These highlights do not include all the information needed to use TRANYLCYPROMINE SULFATE TABLETS safely and effectively. See full prescribing information for TRANYLCYPROMINE SULFATE TABLETS.   TRANYLCYPROMINE SULFATE USP tablets, for oral use Initial U.S. Approval: 1961

RECENT MAJOR CHANGES

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

Suicidal Thoughts and BehaviorsAntidepressants 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 sulfate is not approved for use in pediatric patients [see Use in Specific Populations (8.4)].Hypertensive Crisis with Significant Tyramine UseExcessive consumption of foods or beverages with significant tyramine content or the use of certain drugs with tranylcypromine sulfate or after tranylcypromine sulfate discontinuation can precipitate hypertensive crisis. Monitor blood pressure and allow for medication-free intervals between administration of tranylcypromine sulfate 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 Sulfate is indicated for the treatment of major depressive disorder (MDD) in adult patients who have not responded adequately to other antidepressants. Tranylcypromine Sulfate 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 [see Contraindications (4), Warnings and Precautions (5), and Drug Interactions (7)].

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

Tranylcypromine Sulfate Tablets, USP 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 SulfateAfter 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 sulfate. 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 sulfate to reduce the risk of additive effects [see Contraindications (4.1) and Drug Interactions (7.1)].Switching from Tranylcypromine Sulfate to Other MAOIs or Contraindicated AntidepressantsAfter stopping tranylcypromine sulfate 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 sulfate therapy. Higher daily doses and longer duration of use appear to be associated with a higher risk of withdrawal effects. Consider discontinuing tranylcypromine sulfate 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 Sulfate

Prior to initiating treatment with tranylcypromine sulfate:

• 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, dark pink, film‑coated, and debossed on one side with “250” on one side and “K” on the other side.

4 CONTRAINDICATIONS

4.1 Combination with Certain Drugs

Concomitant use of tranylcypromine sulfate 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 sulfate 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 Sulfate

4.2 Pheochromocytoma and Catecholamine-Releasing Paragangliomas

Tranylcypromine Sulfate is 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

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 sulfate, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. 

5.2 Hypertensive Crisis and Hypertension

Hypertensive CrisisMAOIs, including tranylcypromine sulfate, 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 sulfate and for 2 weeks after stopping tranylcypromine sulfate [see Drug Interactions (7.2)]. Careful evaluation of the benefits and risks of tranylcypromine sulfate therapy is necessary in patients with:

In all patients taking tranylcypromine sulfate, 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 sulfate, 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.HypertensionClinically significant increases in blood pressure have also been reported after the administration of MAOIs, including tranylcypromine sulfate, in patients not ingesting tyramine-rich foods or beverages. Assess blood pressure before prescribing tranylcypromine sulfate and closely monitor blood pressure in all patients taking tranylcypromine sulfate.

• 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.

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 sulfate.  In some cases of an interaction between tranylcypromine sulfate and SSRIs or SNRIs, the features of the syndrome resembled neuroleptic malignant syndrome.

The concomitant use, or use in rapid succession, of tranylcypromine sulfate 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 sulfate must be discontinued as soon as possible before initiating treatment with the other agent.

Treatment with tranylcypromine sulfate 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/Hypomania

In patients with bipolar disorder, treating a depressive episode with tranylcypromine sulfate or another antidepressant may precipitate a mixed/manic episode.  Prior to initiating treatment with tranylcypromine sulfate, 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 sulfate. 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 sulfate. 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 sulfate is 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.

5.6 Hypotension and Hypertension during Anesthesia and Perioperative Care

It is recommended that tranylcypromine sulfate be discontinued at least 10 days prior to elective surgery. If this is not possible, for general anesthesia, regional and local anesthesia, and perioperative care avoid the use of agents that are contraindicated for concomitant use with tranylcypromine sulfate. Carefully consider the risk of agents and techniques that increase the risk for hypotension (e.g., epidural or spinal anesthesia) or other adverse reactions to tranylcypromine sulfate (e.g., hypertension associated with the use of vasoconstrictors in local anesthetics).

5.7 Need for Emergency Treatment with Contraindicated Drugs

If in the absence of therapeutic alternatives emergency treatment with a contraindicated product (e.g., linezolid, intravenous methylene blue, direct-acting sympathomimetic drugs such as epinephrine) becomes necessary and cannot be delayed, discontinue tranylcypromine sulfate as soon as possible before initiating treatment with the other product and monitor closely for adverse reactions [see Drug Interactions (7.1)]

5.8 Discontinuation Syndrome

Abrupt discontinuation or dosage reduction of tranylcypromine sulfate has been associated with the appearance of new symptoms that include dizziness, nausea, headache, irritability, insomnia, diarrhea, anxiety, fatigue, abnormal dreams, and hyperhidrosis. In general, discontinuation events occurred more frequently with longer duration of therapy.

There have been spontaneous reports of adverse reactions occurring upon discontinuation of MAOIs, particularly when abrupt, including dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesia, such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these reactions are generally self-limiting, there have been reports of prolonged discontinuation symptoms.

Patients should be monitored for these symptoms when discontinuing treatment with tranylcypromine sulfate. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible [see Dosage and Administration (2.3) and Adverse Reactions (6)].

5.9 Risk of Clinically Significant Adverse Reactions due to Persistence of MAO Inhibition after Discontinuation

Although excretion of tranylcypromine sulfate is rapid, inhibition of MAO may persist up to 10 days following discontinuation. This should be taken into account when considering the use of potentially interacting substances or the consumption of tyramine-rich food or beverages [see Drug Interactions (7.2)], or when interpreting adverse reactions observed after discontinuation of tranylcypromine sulfate. Care should be taken to differentiate symptoms of persistent MAO inhibition from withdrawal symptoms [see Drug Abuse and Dependence (9.3)].

5.10 Hepatotoxicity

Hepatitis and elevated aminotransferases have been reported in association with tranylcypromine sulfate administration. Patients should be monitored accordingly. Tranylcypromine Sulfate should be discontinued in patients who develop signs and symptoms of hepatotoxicity.

Sedation has occurred in tranylcypromine sulfate-treated patients with cirrhosis.  Patients with cirrhosis receiving tranylcypromine sulfate should be monitored for possible increased risks of central nervous system adverse reactions, such as excessive drowsiness.

5.11 Seizures

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

5.12 Hypoglycemia in Diabetic Patients

Some MAOIs have contributed to hypoglycemic episodes in diabetic patients receiving insulin or other blood-glucose-lowering agents. Monitor blood glucose in patients receiving both tranylcypromine sulfate and blood-glucose-lowering agents. A reduction of the dosage of such agents may be necessary [see Drug Interactions (7.1)]

5.13 Aggravation of Coexisting Symptoms of Depression

Tranylcypromine sulfate may aggravate coexisting symptoms in depression, such as anxiety and agitation.

5.14 Adverse Effects on the Ability to Drive and Operate Machinery

Some tranylcypromine sulfate adverse reactions (e.g., hypotension, faintness, drowsiness, confusion, disorientation) can impair a patient’s ability to operate machinery or use an automobile.   Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that tranylcypromine sulfate therapy does not impair their ability to engage in such activities.

6 ADVERSE REACTIONS

The following adverse reactions are described in greater detail in other sections:  

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Based on clinical trial data, the most common adverse reactions to tranylcypromine were dry mouth, dizziness, insomnia, sedation, and headache (>30%) and overexcitement, constipation, blurred vision, and tremor (>10%). The following adverse reactions have been identified in clinical trials or during postapproval use of tranylcypromine sulfate:Blood and lymphatic system disorders: agranulocytosis, leukopenia, thrombocytopenia, anemiaEndocrine disorders: impaired water excretion compatible with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH)Metabolism and nutrition disorders: significant anorexia, weight gainPsychiatric disorders: excessive stimulation/overexcitement, manic symptoms/hypomania, agitation, insomnia, anxiety, confusion, disorientation, loss of libidoNervous system disorders: dizziness, restlessness/akathisia, akinesia, ataxia, myoclonic jerks, tremor, hyper-reflexia, muscle spasm, paresthesia, numbness, memory loss, sedation, drowsiness, dysgeusia, headaches (without blood pressure elevation)Eye disorders: blurred vision, nystagmusEar and labyrinth disorders: tinnitusCardiac disorders: tachycardia, palpitationsVascular disorders: hypertensive crisis, hypertension, hypotension (including postural hypotension with syncope)Gastrointestinal disorders: diarrhea, constipation, nausea, abdominal pain, dry mouth, fissuring in corner of mouthHepatobiliary disorders: hepatitis, elevated aminotransferasesSkin and subcutaneous tissue disorders: localized scleroderma, flare-up of cystic acne, urticaria, rash, alopecia, sweatingRenal and urinary disorders: urinary retention, urinary incontinence, urinary frequencyReproductive system and breast disorders: impotence, delayed ejaculationGeneral disorders and administration site conditions: edema, chills, weakness, fatigue/lethargy

• Suicidal thoughts and behaviors [see Warnings and Precautions (5.1)]
• Hypertensive crisis and hypertension [see Warnings and Precautions (5.2)]
• Serotonin syndrome [see Warnings and Precautions (5.3)]
• Activation of mania/hypomania [see Warnings and Precautions (5.4)]
• Hypotension [see Warnings and Precautions (5.5)]
• Hypotension and hypertension during anesthesia and perioperative care [see Warnings and Precautions (5.6)]
• Discontinuation syndrome [ see Warnings and Precautions (5.8)]
• Persistence of MAO inhibition after discontinuation [see Warnings and Precautions (5.9)]
• Hepatotoxicity [see Warnings and Precautions (5.10)]
• Seizures[see Warnings and Precautions (5.11)]
• Hypoglycemia in diabetic patients [see Warnings and Precautions (5.12)]
• Aggravation of coexisting symptoms of depression [see Warnings and Precautions (5.13)]
• Adverse effects on the ability to drive and operate machinery [see Warnings and Precautions (5.14)]  

7 DRUG INTERACTIONS

7.1 Clinically Significant Drug Interactions

Tables 3 and 4 lists drug classes and individual products, respectively, with a potential for interaction with tranylcypromine sulfate, describes the predominant observed or anticipated risks, and provides advice on concomitant use.  Given serious adverse reactions with multiple agents, patients should avoid taking over-the-counter medications or dietary supplements without prior consultation with a healthcare provider able to provide advice on the potential for interactions.

Time to Start Tranylcypromine Sulfate after Discontinuation of a Contraindicated Drug

 For products that are contraindicated with tranylcypromine sulfate, a time period of 4 to 5 half-lives of the other product or any active metabolite should elapse before starting treatment with tranylcypromine sulfate.   After stopping treatment with an MAO inhibitor antidepressant, a time period of at least 1 week or 4 to 5 half-lives of the other MAO inhibitor (whichever is longer) should elapse before starting treatment with tranylcypromine sulfate because of the risk for clinically significant adverse reactions after discontinuation due to persistent MAO inhibition [see Dosage and Administration (2.2), Warnings and Precautions (5.9) ].  This period can be several weeks long (e.g., a minimum of 5 weeks for fluoxetine given fluoxetine's long half-life).  Refer to the prescribing information of the contraindicated product for relevant information.

Time to Start Contraindicated Drug after Discontinuation of Tranylcypromine SulfateThe potential for interactions persists after discontinuation of tranylcypromine sulfate until MAO activity has sufficiently recovered.  Inhibition of MAO may persist up to 10 days following discontinuation [see Warnings and Precautions (5.9)].  After stopping tranylcypromine sulfate, at least 1 week should elapse before starting another MAOI (intended to treat MDD) or other contraindicated antidepressants. Refer to the prescribing information of any agent considered for subsequent use for recommendations on the duration of a waiting period after discontinuation of a MAO inhibitor.  

If in the absence of therapeutic alternatives and emergency treatment with a contraindicated drug (e.g., linezolid, intravenous methylene blue, direct-acting sympathomimetic drugs such as epinephrine) becomes necessary and cannot be delayed, discontinue tranylcypromine sulfate as soon as possible before initiating treatment with the other agent, and monitor closely for adverse reactions.

Table 3 Clinically Significant Drug Interactions with Drug Classes*

* Some drugs in these groups may also be listed in Table 4 below.** Sympathomimetic drugs include amphetamines as well as cold, hay fever or weight-reducing products that contain vasoconstrictors such as pseudoephedrine, phenylephrine, and ephedrine)a[See Contraindications (4.1)]; b[See Warnings and Precautions (5.2)]; c[See Warnings and Precautions (5.3)]d If not otherwise specified in this table, consider avoiding concomitant use (see also information on medication-free intervals, use agent at the lowest appropriate dosage, monitor for effects of the interaction, advise the patient to report potential effects).e [See Warnings and Precautions (5.5)]; f [See Warnings and Precautions (5.14)]; g[See Overdosage (10.1)] Table 4: Clinically Significant Drug Interactions with Individual Products*

*Some drugs in this table may also belong to groups listed in Table 3 above, and may be associated with additional interactions. a[See Contraindications (4.1)]; b[See Warnings and Precautions (5.3)]; c[See Warnings and Precautions (5.7)] dIf not otherwise specified in this table, consider avoiding concomitant use (see also information on medication-free intervals , use agent at the lowest appropriate dose, monitor for effects of the interaction, advise the patient to report potential effects, and be prepared to discontinue the agent and treat effects of the interactione[See Warnings and Precautions (5.5)]

7.2 Tyramine-Containing Foods and Beverages

Tranylcypromine Sulfate 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 Warnings and Precautions (5.2)]. Instruct tranylcypromine sulfate-treated patients to avoid foods and beverages with significant tyramine content during treatment with tranylcypromine sulfate or within 2 weeks of stopping treatment (see Table 5 for a list of food and beverages containing significant amounts of tyramine).

Table 5: Foods and Beverages with and without Significant Amounts of Tyramine

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk SummaryThere are limited published reports of placental infarction and congenital anomalies in association with use of tranylcypromine sulfate during pregnancy; however, these reports may not adequately inform the presence or absence of drug-associated risk with the use of tranylcypromine sulfate during pregnancy. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Animal embryo-fetal development studies were not conducted with tranylcypromine; however, published animal reproduction studies report placental transfer of tranylcypromine in rats and a dose-dependent decrease in uterine blood flow in pregnant sheep. Advise pregnant women of the potential risk to a fetus.

Clinical ConsiderationsLabor or Delivery During labor and delivery, the potential for interactions between tranylcypromine sulfate and drugs or procedures (e.g., epidural anesthesia) should be taken into account in women who have received tranylcypromine sulfate [see Warnings and Precautions (5.6) and Drug Interactions (7.1)].

8.2 Lactation

Risk SummaryTranylcypromine is present in human milk. There is no available information on the effects of tranylcypromine on milk production. There is no available information on the effects of tranylcypromine on a breastfed child; however, because of the potential for serious adverse reactions in a breastfed infant, advise nursing women to discontinue breastfeeding during treatment with tranylcypromine sulfate.

8.4 Pediatric Use

Safety and effectiveness of tranylcypromine sulfate in the pediatric population have not been established. All risks associated with the use of tranylcypromine sulfate, including the risk of suicidal thoughts and behavior, apply to adults and pediatric patients [see Boxed Warning and Warnings and Precautions (5)].

8.5 Geriatric Use

Older patients may be at greater risk of postural hypotension and other serious adverse reactions[see Warnings and Precautions (5)]. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

9 DRUG ABUSE AND DEPENDENCE

9.2 Abuse

Abuse of tranylcypromine sulfate has been reported. Some of these patients had a history of previous substance abuse.

The potential for abuse and the increased risk of serious adverse reactions with higher doses should be taken into account when considering the use of tranylcypromine sulfate for patients at increased risk for substance abuse.

9.3 Dependence

Dependence, evidenced by precipitation of withdrawal effects following abrupt discontinuation of tranylcypromine sulfate has been reported.  Reported withdrawal effects included delirium (even with low daily doses), restlessness, anxiety, confusion, hallucinations, headache, weakness, diarrhea, and/or rapid relapse into depression.  Thrombocytopenia and liver enzyme increases have also been observed in association with tranylcypromine sulfate withdrawal from high doses [see Overdosage (10.1)]

Withdrawal effects have appeared within 1 to 3 days of discontinuation and have persisted for several weeks after discontinuation.  The use of daily doses greater than recommended and longer duration of use appear to be associated with a higher risk of withdrawal effects.

Monitor for withdrawal effects for at least 1 week after discontinuation. Consider discontinuing tranylcypromine sulfate therapy by slow, gradual dose reduction [see Dosage and Administration (2.3)].

10 OVERDOSAGE

10.1 Overdosage Symptoms, Signs, and Laboratory Abnormalities

Overdose of tranylcypromine sulfate can cause the adverse reactions generally associated with tranylcypromine sulfate administration [see Warnings and Precautions (5), Adverse Reactions (6)and Drug Interactions (7.1)].  However, these reactions may be more severe, including fatal reactions.  Effects reported with overdosage of tranylcypromine sulfate and/or other MAOIs include:

• Insomnia, restlessness, and anxiety, progressing in severe cases to agitation, mental confusion, and incoherence; delirium; seizures
• Hypotension, dizziness, weakness, and drowsiness, progressing in severe cases to extreme dizziness and shock
• Hypertension with severe headache and other symptoms/complications
• Twitching or myoclonic fibrillation of skeletal muscles, with hyperpyrexia, sometimes progressing to generalized rigidity and coma

10.2 Overdosage Management

There are no specific antidotes for tranylcypromine sulfate.  For current information on the management of poisoning or overdosage, contact a poison control center at 1-800-222-1222. Abrupt withdrawal of tranylcypromine sulfate following overdosage can precipitate withdrawal symptoms, including delirium [see Warnings and Precautions 5.9)and Drug Abuse and Dependence (9.3)].   Medical management should normally consist of general supportive measures, close observation of vital signs, and steps to counteract specific manifestations as they occur [see Warnings and Precautions (5)].The toxic effects of tranylcypromine sulfate may be delayed or prolonged following the last dose of the drug [see Clinical Pharmacology (12.2)]. Therefore, the patient should be closely observed for at least 1 week.

Data on the dialyzability of tranylcypromine are lacking.

11 DESCRIPTION

Tranylcypromine sulfate, the active ingredient of Tranylcypromine Sulfate Tablets USP, is a non-hydrazine MAOI. The chemical name is (±)‑trans‑2‑phenylcyclopropylamine sulfate (2:1). The molecular formula is (C9H11N)2•H2SO4 and its molecular weight is 364.46. The structural formula is:

Tranylcypromine Sulfate film-coated tablets are intended for oral administration. Each round, dark pink tablet is debossed with “250” on one side and “K” on the other side and contains tranylcypromine sulfate equivalent to 10 mg of tranylcypromine.

Inactive ingredients consist of colloidal silicon dioxide, croscarmellose sodium, dibasic calcium phosphate anhydrous, magnesium stearate, microcrystalline cellulose, talc, and Opadry® II pink 85F14289. Opadry pink is used for purposed of coating and contains the following: FD&C Red # 40, polyethylene glycol 3350, polyvinyl alcohol, talc and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of tranylcypromine sulfate 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 inhibition of the enzyme monoamine oxidase (MAO).

12.2 Pharmacodynamics

Although tranylcypromine is eliminated in 24 hours, recovery MAO activity take up to 3 to 5 days [see Warnings and Precautions (5.9)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenesis, mutagenesis, or fertility impairment studies were conducted. 

16 HOW SUPPLIED/STORAGE AND HANDLING

Tranylcypromine Sulfate Tablets, USP are supplied as round, dark pink, film-coated tablets debossed with "250" on one side and "K" on the other side and contains tranylcypromine sulfate equivalent to 10 mg of tranylcypromine, in bottle of 100 with a desiccant.

Tranylcypromine Sulfate tablets are available as:

Store between 20° to 25°C (68° and 77°F); excursions permitted to 15° to 30°C (59° and 86°F).

Dispense in a tight, light resistant container.

• 10 mg: bottles of 100 tablets:  NDC 49884-032-01

17 PATIENT COUNSELING INFORMATION

Advise the patient to read FDA-approved patient labeling (Medication Guide).

Suicidal Thoughts and BehaviorsAdvise patients and caregivers to look for the emergence of suicidal thoughts and behaviors, especially early during treatment and when the dosage is adjusted up or down [see Box Warning and Warnings and Precautions (5.1)]. Hypertensive CrisisAdvise the patient on possible symptoms and instruct the patient to seek immediate medical attention if related signs or symptoms are present [see Boxed Warning and Warnings and Precautions (5.2)] Serotonin SyndromeAdvise the patient on possible symptoms, and explain the potentially fatal nature of serotonin syndrome and that it may result from an interaction with other serotonergic drugs.  Instruct the patient to seek immediate medical attention if related signs or symptoms are present [see Warnings and Precautions (5.3)]

Interaction with Other Drugs and Dietary Supplements[see Contraindications (4.1)and Drug Interactions (7.1)]

Interaction with Foods and Beverages[see Contraindications (4.1)and Drug Interactions (7.2)]

Hypotension

Advise the patient to report any symptoms of hypotension in the initial phase of treatment to the healthcare provider, because occurrence of such symptoms may require discontinuation [see Dosage and Administration (2.1) and Warnings and Precautions (5.5)].

Withdrawal Symptoms

Warn the patient not to stop tranylcypromine sulfate treatment abruptly, as withdrawal symptoms may occur and that the effect of tranylcypromine sulfate may continue even after discontinuation [see Warnings and Precautions (5.8, 5.9)].

Aggravation of Coexisting Symptoms of Depression

Inform the patient that tranylcypromine sulfate may aggravate coexisting symptoms in depression, such as anxiety and agitation and instruct them to contact their healthcare provider if they experience such symptoms [see Warnings and Precautions (5.13)].

Effects on Ability to Drive or Use Machinery[see Warnings and Precautions (5.14)]

Manufactured by:

Par Pharmaceutical

Chestnut Ridge, NY 10977

Revised: 08/2018

• Warn the patient not to take concomitant medications, whether prescription or over‑the‑counter drugs, or dietary supplements without prior consultation with a health care provider able to provide advice on the potential for interactions.
• Explain to the patient that some other drugs may require a medication-free interval even after discontinuation of tranylcypromine sulfate.
• Advise the patient to inform other physicians, pharmacists, and dentists about the treatment with tranylcypromine sulfate.

MEDICATION GUIDE

What is the most important information I should know about Tranylcypromine Sulfate tablets? Tranylcypromine Sulfate tablets can cause serious side effects including:

How can I watch for and try to prevent suicidal thoughts and actions?

Call a healthcare provider right away if you have any of the following symptoms, especially if they are new, worse, or worry you:

 A hypertensive crisis can also happen if you take Tranylcypromine Sulfate with certain other medicines. See, “Who should not take Tranylcypromine Sulfate?”  Avoid foods and drinks with a lot of tyramine while taking Tranylcypromine Sulfate and for 2 weeks after you stop taking it. For a list of some of the foods and drinks you should avoid during treatment with Tranylcypromine Sulfate see, “What should I avoid while taking Tranylcypromine Sulfate?”

• Increase in suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment and when the Tranylcypromine Sulfate dose is changed. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have, or have a family history of, bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. Tranylcypromine Sulfate is not for use in children.

What is Tranylcypromine Sulfate?Tranylcypromine Sulfate is a prescription medicine used to treat adults with a certain type of depression called major depressive disorder (MDD) who have not responded well to treatment with other medicines used to treat depression (antidepressants). Tranylcypromine Sulfate belongs to a class of medicines called monoamine oxidase inhibitors (MAOIs).

• It is important to talk with your healthcare provider about the risks of treating depression and the risk of not treating it. Talk with your healthcare provider about all your treatment choices.
• Tranylcypromine Sulfate is not for use as the first medicine to treat MDD.
• It is not known if Tranylcypromine Sulfate is safe and effective for use in children.

Who should not take Tranylcypromine Sulfate? Taking Tranylcypromine Sulfate with certain antidepressants and certain pain, allergy symptom, and cold and cough symptom medicines may cause a potentially life-threatening hypertensive crisis or a problem called serotonin syndrome. See, "What is the most important information I should know about Tranylcypromine Sulfate?” and “What are the possible side effects of Tranylcypromine Sulfate?”

Do not take Tranylcypromine Sulfate if you:

        Ask your healthcare provider or pharmacist if you are not sure if you take any of these medicines.

• take certain medicines, including:  antidepressants, such as: other monoamine oxidase inhibitors (MAOIs)selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs)tricyclic antidepressantsother antidepressants, such as amoxapine, bupropion, maprotiline, nefazodone, trazodone, vilazodone, vortioxetineamphetamines and methylphenidatesmedicines that can raise blood pressure (sympathomimetic medicine), such as pseudoephedrine, phenylephrine and ephedrine. These medicines are in some cold, hay fever or weight-loss medicines.sympathomimetic herbal medicines or dietary supplementsantihistamines (allergy medicines)triptansbuspironecarbamazepinedextromethorphandopaminehydroxytryptophan and tryptophanlevodopa and methyldopameperidinerasaglineresperines-adenosyl-L-methionine (SAM-e)tapentadoltetrabenazine

Before taking Tranylcypromine Sulfate, tell your healthcare provider about all your medical conditions, including if you:

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Tranylcypromine Sulfate and some other medicines may affect each other causing serious side effects. Tranylcypromine Sulfate may affect the way other medicines work, and other medicines may affect how Tranylcypromine Sulfate works.Some medicines need to be stopped for a period of time before you can start taking Tranylcypromine Sulfate and for a period of time after you stop taking Tranylcypromine Sulfate.Know the medicines you take. Keep a list of them to show your healthcare providers, pharmacist, and dentist when you get a new medicine.

• have high or low blood pressure
• have heart problems
• have cerebrovascular problems or have had a stroke
• have headaches
• have, or have a family history of, bipolar disorder, mania, or hypomania
• plan to have surgery
• have liver or thyroid problems
• have or have had seizures or convulsions
• have diabetes
• are pregnant or plan to become pregnant. Tranylcypromine Sulfate may harm your unborn baby.
• are breastfeeding or plan to breastfeed. Tranylcypromine Sulfate passes into your breast milk. Do not breastfeed during treatment with Tranylcypromine Sulfate. Talk to your healthcare provider about the best way to feed your baby while taking Tranylcypromine Sulfate.

How should I take Tranylcypromine Sulfate tablets?

• Take Tranylcypromine Sulfate tablets exactly as your healthcare provider tells you to take it.
• Your healthcare provider may need to change your dose of Tranylcypromine Sulfate tablets until it is the right dose for you.
• Do not stop taking Tranylcypromine Sulfate tablets without first talking to your healthcare provider. Stopping Tranylcypromine Sulfate suddenly may cause withdrawal symptoms. See, “What are the possible side effects of Tranylcypromine Sulfate tablets?”
• Tell your healthcare provider if you think your condition has gotten worse during treatment with Tranylcypromine Sulfate tablets.
• If you take too much Tranylcypromine Sulfate tablets (overdose) call your healthcare provider or poison control, or go to the nearest    hospital emergency room right away.

What should I avoid while taking Tranylcypromine Sulfate tablets?

The table below lists some of the foods and drinks you should avoid while you take Tranylcypromine Sulfate tablets.

• Do not eat foods or have drinks that have high amounts of tyramine while taking Tranylcypromine Sulfate tablets or for 2 weeks after you stop taking Tranylcypromine Sulfate tablets. All foods you eat should be fresh or properly frozen.Avoid foods when you do not know how those foods should be stored.Ask your healthcare provider if you are not sure if certain foods and drinks contain tyramine.

What are the possible side effects of Tranylcypromine Sulfate Tablets?

Tranylcypromine Sulfate tablets may cause serious side effects, including:

If you have these symptoms, call your healthcare provider or go to the nearest hospital emergency room right away.

The most common side effects of Tranylcypromine Sulfate tablets include:

These are not all the side effects of Tranylcypromine Sulfate.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

• See "What is the most important information I should know about Tranylcypromine Sulfate tablets?"

How do I store Tranylcypromine Sulfate tablets?

Keep Tranylcypromine Sulfate tablets and all medicines out of the reach of children.

• Store Tranylcypromine Sulfate tablets at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature]
• Store Tranylcypromine Sulfate tablets in a tight, light resistant container.

General information about the safe and effective use of  Tranylcypromine Sulfate tablets.Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not take  Tranylcypromine Sulfate tablets for a condition for which it was not prescribed. Do not give  Tranylcypromine Sulfate tablets to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about  Tranylcypromine Sulfate tablets that is written for health professionals.

What are the ingredients in Tranylcypromine Sulfate tablets? Active Ingredient: tranylcypromine sulfateInactive Ingredients: colloidal silicon dioxide, croscarmellose sodium, dibasic calcium phosphate anhydrous, magnesium stearate, microcrystalline cellulose, talc, and Opadry® II pink 85F14289. Opadry pink is used for purposed of coating and contains the following: FD&C Red # 40, polyethylene glycol 3350, polyvinyl alcohol, talc and titanium dioxide.

Manufactured by:Par Pharmaceutical

Chestnut Ridge, NY 10977

For more information, contact Par Pharmaceutical at 1-800-828-9393

This Medication Guide has been approved by the U.S. Food and Drug Administration. R08/2018