Prescription Drugs

CLINICAL PHARMACOLOGY Pharmacodynamics The mechanism of action of REMERONSolTab® (mirtazapine) Orally Disintegrating Tablets, as with other drugs effective in the treatment of major depressive disorder, is unknown. Evidence gathered in preclinical studies suggests that mirtazapine enhances central noradrenergic and serotonergic activity. These studies have shown that mirtazapine acts as an antagonist at central presynaptic α2 adrenergic inhibitory autoreceptors and heteroreceptors, an action that is postulated to result in an increase in central noradrenergic and serotonergic activity. Mirtazapine is a potent antagonist of 5-HT2 and 5-HT3 receptors. Mirtazapine has no significant affinity for the 5-HT1A and 5-HT1B receptors. Mirtazapine is a potent antagonist of histamine (H1) receptors, a property that may explain its prominent sedative effects. Mirtazapine is a moderate peripheral α1 adrenergic antagonist, a property that may explain the occasional orthostatic hypotension reported in association with its use. Mirtazapine is a moderate antagonist at muscarinic receptors, a property that may explain the relatively low incidence of anticholinergic side effects associated with its use. Pharmacokinetics REMERONSolTab® (mirtazapine) Orally Disintegrating Tablets are rapidly and completely absorbed following oral administration and have a half-life of about 20-40 hours. Peak plasma concentrations are reached within about 2 hours following an oral dose. The presence of food in the stomach has a minimal effect on both the rate and extent of absorption and does not require a dosage adjustment. REMERONSolTab® (mirtazapine) Orally Disintegrating Tablets are bioequivalent to REMERON® (mirtazapine) Tablets. Mirtazapine is extensively metabolized after oral administration. Major pathways of biotransformation are demethylation and hydroxylation followed by glucuronide conjugation. In vitro data from human liver microsomes indicate that cytochrome 2D6 and 1A2 are involved in the formation of the 8-hydroxy metabolite of mirtazapine, whereas cytochrome 3A is considered to be responsible for the formation of the N-desmethyl and N-oxide metabolite. Mirtazapine has an absolute bioavailability of about 50%. It is eliminated predominantly via urine (75%) with 15% in feces. Several unconjugated metabolites possess pharmacological activity but are present in the plasma at very low levels. The (-) enantiomer has an elimination half-life that is approximately twice as long as the (+) enantiomer and therefore achieves plasma levels that are about three times as high as that of the (+) enantiomer. Plasma levels are linearly related to dose over a dose range of 15-80 mg. The mean elimination half-life of mirtazapine after oral administration ranges from approximately 20-40 hours across age and gender subgroups, with females of all ages exhibiting significantly longer elimination half-lives than males (mean half-life of 37 hours for females vs. 26 hours for males). Steady state plasma levels of mirtazapine are attained within 5 days, with about 50% accumulation (accumulation ratio = 1.5). Mirtazapine is approximately 85% bound to plasma proteins over a concentration range of 0.01-10 µg/mL. Special Populations Geriatric Following oral administration of REMERON® (mirtazapine) Tablets 20 mg/day for 7 days to subjects of varying ages (range, 25-74), oral clearance of mirtazapine was reduced in the elderly compared to the younger subjects. The differences were most striking in males, with a 40% lower clearance in elderly males compared to younger males, while the clearance in elderly females was only 10% lower compared to younger females. Caution is indicated in administering REMERONSolTab® (mirtazapine) Orally Disintegrating Tablets to elderly patients (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). Pediatrics Safety and effectiveness of mirtazapine in the pediatric population have not been established (see PRECAUTIONS). Gender The mean elimination half-life of mirtazapine after oral administration ranges from approximately 20-40 hours across age and gender subgroups, with females of all ages exhibiting significantly longer elimination half-lives than males (mean half-life of 37 hours for females vs. 26 hours for males) (see Pharmacokinetics). Race There have been no clinical studies to evaluate the effect of race on the pharmacokinetics of REMERONSolTab® (mirtazapine) . Renal Insufficiency The disposition of mirtazapine was studied in patients with varying degrees of renal function. Elimination of mirtazapine is correlated with creatinine clearance. Total body clearance of mirtazapine was reduced approximately 30% in patients with moderate (Clcr = 11-39 mL/min/1.73 m2) and approximately 50% in patients with severe (Clcr = < 10 mL/min/1.73 m2) renal impairment when compared to normal subjects. Caution is indicated in administering REMERONSolTab® (mirtazapine) to patients with compromised renal function (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). Hepatic Insufficiency Following a single 15 mg oral dose of REMERON®, the oral clearance of mirtazapine was decreased by approximately 30% in hepatically impaired patients compared to subjects with normal hepatic function. Caution is indicated in administering REMERONSolTab® (mirtazapine) to patients with compromised hepatic function (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). Clinical Trials Showing Effectiveness The efficacy of REMERON® (mirtazapine) Tablets as a treatment for major depressive disorder was established in four placebo-controlled, 6-week trials in adult outpatients meeting DSM-III criteria for major depressive disorder. Patients were titrated with mirtazapine from a dose range of 5 mg up to 35 mg/day. Overall, these studies demonstrated mirtazapine to be superior to placebo on at least three of the following four measures: 21-Item Hamilton Depression Rating Scale (HDRS) total score; HDRS Depressed Mood Item; CGI Severity score; and Montgomery and Asberg Depression Rating Scale (MADRS). Superiority of mirtazapine over placebo was also found for certain factors of the HDRS, including anxiety/somatization factor and sleep disturbance factor. The mean mirtazapine dose for patients who completed these four studies ranged from 21-32 mg/day. A fifth study of similar design utilized a higher dose (up to 50 mg) per day and also showed effectiveness. Examination of age and gender subsets of the population did not reveal any differential responsiveness on the basis of these subgroupings. In a longer-term study, patients meeting (DSM-IV) criteria for major depressive disorder who had responded during an initial 8-12 weeks of acute treatment on REMERON® were randomized to continuation of REMERON® or placebo for up to 40 weeks of observation for relapse. Response during the open phase was defined as having achieved a HAM-D 17 total score of ≤ 8 and a CGI-Improvement score of 1 or 2 at two consecutive visits beginning with week 6 of the 8-12 weeks in the open-label phase of the study. Relapse during the double-blind phase was determined by the individual investigators. Patients receiving continued REMERON® treatment experienced significantly lower relapse rates over the subsequent 40 weeks compared to those receiving placebo. This pattern was demonstrated in both male and female patients.

REMERONSolTab® (mirtazapine) Orally Disintegrating Tablets Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of REMERONSolTab® (mirtazapine) Orally Disintegrating Tablets or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. REMERONSolTab® (mirtazapine) is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use) DESCRIPTION REMERONSolTab® (mirtazapine) Orally Disintegrating Tablets are an orally administered drug. Mirtazapine has a tetracyclic chemical structure and belongs to the piperazino-azepine group of compounds. It is designated 1,2,3,4,10,14b-hexahydro-2-methylpyrazino [2,1-a] pyrido [2,3-c] benzazepine and has the empirical formula of C17H19N3. Its molecular weight is 265.36. The structural formula is the following and it is the racemic mixture: Mirtazapine is a white to creamy white crystalline powder which is slightly soluble in water. REMERONSolTab® (mirtazapine) is available for oral administration as an orally disintegrating tablet containing 15, 30, or 45 mg of mirtazapine. It disintegrates in the mouth within seconds after placement on the tongue allowing its contents to be subsequently swallowed with or without water. REMERONSolTab® (mirtazapine) also contains the following inactive ingredients: aspartame, citric acid, crospovidone, hypromellose, magnesium stearate, mannitol, microcrystalline cellulose, natural and artificial orange flavor, polymethacrylate, povidone, sodium bicarbonate, starch, and sucrose.

INDICATIONS REMERONSolTab® (mirtazapine) Orally Disintegrating Tablets are indicated for the treatment of major depressive disorder. The efficacy of REMERON® (mirtazapine) Tablets in the treatment of major depressive disorder was established in six-week controlled trials of outpatients whose diagnoses corresponded most closely to the Diagnostic and Statistical Manual of Mental Disorders - 3rd edition (DSM-III) category of major depressive disorder (see CLINICAL PHARMACOLOGY). A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least five of the following nine symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation. The effectiveness of REMERONSolTab® (mirtazapine) in hospitalized depressed patients has not been adequately studied. The efficacy of REMERON® in maintaining a response in patients with major depressive disorder for up to 40 weeks following 8-12 weeks of initial open-label treatment was demonstrated in a placebo- controlled trial. Nevertheless, the physician who elects to use REMERON® for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see CLINICAL PHARMACOLOGY). DOSAGE AND ADMINISTRATION Initial Treatment The recommended starting dose for REMERONSolTab® (mirtazapine) Orally Disintegrating Tablets is 15 mg/day, administered in a single dose, preferably in the evening prior to sleep. In the controlled clinical trials establishing the efficacy of REMERON® in the treatment of major depressive disorder, the effective dose range was generally 15-45 mg/day. While the relationship between dose and satisfactory response in the treatment of major depressive disorder for REMERON® has not been adequately explored, patients not responding to the initial 15 mg dose may benefit from dose increases up to a maximum of 45 mg/day. REMERON® has an elimination half-life of approximately 20-40 hours; therefore, dose changes should not be made at intervals of less than one to two weeks in order to allow sufficient time for evaluation of the therapeutic response to a given dose. Administration of REMERONSolTab® (mirtazapine) Orally Disintegrating Tablets Patients should be instructed to open tablet blister pack with dry hands and place the tablet on the tongue. The tablet should be used immediately after removal from its blister; once removed, it cannot be stored. REMERONSolTab® (mirtazapine) Orally Disintegrating Tablets will disintegrate rapidly on the tongue and can be swallowed with saliva. No water is needed for taking the tablet. Patients should not attempt to split the tablet. Elderly and Patients with Renal or Hepatic Impairment The clearance of mirtazapine is reduced in elderly patients and in patients with moderate to severe renal or hepatic impairment. Consequently, the prescriber should be aware that plasma mirtazapine levels may be increased in these patient groups, compared to levels observed in younger adults without renal or hepatic impairment (see PRECAUTIONS and CLINICAL PHARMACOLOGY). Maintenance/Extended Treatment It is generally agreed that acute episodes of depression require several months or longer of sustained pharmacological therapy beyond response to the acute episode. Systematic evaluation of REMERON® (mirtazapine) has demonstrated that its efficacy in major depressive disorder is maintained for periods of up to 40 weeks following 8-12 weeks of initial treatment at a dose of 15-45 mg/day (see CLINICAL PHARMACOLOGY). Based on these limited data, it is unknown whether or not the dose of REMERON® needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment. Switching Patients To or From a Monoamine Oxidase Inhibitor At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with REMERONSolTab® (mirtazapine) Orally Disintegrating Tablets. In addition, at least 14 days should be allowed after stopping REMERONSolTab® (mirtazapine) before starting an MAOI. HOW SUPPLIED REMERONSolTab® (mirtazapine) Orally Disintegrating Tablets are supplied as: 15 mg Tablets — round, white, with “T1Z” debossed on one side. Box of 30...............5 x 6 Unit Dose Blisters..................NDC 0052-0106-30 Long Term Care Carton Box of 30...............5 x 6 Unit Dose Blisters..................NDC 0052-0106-93 30 mg Tablets — round, white, with “T2Z” debossed on one side. Box of 30...............5 x 6 Unit Dose Blisters..................NDC 0052-0108-30 Long Term Care Carton Box of 30..................5 x 6 Unit Dose Blisters..................NDC 0052-0108-93 45 mg Tablets — round, white, with T4Z” debossed on one side. Box of 30..................5 x 6 Unit Dose Blisters..................NDC 0052-0110-30 Storage Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from light and moisture. Use immediately upon opening individual tablet blister. Manufactured for Organon USA Inc., Roseland, NJ 07068 by CIMA Labs Inc., Eden Prairie, MN 55344. FDA Rev date: 7/30/2007

PATIENT INFORMATION Medication Guide REMERONSolTab® (rem' - e - ron - sol' - tab) (mirtazapine) Orally Disintegrating Tablets Read the Medication Guide that comes with REMERONSolTab before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. If you have any questions about REMERONSolTab, talk to your healthcare provider. What is the most important information I should know about REMERONSolTab®? REMERONSolTab and other antidepressant medicines may cause serious side effects, including: 1. Suicidal thoughts or actions: REMERONSolTab and other antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment or when the dose is changed. Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions. Watch for these changes and call your healthcare provider right away if you notice: New or sudden changes in mood, behavior, actions, thoughts, or feelings, especially if severe. Pay particular attention to such changes when REMERONSolTab is started or when the dose is changed. Keep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms. Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency, especially if they are new, worse, or worry you: attempts to commit suicide acting on dangerous impulses acting aggressive or violent thoughts about suicide or dying new or worse depression new or worse anxiety or panic attacks feeling agitated, restless, angry or irritable trouble sleeping an increase in activity or talking more than what is normal for you other unusual changes in behavior or mood Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency. REMERONSolTab may be associated with these serious side effects: 2. Manic episodes: greatly increased energy severe trouble sleeping racing thoughts reckless behavior unusually grand ideas excessive happiness or irritability talking more or faster than usual 3. Decreased White Blood Cells called neutrophils, which are needed to fight infections. Tell your doctor if you have any indication of infection such as fever, chills, sore throat, or mouth or nose sores, especially symptoms which are flu-like. 4. Serotonin Syndrome. This condition can be life-threatening and may include: agitation, hallucinations, coma or other changes in mental status coordination problems or muscle twitching (overactive reflexes) racing heartbeat, high or low blood pressure sweating or fever nausea, vomiting, or diarrhea muscle rigidity 5. Seizures 6. Low salt (sodium) levels in the blood. Elderly people may be at greater risk for this. Symptoms may include: headache weakness or feeling unsteady confusion, problems concentrating or thinking or memory problems 7. Sleepiness. It is best to take REMERONSolTab close to bedtime. 8. Severe skin reactions: Call your doctor right away if you have any or all of the following symptoms: severe rash with skin swelling (including on the palms of the hands and soles of the feet) painful reddening of the skin and/or blisters/ulcers on the body or in the mouth 9. Severe allergic reactions: trouble breathing, swelling of the face, tongue, eyes or mouth rash, itchy welts (hives) or blisters, alone or with fever or joint pain 10. Increases in appetite or weight. Children and adolescents should have height and weight monitored during treatment. 11. Increased cholesterol and triglyceride levels in your blood Do not stop REMERONSolTab without first talking to your healthcare provider. Stopping REMERONSolTab too quickly may cause potentially serious symptoms including: dizziness abnormal dreams agitation anxiety fatigue confusion headache shaking tingling sensation nausea, vomiting sweating What is REMERONSolTab? REMERONSolTab is a prescription medicine used to treat depression. It is important to talk with your healthcare provider about the risks of treating depression and also the risks of not treating it. You should discuss all treatment choices with your healthcare provider. Talk to your healthcare provider if you do not think that your condition is getting better with REMERONSolTab treatment. Who should not take REMERONSolTab? Do not take REMERONSolTab if you: • are allergic to mirtazapine or any of the ingredients in REMERONSolTab. See the end of this Medication Guide for a complete list of ingredients in REMERONSolTab. take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take a MAOI, including the antibiotic linezolid. Do not take a MAOI within 2 weeks of stopping REMERONSolTab unless directed to do so by your physician. Do not start REMERONSolTab if you stopped taking a MAOI in the last 2 weeks unless directed to do so by your physician. People who take REMERONSolTab close in time to an MAOI may have serious or even life-threatening side effects. Get medical help right away if you have any of these symptoms: high fever uncontrolled muscle spasms stiff muscles rapid changes in heart rate or blood pressure confusion loss of consciousness (pass out) What should I tell my healthcare provider before taking REMERONSolTab? Ask if you are not sure. Before starting REMERONSolTab, tell your healthcare provider if you: are taking certain drugs such as: Triptans used to treat migraine headache Medicines used to treat mood, anxiety, psychotic or thought disorders, including tricyclics, lithium, SSRIs, SNRIs, or antipsychotics Tramadol used to treat pain Over-the-counter supplements such as tryptophan or St. John's wort Phenytoin, carbamazepine, or rifampicin (these drugs can decrease your blood level of REMERONSolTab) Cimetidine or ketoconazole (these drugs can increase your blood level of REMERONSolTab) Have or had: liver problems kidney problems heart problems seizures or convulsions bipolar disorder or mania a tendency to get dizzy or faint are pregnant or plan to become pregnant. It is not known if REMERONSolTab will harm your unborn baby. Talk to your healthcare provider about the benefits and risks of treating depression during pregnancy are breastfeeding or plan to breastfeed. Some REMERONSolTab may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking REMERONSolTab Tell your healthcare provider about all the medicines that you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. REMERONSolTab and some medicines may interact with each other, may not work as well, or may cause serious side effects. Your healthcare provider or pharmacist can tell you if it is safe to take REMERONSolTab with your other medicines. Do not start or stop any medicine while taking REMERONSolTab without talking to your healthcare provider first. If you take REMERONSolTab, you should not take any other medicines that contain mirtazapine including REMERON Tablets. How should I take REMERONSolTab? Take REMERONSolTab exactly as prescribed. Your healthcare provider may need to change the dose of REMERONSolTab until it is the right dose for you. Take REMERONSolTab at the same time each day, preferably in the evening at bedtime. Open the tablet blister pack with dry hands and place the tablet whole on the tongue, immediately after removal from the blister pack. REMERONSolTab will disintegrate rapidly on the tongue and can be swallowed with saliva. No water is needed for taking it. Do not attempt to split the REMERONSolTab. It is common for antidepressant medicines such as REMERONSolTab to take up to a few weeks before you start to feel better. Do not stop taking REMERONSolTab if you do not feel results right away. Do not stop taking or change the dose of REMERONSolTab without first talking to your doctor, even if you feel better. REMERONSolTab may be taken with or without food. If you miss a dose of REMERONSolTab, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of REMERONSolTab at the same time. If you take too much REMERONSolTab, call your healthcare provider or poison control center right away, or get emergency treatment. What should I avoid while taking REMERONSolTab? REMERONSolTab can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how REMERONSolTab affects you. Avoid drinking alcohol or taking diazepam (a medicine used for anxiety, insomnia and seizures, for example) or similar medicines while taking REMERONSolTab. If you are uncertain about whether certain medication can be taken with REMERONSolTab, please discuss with your doctor. What are the possible side effects of REMERONSolTab? REMERONSolTab may cause serious side effects, including all of those described in the section entitled "What is the most important information I should know about REMERONSolTab?" Common possible side effects in people who take REMERONSolTab include: sleepiness increased appetite, weight gain dry mouth constipation dizziness abnormal dreams Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of REMERONSolTab. For more information, ask your healthcare provider or pharmacist. CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE EFFECTS TO THE FDA AT 1-800-FDA-1088. How should I store REMERONSolTab? Store REMERONSolTab at room temperature 25°C (77°F). Storage at 15°C-30°C (59°F-86°F) is permitted occasionally. Keep REMERONSolTab away from light and moisture. Use immediately upon opening individual tablet blister. Keep REMERONSolTab and all medicines out of the reach of children. General information about REMERONSolTab Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use REMERONSolTab for a condition for which it was not prescribed. Do not give REMERONSolTab to other people, even if they have the same condition. It may harm them. This Medication Guide summarizes the most important information about REMERONSolTab. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about REMERONSolTab that is written for healthcare professionals. For more information about REMERONSolTab call 1-800-526-4099 or go to www.REMERONSolTab.com. What are the ingredients in REMERONSolTab? Active ingredient: mirtazapine Inactive ingredients 15mg, 30mg and 45mg tablets: Aspartame, citric acid anhydrous, crospovidone, magnesium stearate, mannitol, microcrystalline cellulose, natural and artificial orange flavor, sodium bicarbonate, hypromellose, povidone, sugar spheres, Eudragit E100. This Medication Guide has been approved by the U.S. Food and Drug Administration.

OVERDOSE Human Experience There is very limited experience with REMERONSolTab® (mirtazapine) Orally Disintegrating Tablets overdose. In premarketing clinical studies, there were eight reports of REMERON® overdose alone or in combination with other pharmacological agents. The only drug overdose death reported while taking REMERON® was in combination with amitriptyline and chlorprothixene in a non-US clinical study. Based on plasma levels, the REMERON® dose taken was 30-45 mg, while plasma levels of amitriptyline and chlorprothixene were found to be at toxic levels. All other premarketing overdose cases resulted in full recovery. Signs and symptoms reported in association with overdose included disorientation, drowsiness, impaired memory, and tachycardia. There were no reports of ECG abnormalities, coma or convulsions following overdose with REMERON® alone. Overdose Management Treatment should consist of those general measures employed in the management of overdose with any drug effective in the treatment of major depressive disorder. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients. Because of the rapid disintegration of REMERONSolTab® (mirtazapine) Orally Disintegrating Tablets, pill fragments may not appear in gastric contents obtained with lavage. Activated charcoal should be administered. There is no experience with the use of forced diuresis, dialysis, hemoperfusion or exchange transfusion in the treatment of mirtazapine overdosage. No specific antidotes for mirtazapine are known. In managing overdosage, consider the possibility of multiple-drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference (PDR). CONTRAINDICATIONS REMERONSolTab® (mirtazapine) Orally Disintegrating Tablets are contraindicated in patients with a known hypersensitivity to mirtazapine.

SIDE EFFECTS Associated with Discontinuation of Treatment Approximately 16 percent of the 453 patients who received REMERON® (mirtazapine) Tablets in US 6- week controlled clinical trials discontinued treatment due to an adverse experience, compared to 7 percent of the 361 placebo-treated patients in those studies. The most common events ( ≥ 1%) associated with discontinuation and considered to be drug related (i.e., those events associated with dropout at a rate at least twice that of placebo) included: Common Adverse Events Associated with Discontinuation of Treatment in 6-Week US REMERON® Trials Adverse Event Percentage of Patients Discontinuing with Adverse Event REMERON® (n=453) Placebo (n=361) Somnolence 10.4% 2.2% Nausea 1.5% 0% Commonly Observed Adverse Events in US Controlled Clinical Trials The most commonly observed adverse events associated with the use of REMERON® (mirtazapine) Tablets (incidence of 5% or greater) and not observed at an equivalent incidence among placebo-treated patients (REMERON® incidence at least twice that for placebo) were: Common Treatment-Emergent Adverse Events Associated with the Use of REMERON® in 6-Week US Trials Adverse Event Percentage of Patients Reporting Adverse Event REMERON® (n=453) Placebo (n=361) Somnolence 54% 18% Increased Appetite 17% 2% Weight Gain 12% 2% Dizziness 7% 3% Adverse Events Occurring at an Incidence of 1% or More Among REMERON®-Treated Patients The table that follows enumerates adverse events that occurred at an incidence of 1% or more, and were more frequent than in the placebo group, among REMERON® (mirtazapine) Tablets-treated patients who participated in short-term US placebo-controlled trials in which patients were dosed in a range of 5-60 mg/day. This table shows the percentage of patients in each group who had at least one episode of an event at some time during their treatment. Reported adverse events were classified using a standard COSTART-based dictionary terminology. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other investigations involving different treatments, uses and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the side effect incidence rate in the population studied. INCIDENCE OF ADVERSE CLINICAL EXPERIENCES1 ( ≥ 1%) IN SHORT-TERM US CONTROLLED STUDIES Body System Adverse Clinical Experience REMERON® (n=453) Placebo (n=361) Body as a Whole Asthenia 8% 5% Flu Syndrome 5% 3% Back Pain 2% 1% Digestive System Dry Mouth 25% 15% Increased Appetite 17% 2% Constipation 13% 7% Metabolic and Nutritional Disorders Weight Gain 12% 2% Peripheral Edema 2% 1% Edema 1% 0% Musculoskeletal System Myalgia 2% 1% Nervous System Somnolence 54% 18% Dizziness 7% 3% Abnormal Dreams 4% 1% Thinking Abnormal 3% 1% Tremor 2% 1% Confusion 2% 0% Respiratory System Dyspnea 1% 0% Urogenital System Urinary Frequency 2% 1% 1Events reported by at least 1% of patients treated with REMERON® are included, except the following events which had an incidence on placebo ≥ REMERON®: headache, infection, pain, chest pain, palpitation, tachycardia, postural hypotension, nausea, dyspepsia, diarrhea, flatulence, insomnia, nervousness, libido decreased, hypertonia, pharyngitis, rhinitis, sweating, amblyopia, tinnitus, taste perversion. ECG Changes The electrocardiograms for 338 patients who received REMERON® (mirtazapine) Tablets and 261 patients who received placebo in 6-week, placebo-controlled trials were analyzed. Prolongation in QTc ≥ 500 msec was not observed among mirtazapine-treated patients; mean change in QTc was +1.6 msec for mirtazapine and -3.1 msec for placebo. Mirtazapine was associated with a mean increase in heart rate of 3.4 bpm, compared to 0.8 bpm for placebo. The clinical significance of these changes is unknown. Other Adverse Events Observed During the Premarketing Evaluation of REMERON® During its premarketing assessment, multiple doses of REMERON® (mirtazapine) Tablets were administered to 2796 patients in clinical studies. The conditions and duration of exposure to mirtazapine varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, fixed dose and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. In the tabulations that follow, reported adverse events were classified using a standard COSTART-based dictionary terminology. The frequencies presented, therefore, represent the proportion of the 2796 patients exposed to multiple doses of REMERON® who experienced an event of the type cited on at least one occasion while receiving REMERON®. All reported events are included except those already listed in the previous table, those adverse experiences subsumed under COSTART terms that are either overly general or excessively specific so as to be uninformative, and those events for which a drug cause was very remote. It is important to emphasize that, although the events reported occurred during treatment with REMERON®, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Only those events not already listed in the previous table appear in this listing. Events of major clinical importance are also described in the WARNINGS and PRECAUTIONS sections. Body as a Whole: frequent: malaise, abdominal pain, abdominal syndrome acute; infrequent: chills, fever, face edema, ulcer, photosensitivity reaction, neck rigidity, neck pain, abdomen enlarged; rare: cellulitis, chest pain substernal. Cardiovascular System: frequent: hypertension, vasodilatation; infrequent: angina pectoris, myocardial infarction, bradycardia, ventricular extrasystoles, syncope, migraine, hypotension; rare: atrial arrhythmia, bigeminy, vascular headache, pulmonary embolus, cerebral ischemia, cardiomegaly, phlebitis, left heart failure. Digestive System: frequent: vomiting, anorexia; infrequent: eructation, glossitis, cholecystitis, nausea and vomiting, gum hemorrhage, stomatitis, colitis, liver function tests abnormal; rare: tongue discoloration, ulcerative stomatitis, salivary gland enlargement, increased salivation, intestinal obstruction, pancreatitis, aphthous stomatitis, cirrhosis of liver, gastritis, gastroenteritis, oral moniliasis, tongue edema. Endocrine System: rare: goiter, hypothyroidism. Hemic and Lymphatic System: rare: lymphadenopathy, leukopenia, petechia, anemia, thrombocytopenia, lymphocytosis, pancytopenia. Metabolic and Nutritional Disorders: frequent: thirst; infrequent: dehydration, weight loss; rare: gout, SGOT increased, healing abnormal, acid phosphatase increased, SGPT increased, diabetes mellitus. Musculoskeletal System: frequent: myasthenia, arthralgia; infrequent: arthritis, tenosynovitis; rare: pathologic fracture, osteoporosis fracture, bone pain, myositis, tendon rupture, arthosis, bursitis. Nervous System: frequent: hypesthesia, apathy, depression, hypokinesia, vertigo, twitching, agitation, anxiety, amnesia, hyperkinesia, paresthesia; infrequent: ataxia, delirium, delusions, depersonalization, dyskinesia, extrapyramidal syndrome, libido increased, coordination abnormal, dysarthria, hallucinations, manic reaction, neurosis, dystonia, hostility, reflexes increased, emotional lability, euphoria, paranoid reaction; rare: aphasia, nystagmus, akathisia, stupor, dementia, diplopia, drug dependence, paralysis, grand mal convulsion, hypotonia, myoclonus, psychotic depression, withdrawal syndrome. Respiratory System: frequent: cough increased, sinusitis; infrequent: epistaxis, bronchitis, asthma, pneumonia; rare: asphyxia, laryngitis, pneumothorax, hiccup. Skin and Appendages: frequent: pruritus, rash; infrequent: acne, exfoliative dermatitis, dry skin, herpes simplex, alopecia; rare: urticaria, herpes zoster, skin hypertrophy, seborrhea, skin ulcer. Special Senses: infrequent: eye pain, abnormality of accommodation, conjunctivitis, deafness, keratoconjunctivitis, lacrimation disorder, glaucoma, hyperacusis, ear pain; rare: blepharitis, partial transitory deafness, otitis media, taste loss, parosmia. Urogenital System: frequent: urinary tract infection; infrequent: kidney calculus, cystitis, dysuria, urinary incontinence, urinary retention, vaginitis, hematuria, breast pain, amenorrhea, dysmenorrhea, leukorrhea, impotence; rare: polyuria, urethritis, metrorrhagia, menorrhagia, abnormal ejaculation, breast engorgement, breast enlargement, urinary urgency. Other Adverse Events Observed During Postmarketing Evaluation of REMERON® Adverse events reported since market introduction, which were temporally (but not necessarily causally) related to mirtazapine therapy, include four cases of the ventricular arrhythmia torsades de pointes. In three of the four cases, however, concomitant drugs were implicated. All patients recovered. Drug Abuse And Dependence Controlled Substance Class REMERONSolTab® (mirtazapine) Orally Disintegrating Tablets are not a controlled substance. Physical and Psychologic Dependence REMERONSolTab® (mirtazapine) Orally Disintegrating Tablets have not been systematically studied in animals or humans for its potential for abuse, tolerance or physical dependence. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted and/or abused once marketed. Consequently, patients should be evaluated carefully for history of drug abuse, and such patients should be observed closely for signs of REMERONSolTab® (mirtazapine) misuse or abuse (e.g., development of tolerance, incrementations of dose, drug- seeking behavior). DRUG INTERACTIONS As with other drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic inhibition or enhancement, etc.) is a possibility (see CLINICAL PHARMACOLOGY). Drugs Affecting Hepatic Metabolism The metabolism and pharmacokinetics of REMERONSolTab® (mirtazapine) Orally Disintegrating Tablets may be affected by the induction or inhibition of drug-metabolizing enzymes. Drugs that are Metabolized by and/or Inhibit Cytochrome P450 Enzymes Many drugs are metabolized by and/or inhibit various cytochrome P450 enzymes, e.g., 2D6, 1A2, 3A4, etc.In vitro studies have shown that mirtazapine is a substrate for several of these enzymes, including 2D6, 1A2, and 3A4. While in vitro studies have shown that mirtazapine is not a potent inhibitor of any of these enzymes, an indication that mirtazapine is not likely to have a clinically significant inhibitory effect on the metabolism of other drugs that are substrates for these cytochrome P450 enzymes, the concomitant use of REMERONSolTab® (mirtazapine) with most other drugs metabolized by these enzymes has not been formally studied. Consequently, it is not possible to make any definitive statements about the risks of coadministration of REMERONSolTab® (mirtazapine) with such drugs. Alcohol Concomitant administration of alcohol (equivalent to 60 g) had a minimal effect on plasma levels of mirtazapine (15 mg) in 6 healthy male subjects. However, the impairment of cognitive and motor skills produced by REMERON® were shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking REMERONSolTab® (mirtazapine) . Diazepam Concomitant administration of diazepam (15 mg) had a minimal effect on plasma levels of mirtazapine (15 mg) in 12 healthy subjects. However, the impairment of motor skills produced by REMERON® has been shown to be additive with those caused by diazepam. Accordingly, patients should be advised to avoid diazepam and other similar drugs while taking REMERONSolTab® (mirtazapine) .