TRANYLCYPROMINE SULFATE: Package Insert and Label Information (Page 2 of 4)

5.4 Activation of Mania/Hypomania

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

5.5 Hypotension

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

5.6 Hypotension and Hypertension during Anesthesia and Perioperative Care

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

5.7 Need for Emergency Treatment with Contraindicated Drugs

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

5.8 Discontinuation Syndrome

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

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

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

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

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

5.10 Hepatotoxicity

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

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

5.11 Seizures

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

5.12 Hypoglycemia in Diabetic Patients

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

5.13 Aggravation of Coexisting Symptoms of Depression

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

5.14 Adverse Effects on the Ability to Drive and Operate Machinery

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

6 ADVERSE REACTIONS

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

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

7 DRUG INTERACTIONS

7.1 Clinically Significant Drug Interactions

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

Time to Start Tranylcypromine Sulfate after Discontinuation of a Contraindicated Drug

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

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

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

Table 3 Clinically Significant Drug Interactions with Drug Classes*

Product Clinical Comment on Concomitant Usea Predominant 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 the 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 and derivatives 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 [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 Usea Predominant 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 [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 interactione [See Warnings and Precautions (5.5)]

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