Tranylcypromine

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: B lood and lymphatic system disorders: agranulocytosis, leukopenia, thrombocytopenia, anemia E ndocrine disorders: impaired water excretion compatible with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) Me tabolism and nutrition disorders: significant anorexia, weight gain P sychiatric 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) Ey e disorders: blurred vision, nystagmus E ar and labyrinth disorders: tinnitus Cardiac disorders: tachycardia, palpitations V ascular disorders: hypertensive crisis, hypertension, hypotension (including postural hypotension with syncope) G astrointestinal disorders: diarrhea, constipation, nausea, abdominal pain, dry mouth, fissuring in corner of mouth He patobiliary disorders: hepatitis, elevated aminotransferases Skin and subcutaneous tissue disorders: localized scleroderma, flare-up of cystic acne, urticaria, rash, alopecia, sweating Re nal and urinary disorders: urinary retention, urinary incontinence, urinary frequency Re productive 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 Novitium Pharma LLC at 1-855-204-1431 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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 Dr ug 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)].

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

2 DOSAGE & 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)].

1 INDICATIONS & 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)

9.2 Abuse Abuse of tranylcypromine tablets 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 tablets for patients at increased risk for substance abuse.

9.3 Dependence Dependence, evidenced by precipitation of withdrawal effects following abrupt discontinuation of tranylcypromine tablets 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 tablets 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 tablets therapy by slow, gradual dose reduction [see Dosage and Administration (2.3)] .

9 DRUG ABUSE AND DEPENDENCE 9.2 Abuse Abuse of tranylcypromine tablets 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 tablets for patients at increased risk for substance abuse. 9.3 Dependence Dependence, evidenced by precipitation of withdrawal effects following abrupt discontinuation of tranylcypromine tablets 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 tablets 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 tablets 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 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.

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, SS, and HRg Amphetamines and methylphenidates andderivatives Contraindicateda HR Sympathomimetic drugs** Contraindicateda HR; Including risk of intracerebral hemorrhage Triptans Contraindicateda 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 [S ee Contraindications (4.1)]; b [S ee Warnings and Precautions (5.2)]; c [ S ee 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 [S ee Warnings and Precautions (5.5)]; f [S ee Warnings and Precautions (5.14)]; g [S ee Overdosage (10.1)] Table 4: Clinically Significant Drug Interactions with Individual Products* P r oduct C linical Comment on Concomitant Usea P r e dominant Effect/Risk [Hypertensive Reaction (HR)b or Serotonin Syndrome (SS)c] Altretamine Use with cautiond Orthostatic hypotensione Buspirone Contraindicateda HR Carbamazepine Contraindicateda SS Chlorpromazine Use with cautiond Hypotensive effectse Cyclobenzaprine Contraindicateda SS Dextromethorphan Contraindicateda SS; Psychosis, bizarre behavior Dopamine Contraindicateda HR Droperidol Use with cautiond QT interval prolongation Entacapone Use with cautiond HR Fentanyl Use with cautiond SS Hydroxytryptophan Contraindicateda SS Levodopa Contraindicateda HR Lithium Use with cautiond SS Meperidine Contraindicateda SS Methadone Use with cautiond SS Methyldopa Contraindicateda HR Metoclopramide Use with cautiond HR/SS Mirtazapine Contraindicateda SS Oxcarbazepine Use with cautiond because of close structural relationship with tricyclic antidepressants SS Rasagiline Contraindicateda HR Reserpine Contraindicateda HR S-adenosyl-L-methionine (SAM-e) Contraindicateda SS Tapentadol Contraindicateda HR/SS Tetrabenazine Contraindicateda HR Tolcapone Use with cautiond HR Tramadol Use with cautiond SS; Increased seizure risk Tryptophan Contraindicateda SS * Some drugs in this table may also belong to groups listed in Table 3 above, and may be associated with additional interactions. a [S ee Contraindications (4.1)]; b [S ee Warnings and Precautions (5.3)]; c [ S ee 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 [S ee Warnings and Precautions (5.5) 7.2 Tyramine-Containing Foods and Beverages Tranylcypromine tablets 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 tablet-treated patients to avoid foods and beverages with significant tyramine content during treatment with tranylcypromine tablets 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 C lass of F ood or Beverage Tyramine-Rich Foods and Beverages to Avoid Acce ptable Foods and Dr inks, Containing No or Little Tyramine Meat, Poultry, and Fish Air dried, aged and fermented meats, sausages and salamis (including cacciatore, hard salami and mortadella); pickled herring; and any spoiled or improperly stored meat, poultry, and fish (e.g., foods that have undergone changes in coloration, odor, or become moldy); spoiled or improperly stored animal livers Fresh meat, poultry, and fish, including fresh processed meats (e.g., lunch meats, hot dogs, breakfast sausage, and cooked sliced ham) Vegetables Broad bean pods (fava bean pods) All other vegetables Dairy Aged cheeses Processed cheeses, mozzarella, ricotta cheese, cottage cheese, and yogurt Beverages All varieties of tap beer and beers that have not been pasteurized so as to allow for ongoing fermentation and excessive amounts of caffeine. Concomitant use of alcohol with tranylcypromine tablets is not recommended. (Bottled and canned beers and wines contain little or no tyramine.) Other Concentrated yeast extract (e.g., Marmite), sauerkraut, most soybean products (including soy sauce and tofu), OTC supplements containing tyramine, and chocolate Brewer’s yeast, baker’s yeast, soy milk, commercial chain restaurant pizzas prepared with cheeses low in tyramine

12 CLINICAL PHARMACOLOGY 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). 12.2 Pharmacodynamics Although tranylcypromine is eliminated in 24 hours, recovery MAO activity takes up to 3 to 5 days [see Warnings and Precautions (5.9)] .

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).

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

20210618

1

3 DOSAGE FORMS & STRENGTHS Tablets containing tranylcypromine sulfate equivalent to 10 mg tranylcypromine are round, red-rose, film coated tablets, debossed with N538 on one side and plain on other side. Tablets: 10 mg (3)

Tranylcypromine Tranylcypromine TRANYLCYPROMINE SULFATE TRANYLCYPROMINE CELLULOSE, MICROCRYSTALLINE CALCIUM SULFATE DIHYDRATE CARBOXYMETHYLCELLULOSE SODIUM CROSCARMELLOSE SODIUM FD&C BLUE NO. 2 FD&C RED NO. 40 FD&C YELLOW NO. 6 HYPROMELLOSE 2910 (5 MPA.S) MAGNESIUM STEARATE POLYETHYLENE GLYCOL 6000 STARCH, CORN TALC TITANIUM DIOXIDE Red-rose N538

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility No carcinogenesis, mutagenesis, or fertility impairment studies were conducted.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility No carcinogenesis, mutagenesis, or fertility impairment studies were conducted.

ANDA206856

Tranylcypromine

Tranylcypromine

70954-538

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Tranylcypromine Tablets, USP 10 mg - Bottles of 100 tablets: NDC 70954-538-10 label

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

17 PATIENT COUNSELING INFORMATION Advise the patient to read FDA-approved patient labeling (Medication Guide). Suicidal Thoughts and Behaviors Advise 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 Crisis Advise 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 Syndrome Advise 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)] 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 tablets. Advise the patient to inform other physicians, pharmacists, and dentists about the treatment with tranylcypromine tablets. Interaction with Foods and Beverages [see Contraindications (4.1) and Drug Interactions (7.2)] Warn the patient to avoid tyramine-rich foods and beverages. Advise the patient to avoid eating foods if storage conditions or freshness is unknown and to be cautious of foods of unknown age or composition even if refrigerated. 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 tablets treatment abruptly, as withdrawal symptoms may occur and that the effect of tranylcypromine tablets may continue even after discontinuation [see Warnings and Precautions (5.8, 5.9)]. Aggravation of Coexisting Symptoms of Depression Inform the patient that tranylcypromine tablets 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)] Warn the patient about the possible adverse reactions that can impair the performance of potentially hazardous tasks such as driving a car or operating machinery. Tell the patient not to operate hazardous machinery and automobiles until they are reasonably certain that their ability to engage in such activities is not impaired. All trademarks are the property of their respective owners. Manufactured by: Novitium Pharma LLC 70 Lake Drive, East Windsor New Jersey 08520. Issued: 05/2021 LB4346-00

SPL MEDGUIDE SECTION MEDICATION GUIDE Tranylcypromine Tablets, USP (tran-ill-SIP-row-meen) What is the most important information I should know about tranylcypromine tablets? Tranylcypromine tablets can cause serious side effects including: Increase in suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment and when the tranylcypromine tablets 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 tablets are not for use in children. How can I watch for and try to prevent suicidal thoughts and actions? Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. Keep all follow-up visits with your healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. Call a healthcare provider right away if you have any of the following symptoms, especially if they are new, worse, or worry you: thoughts about suicide or dying new or worse depression feeling agitated, restless, angry or irritable trouble sleeping acting aggressive, being angry or violent an extreme increase in activity or talking (mania) attempts to commit suicide new or worse anxiety panic attacks new or worse irritability acting on dangerous impulses other unusual changes in behavior or mood A sudden, severe increase in blood pressure (hypertensive crisis). A hypertensive crisis can happen when you eat certain foods and drinks certain beverages during or after tranylcypromine tablets treatment. A hypertensive crisis can lead to stroke and death. People who have thyroid problems (hyperthyroidism) may have a higher chance of having a hypertensive crisis. Symptoms of a hypertensive crisis may include: sudden, severe headache vomiting a fast heartbeat (palpitations) or a change in the way your heart beats the pupils in your eyes increase in size fast or slow heart beat with chest pain nausea stiff or sore neck excessive sweating, sometimes with fever or cold, clammy skin light bothers your eyes bleeding in your brain A hypertensive crisis can also happen if you take tranylcypromine tablets with certain other medicines. See, “Who should not take tranylcypromine tablets?” Avoid foods and drinks with a lot of tyramine while taking tranylcypromine tablets 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 tablets see, “What should I avoid while taking tranylcypromine tablets?” What are tranylcypromine tablets? Tranylcypromine tablets are 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 tablets belong 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 tablets are not for use as the first medicine to treat MDD. It is not known if tranylcypromine tablets are safe and effective for use in children. Who should not take tranylcypromine tablets? Taking tranylcypromine tablets 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 tablets?” and “What are the possible side effects of tranylcypromine tablets?” Do not take tranylcypromine tablets if you: 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 antidepressants other antidepressants, such as amoxapine, bupropion, maprotiline, nefazodone, trazodone, vilazodone, vortioxetine amphetamines and methylphenidates medicines 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 supplements antihistamines (allergy medicines) triptans buspirone carbamazepine dextromethorphan dopamine hydroxytryptophan and tryptophan levodopa and methyldopa meperidine rasagline reserpine s-adenosyl-L-methionine (SAM-e) tapentadol tetrabenazine Ask your healthcare provider or pharmacist if you are not sure if you take any of these medicines. have a tumor on your adrenal gland called a pheochromocytoma or a type of tumor called a paraganglioma. Before taking tranylcypromine tablets, tell your healthcare provider about all your medical conditions, including if you: 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 tablets may harm your unborn baby. are breastfeeding or plan to breastfeed. Tranylcypromine passes into your breast milk. Do not breastfeed during treatment with tranylcypromine tablets. Talk to your healthcare provider about the best way to feed your baby while taking tranylcypromine tablets. Tell your healthcare provider about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. Tranylcypromine tablets and some other medicines may affect each other causing serious side effects. Tranylcypromine tablets may affect the way other medicines work, and other medicines may affect how tranylcypromine tablets work. Some medicines need to be stopped for a period of time before you can start taking tranylcypromine tablets and for a period of time after you stop taking tranylcypromine tablets. Know the medicines you take. Keep a list of them to show your healthcare providers, pharmacist, and dentist when you get a new medicine. How should I take tranylcypromine tablets? Take tranylcypromine tablets exactly as your healthcare provider tells you to take it. Your healthcare provider may need to change your dose of tranylcypromine tablets until it is the right dose for you. Do not stop taking tranylcypromine tablets without first talking to your healthcare provider. Stopping tranylcypromine tablets suddenly may cause withdrawal symptoms. See, “What are the possible side effects of tranylcypromine tablets?” Tell your healthcare provider if you think your condition has gotten worse during treatment with tranylcypromine tablets. If you take too much tranylcypromine 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 tablets? Do not eat foods or have drinks that have high amounts of tyramine while taking tranylcypromine tablets or for 2 weeks after you stop taking tranylcypromine 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. The table below lists some of the foods and drinks you should avoid while you take tranylcypromine tablets. Type of Food and Drink that contain Tyramine Meat, Poultry, and Fish air dried, aged and fermented meats, sausages, and salamis pickled herring any spoiled or improperly stored meat, poultry, and fish. These foods have a change in color, odor, or are moldy. spoiled or improperly stored animal livers Vegetables broad bean pods (fava bean pods) Dairy (milk products) aged cheeses Drinks all tap beers and other beers that have not been pasteurized Other concentrated yeast extract (such as Marmite) most soybean products (including soy sauce and tofu) sauerkraut ·over-the-counter supplements containing tyramine Do not drive, operate heavy machinery, or do other dangerous activities until you know how tranylcypromine tablets affect you. You should not drink alcohol while taking tranylcypromine tablets. What are the possible side effects of tranylcypromine tablets? Tranylcypromine tablets may cause serious side effects, including: See “What is the most important information I should know about tranylcypromine tablets?” Serotonin Syndrome. A potentially life-threatening problem called serotonin syndrome can happen when you take tranylcypromine tablets with certain other medicines. See, “Who should not take tranylcypromine tablets?” Symptoms of serotonin syndrome may include: agitation, confusion coma changes in blood pressure sweating high body temperature (hyperthermia) seizures becoming unstable seeing or hearing things that are not real (hallucinations) rapid pulse dizziness flushing fever tremors, stiff muscles, or muscle twitching nausea, vomiting, diarrhea If you have any of these symptoms, call your healthcare provider or go to the nearest hospital emergency room right away. Mania or hypomania (manic episodes) in people who have a history of bipolar disorder. greatly increased energy racing thoughts unusually grand ideas talking more or faster than usual severe problems sleeping reckless behavior excessive happiness or irritability Low blood pressure (hypotension) including a drop in your blood pressure when you stand or sit up (postural hypotension). This can happen more often in people who have high blood pressure (hypertension) and when the tranylcypromine tablets dose is changed. Postural hypotension may cause you to feel dizzy and faint (syncope). Changes in your blood pressure (hypotension or hypertension) during surgery and during the time around surgery (perioperative). Taking tranylcypromine tablets with certain medicines used for anesthesia can cause hypotension or hypertension. If you plan to have surgery, tell your surgeon or the healthcare provider who will give you anesthesia that you take tranylcypromine tablets. Your healthcare provider should stop tranylcypromine tablets at least 10 days before you have surgery. Withdrawal symptoms. Talk with your healthcare provider before you stop taking tranylcypromine tablets. Symptoms of withdrawal may include: dizziness irritability and agitation anxiety confusion changes in your mood seizures nausea problems sleeping abnormal dreams electric shock sensation (paresthesia) hypomania headache diarrhea sweating tiredness ringing in your ears (tinnitus) Liver problems Seizures (convulsions). Seizures have happened in people who take too much tranylcypromine tablets. Low blood sugar (hypoglycemia). Hypoglycemia has happened in people with diabetes who take medicines to lower blood sugar. Talk with your healthcare provider about checking your blood sugar during treatment with tranylcypromine tablets. Tell your healthcare provider if your blood sugar gets low. Worsening of symptoms that can happen with depression, such as anxiety and agitation. The most common side effects of tranylcypromine tablets include: dry mouth problems sleeping headache constipation shakiness (tremor) dizziness feeling sleepy overexcitement blurry vision These are not all the side effects of tranylcypromine tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How do I store tranylcypromine tablets? Store tranylcypromine tablets between 68°F to 77°F (20°C to 25°C). Store tranylcypromine tablets in a tight, light resistant container. Keep tranylcypromine tablets and all medicines out of the reach of children. General information about the safe and effective use of tranylcypromine tablets. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not take tranylcypromine tablets for a condition for which it was not prescribed. Do not give tranylcypromine 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 tablets that is written for health professionals. What are the ingredients in tranylcypromine tablets? Active Ingredient: tranylcypromine sulfate Inactive Ingredients: 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. All trademarks are the property of their respective owners. Manufactured by: Novitium Pharma LLC 70 Lake Drive, East Windsor New Jersey 08520. Issued: 05/2021 LB4346-00 For more information, contact Novitium Pharma LLC at 1-855-204-1431. This Medication Guide has been approved by the U.S. Food and Drug Administration.

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.

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)].

8.1 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 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Tranylcypromine Tablets, USP are available as round, red-rose, film coated tablets, debossed with N538 on one side and plain on other side, and contain tranylcypromine sulfate equivalent to 10 mg of tranylcypromine. They are supplied in bottles of 100 with a desiccant. 10 mg, bottles of 100 tablets: NDC 70954-538-10 Store 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]. Dispense in a tight, light resistant container.

BOXED WARNING WARNING: SUICIDAL THOUGHTS AND BEHAVIORS and HYPERTENSIVE CRISIS WITH SIGNIFICANT TYRAMINE USE Suicidal Thoughts and Behaviors A ntidepressants 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)]. WARNING: SUICIDAL THOUGHTS AND BEHAVIORS and HYPERTENSIVE CRISIS WITH SIGNIFICANT TYRAMINE USE See full prescribing information for complete boxed warning . Increased risk of suicidal thoughts and behavior in pediatric and young adult patients taking antidepressants. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors. Tranylcypromine tablets are not approved for use in pediatric patients. (5.1, 8.4) Excessive consumption of foods or beverages with significant tyramine content or certain drugs can precipitate hypertensive crisis. Monitor blood pressure, allow for medication free intervals, and advise patients to avoid foods and beverages with high tyramine content. (5.2, 7.1, 7.2)