Tranylcypromine Sulfate: Package Insert and Label Information

TRANYLCYPROMINE SULFATE- tranylcypromine sulfate tablet, film coated
Alvogen Inc.

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS and HYPERTENSIVE CRISIS WITH SIGNIFICANT TYRAMINE USE

Suicidal Thoughts and Behaviors
Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors [see Warnings and Precautions (5.1)]. Tranylcypromine tablets are not approved for use in pediatric patients [see Use in Specific Populations (8.4)].

Hypertensive Crisis with Significant Tyramine Use
Excessive consumption of foods or beverages with significant tyramine content or the use of certain drugs with tranylcypromine tablets or after tranylcypromine tablets discontinuation can precipitate hypertensive crisis. Monitor blood pressure and allow for medication-free intervals between administration of tranylcypromine tablets and interacting drugs. Instruct patients to avoid ingestion of foods and beverages with high tyramine content [see Warnings and Precautions (5.2) and Drug Interactions (7.1, 7.2)].

1 INDICATIONS AND USAGE

Tranylcypromine tablets are indicated for the treatment of major depressive disorder (MDD) in adult patients who have not responded adequately to other antidepressants. Tranylcypromine tablets are 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 [see Contraindications (4), Warnings and Precautions (5) , and Drug Interactions (7)].

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

Tranylcypromine tablets are for oral use. The recommended dosage is 30 mg per day (in divided doses). If patients do not have an adequate response, increase the dosage in increments of 10 mg per day every 1 to 3 weeks to a maximum 30 mg twice daily (60 mg per day). Dosage increases should be made more gradually in patients at risk for hypotension (e.g., geriatric patients) [see Warnings and Precautions (5.5)].

2.2 Switching to or from Other Antidepressants

Switching from Contraindicated Antidepressants to Tranylcypromine Tablets
After stopping treatment with contraindicated antidepressants, a time period of 4 to 5 half-lives of the other antidepressant or any active metabolite should elapse before starting treatment with tranylcypromine tablets. After stopping treatment with an MAO inhibitor antidepressant, a time period of at least one week or 4 to 5 half-lives of the other MAO inhibitor (whichever is longer) should elapse before starting treatment with tranylcypromine tablets to reduce the risk of additive effects [see Contraindications (4.1) and Drug Interactions (7.1)].

Switching from Tranylcypromine Tablets to Other MAOIs or Contraindicated Antidepressants
After stopping tranylcypromine tablets treatment, at least one week should elapse before starting another MAOI (intended to treat MDD) or other contraindicated antidepressants. Refer to the prescribing information of the subsequently used drug for product-specific advice on a medication-free interval [see Contraindications (4.1) and Drug Interactions (7.1)].

2.3 Discontinuing Treatment

Withdrawal effects, including delirium, have been reported with abrupt discontinuation of tranylcypromine tablets therapy. Higher daily doses and longer duration of use appear to be associated with a higher risk of withdrawal effects. Consider discontinuing tranylcypromine tablets therapy by slow, gradual dosage reduction [see Warnings and Precautions (5.8) and Drug Abuse and Dependence (9.3)].

2.4 Screen for Bipolar Disorder and Elevated Blood Pressure Prior to Starting Tranylcypromine Tablets

Prior to initiating treatment with tranylcypromine tablets:

  • Screen patients for a history of mania [see Warnings and Precautions (5.4)].
  • Measure blood pressure [see Warnings and Precautions (5.2, 5.5)].

3 DOSAGE FORMS AND STRENGTHS

Tablets containing tranylcypromine sulfate equivalent to 10 mg tranylcypromine are round, red-rose, film-coated tablets debossed with TR on one side and plain on other side.

4 CONTRAINDICATIONS

4.1 Combination with Certain Drugs

Concomitant use of tranylcypromine tablets or use in rapid succession with the products in Table 1 is contraindicated. Such use may cause severe or life-threatening reactions such as hypertensive crises or serotonin syndrome [see Drug Interactions (7.1)]. Medication-free periods between administration of tranylcypromine tablets and contraindicated agents are recommended [see Dosage and Administration (2.2) and Drug Interactions (7.1)].
Table 1: Products Contraindicated with the Use of Tranylcypromine Tablets

Drug Classes
Non-selective H1 receptor antagonists
Antidepressants including but not limited to:
  • Other monoamine oxidase inhibitors (MAOIs)
  • Selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs)
  • Tricyclic antidepressants
  • Other antidepressants (e.g., amoxapine, bupropion, maprotiline, nefazodone, trazodone, vilazodone, vortioxetine)
Amphetamines and methylphenidates and derivatives
Sympathomimetic products (e.g., cold, hay fever or weight-reducing products that contain vasoconstrictors such as pseudoephedrine, phenylephrine, and ephedrine; or dietary supplements that contain sympathomimetics)
Triptans
Individual Drugs (not included in the above classes)
buspirone levodopa s-adenosyl-L-methionine (SAM-e)
carbamazepine meperidine tapentadol
cyclobenzaprine methyldopa tetrabenazine
dextromethorphan milnacipran tryptophan
dopamine rasagiline
hydroxytryptophan reserpine

4.2 Pheochromocytoma and Catecholamine-Releasing Paragangliomas

Tranylcypromine tablets are contraindicated in the presence of pheochromocytoma or other catecholamine-releasing paragangliomas because such tumors secrete pressor substances and can lead to hypertensive crisis [see Warnings and Precautions (5.3)].

5 WARNINGS AND PRECAUTIONS

5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults

In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 2.

Table 2: Risk Differences of the Number of Patients of Suicidal Thoughts and Behavior in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients

Age Range Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1000 Patients Treated
Increases Compared to Placebo
<18 years old 14 additional patients
18-24 years old 5 additional patients
Decreases Compared to Placebo
25-64 years old 1 fewer patient
≥65 years old 6 fewer patients

It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors.

Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing tranylcypromine tablets, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

5.2 Hypertensive Crisis and Hypertension

Hypertensive Crisis
MAOIs, including tranylcypromine tablets, have been associated with hypertensive crises caused by the ingestion of foods or beverages with a high concentration of tyramine. In addition, hypertensive reactions and crises may occur with concomitant use of other drugs [see Drug Interactions (7.1)]. Patients with hyperthyroidism may be at greater risk of hypertensive crisis.
Signs, Symptoms, and Complications of Hypertensive Crisis: In some patients a hypertensive crisis constitutes a hypertensive emergency, which requires immediate attention to prevent serious complications or fatal outcome. These emergencies are characterized by severe hypertension (e.g., with a blood pressure of more than 180/120 mm Hg) and evidence of organ dysfunction. Symptoms may include occipital headache (which may radiate frontally), palpitations, neck stiffness or soreness, nausea or vomiting, sweating (sometimes with fever or cold, clammy skin), dilated pupils, photophobia, shortness of breath, or confusion. Either tachycardia or bradycardia may be present and may be associated with constricting chest pain. Seizures may also occur. Intracranial bleeding, sometimes fatal, has been reported in association with the increase in blood pressure.
Strategies to Reduce the Risk of Hypertensive Crisis: Instruct patients to avoid foods and beverages with high tyramine content while being treated with tranylcypromine tablets and for 2 weeks after stopping tranylcypromine tablets [see Drug Interactions (7.2)]. Careful evaluation of the benefits and risks of tranylcypromine tablets therapy is necessary in patients with:

  • Hypertension or confirmed or suspected cerebrovascular or cardiovascular disorders that constitute an increased risk for complications from severe hypertension, and
  • A history of headaches that can mask the occurrence of headaches as prodromal of a hypertensive crisis.

In all patients taking tranylcypromine tablets, monitor blood pressure closely to detect evidence of increased blood pressure. Full reliance should not be placed on blood pressure readings. The patient should also be observed for other signs and symptoms of hypertensive crisis.
Treatment of Hypertensive Crisis: Therapy should be interrupted with symptoms that may be prodromal or a manifestation of a hypertensive crisis, such as palpitations or headaches, and patients should be evaluated immediately. Discontinue tranylcypromine tablets, other drugs, foods or beverages suspected to contribute to the hypertensive crisis immediately [see Drug Interactions (7.1, 7.2)].
Patients with severe elevations in blood pressure (e.g., more than 180/120 mm Hg) with evidence of organ dysfunction require immediate blood pressure reduction. Fever should be managed by means of external cooling. However, additional measures to control the causes of hyperthermia (psychomotor agitation, increased neuromuscular activity, persistent seizures) may be required.
Hypertension
Clinically significant increases in blood pressure have also been reported after the administration of MAOIs, including tranylcypromine tablets, in patients not ingesting tyramine-rich foods or beverages. Assess blood pressure before prescribing tranylcypromine tablets and closely monitor blood pressure in all patients taking tranylcypromine tablets.

5.3 Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome has been reported with MAOIs when used concomitantly with other serotonergic drugs. Such drugs include SSRIs, SNRIs, tricyclic antidepressants, triptans, fentanyl, lithium, 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).
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 tranylcypromine tablets. In some cases of an interaction between tranylcypromine tablets and SSRIs or SNRIs, the features of the syndrome resembled neuroleptic malignant syndrome.
The concomitant use, or use in rapid succession, of tranylcypromine tablets 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, tranylcypromine tablets must be discontinued as soon as possible before initiating treatment with the other agent.
Treatment with tranylcypromine tablets and any concomitant serotonergic agents should be discontinued immediately if the above events occur, and supportive symptomatic treatment should be initiated.

5.4 Activation of Mania or Hypomania

In patients with bipolar disorder, treating a depressive episode with tranylcypromine tablets or another antidepressant may precipitate a mixed/manic episode. Prior to initiating treatment with tranylcypromine tablets, screen patients for any personal or family history of bipolar disorder, mania, or hypomania.

5.5 Hypotension

Hypotension, including postural hypotension, has been observed during therapy with tranylcypromine tablets. At doses above 30 mg daily, postural hypotension is a major adverse reaction and may result in syncope. Symptoms of postural hypotension are seen most commonly, but not exclusively, in patients with pre-existing hypertension. Blood pressure usually returns rapidly to pretreatment levels upon discontinuation of tranylcypromine tablets.
Dosage increases should be made more gradually in patients with a tendency toward hypotension and/or postural hypotension (e.g., elderly patients) [see Dosage and Administration (2.2) and Use in Specific Populations (8.5)]. Such patients should be closely observed for postural changes in blood pressure throughout treatment. Also, when tranylcypromine tablets are used concomitantly with other agents known to cause hypotension, the possibility of additive hypotensive effects should be considered [see Drug Interactions (7.1)]. Postural hypotension may be relieved by having patients lie down until blood pressure returns to normal.

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