For the treatment of Major Depressive Episode Without Melancholia. Parnate should be used in adult patients who can be closely supervised. It should rarely be the first antidepressant drug given. Rather, the drug is suited for patients who have failed to respond to the drugs more commonly administered for depression.
PARNATE- tranylcypromine sulfate tablet, film coated
Suicidality and Antidepressant Drugs
Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of PARNATE or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. PARNATE is not approved for use in pediatric patients. (See WARNINGS TO PHYSICIANS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use.)
Chemically, tranylcypromine sulfate is (±)-trans-2-phenylcyclopropylamine sulfate (2:1). Each round, rose-red, film-coated tablet is debossed with the product name PARNATE and SB and contains tranylcypromine sulfate equivalent to 10 mg of tranylcypromine. Inactive ingredients consist of cellulose, citric acid, croscarmellose sodium, D&C Red No. 7, FD&C Blue No. 2, FD&C Red No. 40, FD&C Yellow No. 6, gelatin, lactose, magnesium stearate, talc, titanium dioxide, and trace amounts of other inactive ingredients.
Tranylcypromine is a non-hydrazine monoamine oxidase inhibitor with a rapid onset of activity. It increases the concentration of epinephrine, norepinephrine, and serotonin in storage sites throughout the nervous system and, in theory, this increased concentration of monoamines in the brain stem 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.
For the treatment of Major Depressive Episode Without Melancholia.
PARNATE should be used in adult patients who can be closely supervised. It should rarely be the first antidepressant drug given. Rather, the drug is suited for patients who have failed to respond to the drugs more commonly administered for depression.
The effectiveness of PARNATE has been established in adult outpatients, most of whom had a depressive illness which would correspond to a diagnosis of Major Depressive Episode Without Melancholia. As described in the American Psychiatric Association’s Diagnostic and Statistical Manual, third edition (DSM III), Major Depressive Episode implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning and includes at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigability, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and suicidal ideation or attempts.
The effectiveness of PARNATE in patients who meet the criteria for Major Depressive Episode with Melancholia (endogenous features) has not been established.
PARNATE should not be administered in combination with any of the following: MAO inhibitors or dibenzazepine derivatives; sympathomimetics (including amphetamines); some central nervous system depressants (including narcotics and alcohol); antihypertensive, diuretic, antihistaminic, sedative, or anesthetic drugs; bupropion HCl; buspirone HCl; dextromethorphan; cheese or other foods with a high tyramine content; or excessive quantities of caffeine.
PARNATE should not be administered to any patient with a confirmed or suspected cerebrovascular defect or to any patient with cardiovascular disease, hypertension, or history of headache.
(For complete discussion of contraindications and warnings, see below.)
PARNATE is contraindicated:
1. In patients with cerebrovascular defects or cardiovascular disorders
PARNATE should not be administered to any patient with a confirmed or suspected cerebrovascular defect or to any patient with cardiovascular disease or hypertension.
2. In the presence of pheochromocytoma
PARNATE should not be used in the presence of pheochromocytoma since such tumors secrete pressor substances.
3. In combination with MAO inhibitors or with dibenzazepine-related entities
PARNATE should not be administered together or in rapid succession with other MAO inhibitors or with dibenzazepine-related entities. Hypertensive crises or severe convulsive seizures may occur in patients receiving such combinations.
In patients being transferred to PARNATE from another MAO inhibitor or from a dibenzazepine-related entity, allow a medication-free interval of at least a week, then initiate PARNATE using half the normal starting dosage for at least the first week of therapy. Similarly, at least a week should elapse between the discontinuance of PARNATE and the administration of another MAO inhibitor or a dibenzazepine-related entity, or the readministration of PARNATE.
The following list includes some other MAO inhibitors, dibenzazepine-related entities and tricyclic antidepressants, and the companies which market them.
Other MAO Inhibitors
|Isocarboxazid||Marplan®(Oxford Pharm Services)|
|Pargyline HCl and methyclothiazide|
|Procarbazine HCl||Matulane®(Sigma Tau)|
Dibenzazepine-Related and Other Tricyclics
|Perphenazine and amitriptyline HCl||(Sandoz)|
|Protriptyline HCl||Vivactil®(Odyssey Pharmaceuticals, Inc.)|
|Cyclobenzaprine HCl|| |
|Trimipramine maleate||Surmontil®(Odyssey Pharmaceuticals, Inc.)|
4. In combination with bupropion
The concurrent administration of an MAO inhibitor and bupropion hydrochloride (Wellbutrin®, Wellbutrin SR®, Wellbutrin XL®, Zyban®, GlaxoSmithKline) is contraindicated. At least 14 days should elapse between discontinuation of an MAO inhibitor and initiation of treatment with bupropion hydrochloride.
5. In combination with selective serotonin reuptake inhibitors (SSRIs) or selective norepinephrine reuptake inhibitors (SNRIs)
As a general rule, PARNATE should not be administered in combination with any SSRI or SNRI. There have been reports of serious, sometimes fatal, reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) in patients receiving a SSRI (e.g., fluoxetine, Prozac®, Eli Lilly and Company) or a SNRI (e.g., venlafaxine, Effexor®, Effexor XR®, Wyeth) in combination with a monoamine oxidase inhibitor (MAOI), and in patients who have recently discontinued a SSRI or SNRI and are then started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore SSRIs and SNRIs should not be used in combination with an MAOI, or within 14 days of discontinuing therapy with an MAOI.
Since fluoxetine and its major metabolite have very long elimination half-lives, at least 5 weeks should be allowed after stopping fluoxetine before starting an MAOI.
At least 2 weeks should be allowed after stopping sertraline (Zoloft®, Pfizer) or paroxetine (Paxil®, Paxil CR®, GlaxoSmithKline) before starting an MAOI.
At least one week should be allowed after stopping a SNRI (e.g., venlafaxine) before starting a MAOI.
6. In combination with buspirone
PARNATE should not be used in combination with buspirone HCl, since several cases of elevated blood pressure have been reported in patients taking MAO inhibitors who were then given buspirone HCl. At least 10 days should elapse between the discontinuation of PARNATE and the institution of buspirone HCl.
7. In combination with sympathomimetics
PARNATE should not be administered in combination with sympathomimetics, including amphetamines which may be found in many herbal preparations as well as over-the-counter drugs such as cold, hay fever or weight-reducing preparations that contain vasoconstrictors.
During therapy with PARNATE, it appears that certain patients are particularly vulnerable to the effects of sympathomimetics when the activity of certain enzymes is inhibited. Use of sympathomimetics and compounds such as guanethidine, methyldopa, reserpine, dopamine, levodopa, and tryptophan with PARNATE may precipitate hypertension, headache, and related symptoms. Cerebral hemorrhage may also occur. The combination of MAOIs and tryptophan has been reported to cause behavioral and neurologic syndromes including disorientation, confusion, amnesia, delirium, agitation, hypomanic signs, ataxia, myoclonus, hyperreflexia, shivering, ocular oscillations, and Babinski’s signs.
8. In combination with meperidine
Do not use meperidine concomitantly with MAO inhibitors or within 2 or 3 weeks following MAOI therapy. Serious reactions have been precipitated with concomitant use, including coma, severe hypertension or hypotension, severe respiratory depression, convulsions, malignant hyperpyrexia, excitation, peripheral vascular collapse, and death. It is thought that these reactions may be mediated by accumulation of 5-HT (serotonin) consequent to MAO inhibition.
9. In combination with dextromethorphan
The combination of MAO inhibitors and dextromethorphan has been reported to cause brief episodes of psychosis or bizarre behavior.
10. In combination with cheese or other foods with a high tyramine content
When excessive amounts of tyramine are consumed in conjunction with tranylcypromine, or within 2 weeks of stopping treatment, a serious and sometimes fatal hypertensive reaction may occur.
Tyramine occurs naturally in some foods or may occur from the bacterial breakdown of protein in foods which are fermented, aged, or spoiled. Foods that have reliably been shown to contain a high tyramine content and may also have been reported to induce a serious hypertensive reaction when consumed with tranylcypromine are:
- all matured or aged cheeses (note: all cheeses are considered matured or aged except fresh cottage cheese, cream cheese, ricotta, and processed cheese. All non-cheese dairy products can be consumed providing they are fresh)
- all aged, cured or fermented meat, fish, or poultry (note: meat, fish, or poultry that has not undergone aging, curing or fermenting and that is bought fresh, stored correctly and eaten fresh is not contraindicated)
- all fermented soybean products (e.g., soy sauce, miso, fermented tofu)
- fava or broad bean pods
- banana peel (but not the pulp)
- concentrated yeast extracts (e.g., Marmite or Vegemite spread)
- all tap/draught beers (note: some bottled beers, including non-alcoholic beer, may also pose a risk).
Patients should be advised to minimize or avoid use of all alcoholic beverages while taking PARNATE. Patients should be advised to adhere to the following dietary guidance about eating fresh foods:
Foods may be deliberately aged as part of their processing and these are contraindicated (see list above). Foods may also naturally age over time, even if they are refrigerated. It is therefore extremely important that patients are instructed to buy and eat only fresh foods or those which have been properly frozen. They should avoid eating foods if they are unsure of their storage conditions or freshness and they should be cautious of foods 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 it in strict moderation if it is not otherwise contraindicated.
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.
11. In patients undergoing elective surgery
Patients taking PARNATE should not undergo elective surgery requiring general anesthesia. Also, they should not be given cocaine or local anesthesia containing sympathomimetic vasoconstrictors. The possible combined hypotensive effects of PARNATE and spinal anesthesia should be kept in mind. PARNATE should be discontinued at least 10 days prior to elective surgery.
In general, the physician should bear in mind the possibility of a lowered margin of safety when PARNATE is administered in combination with potent drugs.
1. PARNATE should not be used in combination with some central nervous system depressants such as narcotics and alcohol, or with hypotensive agents. A marked potentiating effect on these classes of drugs has been reported.
2. Anti-parkinsonism drugs should be used with caution in patients receiving PARNATE since severe reactions have been reported.
3. PARNATE should not be used in patients with a history of liver disease or in those with abnormal liver function tests.
4. Excessive use of caffeine in any form should be avoided in patients receiving PARNATE.
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1.
|Age Range||Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients Treated|
|Increases Compared to Placebo|
|<18||14 additional cases|
|18-24||5 additional cases|
|Decreases Compared to Placebo|
|25-64||1 fewer case|
|≥65||6 fewer cases|
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for PARNATE should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.