Panex

Panex hydrochloride and Panex mesylate belong to a class of antidepressant agents known as selective serotonin-reuptake inhibitors (SSRIs). Despite distinct structural differences between compounds in this class, SSRIs possess similar pharmacological activity. As with other antidepressant agents, several weeks of therapy may be required before a clinical effect is seen. SSRIs are potent inhibitors of neuronal serotonin reuptake. They have little to no effect on norepinephrine or dopamine reuptake and do not antagonize α- or β-adrenergic, dopamine D2 or histamine H1 receptors. During acute use, SSRIs block serotonin reuptake and increase serotonin stimulation of somatodendritic 5-HT1A and terminal autoreceptors. Chronic use leads to desensitization of somatodendritic 5-HT1A and terminal autoreceptors. The overall clinical effect of increased mood and decreased anxiety is thought to be due to adaptive changes in neuronal function that leads to enhanced serotonergic neurotransmission. Side effects include dry mouth, nausea, dizziness, drowsiness, sexual dysfunction and headache. Side effects generally occur during the first two weeks of therapy and are usually less severe and frequent than those observed with tricyclic antidepressants. Panex hydrochloride and mesylate are considered therapeutic alternatives rather than generic equivalents by the US Food and Drug Administration (FDA); both agents contain the same active moiety (i.e. Panex), but are formulated as different salt forms. Clinical studies establishing the efficacy of Panex in various conditions were performed using Panex hydrochloride. Since both agents contain the same active moiety, the clinical efficacy of both agents is thought to be similar. Panex may be used to treat major depressive disorder (MDD), panic disorder with or without agoraphobia, obsessive-compulsive disorder (OCD), social anxiety disorder (social phobia), generalized anxiety disorder (GAD), post-traumatic stress disorder (PTSD) and premenstrual dysphoric disorder (PMDD). Panex has the most evidence supporting its use for anxiety-related disorders of the SSRIs. It has the greatest anticholinergic activity of the agents in this class and compared to other SSRIs, Panex may cause greater weight gain, sexual dysfunction, sedation and constipation.

Major Depressive Disorder

Panex® (Panex mesylate) is indicated for the treatment of MDD.

The efficacy of Panex in the treatment of a major depressive episode was established in 6-week controlled trials of outpatients whose diagnoses corresponded most closely to the DSM-III category of MDD. A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation.

The effects of Panex in hospitalized depressed patients have not been adequately studied.

The efficacy of Panex in maintaining a response in MDD for up to 1 year was demonstrated in a placebo-controlled trial. Nevertheless, the physician who elects to use Panex® (Panex mesylate) for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

Obsessive Compulsive Disorder

Panex® (Panex mesylate) is indicated for the treatment of obsessions and compulsions in patients with OCD as defined in the DSM-IV. The obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning.

The efficacy of Panex was established in two 12-week trials with obsessive compulsive outpatients whose diagnoses corresponded most closely to the DSM-IIIR category of OCD.

OCD is characterized by recurrent and persistent ideas, thoughts, impulses, or images (obsessions) that are egodystonic and/or repetitive, purposeful, and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable.

Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In this trial, patients assigned to Panex showed a lower relapse rate compared to patients on placebo. Nevertheless, the physician who elects to use Panex® (Panex mesylate) for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

Panic Disorder

Panex® (Panex mesylate) is indicated for the treatment of PD, with or without agoraphobia, as defined in DSM-IV. PD is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks.

The efficacy of Panex was established in three 10- to 12-week trials in PD patients whose diagnoses corresponded to the DSM-IIIR category of PD.

PD (DSM-IV) is characterized by recurrent unexpected panic attacks, ie, a discrete period of intense fear or discomfort in which 4 (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.

Long-term maintenance of efficacy was demonstrated in a 3-month relapse prevention trial. In this trial, patients with PD assigned to Panex demonstrated a lower relapse rate compared to patients on placebo. Nevertheless, the physician who prescribes Panex® (Panex mesylate) for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

Generalized Anxiety Disorder

Panex is indicated for the treatment of Generalized Anxiety Disorder (GAD), as defined in DSM-IV. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic.

The efficacy of Panex in the treatment of GAD was established in two 8-week placebo-controlled trials in adults with GAD. Panex has not been studied in children or adolescents with Generalized Anxiety Disorder.

Generalized Anxiety Disorder (DSM-IV) is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to control. It must be associated with at least 3 of the following 6 symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, sleep disturbance.

The efficacy of Panex in maintaining a response in patients with Generalized Anxiety Disorder, who responded during an 8-week acute treatment phase while taking Panex and were then observed for relapse during a period of up to 24 weeks, was demonstrated in a placebo-controlled trial. Nevertheless, the physician who elects to use Panex for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

Panex is an antidepressant in a group of drugs called selective serotonin reuptake inhibitors (SSRIs). Panex affects chemicals in the brain that may become unbalanced.

Panex is used to treat depression, obsessive-compulsive disorder, anxiety disorders, post-traumatic stress disorder (PTSD), and premenstrual dysphoric disorder (PMDD).

The Panex brand of Panex is used to treat hot flashes related to menopause. Panex is not for treating any other conditions.

Panex may also be used for purposes not listed in this medication guide.

Major Depressive Disorder

Usual Initial

Dosage: Panex® (Panex mesylate) should be administered as a single daily dose with or without food, usually in the morning. The recommended initial dose is 20 mg/day. Patients were dosed in a range of 20 to 50 mg/day in the clinical trials demonstrating the effectiveness of Panex in the treatment of MDD. As with all drugs effective in the treatment of MDD, the full effect may be delayed. Some patients not responding to a 20 mg dose may benefit from dose increases, in 10 mg/day increments, up to a maximum of 50 mg/day. Dose changes should occur at intervals of at least 1 week.

Maintenance Therapy: There is no body of evidence available to answer the question of how long the patient treated with Panex should remain on it. It is generally agreed that acute episodes of MDD require several months or longer of sustained pharmacologic therapy. Whether the dose needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown.

Systematic evaluation of the efficacy of Panex has shown that efficacy is maintained for periods of up to 1 year with doses that averaged about 30 mg.

Obsessive Compulsive Disorder

Usual Initial

Dosage: Panex® (Panex mesylate) should be administered as a single daily dose with or without food, usually in the morning. The recommended dose of Panex in the treatment of OCD is 40 mg daily. Patients should be started on 20 mg/day and the dose can be increased in 10 mg/day increments. Dose changes should occur at intervals of at least 1 week. Patients were dosed in a range of 20 to 60 mg/day in the clinical trials demonstrating the effectiveness of Panex in the treatment of OCD. The maximum dosage should not exceed 60 mg/day.

Maintenance Therapy: Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In this trial, patients with OCD assigned to Panex demonstrated a lower relapse rate compared to patients on placebo. OCD is a chronic condition, and it is reasonable to consider continuation for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment.

Panic Disorder

Usual Initial

Dosage: Panex® (Panex mesylate) should be administered as a single daily dose with or without food, usually in the morning. The target dose of Panex in the treatment of PD is 40 mg/day. Patients should be started on 10 mg/day. Dose changes should occur in 10 mg/day increments and at intervals of at least 1 week. Patients were dosed in a range of 10 to 60 mg/day in the clinical trials demonstrating the effectiveness of Panex. The maximum dosage should not exceed 60 mg/day.

Maintenance Therapy: Long-term maintenance of efficacy was demonstrated in a 3-month relapse prevention trial. In this trial, patients with PD assigned to Panex demonstrated a lower relapse rate compared to patients on placebo. PD is a chronic condition, and it is reasonable to consider continuation for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment.

Generalized Anxiety Disorder

Usual Initial

Dosage: Panex® (Panex mesylate) should be administered as a single daily dose with or without food, usually in the morning. In clinical trials the effectiveness of Panex was demonstrated in patients dosed in a range of 20 to 50 mg/day. The recommended starting dosage and the established effective dosage is 20 mg/day. There is not sufficient evidence to suggest a greater benefit to doses higher than 20 mg/day. Dose changes should occur in 10 mg/day increments and at intervals of at least 1 week.

Maintenance Therapy: Systematic evaluation of continuing Panex for periods of up to 24 weeks in patients with GAD who had responded while taking Panex during an 8-week acute treatment phase has demonstrated a benefit of such maintenance. Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment.

Special Populations

Treatment of Pregnant Women During the Third Trimester: Neonates exposed to Panex and other SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. When treating pregnant women with Panex during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.

Dosage for Elderly or Debilitated, and Patients with Severe Renal or Hepatic Impairment : The recommended initial dose is 10 mg/day for elderly patients, debilitated patients, and/or patients with severe renal or hepatic impairment. Increases may be made if indicated. Dosage should not exceed 40 mg/day.

Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders:

At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Panex®. Conversely, at least 14 days should be allowed after stopping Panex® before starting an MAOI intended to treat psychiatric disorders.

Use of Panex® With Other MAOIs, Such as Linezolid or Methylene Blue:

Do not start Panex® in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered.

In some cases, a patient already receiving Panex® therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Panex® should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Panex® may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue.

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with Panex® is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use.

Discontinuation of Treatment with Panex® (Panex mesylate): Symptoms associated with discontinuation of Panex have been reported. Patients should be monitored for these symptoms when discontinuing treatment, regardless of the indication for which Panex is being prescribed. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.

See also:
What is the most important information I should know about Panex?

Monoamine Oxidase Inhibitors

Concomitant use of an MAOI with Panex or within 14 days of stopping treatment with Panex is contraindicated because of an increased risk of serotonin syndrome. The use of Panex within 14 days of stopping an MAOI is also contraindicated.

Starting Panex in a patient who is being treated with linezolid or intravenous methylene blue, both of which inhibit monoamine oxidase, is also contraindicated because of an increased risk of serotonin syndrome.

Thioridazine

Concomitant use of Panex with thioridazine is contraindicated, because thioridazine prolongs the QT interval, and Panex can increase thioridazine levels.

Pimozide

Concomitant use of Panex with pimozide is contraindicated because pimozide prolongs the QT interval, and Panex increases pimozide levels.

Hypersensitivity to any Ingredient in Panex

Panex are contraindicated in patients with a history of hypersensitivity to Panex or any of the other ingredients in Panex.

Pregnancy

Menopausal VMS does not occur during pregnancy and Panex may cause fetal harm.

Use Panex as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Panex comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Panex refilled.
• Take Panex by mouth with or without food.
• Swallow Panex whole. Do not break, crush, or chew before swallowing.
• Taking Panex at the same time each day will help you remember to take it.
• Continue to take Panex even if you feel well. Do not miss any doses.
• Do not suddenly stop taking Panex without checking with your doctor. Side effects may occur. They may include mental or mood changes, numbness or tingling of the skin, dizziness, confusion, headache, trouble sleeping, or unusual tiredness. You will be closely monitored when you start Panex and whenever a change in dose is made.
• If you miss a dose of Panex, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Panex.

Panex is used to treat depression, panic attacks, anxiety disorders, and a severe form of premenstrual syndrome (premenstrual dysphoric disorder). It works by helping to restore the balance of a certain natural substance (serotonin) in the brain.

Panex is known as a selective serotonin reuptake inhibitor (SSRI). This medication may improve your mood, sleep, appetite, and energy level and may help restore your interest in daily living. It may decrease fear, anxiety, unwanted thoughts, and the number of panic attacks. Panex may lessen premenstrual symptoms such as irritability, increased appetite, and depression.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This medication may also be used to treat other mental/mood disorders (such as obsessive-compulsive disorder-OCD, post-traumatic stress disorder). It may also be used to treat hot flashes that occur with menopause.

How to use Panex

Read the Medication Guide and, if available, the Patient Information Leaflet provided by your pharmacist before you start taking Panex and each time you get a refill. If you have any questions, ask your doctor or pharmacist.

Take this medication by mouth with or without food as directed by your doctor, usually once daily in the morning. Taking this medication with food may decrease nausea. If this medication makes you sleepy during the day, talk to your doctor about taking it in the evening. Do not crush or chew this medication. Doing so can release all of the drug at once, increasing the risk of side effects. Also, do not split the tablets unless they have a score line and your doctor or pharmacist tells you to do so. Swallow the whole or split tablet without crushing or chewing.

The dosage is based on your medical condition, response to treatment, age, and other medications you may be taking. Be sure to tell your doctor and pharmacist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products). To reduce your risk of side effects, your doctor may start you at a low dose and gradually increase your dose. Follow your doctor's instructions carefully. Do not increase your dose or use this drug more often or for longer than prescribed. Your condition will not improve any faster, and your risk of side effects will increase. Take this medication regularly to get the most benefit from it. To help you remember, take it at the same time each day.

If you are taking Panex for premenstrual problems, your doctor may direct you to take it every day of the month or just for the 2 weeks before your period through the first full day of your period.

It is important to continue taking this medication even if you feel well. Do not stop taking this medication without consulting your doctor. Some conditions may become worse when this drug is suddenly stopped. Also, you may experience symptoms such as mood swings, headache, tiredness, sleep changes, and brief feelings similar to electric shock. To prevent these symptoms while you are stopping treatment with this drug, your doctor may reduce your dose gradually. Consult your doctor or pharmacist for more details. Report any new or worsening symptoms right away.

It may take up to several weeks before you get the full benefit of this drug.

Tell your doctor if your condition does not improve or if it worsens.

See also:
What other drugs will affect Panex?

Tryptophan

As with other serotonin reuptake inhibitors, an interaction between Panex and tryptophan may occur when they are coadministered. Adverse experiences, consisting primarily of headache, nausea, sweating, and dizziness, have been reported when tryptophan was administered to patients taking Panex. Consequently, concomitant use of Panex with tryptophan is not recommended.

Monoamine Oxidase Inhibitors

Pimozide

In a controlled study of healthy volunteers, after Panex was titrated to 60 mg daily, coadministration of a single dose of 2 mg pimozide was associated with mean increases in pimozide AUC of 151% and Cmax of 62%, compared to pimozide administered alone. The increase in pimozide AUC and Cmax is due to the CYP2D6 inhibitory properties of Panex. Due to the narrow therapeutic index of pimozide and its known ability to prolong the QT interval, concomitant use of pimozide and Panex is contraindicated.

Serotonergic Drugs

Based on the mechanism of action of Panex and the potential for serotonin syndrome, caution is advised when Panex is coadministered with other drugs or agents that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, fentanyl, tramadol, or St. John's Wort. The concomitant use of Panex with other SSRIs, SNRIs, or tryptophan is not recommended.

Thioridazine

Warfarin

Preliminary data suggest that there may be a pharmacodynamic interaction (that causes an increased bleeding diathesis in the face of unaltered prothrombin time) between Panex and warfarin. Since there is little clinical experience, the concomitant administration of Panex and warfarin should be undertaken with caution.

Triptans

There have been rare postmarketing reports of serotonin syndrome with the use of an SSRI and a triptan. If concomitant use of Panex with a triptan is warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

Drugs Affecting Hepatic Metabolism

The metabolism and pharmacokinetics of Panex may be affected by the induction or inhibition of drug-metabolizing enzymes.

Cimetidine— Cimetidine inhibits many cytochrome P450 (oxidative) enzymes. In a study where Panex (30 mg qd) was dosed orally for 4 weeks, steady-state plasma concentrations of Panex were increased by approximately 50% during coadministration with oral cimetidine (300 mg tid) for the final week. Therefore, when these drugs are administered concurrently, dosage adjustment of Panex after the 20 mg starting dose should be guided by clinical effect. The effect of Panex on cimetidine's pharmacokinetics was not studied.

Phenobarbital— Phenobarbital induces many cytochrome P450 (oxidative) enzymes. When a single oral 30 mg dose of Panex was administered at phenobarbital steady state (100 mg qd for 14 days), Panex AUC and T½ were reduced (by an average of 25% and 38%, respectively) compared to Panex administered alone. The effect of Panex on phenobarbital pharmacokinetics was not studied. Since Panex exhibits nonlinear pharmacokinetics, the results of this study may not address the case where the 2 drugs are both being chronically dosed. No initial Panex dosage adjustment is considered necessary when coadministered with phenobarbital; any subsequent adjustment should be guided by clinical effect.

Phenytoin— When a single oral 30 mg dose of Panex was administered at phenytoin steady state (300 mg qd for 14 days), Panex AUC and T½ were reduced (by an average of 50% and 35%, respectively) compared to Panex administered alone. In a separate study, when a single oral 300 mg dose of phenytoin was administered at Panex steady state (30 mg qd for 14 days), phenytoin AUC was slightly reduced (12% on average) compared to phenytoin administered alone. Since both drugs exhibit nonlinear pharmacokinetics, the above studies may not address the case where the 2 drugs are both being chronically dosed. No initial dosage adjustments are considered necessary when these drugs are coadministered; any subsequent adjustments should be guided by clinical effect.

Drugs Metabolized by Cytochrome CYP2D6

Many drugs, including most drugs effective in the treatment of MDD (Panex, other SSRIs, and many tricyclics), are metabolized by the cytochrome P450 isozyme CYP2D6. Like other agents that are metabolized by CYP2D6, Panex may significantly inhibit the activity of this isozyme. In most patients ( > 90%), this CYP2D6 isozyme is saturated early during Panex dosing. In one study, daily dosing of Panex (20 mg qd) under steady-state conditions increased single dose desipramine (100 mg) Cmax, AUC, and T½ by an average of approximately 2-, 5-, and 3-fold, respectively. Concomitant use of Panex with risperidone, a CYP2D6 substrate, has also been evaluated. In one study, daily dosing of Panex 20 mg in patients stabilized on risperidone (4 to 8 mg/day) increased mean plasma concentrations of risperidone approximately 4-fold, decreased 9-hydroxyrisperidone concentrations approximately 10%, and increased concentrations of the active moiety (the sum of risperidone plus 9-hydroxyrisperidone) approximately 1.4-fold. The effect of Panex on the pharmacokinetics of atomoxetine has been evaluated when both drugs were at steady state. In healthy volunteers who were extensive metabolizers of CYP2D6, Panex 20 mg daily was given in combination with 20 mg atomoxetine every 12 hours. This resulted in increases in steady state atomoxetine AUC values that were 6- to 8-fold greater and in atomoxetine Cmax values that were 3- to 4-fold greater than when atomoxetine was given alone. Dosage adjustment of atomoxetine may be necessary and it is recommended that atomoxetine be initiated at a reduced dose when it is given with Panex.

Concomitant use of Panex with other drugs metabolized by cytochrome CYP2D6 has not been formally studied but may require lower doses than usually prescribed for either Panex or the other drug.

Therefore, coadministration of Panex® (Panex mesylate) with other drugs that are metabolized by this isozyme, including certain drugs effective in the treatment of MDD (eg, nortriptyline, amitriptyline, imipramine, desipramine, and fluoxetine), phenothiazines, risperidone, and Type 1C antiarrhythmics (eg, propafenone, flecainide, and encainide), or that inhibit this enzyme (eg, quinidine), should be approached with caution.

However, due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, Panex, and thioridazine should not be coadministered.

Tamoxifen is a pro-drug requiring metabolic activation by CYP2D6. Inhibition of CYP2D6 by Panex may lead to reduced plasma concentrations of an active metabolite (endoxifen) and hence reduced efficacy of tamoxifen.

At steady state, when the CYP2D6 pathway is essentially saturated, Panex clearance is governed by alternative P450 isozymes, which, unlike CYP2D6, show no evidence of saturation.

Drugs Metabolized by Cytochrome CYP3A4

An in vivo interaction study involving the coadministration under steady-state conditions of Panex and terfenadine, a substrate for cytochrome CYP3A4, revealed no effect of Panex on terfenadine pharmacokinetics. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than Panex as an inhibitor of the metabolism of several substrates for this enzyme, including terfenadine, astemizole, cisapride, triazolam, and cyclosporine. Based on the assumption that the relationship between Panex's in vitro Ki and its lack of effect on terfenadine's in vivo clearance predicts its effect on other 3A4 substrates, Panex's extent of inhibition of CYP3A4 activity is not likely to be of clinical significance.

Tricyclic Antidepressants (TCA)

Caution is indicated in the coadministration of tricyclic antidepressants (TCAs) with Panex® (Panex mesylate), because Panex may inhibit TCA metabolism. Plasma TCA concentrations may need to be monitored and the dose of TCA may need to be reduced, if a TCA is coadministered with Panex® (Panex mesylate)..

Drugs Highly Bound to Plasma Protein

Because Panex is highly bound to plasma protein, administration of Panex® (Panex mesylate) to a patient taking another drug that is highly protein-bound may cause increased free concentrations of the other drug, potentially resulting in adverse events. Conversely, adverse effects could result from displacement of Panex by other highly bound drugs.

Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)

Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when Panex® (Panex mesylate) is initiated or discontinued.

Alcohol— Although Panex does not increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking Panex® (Panex mesylate).

Lithium— A multiple-dose study has shown that there is no pharmacokinetic interaction between Panex and lithium carbonate. However, due to the potential for serotonin syndrome, the concurrent administration of Panex and lithium should be undertaken with caution.

Digoxin— The steady-state pharmacokinetics of Panex was not altered when administered with digoxin at steady state. Mean digoxin AUC at steady state decreased by 15% in the presence of Panex. Since there is little clinical experience, the concurrent administration of Panex and digoxin should be undertaken with caution.

Diazepam— Under steady-state conditions, diazepam does not appear to affect Panex kinetics. The effects of Panex on diazepam were not evaluated.

Procyclidine— Daily oral dosing of Panex (30 mg qd) increased steady-state AUC0-24, Cmax, and Cmin values of procyclidine (5 mg oral qd) by 35%, 37%, and 67%, respectively, compared to procyclidine alone at steady state. If anticholinergic effects are seen, the dose of procyclidine should be reduced.

Beta-Blockers— In a study where propranolol (80 mg bid) was dosed orally for 18 days, the established steady-state plasma concentrations of propranolol were unaltered during coadministration with Panex (30 mg qd) for the final 10 days. The effects of propranolol on Panex have not been evaluated.

Theophylline— Reports of elevated theophylline levels associated with Panex treatment have been reported. While this interaction has not been formally studied, it is recommended that theophylline levels be monitored when these drugs are concurrently administered.

Fosamprenavir/Ritonavir— Coadministration of fosamprenavir/ ritonavir with Panex significantly decreased plasma levels of Panex. Any dose adjustment should be guided by clinical effect (tolerability and efficacy).

Electroconvulsive Therapy (ECT)— There are no clinical studies of the combined use of ECT and Panex.

See also:
What are the possible side effects of Panex?

The following serious adverse reactions are discussed elsewhere in labeling:

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot directly be compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to Panex in the one 8-week Phase 2 randomized, placebo-controlled trial and the two Phase 3 randomized, placebo-controlled, 12-week and 24-week trials for the treatment of moderate to severe VMS. In these trials, a total of 635 women were exposed to Panex 7.5 mg administered orally once daily and 641 women received placebo. The majority of Panex-treated patients were Caucasian (68%) and African American (30%), with a mean age of 55 years (range 40 to 73 years). Women with a history of suicidal ideation or suicidal behavior were excluded from these studies.

Adverse Reactions Leading to Study Discontinuation: A total of 4.7% of women taking Panex discontinued from the clinical trials due to an adverse reaction, compared to 3.7% of women on placebo; the most frequent adverse reactions leading to discontinuation among Panex-treated women were: abdominal pain (0.3%), attention disturbances (0.3%), headache (0.3%), and suicidal ideation (0.3%).

Common Adverse Reactions: Overall, based on investigators’ determinations about what events were likely to be drug-related, about 20% of women treated with Panex reported at least 1 adverse reaction in the three controlled studies. The most common adverse reactions (≥ 2% and more common among Panex-treated women) reported in these studies were headache, fatigue/malaise/lethargy, and nausea/vomiting. Of these commonly reported adverse reactions, nausea occurred primarily within the first 4 weeks of treatment and fatigue occurred primarily within the first week of treatment, and decreased in frequency with continued therapy.

The adverse reactions that occurred in at least 2% of patients in the Panex group and at a higher incidence than placebo are shown in Table 1 for the pooled Phase 2 and Phase 3 trials.

Certain symptoms were seen more frequently in women at the time of discontinuation of Panex compared to women discontinuing placebo, and have also been reported upon discontinuation of other formulations of Panex, particularly when abrupt. These include increased dreaming/nightmares, muscle cramps/spasms/twitching, headache, nervousness/anxiety, fatigue/tiredness, restless feeling in legs, and trouble sleeping/insomnia. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms with other formulations of Panex.

Serious Adverse Reactions: In the pooled Phase 2 and Phase 3 trials, three Panex-treated patients reported a serious adverse reaction of suicidal ideation and one Panex-treated patient reported a serious adverse reaction of suicide attempt. There were no serious adverse reactions of suicidal ideation or suicide attempt reported among the placebo-treated patients.

Postmarketing Experience

The following adverse reactions have been identified from clinical studies of Panex and during post-approval use of other formulations of Panex. Because some of these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System Disorders: Idiopathic thrombocytopenic purpura, Events related to impaired hematopoiesis (including aplastic anemia, pancytopenia, bone marrow aplasia, agranulocytosis).

Cardiac Disorders: Atrial fibrillation, Pulmonary edema, Ventricular fibrillation, Ventricular tachycardia (including torsades de pointes).

Gastrointestinal Disorders: Pancreatitis, Pancreatitis hemorrhagic, Vomiting.

General Disorders and Administration Site Conditions: Death, Drug withdrawal syndrome, Malaise.

Hepatobiliary Disorders: Drug-induced liver injury, Hepatic failure, Jaundice.

Immune System Disorders: Anaphylactoid reaction, Angioedema, Toxic epidermal necrolysis.

Investigations: Elevated liver tests (the most severe cases were deaths due to liver necrosis, and grossly elevated transaminases associated with severe liver dysfunction).

Metabolism and Nutrition Disorders: Diabetes mellitus inadequate control, Type 2 diabetes mellitus.

Nervous System Disorders: Neuroleptic malignant syndrome, Paresthesia, Somnolence, Tremor.

Psychiatric Disorders: Aggression, Agitation, Anxiety, Confusional state, Depression, Disorientation, Homicidal ideation, Insomnia, Restlessness.

Respiratory, Thoracic and Mediastinal Disorders: Pulmonary hypertension.

Skin and Subcutaneous Tissue Disorders: Hyperhidrosis, Stevens-Johnson syndrome.