PARNATE Film-coated tablet Ref.[10919] Active ingredients:

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:

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 PARNATE, 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 PARNATE, 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 [see Drug Interactions (7.1)]. 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 PARNATE and for 2 weeks after stopping PARNATE [see Drug Interactions (7.2)].

Careful evaluation of the benefits and risks of PARNATE 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 PARNATE, 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 PARNATE, other drugs, foods or beverages suspected to contribute to the hypertensive crisis immediately [see Drug Interactions (7.1, 7.2)].

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

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

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

Treatment with PARNATE 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/Hypomania

In patients with bipolar disorder, treating a depressive episode with PARNATE or another antidepressant may precipitate a mixed/manic episode. Prior to initiating treatment with PARNATE, 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 PARNATE. 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 PARNATE.

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 PARNATE 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 PARNATE 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 PARNATE. 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 PARNATE (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 PARNATE 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 PARNATE 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 PARNATE. 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 PARNATE 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 PARNATE. 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 PARNATE administration. Patients should be monitored accordingly. PARNATE should be discontinued in patients who develop signs and symptoms of hepatotoxicity.

Sedation has occurred in PARNATE-treated patients with cirrhosis. Patients with cirrhosis receiving PARNATE 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 PARNATE 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 PARNATE 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

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

5.14 Adverse Effects on the Ability to Drive and Operate Machinery

Some PARNATE 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 PARNATE therapy does not impair their ability to engage in such activities.

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 PARNATE:

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

7.1 Clinically Significant Drug Interactions

Tables 3 and 4 lists drug classes and individual products, respectively, with a potential for interaction with PARNATE, 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 PARNATE after Discontinuation of a Contraindicated Drug

For products that are contraindicated with PARNATE, a time period of 4 to 5 half-lives of the other product or any active metabolite should elapse before starting treatment with PARNATE. 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 PARNATE 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 PARNATE

The potential for interactions persists after discontinuation of PARNATE 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 PARNATE, 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 PARNATE 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^*:

^* 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*:

^* 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)] ^dIf 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

PARNATE 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 PARNATE-treated patients to avoid foods and beverages with significant tyramine content during treatment with PARNATE 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:

Risk Summary

There are limited published reports of placental infarction and congenital anomalies in association with use of PARNATE during pregnancy; however, these reports may not adequately inform the presence or absence of drug-associated risk with the use of PARNATE 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 PARNATE and drugs or procedures (e.g., epidural anesthesia) should be taken into account in women who have received PARNATE [see Warnings and Precautions (5.6) and Drug Interactions (7.1)].

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 PARNATE.

Safety and effectiveness of PARNATE in the pediatric population have not been established. All risks associated with the use of PARNATE, including the risk of suicidal thoughts and behavior, apply to adults and pediatric patients [see Boxed Warning and Warnings and Precautions (5)].

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.

Abuse of PARNATE 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 PARNATE for patients at increased risk for substance abuse.

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