TRANYLCYPROMINE Drug Interactions: What You Need to Know

INTERACTIONS 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) , Warnings and Precautions (5.9) ]</span> . This period can be several weeks long (e.g., a minimum of 5 weeks for fluoxetine given fluoxetine&apos;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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.9)]</span> . 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2)]</span>. 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).

Table

5: Foods and Beverages with and without Significant Amounts of Tyramine Class of Food or Beverage Tyramine-Rich Foods and Beverages to Avoid Acceptable Foods and Drinks, 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 sulfate tabletsis 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

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 <span class="opacity-50 text-xs">[see Drug Interactions (7.1)]</span>. 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3)]</span>.

AND PRECAUTIONS 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 <span class="opacity-50 text-xs">[see Drug Interactions (7.1)]</span> . 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 <span class="opacity-50 text-xs">[see Drug Interactions (7.2)]</span>. 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 <span class="opacity-50 text-xs">[see Drug Interactions (7.1, 7.2)]</span>. 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. Treatment with tranylcypromine sulfate tablets and any concomitant serotonergic agents should be discontinued immediately if the above events occur, and supportive symptomatic treatment should be initiated.

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

5.5 Hypotension Hypotension, including postural hypotension, has been observed during therapy with tranylcypromine sulfate tablets. At doses above 30 mg daily, postural hypotension is a major adverse reaction and may result in syncope. Symptoms of postural hypotension are seen most commonly, but not exclusively, in patients with pre-existing hypertension. Blood pressure usually returns rapidly to pretreatment levels upon discontinuation of tranylcypromine sulfate tablets. Dosage increases should be made more gradually in patients with a tendency toward hypotension and/or postural hypotension (e.g., elderly patients) <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) and Use in Specific Populations (8.5)]</span>. Such patients should be closely observed for postural changes in blood pressure throughout treatment. Also, when tranylcypromine sulfate tablets are used concomitantly with other agents known to cause hypotension, the possibility of additive hypotensive effects should be considered <span class="opacity-50 text-xs">[see Drug Interactions (7.1)]</span>. Postural hypotension may be relieved by having patients lie down until blood pressure returns to normal.

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

5.7 Need for Emergency Treatment with Contraindicated Drugs If in the absence of therapeutic alternatives emergency treatment with a contraindicated product (e.g., linezolid, intravenous methylene blue, direct-acting sympathomimetic drugs such as epinephrine) becomes necessary and cannot be delayed, discontinue tranylcypromine sulfate tablets as soon as possible before initiating treatment with the other product and monitor closely for adverse reactions <span class="opacity-50 text-xs">[see Drug Interactions (7.1)]</span>.

5.8 Discontinuation Syndrome Abrupt discontinuation or dosage reduction of tranylcypromine sulfate tablets has been associated with the appearance of new symptoms that include dizziness, nausea, headache, irritability, insomnia, diarrhea, anxiety, fatigue, abnormal dreams, and hyperhidrosis. In general, discontinuation events occurred more frequently with longer duration of therapy. There have been spontaneous reports of adverse reactions occurring upon discontinuation of MAOIs, particularly when abrupt, including dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesia, such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these reactions are generally self-limiting, there have been reports of prolonged discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with tranylcypromine sulfate tablets. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) and Adverse Reactions (6)]</span>.

5.9 Risk of Clinically Significant Adverse Reactions due to Persistence of MAO Inhibition after Discontinuation Although excretion of tranylcypromine sulfate tablet is rapid, inhibition of MAO may persist up to 10 days following discontinuation. This should be taken into account when considering the use of potentially interacting substances or the consumption of tyramine-rich food or beverages <span class="opacity-50 text-xs">[see Drug Interactions (7.2)]</span> , or when interpreting adverse reactions observed after discontinuation of tranylcypromine sulfate tablets. Care should be taken to differentiate symptoms of persistent MAO inhibition from withdrawal symptoms <span class="opacity-50 text-xs">[see Drug Abuse and Dependence (9.3)]</span>.

5.10 Hepatotoxicity Hepatitis and elevated aminotransferases have been reported in association with tranylcypromine sulfate tablets administration. Patients should be monitored accordingly. Tranylcypromine sulfate tablets should be discontinued in patients who develop signs and symptoms of hepatotoxicity. Sedation has occurred in tranylcypromine sulfate tablets-treated patients with cirrhosis. Patients with cirrhosis receiving tranylcypromine sulfate tablets should be monitored for possible increased risks of central nervous system adverse reactions, such as excessive drowsiness.

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

5.12 Hypoglycemia in Diabetic Patients Some MAOIs have contributed to hypoglycemic episodes in diabetic patients receiving insulin or other blood-glucose-lowering agents. Monitor blood glucose in patients receiving both tranylcypromine sulfate tablets and blood-glucose-lowering agents. A reduction of the dosage of such agents may be necessary <span class="opacity-50 text-xs">[see Drug Interactions (7.1 )]</span>

5.13 Aggravation of Coexisting Symptoms of Depression Tranylcypromine sulfate tablets may aggravate coexisting symptoms in depression, such as anxiety and agitation.

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