TRANYLCYPROMINE

Boxed Warning 1/2018 Dosage and Administration ( 2 ) 1/2018 Contraindications ( 4 ) 1/2018 Warnings and Precautions ( 5 ) 1/2018

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) ] . • Tranylcypromine 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 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 )

2 DOSAGE AND ADMINISTRATION • Recommended daily dosage is 30 mg in divided doses ( 2.1 ) • If no adequate response, increase dosage in increments of 10 mg per day every 1 to 3 weeks to a maximum dosage of 30 mg twice daily (60 mg per day). Consider more gradual dosage increases in patients at risk for hypotension ( 2.1 ) • Consider discontinuing tranylcypromine tablets therapy gradually because of the risk for withdrawal effects ( 2.3 , 5.8 , 9.3 ) • Switching from or to other MAOIs or other antidepressants: See full prescribing information for instructions ( 2.2 , 7.1 ) 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, film-coated, and debossed on one side with "10" and plain on the other side. • Tablets: 10 mg ( 3 )

4 CONTRAINDICATIONS • 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 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) ] .

6 ADVERSE REACTIONS 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 postapproval use of tranylcypromine 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, hyperreflexia, 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 Solco Healthcare US, LLC at 1-866-257-2597 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS See Full Prescribing Information for a list of products, foods and beverages that can interact with tranylcypromine 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 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. T ime to Start Tranylcypromine Tablets after Discontinuation of a Contraindicated Drug For products that are contraindicated with tranylcypromine 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 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 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. T ime to Start Contraindicated Drug after Discontinuation of Tranylcypromine Tablets The potential for interactions persists after discontinuation of tranylcypromine 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 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 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* P r oduct C linical Comment on Concomitant Usea P r e dominant Effect/Risk [Hypertensive Reaction (HR)b or Serotonin Syndrome (SS)c] Agents with blood pressure-reducing effects Use with cautiond Hypotensione Non-selective H1 receptor antagonists Contraindicateda Increased anticholinergic effects Beta-adrenergic blockers (see also agents or procedures with blood pressure-reducing effects) Use with cautiond More pronounced bradycardia, postural hypotensione 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 cautiond Increased CNS depression Dietary supplements containing sympathomimetics Contraindicateda 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 Contraindicateda SS for all antidepressants For MAOIs, increased MAO inhibition and risk of adverse reactions, …

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are limited published reports of placental infarction and congenital anomalies in association with use of tranylcypromine tablets during pregnancy; however, these reports may not adequately inform the presence or absence of drug-associated risk with the use of tranylcypromine tablets 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 Considerations Labor or Delivery During labor and delivery, the potential for interactions between tranylcypromine tablets and drugs or procedures (e.g., epidural anesthesia) should be taken into account in women who have received tranylcypromine 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 tablets. 8.4 Pediatric Use Safety and effectiveness of tranylcypromine tablets in the pediatric population have not been established. All risks associated with the use of tranylcypromine 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.

12.1 Mechanism of Action The mechanism of action of tranylcypromine 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).

11 DESCRIPTION Tranylcypromine sulfate, the active ingredient of Tranylcypromine 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 film-coated tablets are intended for oral administration. Each round, red-rose, film coated tablet is debossed with N538 on one side and plain on other side, and contains tranylcypromine sulfate equivalent to 10 mg of tranylcypromine. Inactive ingredients consist of calcium sulfate, carboxymethyl cellulose sodium, croscarmellose sodium, FD&C Blue No. 2 lake, FD&C Red No. 40 lake, FD&C Yellow No. 6 lake, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, pregelatinized starch, talc and titanium dioxide. structure

10 OVERDOSAGE 10.1 Overdosage Symptoms, Signs, and Laboratory Abnormalities Overdose of tranylcypromine tablets can cause the adverse reactions generally associated with tranylcypromine tablets 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 tablets 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 tablets. For current information on the management of poisoning or overdosage, contact a poison control center at 1-800-222-1222. Abrupt withdrawal of tranylcypromine tablets 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 tablets 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Tranylcypromine Tablets, USP are available as round, red, film-coated tablets debossed with "10" on one side and plain on the other side, containing tranylcypromine sulfate equivalent to 10 mg of tranylcypromine. They are supplied in NDC: 70518-4708-00 NDC: 70518-4708-01 OUTER PACKAGING: 100 in 1 BOX PACKAGING: 1 in 1 POUCH Store between 15° and 30°C (59° and 86°F). [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container. Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762