. 6. Dosage Forms, Strengths, Composition, and Packaging ................................................... 8
7. 7.

   Warnings and Precautions ............................................................................................... 8

   Cardiovascular ...................................................................................................................... 8

   Dependence, Tolerance and/or Abuse Liability .................................................................... 9

   Driving and Operating Machinery ......................................................................................... 9

   Endocrine and Metabolism ................................................................................................. 10

   Hematologic ....................................................................................................................... 10

   Hepatic/Biliary/Pancreatic .................................................................................................. 10

   Immune .............................................................................................................................. 10

   Monitoring and Laboratory Tests ....................................................................................... 10

   Neurologic .......................................................................................................................... 10

   Ophthalmologic .................................................................................................................. 11

   Perioperative Considerations ............................................................................................. 11

   Psychiatric ........................................................................................................................... 11

   Renal ................................................................................................................................... 13

   7.1. Special Populations ................................................................................................ 13

   7.1.1. Pregnancy ...................................................................................................... 13

   7.1.2. Breastfeeding ................................................................................................ 13

   7.1.3. Pediatrics ....................................................................................................... 13

   7.1.4. Geriatrics ....................................................................................................... 13

8. 8.

   Adverse Reactions ......................................................................................................... 13

   8.1. Adverse Reaction Overview .................................................................................... 13

   8.5. Post-Market Adverse Reactions ............................................................................. 13

9. 9.

   Drug Interactions ........................................................................................................... 14

   9.1. Serious Drug Interactions ....................................................................................... 14

   9.2. Drug Interactions Overview .................................................................................... 15

   9.4. Drug-Drug Interactions ........................................................................................... 15

   9.5. Drug-Food Interactions........................................................................................... 17

   9.6. Drug-Herb Interactions ........................................................................................... 18

   9.7. Drug-Laboratory Test Interactions ......................................................................... 18

10. 10.

    Clinical Pharmacology ................................................................................................... 18

    10.1. Mechanism of Action .............................................................................................. 18

    10.2. Pharmacodynamics ................................................................................................ 19

    10.3. Pharmacokinetics ................................................................................................... 19

11. 11. Storage, Stability, and Disposal ...................................................................................... 19

Part 2: Scientific Information ................................................................................................ 20

1. 13. Pharmaceutical Information .......................................................................................... 20
2. 14. Clinical Trials .................................................................................................................. 20
3. 16. Non-Clinical Toxicology .................................................................................................. 20

Patient Medication Information ........................................................................................... 21

Part 1: Healthcare Professional Information

1. Indications

PARNATE (tranylcypromine sulfate) is indicated for the treatment of major depressive disorder (MDD) in adult patients who have not responded adequately to other antidepressants. PARNATE is not indicated for the initial treatment of MDD due to the potential for serious adverse reactions and drug interactions, and the need for dietary restrictions.

1.1. Pediatrics

Pediatrics (<18 years of age): PARNATE is not indicated for use in children or adolescents less than 18 years of age.

1.2. Geriatrics

Geriatrics: No data are available.

2. Contraindications

PARNATE is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 Dosage Forms, Strengths, Composition, and Packaging.

PARNATE is contraindicated in patients with the following (see 7 Warnings and Precautions):

• Confirmed or suspected cerebrovascular or cardiovascular disorders (e.g., arteriosclerosis, hypertension).
• History of recurrent or frequent headaches.
• Liver damage or blood dyscrasias.
• Phaeochromocytoma and catecholamine-releasing paragangliomas.

PARNATE is contraindicated in combination with the following medications (before, during or shortly after). (see 4 Dosage and Administration, 7 Warnings and Precautions and 9 Drug Interactions):

• Other monoamine oxidase inhibitors (MAOIs) (e.g. phenelzine sulphate, isocarboxazid, nialamide, pargyline)
• Selective serotonin reuptake inhibitors (SSRIs) or serotonin and noradrenaline reuptake inhibitors (SNRIs) (e.g. venlafaxine)
• Tricyclic antidepressants (dibenzazepine derivatives, e.g. amitriptyline, nortriptyline, protriptyline, desipramine, imipramine, doxepin, perphenazine, carbamazepine, cyclobenzaprine, amoxapine, maprotiline, trimipramine, and clomipramine hydrochloride)
• Other antidepressant drugs (e.g. amoxapine, bupropion, maprotiline, nefazodone, trazodone, vilazodone, vortioxetine)
• Serotonin releasing agents (e.g. amphetamine and methylphenidate and their derivatives)
• Triptans (e.g. sumatriptan or rizatriptan)
• Sympathomimetics (e.g. pseudoephedrine, phenylephedine, ephedrine, methyldopa, dopamine, and levodopa and tryptophan), including those contained in cold, hay fever or weight-reducing products, herbal products, and diet supplements

• Other individual drugs in the following list: buspirone, carbamazepine, cyclobenzaprine, dextromethorphan, dopamine, hydroxytryptophan, levodopa, meperidine, methyldopa,

  • milnacipran, rasagiline, reserpine, s-adenosyl-L-methionine (SAM-e), tapentadol, tramadol, tetrabenazine, tryptophan
• Foods and beverages with a high tyramine content

3. Serious Warnings and Precautions Box

4. Dosage and Administration

4.1. Dosing Considerations

Dosage should be adjusted to the requirements of the individual patient. If the patient responds to therapy, the response is usually seen within 48 hours to 3 weeks after starting medication.

4.2. Recommended Dose and Dosage Adjustment

Recommended starting dosage is 20 mg per day (10 mg in the morning and 10 mg in the afternoon).

If no signs of a response appear within 2 to 3 weeks, increase dosage to 30 mg daily (20 mg in the morning and 10 mg in the afternoon). Continue this dosage for at least 1 week. If no improvement occurs, continued administration is unlikely to be beneficial. Although dosages above 30 mg per day have been used, consider that the incidence and severity of side effects may increase as dosage is raised.

Dosage increases should be made in increments of 10 mg per day at intervals of 1 to 3 weeks to a maximum daily dose of 60 mg.

When a satisfactory response is obtained, dosage may be reduced to a maintenance level. Some patients will be maintained on 20 mg per day; many will need only 10 mg daily.

When Electroconvulsive therapy (ECT) is being administered concurrently with PARNATE, 10 mg BID can usually be given during the series, then reduced to 10 mg daily for maintenance therapy.

Switching to or from other Contraindicated Drugs

Allow 1 week to elapse between the discontinuance of PARNATE and the administration of any other drug that is contraindicated with PARNATE. The prescribing information for individual products should be consulted.

Because the effect of many antidepressant drugs may persist for 10 to 20 days, do not start PARNATE treatment within less than 1 week of discontinuing treatment with such drugs; then use half the normal dosage for the first week.

4.2.1. Discontinuing Treatment

Consider discontinuing PARNATE therapy by slow, gradual dosage reduction.

Withdrawal effects, including delirium, have been reported with abrupt discontinuation of PARNATE therapy. Higher daily doses and longer duration of use appear to be associated with a higher risk of withdrawal effects.

When tranylcypromine is withdrawn, monoamine oxidase activity is recovered in 3 to 5 days, although the drug is excreted in 24 hours; however, inhibition of MAO activity may persist for up to 1 week.

Geriatrics (>60 years of age): Use with caution. Consider more gradual dosage increases as this population may have an increased risk for hypotension (see 7 Warnings and Precautions, Special Populations, Geriatrics).

Pediatrics (<18 years of age): PARNATE is not indicated for use in children or adolescents less than 18 years of age.

4.4. Administration

Instruct patients to:

• avoid foods and beverages with high tyramine content while being treated with PARNATE and for 2 weeks after stopping PARNATE (see 2 Contraindications

  , and

  9 Drug Interactions

  ).

• avoid use of all alcoholic beverages while taking PARNATE
• take their dose of PARNATE at approximately the same time each day. Taking the last dose before 3 p.m. may be a potential method for managing insomnia.

4.5. Missed Dose

In the case of a missed dose of PARNATE, instruct patients to take their next dose at its regularly scheduled time.

5. Overdose

Symptoms

The characteristic symptoms are usually those which have already been described under 7 Warnings and Precautions and 8 Adverse Reactions; however, an intensification of these symptoms and sometimes severe additional manifestations may be seen, depending on the degree of overdosage and on individual susceptibility.

Some patients exhibit insomnia, restlessness and anxiety, progressing in severe cases to agitation, mental confusion and incoherence. Hypotension, dizziness, weakness and drowsiness may occur, progressing in severe cases to extreme dizziness and shock. A few patients have displayed hypertension with severe headache and other symptoms. Rare instances have been reported in which hypertension was accompanied by twitching or myoclonic fibrillation of skeletal muscles with hyperpyrexia, sometimes progressing to generalized rigidity and coma.

Treatment

Treatment normally consists of general supportive measures, close observation of vital signs and steps to counteract specific symptoms as they occur.

The management of hypertensive crisis is described in 7 Warnings and Precautions, Cardiovascular, Hypertensive crisis.

1. 6. Dosage Forms, Strengths, Composition, and Packaging

Table 1 – Dosage Forms, Strengths, and Composition

This drug product contains FD&C yellow No. 6 aluminium lake (Sunset Yellow) and D&C Red No. 7 (Lithol Rubin B Calcium Lake), as well as lactose. See 7 Warnings and Precautions, Immune, and Endocrine and Metabolism.

Description

PARNATE tablets are biconvex, rose-red, round, film-coated tablets, debossed with “PARNATE” and “SB” on one side.

Available in bottles of 100 tablets.

7. Warnings and Precautions

Please see 3 Serious Warnings and Precautions Box.

Cardiovascular

Hypertensive crisis: The most important adverse reaction associated with PARNATE is hypertensive crisis, which has sometimes been fatal. This response is not usually dose-related. It is associated with a distinctive reaction characterized by some or all of the following symptoms: occipital headache which may radiate frontally, palpitation, neck stiffness or soreness, nausea or vomiting, sweating (sometimes

with fever and sometimes with cold, clammy skin) with early pallor followed later by flushing, and photophobia. Either tachycardia or bradycardia may be present, sometimes associated with constricting chest pain. Mydriasis may occur.

The occipital headache, together with pain and stiffness in the cervical muscles, may mimic subarachnoid hemorrhage, 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.

Blood pressure should be followed closely in patients taking PARNATE to detect evidence of any pressor response. It is emphasized that full reliance should not be placed on blood pressure readings, but that the patient should also be observed frequently.

If a hypertensive reaction occurs, PARNATE should be discontinued. Patients should be managed according to standard of care.

Hypotension: Hypotension, which may be postural, has been observed during PARNATE therapy, particularly at doses above 30 mg daily. It is seen most commonly (but not exclusively) in patients with pre-existing hypertension. In most instances, it affects the systolic readings. Rare instances of syncope have been seen. Dosage increases should be made more gradually in patients showing a tendency toward hypotension at the starting dose. Postural hypotension can usually be relieved by having the patient lie down until blood pressure returns to normal. This side effect is usually temporary, but if it persists, PARNATE should be discontinued. Blood pressure usually returns rapidly to pre-treatment levels upon discontinuation of PARNATE.

When PARNATE is combined with phenothiazine derivatives (e.g. trifluoperazine, chlorpromazine) or other compounds known to cause hypotension, the possibility of additive hypotensive effects should be considered. There is a risk of hypertensive crisis with the concomitant usage of phenothiazine derivates (e.g. trifluoperazine, chlorpromazine) with PARNATE (see 9 Drug Interactions).

Angina: MAOIs may have the capacity to suppress anginal pain that would otherwise serve as a warning of myocardial ischemia.

Dependence, Tolerance and/or Abuse Liability

There have been reports of drug dependency in patients using doses of PARNATE significantly in excess of the therapeutic range. Some of these patients had a history of previous substance abuse.

PARNATE should be tapered according to the patient’s clinical reaction when discontinuation is necessary. Symptoms reported after stopping PARNATE without tapering include sleep disturbances, depression, confusion, delirium, tremor, agitation, convulsion, anxiety, hallucinations, fatigue, dysphoric mood, irritability, dizziness, sensory disturbances (e.g. paresthesia, such as electric shock sensation), lethargy, emotional lability, hypomania, tinnitus, seizures, and headache (see 4.2.1 Discontinuing Treatment).

Driving and Operating Machinery

Some PARNATE adverse reactions (e.g. dizziness, drowsiness, etc.) may affect the patient’s ability to drive or operate machinery. While taking PARNATE, patients should be cautioned not to drive, operate dangerous machinery or engage in activities that require alertness or physical coordination if they are experiencing any of these effects.

Endocrine and Metabolism

Hyperthyroidism: Use PARNATE with caution in hyperthyroid patients because of their increased sensitivity to pressor amines.

Diabetes: Some MAOIs have contributed to hypoglycemic episodes in diabetic patients receiving insulin or oral hypoglycemic agents. Therefore, PARNATE should be used with caution in diabetics under treatment with these drugs.

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. See 6. Dosage Forms, Strengths, Composition, and Packaging.

Hematologic

Patients with blood dyscrasia: Patients with blood dyscrasia should not be treated with PARNATE (see 2. Contraindications).

Hepatic/Biliary/Pancreatic

Patients with liver damage: Extensive clinical use and laboratory tests have revealed no evidence of liver toxicity due to PARNATE therapy. Because rare cases of hepatitis have been reported, it is recommended that patients with known liver disease or those with abnormal liver function tests should not be treated with PARNATE. See 2. Contraindications.

Immune

Hypersensitivity: The tablet coating contains an azo dye (FD&C Yellow No. 6 aluminium lake (Sunset Yellow) and D&C Red No. 7 (Lithol Rubin B Calcium Lake)) which may cause allergic reactions.

Monitoring and Laboratory Tests

Cardiovascular Monitoring: Blood pressure should be followed closely in patients taking PARNATE to detect evidence of any pressor response. It is emphasized that full reliance should not be placed on blood pressure readings, but that the patient should also be observed frequently.

Blood Glucose Monitoring: Monitor blood glucose in patients receiving both PARNATE and blood-glucose-lowering agents. A reduction of the dosage of such agents may be necessary (see 9.4 Drug-Drug Interactions).

Neurologic

Epilepsy: Because the influence of PARNATE on the convulsive threshold is variable in animal experiments, suitable precautions should be taken if epileptic patients are treated.

Seizures: Seizures have been reported with PARNATE withdrawal after abuse, and with overdose. Patients at risk for seizures should be monitored accordingly.

Serotonin toxicity/Serotonin Syndrome: Serotonin toxicity, also known as serotonin syndrome, is a potentially life-threatening condition and has been reported with MAOIs, including PARNATE, when used concomitantly with other serotonergic drugs. Such drugs include SSRIs, SNRIs, tricyclic antidepressants, triptans, fentanyl, tramadol, tryptophan, buspirone, St. John’s wort, S-adenosyl-L-methionine (SAM-e), and other MAOIs used to treat nonpsychiatric disorders (such as linezolid or intravenous methylene blue) (see 2. Contraindications and 9.4 Drug-Drug Interactions).

Manifestations of the serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia; with possible rapid fluctuations of vital signs), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyper-reflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Fatal outcome of serotonin syndrome has been reported, including in patients who had been treated with PARNATE. In some cases of an interaction between PARNATE and SSRIs or SNRIs, the features of the syndrome resembled neuroleptic malignant syndrome.

The concomitant use, or use in rapid succession, of PARNATE with other serotonergic drugs is contraindicated. However, there may be circumstances when treatment with other serotonergic substances (such as linezolid or intravenous methylene blue) is necessary and cannot be delayed. In such cases, PARNATE must be discontinued as soon as possible before initiating treatment with the other agent.

Treatment with PARNATE and any concomitant serotonergic agents should be discontinued immediately if the above events occur, and supportive symptomatic treatment should be initiated.

Ophthalmologic

Angle-closure Glaucoma: As with other antidepressants, PARNATE can cause mydriasis, which may trigger an angle-closure attack in a patient with anatomically narrow ocular angles. Patients should be examined to determine whether they are susceptible to angle-closure and be informed to seek immediate medical assistance if they experience eye pain, changes in vision or swelling or redness in or around the eye.

Perioperative Considerations

Discontinue PARNATE at least 7 days before elective surgery because of possible interference with the action of certain anesthetics and analgesics.

As with other MAOIs, PARNATE should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours after the procedure.

Psychiatric

Potential Association with the Occurrence of Behavioural and Emotional Changes, Including Self-Harm: It is unknown whether increased risk of suicidal ideation and behaviour is associated with the use of PARNATE in pediatric patients and/ or adults.

However, recent analyses of placebo-controlled clinical trial safety databases from SSRIs and other newer antidepressants suggest that use of these drugs in patients under the age of 18 may be associated with behavioural and emotional changes, including an increased risk of suicidal ideation and behaviour over that of placebo. Thus, rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised in patients of all ages given any antidepressant drug. This includes monitoring for emotional and behavioural changes.

Clinical worsening and suicide risk in adults with psychiatric disorders: Patients with depression may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviours (suicidality) whether or not they are taking antidepressant medications. 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 for clinical worsening (including development of new symptoms) and suicidality, especially at the beginning of a course of treatment, or at the time of dose changes, either increases or decreases. It is general clinical experience with all antidepressant therapies that the risk of suicide may increase in the early stages of recovery.

Patients with a history of suicidal behaviour or thoughts, and those patients exhibiting a significant degree of suicidal ideation prior to commencement of treatment, are at a greater risk of suicidal thoughts or suicide attempts and should receive careful monitoring during treatment.

Patients (and caregivers of patients) should be alerted about the need to monitor for any worsening of their condition (including development of new symptoms) and / or the emergence of suicidal ideation / behaviour or thoughts of harming themselves and to seek medical advice immediately if these symptoms present. It should be recognized that the onset of some neuropsychiatric symptoms could be related either to the underlying disease state or the drug therapy (see Mania and bipolar disorder below).

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who experience clinical worsening (including development of new symptoms) and / or the emergence of suicidal ideation / behaviour, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

Depression: PARNATE may aggravate coexisting symptoms in depression, such as anxiety and agitation. In depressed patients, the possibility of suicide should always be considered, and adequate precautions taken. Exclusive reliance on drug therapy to prevent suicidal attempts is unwarranted, as there may be a delay in the onset of therapeutic effect or an increase in anxiety and agitation. Also, some patients fail to respond to drug therapy or may respond only temporarily.

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 an antidepressant alone can increase the likelihood of precipitation 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; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. As with all antidepressants, tranylcypromine should be used with caution in patients with a history of mania.

Insomnia: It is the most frequent adverse reaction to PARNATE, which can usually be overcome by giving the last dose of the day no later than 3 p.m., by reducing the dose, or other measures of standard of care.

Renal

The usual precautions should be observed in patients with impaired renal function since there is a possibility of cumulative effects in such patients.

7.1. Special Populations

7.1.1. Pregnancy

Adequate human data on use during pregnancy and adequate animal reproduction studies are not available. PARNATE has been shown to pass through the placental barrier to the fetus of the rat. PARNATE is not recommended for a pregnant patient.

7.1.2. Breastfeeding

Adequate human data on use during lactation are not available. PARNATE has been shown to pass into the human milk. PARNATE is not recommended for a breastfeeding patient.

7.1.3. Pediatrics

Pediatrics (<18 years of age): No data are available to Health Canada; therefore Health Canada has not authorized an indication for pediatric use.

7.1.4. Geriatrics

Geriatrics (>60 years of age): Caution is advised in this population because of higher risks of cardiovascular abnormalities. (see 7 Warnings and Precautions, Cardiovascular).

8. Adverse Reactions

8.1. Adverse Reaction Overview

The most serious adverse reactions are as follows:

• Hypertensive crisis (see 3 Serious Warnings and Precautions Box)
• New or Worsened Emotional or Behavioural Problems (see 3 Serious Warnings and Precautions Box)
• Hypotension (see 7 Warnings and Precautions, Cardiovascular, Hypotension)

8.5. Post-Market Adverse Reactions

The following adverse reactions have been identified in clinical trials or during post-approval use of PARNATE.

Blood and lymphatic system disorders: agranulocytosis, leukopenia, thrombocytopenia, anemia

Metabolism and nutrition disorders: anorexia

Psychiatric disorders: overstimulation, manic symptoms, agitation, insomnia, anxiety, confusion, depression, delirium, hallucinations, habituation

Nervous system disorders: dizziness, restlessness, tremor, muscle spasm, paresthesia, drowsiness, headaches (without blood pressure elevation), convulsion, akinesia, ataxia, myoclonic jerks, hyperreflexia, dysgeusia

Eye disorders: blurred vision, nystagmus

Ear and labyrinth disorders: tinnitus

Cardiac disorders: tachycardia, palpitations

Vascular disorders: hypertensive crisis, hypotension, hypertension

Gastrointestinal disorders: diarrhea, constipation, nausea, abdominal pain, dry mouth, angular cheilitis

Hepatobiliary disorders: hepatitis

Skin and subcutaneous tissue disorders: rash, alopecia, sweating

Renal and urinary disorders: urinary retention, micturition

Reproductive system and breast disorders: impotence

General disorders and administration site conditions: edema, chills, weakness, fatigue, sleep disturbances

9. Drug Interactions

9.1. Serious Drug Interactions

9.2. Drug Interactions Overview

In general, the physician should bear in mind the possibility of a lowered margin of safety when PARNATE (tranylcypromine sulfate) is administered in combination with potent drugs and should adjust dosage accordingly.

9.4. Drug-Drug Interactions

The drugs listed in this Table 2 are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Table 2 – Established or Potential Drug-Drug Interactions

9.5. Drug-Food Interactions

PARNATE inhibits intestinal MAO, which is responsible for the catabolism of tyramine in food and beverages. As a result of this inhibition, large amounts of tyramine may enter the systemic circulation and precipitate a sudden elevation in blood pressure or hypertensive crisis (see 7 Warnings and Precautions). Instruct PARNATE-treated patients to avoid foods and beverages with significant tyramine content during treatment with PARNATE or within 2 weeks of stopping treatment (see Table 3 for a list of food and beverages containing significant amounts of tyramine).

Table 3 - Foods and Beverages with and without Significant Amounts of Tyramine

Food may be deliberately aged as part of its processing and should be avoided (see list above). Food may also naturally age over time, even if it is refrigerated. It is therefore extremely important that patients are instructed to buy and eat only fresh food or that which has been properly frozen. They should avoid eating food if they are unsure of its storage conditions or freshness and they should be cautious of food of unknown age or composition even if refrigerated.

The longer food is left to deteriorate and the larger the quantity of food eaten, the greater the potential quantity of tyramine ingested. Where there is any doubt, patients should be advised to either avoid the food or consume in strict moderation.

Patients should also be warned that tyramine levels may vary by brand or even batch and a person may absorb different amounts of tyramine from a particular food at different times. Therefore, if they have accidentally consumed a prohibited food on one occasion and not had a reaction, this does not mean that they will not have a serious hypertensive reaction if they consume the same food on a different occasion.

PARNATE may potentiate the effects of alcoholic beverages.

9.6. Drug-Herb Interactions

Caution should be exercised when giving PARNATE with St. John’s wort, as the development of serotonin toxicity has been reported with MAOIs when given before, with, or shortly after discontinuation of this drug. Observation of tranylcypromine washout period of at least 1 week is recommended.

9.7. Drug-Laboratory Test Interactions

Drugs which lower the seizure threshold, including MAO inhibitors, should not be used with metrizamide.

10. Clinical Pharmacology

10.1. Mechanism of Action

The mechanism of action of tranylcypromine as an antidepressant is not fully understood but is presumed to be linked to potentiation of monoamine neurotransmitter activity in the central nervous system (CNS) resulting from its irreversible and nonselective inhibition of the enzyme monoamine oxidase (MAO). It increases the concentration of epinephrine, norepinephrine, dopamine 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.

10.2. Pharmacodynamics

Tranylcypromine increases serotonergic activity in the central nervous system which can be potentiated in combination with other serotonergic drugs. When tranylcypromine is withdrawn, monoamine oxidase activity is gradually restored within a week, although the drug is excreted within 24 hours.

10.3. Pharmacokinetics

Absorption

Tranylcypromine is rapidly absorbed from the gastrointestinal tract following oral administration. Peak plasma concentrations occur within 1 hour of dosing.

Distribution

Tranylcypromine is distributed widely throughout the body.

Metabolism

No text available.

Elimination

The drug is excreted in the urine, mainly in the form of metabolites.

1. 11. Storage, Stability, and Disposal

PARNATE tablet should be stored at 15-30°C. Keep out of the sight and reach of children.

Part 2: Scientific Information

13. Pharmaceutical Information

Drug Substance

Non-proprietary name of the drug substance(s): tranylcypromine sulfate

Chemical name: (±)-trans-2-phenylcyclopropylamine sulfate (2:1)

Molecular formula: (C₉H₁₁N)₂.H₂SO₄

Molecular Mass: 133.19 (free base)

364.47 (sulfate salt)

Structural formula:

Physicochemical properties: A white or almost white, crystalline powder; odourless or with a faint odour similar to that of cinnamaldehyde. It is soluble in water, very slightly soluble in ethanol (96%) and in ether, insoluble in chloroform.

14. Clinical Trials

Not Available.

16. Non-Clinical Toxicology

No further information of clinical relevance.