Remeron (Remergil) - Treatment for Depression & Anxiety

Remeron (Mirtazapine)

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® is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use)

Remeron 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® 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® also contains the following inactive ingredients: aspartame, citric acid, crospovidone, hydroxypropyl methylcellulose, magnesium stearate, mannitol, microcrystalline cellulose, natural and artificial orange flavor, polymethacrylate, povidone, sodium bicarbonate, starch, and sucrose.

Remeron - 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® 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®.

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® 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® 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.

Indications and Usage for Remeron

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® 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).

Contraindications

RemeronSolTab® (mirtazapine) Orally Disintegrating Tablets are contraindicated in patients with a known hypersensitivity to mirtazapine.

Warnings

Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. 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 with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for RemeronSolTab® (mirtazapine) Orally Disintegrating Tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that RemeronSolTab® (mirtazapine) Orally Disintegrating Tablets are not approved for use in treating bipolar depression.

Agranulocytosis
In premarketing clinical trials, two (one with Sjögren’s Syndrome) out of 2796 patients treated with Remeron® (mirtazapine) Tablets developed agranulocytosis [absolute neutrophil count (ANC) < 500/mm3 with associated signs and symptoms, e.g., fever, infection, etc.] and a third patient developed severe neutropenia (ANC < 500/mm3 without any associated symptoms). For these three patients, onset of severe neutropenia was detected on days 61, 9, and 14 of treatment, respectively. All three patients recovered after Remeron® was stopped. These three cases yield a crude incidence of severe neutropenia (with or without associated infection) of approximately 1.1 per thousand patients exposed, with a very wide 95% confidence interval, i.e., 2.2 cases per 10,000 to 3.1 cases per 1000. If a patient develops a sore throat, fever, stomatitis or other signs of infection, along with a low WBC count, treatment with RemeronSolTab® (mirtazapine) Orally Disintegrating Tablets should be discontinued and the patient should be closely monitored.

MAO Inhibitors
In patients receiving other drugs for major depressive disorder in combination with a monoamine oxidase inhibitor (MAOI) and in patients who have recently discontinued a drug for major depressive disorder and then are started on an MAOI, there have been reports of serious and sometimes fatal reactions, including nausea, vomiting, flushing, dizziness, tremor, myoclonus, rigidity, diaphoresis, hyperthermia, autonomic instability with rapid fluctuations of vital signs, seizures, and mental status changes ranging from agitation to coma. Although there are no human data pertinent to such an interaction with RemeronSolTab® (mirtazapine) Orally Disintegrating Tablets, it is recommended that RemeronSolTab® not be used in combination with an MAOI, or within 14 days of initiating or discontinuing therapy with an MAOI.

More detailed information on Remeron

Most important fact about Remeron (Mirtazapine)

Remeron makes some people drowsy or less alert, and may affect judgment and thinking. Don't drive or participate in any hazardous activity that requires full mental alertness until you know whether Remeron has this effect on you.

How should you take Remeron?

Remeron may be taken with or without food. It is preferable to take it in the evening before you go to sleep. Even though you may begin to feel better in 1 to 4 weeks, continue taking Remeron exactly as prescribed. Regular daily doses are needed for the drug to work properly.

If you are using Remeron SolTabs, an orally disintegrating form of the drug, make sure your hands are dry before removing the tablet from the blister pack and immediately place the tablet on your tongue. Do not attempt to split the tablet; it will fall apart rapidly and can be swallowed with saliva.

If you miss a dose...
Take the forgotten dose if you remember within a few hours. Otherwise, skip the dose. Never try to "catch up" by doubling the dose.

Storage instructions...
Store at room temperature in a tight, light-resistant container.

What side effects may occur?

Side effects cannot be anticipated. If any develop or change in intensity, tell your doctor as soon as possible. Only your doctor can determine if it is safe for you to continue taking Remeron.

More common side effects may include:
Abnormal dreams and thinking, constipation, dizziness, dry mouth, flu-like symptoms, increased appetite, sleepiness, weakness, weight gain

Why should Remeron not be prescribed?

If you have ever had an allergic reaction to Remeron or similar drugs such as Ludiomil and Desyrel, you should not take Remeron. Be sure to tell your doctor about any drug reactions you have experienced.

You should also avoid Remeron if you are taking the antidepressants Nardil or Parnate (see "Special warnings about Remeron").

Special warnings about Remeron

In clinical studies, antidepressants increased the risk of suicidal thinking and behavior in children and adolescents with depression and other psychiatric disorders. Anyone considering the use of Remeron or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Remeron has not been studied in children or adolescents and is not approved for treating anyone less than 18 years old.

Additionally, the progression of major depression is associated with a worsening of symptoms and/or the emergence of suicidal thinking or behavior in both adults and children, whether or not they are taking antidepressants. Individuals being treated with Remeron and their caregivers should watch for any change in symptoms or any new symptoms that appear suddenly--especially agitation, anxiety, hostility, panic, restlessness, extreme hyperactivity, and suicidal thinking or behavior--and report them to the doctor immediately. Be especially observant at the beginning of treatment or whenever there is a change in dose.

Serious, sometimes fatal reactions have been known to occur when drugs such as Remeron are taken in combination with other drugs known as MAO inhibitors, including the antidepressants Nardil and Parnate. Never take Remeron with one of these drugs or within 14 days of discontinuing therapy with one of them; and allow at least 14 days between stopping Remeron and starting an MAO inhibitor.

If you develop flu-like symptoms, a sore throat, chills or fever, mouth sores, or any other signs of infection, call your doctor; these symptoms may signal a serious underlying condition.

Remeron tends to raise cholesterol levels in some people. If you have a cholesterol problem, be sure to mention it to your doctor before starting therapy with Remeron.

Remeron should be used with caution if you have active liver or kidney disease, or heart or blood pressure problems. Also be sure to tell your doctor if you have a history of seizures, mania (extremely high spirits), hypomania (mild excitability), drug use, or any other physical or emotional problems.

While first taking Remeron you may feel dizzy or light-headed, especially when getting up from a lying or sitting position. If getting up slowly doesn't help, or if this problem continues, notify your doctor.

If you must avoid phenylalanine, do not use the SolTab form of Remeron, which contains this substance.

Possible food and drug interactions when taking Remeron

Never combine Remeron with an MAO inhibitor; and do not drink alcohol while taking Remeron. If Remeron is taken with certain other drugs, the effects of either could be increased, decreased, or altered. It is especially important to check with your doctor before combining Remeron with tranquilizers such as Valium, Xanax, and Ativan.

Special information if you are pregnant or breastfeeding

The effects of Remeron during pregnancy have not been adequately studied. If you are pregnant or plan to become pregnant, tell your doctor immediately. It is not known whether Remeron appears in breast milk. However, because many drugs do make their way into breast milk, you should tell your doctor if you are breastfeeding or plan to breastfeed.

Recommended dosage

ADULTS
The usual starting dose is 15 milligrams taken daily before going to sleep. Depending upon your response, your dosage may be increased to as much as 45 milligrams a day.

CHILDREN
The safety and effectiveness of Remeron have not been established in children.

Overdosage

Any medication taken in excess can have serious consequences. If you suspect an overdose, seek medical attention immediately.

Symptoms of Remeron overdose include:
Drowsiness, impaired memory, mental confusion, rapid heartbeat