Tranylcypromine Sulfate

Tranylcypromine sulfate tablets are indicated for the treatment of major depressive disorder (MDD) in adult patients who have not responded adequately to other antidepressants. Tranylcypromine sulfate 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)]. Tranylcypromine sulfate tablets are a monoamine oxidase inhibitor (MAOI) indicated for the treatment of major depressive disorder (MDD) in adult patients who have not responded adequately to other antidepressants ( 1 ) Tranylcypromine sulfate 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 ( 1 , 4 , 5 , 7 )

Tablets containing tranylcypromine sulfate equivalent to 10 mg tranylcypromine are round, rose-red, film-coated, and debossed on one side with "PARNATE" and "SB." Tablets: 10 mg

Concomitant use or use in rapid succession with other MAOIs; selective serotonin reuptake inhibitors; serotonin and norepinephrine reuptake inhibitors; tricyclic antidepressants; sympathomimetic drugs; and numerous other drugs. See Full Prescribing Information for the full list of contraindicated products ( 4.1 , 7.1 ) Pheochromocytoma, other catecholamine-releasing paraganglioma ( 4.2 )

4.1 Combination with Certain Drugs Concomitant use of tranylcypromine sulfate 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 sulfate 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 Sulfate 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 sulfate 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)].

Activation of Mania/Hypomania: May be precipitated by antidepressant treatment in patients with bipolar disorder. Screen patients prior to treatment (5.4) Hypotension (including syncope): Monitor patients and adjust tranylcypromine sulfate tablets dosage or concomitant medication as necessary (5.5) Hypotension and Hypertension during Anesthesia and Perioperative Care: If possible, discontinue tranylcypromine sulfate tablets prior to elective surgery (5.6) Hepatitis and Elevated Liver Enzymes: Monitor accordingly (5.10)

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 sulfate 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 sulfate 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 sulfate tablets and for 2 weeks after stopping tranylcypromine sulfate tablets [see Drug Interactions (7.2)]. Careful evaluation of the benefits and risks of tranylcypromine sulfate 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 sulfate 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 sulfate 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 sulfate tablets, in patients not ingesting tyramine-rich foods or beverages. Assess blood pressure before prescribing tranylcypromine sulfate tablets and closely monitor blood pressure in all patients taking tranylcypromine sulfate 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 sulfate tablets. In some cases of an interaction between tranylcypromine sulfate tablets and SSRIs or SNRIs, the features of the syndrome resembled neuroleptic malignant syndrome. The concomitant use, or use in rapid succession, of tranylcypromine sulfate 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 sulfate tablets must be discontinued as soon as possible before initiating treatment with the other agent. […]

The following adverse reactions are described in greater detail in other sections: 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)] 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 post approval use of tranylcypromine sulfate tablets: Blood and lymphatic system disorders: agranulocytosis, leukopenia, thrombocytopenia, anemia Endocrine disorders: impaired water excretion compatible with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) Metabolism and nutrition disorders: significant anorexia, weight gain Psychiatric disorders: excessive stimulation/overexcitement, manic symptoms/hypomania, agitation, insomnia, anxiety, confusion, disorientation, loss of libido Nervous 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, nystagmus Ear and labyrinth disorders: tinnitus Cardiac disorders: tachycardia, palpitations Vascular disorders: hypertensive crisis, hypertension, hypotension (including postural hypotension with syncope) Gastrointestinal disorders: diarrhea, constipation, nausea, abdominal pain, dry mouth, fissuring in corner of mouth Hepatobiliary disorders: hepatitis, elevated aminotransferases Skin and subcutaneous tissue disorders: localized scleroderma, flare-up of cystic acne, urticaria, rash, alopecia, sweating Renal and urinary disorders : urinary retention, urinary incontinence, urinary frequency Reproductive system and breast disorders : impotence, delayed ejaculation General disorders and administration site conditions: edema, chills, weakness, fatigue/lethargy Most common adverse reactions (>10%) were dry mouth, dizziness, insomnia, sedation, headache, overexcitement, constipation, blurred vision, and tremor (6) To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals USA, Inc. at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

See Full Prescribing Information for a list of products, foods and beverages that can interact with tranylcypromine sulfate tablets (7)

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 tablets, 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 Tablets after Discontinuation of a Contraindicated Drug For products that are contraindicated with tranylcypromine sulfate tablets, 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 tablets. 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 tablets 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 Sulfate Tablets The potential for interactions persists after discontinuation of tranylcypromine sulfate tablets 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 tablets, 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 tablets 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* Product Clinical Comment on Concomitant Use a Predominant Effect/Risk [Hypertensive Reaction (HR) b or Serotonin Syndrome (SS) c ] Agents with blood pressure-reducing effects Use with caution d Hypotension e Non-selective H1 receptor antagonists Contraindicated a Increased anticholinergic effects Beta-adrenergic blockers (see also agents or procedures with blood pressure-reducing effects) Use with the caution d More pronounced bradycardia, postural hypotension e Blood glucose-lowering agents Dosage reduction of such agents may be necessary. Monitor blood glucose. Excessive reduction of blood glucose (additive effect) f CNS depressant agents (including opioids, alcohol, sedatives, hypnotics) Use with caution d Increased CNS depression Dietary supplements containing sympathomimetics Contraindicated a Antidepressants including but not limited to: Other MAOIs (e.g., linezolid, intravenous methylene blue, selective MAOIs) Selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) Tricyclic antidepressants Amoxapine, bupropion, maprotiline, nefazodone, trazodone, vilazodone, vortioxetine Contraindicated a SS for all antidepressants For MAOIs, increased MAO inhibition and risk of adverse reactions, SS, and HR g Amphetamines and methylphenidates and derivatives Contraindicated a HR Sympathomimetic drugs** Contraindicated a HR; Including risk of intracerebral hemorrhage Triptans Contraindicated a SS * 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* Product Clinical Comment on Concomitant Use a Predominant Effect/Risk [Hypertensive Reaction (HR) b or Serotonin Syndrome (SS) c ] Altretamine Use with caution d Orthostatic hypotension e Buspirone Contraindicated a HR Carbamazepine Contraindicated a SS Chlorpromazine Use with caution d Hypotensive effects e Cyclobenzaprine Contraindicated a SS Dextromethorphan Contraindicated a SS; Psychosis, bizarre behavior Dopamine Contraindicated a HR Droperidol Use with caution d QT interval prolongation Entacapone Use with caution d HR Fentanyl Use with caution d SS Hydroxytryptophan Contraindicated a SS Levodopa Contraindicated a HR Lithium Use with caution d SS Meperidine Contraindicated a SS Methadone Use with caution d SS Methyldopa Contraindicated a HR Metoclopramide Use with caution d HR/SS Mirtazapine Contraindicated a SS Oxcarbazepine Use with caution d because of close structural relationship with tricyclic antidepressants SS Rasagiline Contraindicated a HR Reserpine Contraindicated a HR S-adenosyl-L-methionine (SAM-e) Contraindicated a SS Tapentadol Contraindicated a HR/SS Tetrabenazine Contraindicated a HR Tolcapone Use with caution d HR Tramadol Use with caution d SS; Increased seizure risk Tryptophan Contraindicated a SS * 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)] 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 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 interaction e [ See Warnings and Precautions (5.5)]

7.2 Tyramine-Containing Foods and Beverages Tranylcypromine sulfate tablets inhibit 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 tablets-treated patients to avoid foods and beverages with significant tyramine content during treatment with tranylcypromine sulfate tablets or within 2 weeks of stopping treatment (see Table 5 for a list of food and beverages containing significant amounts of tyramine). […]

8.1 Pregnancy Risk Summary There are limited published reports of placental infarction and congenital anomalies in association with use of tranylcypromine sulfate tablets during pregnancy; however, these reports may not adequately inform the presence or absence of drug-associated risk with the use of tranylcypromine sulfate tablets during pregnancy. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, 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 Considerations Labor or Delivery During labor and delivery, the potential for interactions between tranylcypromine sulfate tablets and drugs or procedures (e.g., epidural anesthesia) should be taken into account in women who have received tranylcypromine sulfate tablets [see Warnings and Precautions (5.6) and Drug Interactions (7.1)].

8.2 Lactation Risk Summary Tranylcypromine 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 tablets.

8.4 Pediatric Use Safety and effectiveness of tranylcypromine sulfate tablets in the pediatric population have not been established. All risks associated with the use of tranylcypromine sulfate tablets, 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.

The mechanism of action of tranylcypromine sulfate tablets 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).