Tranylcypromine Sulfate Par

Tranylcypromine Sulfate Par is indicated for the treatment of major depressive disorder (MDD) in adult patients who have not responded adequately to other antidepressants. Tranylcypromine Sulfate Par is 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.

Recommended Dosage

Tranylcypromine Sulfate Par 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).

Switching To Or From Other Antidepressants

Switching From Contraindicated Antidepressants To Tranylcypromine Sulfate Par

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 Sulfate Par. 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 Sulfate Par to reduce the risk of additive effects.

Switching From Tranylcypromine Sulfate Par To Other MAOIs Or Contraindicated Antidepressants

After stopping Tranylcypromine Sulfate Par 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.

Discontinuing Treatment

Withdrawal effects, including delirium, have been reported with abrupt discontinuation of Tranylcypromine Sulfate Par therapy. Higher daily doses and longer duration of use appear to be associated with a higher risk of withdrawal effects. Consider discontinuing Tranylcypromine Sulfate Par therapy by slow, gradual dosage reduction.

Screen For Bipolar Disorder And Elevated Blood Pressure Prior To Starting Tranylcypromine Sulfate Par

Prior to initiating treatment with Tranylcypromine Sulfate Par:

• Screen patients for a history of mania.
• Measure blood pressure.

Combination With Certain Drugs

Concomitant use of Tranylcypromine Sulfate Par 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. Medication-free periods between administration of Tranylcypromine Sulfate Par and contraindicated agents are recommended.

Table 1: Products Contraindicated with the Use of Tranylcypromine Sulfate Par

Pheochromocytoma And Catecholamine-Releasing Paragangliomas

Tranylcypromine Sulfate Par is contraindicated in the presence of pheochromocytoma or other catecholamine-releasing paragangliomas because such tumors secrete pressor substances and can lead to hypertensive crisis.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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

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 Par, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

Hypertensive Crisis And Hypertension

Hypertensive Crisis

MAOIs, including Tranylcypromine Sulfate Par, 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. 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 Par and for 2 weeks after stopping Tranylcypromine Sulfate Par. Careful evaluation of the benefits and risks of Tranylcypromine Sulfate Par 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 Par, 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 Par, other drugs, foods or beverages suspected to contribute to the hypertensive crisis immediately.

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 Par, in patients not ingesting tyramine-rich foods or beverages. Assess blood pressure before prescribing Tranylcypromine Sulfate Par and closely monitor blood pressure in all patients taking Tranylcypromine Sulfate Par.

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 Par. In some cases of an interaction between Tranylcypromine Sulfate Par and SSRIs or SNRIs, the features of the syndrome resembled neuroleptic malignant syndrome.

The concomitant use, or use in rapid succession, of Tranylcypromine Sulfate Par 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 Par must be discontinued as soon as possible before initiating treatment with the other agent.

Treatment with Tranylcypromine Sulfate Par and any concomitant serotonergic agents should be discontinued immediately if the above events occur, and supportive symptomatic treatment should be initiated.

Activation Of Mania Or Hypomania

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

Hypotension

Hypotension, including postural hypotension, has been observed during therapy with Tranylcypromine Sulfate Par. 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 Par.

Dosage increases should be made more gradually in patients with a tendency toward hypotension and/or postural hypotension (e.g., elderly patients). Such patients should be closely observed for postural changes in blood pressure throughout treatment. Also, when Tranylcypromine Sulfate Par is used concomitantly with other agents known to cause hypotension, the possibility of additive hypotensive effects should be considered. Postural hypotension may be relieved by having patients lie down until blood pressure returns to normal.

Hypotension And Hypertension During Anesthesia And Perioperative Care

It is recommended that Tranylcypromine Sulfate Par 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 Par. 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 Par (e.g., hypertension associated with the use of vasoconstrictors in local anesthetics).

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 Par as soon as possible before initiating treatment with the other product and monitor closely for adverse reactions.

Discontinuation Syndrome

Abrupt discontinuation or dosage reduction of Tranylcypromine Sulfate Par 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 Par. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible.

Risk Of Clinically Significant Adverse Reactions Due To Persistence Of MAO Inhibition After Discontinuation

Although excretion of Tranylcypromine Sulfate Par 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 , or when interpreting adverse reactions observed after discontinuation of Tranylcypromine Sulfate Par. Care should be taken to differentiate symptoms of persistent MAO inhibition from withdrawal symptoms.

Hepatotoxicity

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

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

Seizures

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

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 Par and blood-glucose-lowering agents. A reduction of the dosage of such agents may be necessary

Aggravation Of Coexisting Symptoms Of Depression

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

Adverse Effects On The Ability To Drive And Operate Machinery

Some Tranylcypromine Sulfate Par 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 Par therapy does not impair their ability to engage in such activities.

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.

Hypertensive Crisis

Advise the patient on possible symptoms and instruct the patient to seek immediate medical attention if related signs or symptoms are present

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

Interaction With Other Drugs And Dietary Supplements

• 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 Sulfate Par.
• Advise the patient to inform other physicians, pharmacists, and dentists about the treatment with Tranylcypromine Sulfate Par.

Interaction With Foods And Beverages

• 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.

Withdrawal Symptoms

Warn the patient not to stop Tranylcypromine Sulfate Par treatment abruptly, as withdrawal symptoms may occur and that the effect of Tranylcypromine Sulfate Par may continue even after discontinuation.

Aggravation Of Coexisting Symptoms Of Depression

Inform the patient that Tranylcypromine Sulfate Par may aggravate coexisting symptoms in depression, such as anxiety and agitation and instruct them to contact their healthcare provider if they experience such symptoms.

Effects On Ability To Drive Or Use Machinery

• 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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No carcinogenesis, mutagenesis, or fertility impairment studies were conducted.

Use In Specific Populations

Pregnancy

Risk Summary

There are limited published reports of placental infarction and congenital anomalies in association with use of Tranylcypromine Sulfate Par during pregnancy; however, these reports may not adequately inform the presence or absence of drug-associated risk with the use of Tranylcypromine Sulfate Par during pregnancy. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Animal embryo-fetal development studies were not conducted with tranylcypromine; however, published animal reproduction studies report placental transfer of tranylcypromine in rats and a dose-dependent decrease in uterine blood flow in pregnant sheep. Advise pregnant women of the potential risk to a fetus.

Clinical Considerations

Labor Or Delivery

During labor and delivery, the potential for interactions between Tranylcypromine Sulfate Par and drugs or procedures (e.g., epidural anesthesia) should be taken into account in women who have received Tranylcypromine Sulfate Par.

Lactation

Risk Summary

Tranylcypromine is present in human milk. There is no available information on the effects of tranylcypromine on milk production. There is no available information on the effects of tranylcypromine on a breastfed child; however, because of the potential for serious adverse reactions in a breastfed infant, advise nursing women to discontinue breastfeeding during treatment with Tranylcypromine Sulfate Par.

Pediatric Use

Safety and effectiveness of Tranylcypromine Sulfate Par in the pediatric population have not been established. All risks associated with the use of Tranylcypromine Sulfate Par, including the risk of suicidal thoughts and behavior, apply to adults and pediatric patients.

Geriatric Use

Older patients may be at greater risk of postural hypotension and other serious adverse reactions. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

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

• Suicidal thoughts and behaviors
• Hypertensive crisis and hypertension
• Serotonin syndrome
• Activation of mania/hypomania
• Hypotension
• Hypotension and hypertension during anesthesia and perioperative care
• Discontinuation syndrome
• Persistence of MAO inhibition after discontinuation
• Hepatotoxicity
• Seizures
• Hypoglycemia in diabetic patients
• Aggravation of coexisting symptoms of depression
• Adverse effects on the ability to drive and operate machinery

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 Par:

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

Overdosage Symptoms, Signs, And Laboratory Abnormalities

Overdose of Tranylcypromine Sulfate Par can cause the adverse reactions generally associated with Tranylcypromine Sulfate Par administration. However, these reactions may be more severe, including fatal reactions. Effects reported with overdosage of Tranylcypromine Sulfate Par 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

Overdosage Management

There are no specific antidotes for Tranylcypromine Sulfate Par. For current information on the management of poisoning or overdosage, contact a poison control center at 1-800-222-1222.

Abrupt withdrawal of Tranylcypromine Sulfate Par following overdosage can precipitate withdrawal symptoms, including delirium.

Medical management should normally consist of general supportive measures, close observation of vital signs, and steps to counteract specific manifestations as they occur.The toxic effects of Tranylcypromine Sulfate Par may be delayed or prolonged following the last dose of the drug. Therefore, the patient should be closely observed for at least 1 week.

Data on the dialyzability of tranylcypromine are lacking.