Remeron RD

In healthy, CYP2D6 extensive metabolizer patients (n=32), amitriptyline (75 mg daily), at steady state, did not change the pharmacokinetics of steady state mirtazapine (30 mg daily) considerably and mirtazapine also did not change the pharmacokinetics of amitriptyline considerably. During combined use the following adverse reactions have been reported at considerably higher frequencies than with either drug alone: postural hypotension, impaired concentration (about 5 fold higher incidence), nausea (over 4 fold higher incidence) and dizziness (about 2 fold higher incidence). A CYP2D6 slow metabolizer patient experienced a serious adverse event following combined use of amitriptyline and mirtazapine. The subject complained of abdominal discomfort accompanied by dizziness and nausea and then leading to loss of consciousness for about 30 s. Apart from slight tremor (resembling myoclonic contractions) there were no other abnormalities. Caution is advised for the co-administration of amitriptyline with mirtazapine.

The impairment of mental and motor skills produced by mirtazapine has been shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking REMERON RD.

Based on the mechanism of action of mirtazapine and the potential for serotonin syndrome, caution is advised when REMERON RD is co-administered with other drugs or agents that may affect the serotonergic neurotransmitter systems, such as tryptophan, triptans, serotonin reuptake inhibitors, lithium, tramadol or St. John's wort (see Contraindications and Warnings and Precautions, Neurologic, Serotonin Syndrome/Neuroleptic Malignant Syndrome).

Pharmacodynamic interactions between REMERON RD and the herbal remedy St. John’s wort may occur and may result in an increase in undesirable effects. Dose adjustment of REMERON RD should be considered if clinically indicated.

No relevant clinical effects or significant changes in pharmacokinetics have been observed in healthy male subjects on concurrent treatment with subtherapeutic levels of lithium (600 mg/day for 10 days) at steady state and a single 30 mg dose of mirtazapine. The serum levels of lithium were approximately 0.3 mmol/L 10 hrs after dosing. The effects of higher doses of lithium on the pharmacokinetics of mirtazapine are unknown.

In an in vivo interaction study in healthy, CYP2D6 extensive metabolizer patients (n=24), mirtazapine (30 mg/day), at steady state, did not significantly change the pharmacokinetics of steady state paroxetine (40 mg/day), a CYP2D6 inhibitor. However, plasma concentrations of mirtazapine and its demethyl metabolite were slightly higher (about 18 and 25%, respectively) during combined administration with paroxetine. This difference is considered to be without clinical relevance. During combined use, side effects included exanthema (1 of 24 patients) that required withdrawal of the patient. Increases in AST and ALT were also reported, with a greater increase in men due to several outliers (including a patient that was withdrawn due to high AST (about 4 fold higher than the upper normal limit) and ALT (about 2 fold higher than the upper normal limit) levels; this patient also showed elevated WBC, neutrophils, decreased lymphocytes and basophils). AST/ALT levels returned to normal following the end of the treatment. Caution is advised for the co-administration of paroxetine with mirtazapine.

The impairment of motor skills produced by mirtazapine 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 REMERON RD.

In healthy male subjects (n=16) mirtazapine (30 mg daily), at steady state, caused a small (0.2) but statistically significant increase in the International Normalised Ratio (INR) in subjects treated with warfarin to achieve subtherapeutic levels of prothrombin activity (1.5-2.0 INR) at steady state. As at a higher dose of mirtazapine, a more pronounced effect can not be excluded. It is advisable to monitor the INR in case of concomitant treatment of warfarin with mirtazapine.

Combined use of REMERON RD and monoamine oxidase inhibitors (including linezolid, an antibiotic which is a reversible non-selective MAO inhibitor) is contraindicated due to the potential for serious reactions with features resembling serotonin syndrome or neuroleptic malignant syndrome (see Contraindications and Warnings and Precautions, Neurologic, Serotonin Syndrome/Neuroleptic Malignant Syndrome).

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 Action and Clinical Pharmacology).

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

Mirtazapine is extensively metabolized by CYP2D6, CYP3A4, and to a lesser extent by CYP1A2.

Phenytoin: In healthy male patients (n=18), phenytoin (200 mg daily) increased mirtazapine (30 mg daily) clearance, resulting in about a twofold decrease in plasma mirtazapine concentrations. Mirtazapine did not significantly affect the pharmacokinetics of phenytoin. During combined use of mirtazapine and phenytoin, 3 out of 19 patients experienced fatigue and 1 out of 19 patients developed rash (and none had experienced either fatigue or rash with mirtazapine alone or phenytoin alone). The rash was severe enough to necessitate withdrawal from the study.

When phenytoin, carbamazepine or another inducer of hepatic metabolism (such as rifampicin) is added to mirtazapine therapy, the mirtazapine dose may have to be increased. If treatment with such a medicinal product is discontinued, it may be necessary to reduce the mirtazapine dose.

Because mirtazapine is bound to plasma proteins (85%), care should be exercised when REMERON RD is co-administered to a patient who may be receiving another drug which is highly protein-bound.

In healthy, male, Caucasian patients (n=24), co-administration of the potent CYP3A4 inhibitor ketoconazole (200 mg b.i.d. for 6.5 days) increased the peak plasma levels and the AUC of a single 30 mg dose mirtazapine by approximately 40% and 50% respectively. During combined use, 2 severe adverse events have been reported: One patient experienced circulatory collapse and another patient experienced syncope. Both patients have lost consciousness for a brief period. Caution should be exercised when co-administering mirtazapine with potent CYP3A4 inhibitors, HIV protease inhibitors, azole antifungals, erythromycin or nefazodone.

In an in vivo non-randomized, interaction study subjects (n=6) in need of treatment with an antipsychiatric and antidepressant drug, the results of the effect of mirtazapine (30 mg daily) at steady state on the pharmacokinetics of risperidone (up to 3 mg b.i.d.) at steady state is inconclusive, due to high inter-patient variability and low number of patients. The study design does not permit conclusions to be made on the safety on the combined use of mirtazapine and risperidone. However, a case report of a male patient receiving combined treatment with mirtazapine (60 mg daily) and risperidone (3 mg daily) documents that, 6 weeks after initiation of this combination therapy, the patient developed pulmonary embolism and rhabdomyolysis. Caution is advised for the co-administration of risperidone with mirtazapine.

In healthy male patients (n=12), when cimetidine (800 mg b.i.d.) at steady state was co-administered with mirtazapine (30 mg daily) at steady state, the Area Under the Curve (AUC) of mirtazapine increased by about 60%. Mirtazapine did not significantly change the pharmacokinetics of cimetidine. During combined use, side effects included somnolence [10 of 12 patients (including 1 of moderate severity) vs. 7 of 12 with mirtazapine alone and none with cimetidine alone], arrhythmia (2 of 12 patients vs. none with mirtazapine or cimetidine alone). The mirtazapine dose may have to be decreased when concomitant treatment with cimetidine is started, or increased when cimetidine treatment is discontinued.

Patients should be instructed to open the tablet blister pack with dry hands and place the tablet on the tongue. The tablet should be used immediately after removal from the blister; once removed, it cannot be stored. REMERON RD 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 tablets (see Information for the Patient).

Symptoms associated with the discontinuation or dose reduction of REMERON RD Tablets have been reported. Patients should be monitored for these and other symptoms when discontinuing treatment or during dosage reduction of REMERON RD (see Warnings and Precautions and Adverse Reactions).

A gradual reduction in the dose over several weeks, rather than abrupt cessation, is recommended whenever is possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient’s clinical response (see Warnings and Precautions and Adverse Reactions).

(See Warnings and Precautions, Potential Association with Behavioural and Emotional Changes, Including Self-Harm.)

Do not take a double dose to make up for forgotten doses.

If a patient forgets to take the evening dose, advise the patient not to take the missed dose the next morning. Continue treatment in the evening (prior to sleep) with the normal dose.

In elderly patients, and patients with moderate to severe renal or hepatic impairment, limited pharmacokinetic data (see Action and Clinical Pharmacology) demonstrates increased serum concentration and/or reduced clearance of REMERON Tablets. REMERON RD should thus be dosed with care in these populations (see Action and Clinical Pharmacology, Pharmacokinetics).

It is generally agreed that acute episodes of depression require several months or longer of sustained therapy beyond response to the acute episode. Systematic evaluation of REMERON 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 Action and Clinical Pharmacology). Based on these limited data, it is unknown whether or not the dose of REMERON RD needed for continuation treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for continuation treatment and the appropriate dose for such treatment.

REMERON RD (mirtazapine) Orally Disintegrating Tablets should be administered as a single dose, preferably in the evening prior to sleep. The recommended initial dose is 15 mg daily. In clinical trials, patients generally received doses of REMERON Tablets in the range of 15-45 mg/day. While a relationship between dose and antidepressant response for mirtazapine has not been established, patients not responding to the initial 15 mg dose may benefit from dose increases up to a maximum of 45 mg/day. Mirtazapine has an elimination half-life of approximately 20-40 hours, therefore, dose changes should occur in intervals of not less than one week. Dosage adjustments may be made according to the tolerance and based on the patient’s response.

Post-marketing reports indicate that some neonates exposed to SSRI’s or other newer antidepressants, such as REMERON RD, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support and tube feeding (see Warnings and Precautions). When treating pregnant women with REMERON RD during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering REMERON RD in the third trimester.

Elevated cholesterol, serum glucose and triglycerides were the most common blood chemistry parameters observed in U.S. studies.

The plasma samples were drawn from non-fasting patients, and these parameters are affected by diet. Patients taking REMERON Tablets had increased appetite and weight gain, and are likely to have had increased food intake. Increased food intake may account for the increased triglyceride and cholesterol values. Moreover, LDL:HDL ratio data from a limited number of patients suggest that fat metabolism does not change with REMERON treatment, further suggesting that the increase in triglyceride and cholesterol values reflected increased dietary intake.

Mild changes in liver function are shown by increases in liver enzymes. However, changes are temporary, mild, and are not expected to negatively influence liver function. Premature terminations due to liver enzyme abnormalities were, respectively, REMERON Tablets, 1.7% and placebo, 1.1%.

The incidence of neutropenias in all clinical studies for REMERON Tablets was 1.5%. Most of the observed cases of neutropenia were mild, isolated and nonprogressive (see Warnings and Precautions).

Frequent: vomiting, anorexia. Infrequent: eructation, glossitis, cholecystitis, nausea and vomiting, gum hemorrhage, stomatitis, colitis, liver function tests abnormal. Rare: tongue discolouration, ulcerative stomatitis, salivary gland enlargement, increased salivation, intestinal obstruction, pancreatitis, aphthous stomatitis, cirrhosis of liver, gastritis, gastroenteritis, oral moniliasis, tongue edema.

There was evidence of adaptation to some adverse events with continued therapy (e.g., increased appetite, dizziness and somnolence).

Sixteen percent of patients treated with REMERON (mirtazapine) Tablets in U.S. short-term controlled studies discontinued treatment due to an adverse event, compared to 7% of patients treated with placebo. The adverse event that accounted for more than 5% of discontinuations with REMERON Tablets was somnolence (10%).

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.

Frequent: thirst. Infrequent: dehydration, weight loss. Rare: gout, AST increased, healing abnormal, acid phosphatase increased, ALT increased, diabetes mellitus.

Frequent: pruritus, rash. Infrequent: acne, exfoliative dermatitis, dry skin, herpes simplex, alopecia. Rare: urticaria, herpes zoster, skin hypertrophy, seborrhea, skin ulcer.

Frequent: myasthenia, arthralgia. Infrequent: arthritis, tenosynovitis. Rare: pathologic fracture, osteoporosis fracture, bone pain, myositis, tendon rupture, arthosis, bursitis.

The electrocardiograms for 338 patients who received REMERON Tablets and 261 patients who received placebo in the U.S. short-term controlled trials were analyzed, in which the QTc calculations using the method of Fridericia was employed. 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.

Frequent: malaise, abdominal pain, abdominal syndrome acute. Infrequent: chills, fever, face edema, ulcer, photosensitivity reaction, neck rigidity, neck pain, abdomen enlarged. Rare: cellulitis, substernal chest pain.

Frequent: cough increased, sinusitis. Infrequent: epistaxis, bronchitis, asthma, pneumonia. Rare: asphyxia, laryngitis, pneumothorax, hiccup.

There have been reports of adverse reactions upon the discontinuation of REMERON Tablets (particularly when abrupt), including but not limited to the following: dizziness, abnormal dreams, sensory disturbances (including paraethesias and electric shock sensations), agitation, anxiety, fatigue, confusion, headache, tremor, nausea, vomiting and sweating or other symptoms which may be of clinical significance (see Warnings and Precautions and Dosage and Administration).

Patients should be monitored for these or any other symptoms. A gradual reduction in the dosage over several weeks, rather than abrupt cessation, is recommended whenever possible. If intolerable symptoms occur following a decrease in dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient’s clinical response. These events are generally self-limiting. Symptoms associated with discontinuation have been reported for other antidepressants with serotonergic effects (see Warnings and Precautions and Dosage and Administration).

The most commonly observed adverse events related to the use of REMERON Tablets (5% or greater drug-related incidence for REMERON Tablets and at least twice that of placebo) were: somnolence (54% vs. 18%), increased appetite (17% vs. 2%), weight gain (12% vs. 2%), dizziness (7% vs. 3%).

Rare: lymphadenopathy, leukopenia, petechia, anemia, thrombocytopenia, lymphocytosis, pancytopenia.

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.

Rare: goiter, hypothyroidism.

Frequent: hypoesthesia, apathy, depression, hypokinesia, vertigo, twitching, agitation, anxiety, amnesia, hyperkinesia, paraesthesia. Infrequent: ataxia, delirium, delusions, depersonalization, dyskinesia, extrapyramidial 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.

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.

During worldwide controlled and uncontrolled clinical trials, REMERON Tablets were administered to 2796 patients. The listing of events which follows includes those events which were judged by the investigator to be adverse clinical experiences. The investigators used terminology of their own choice to describe the adverse experiences. 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 categories. It is important to emphasize that although the events occurred during treatment with REMERON Tablets, they were not necessarily drug-related. Following the adverse experience tabulations, the incidence of clinically significant laboratory values which occurred at a rate of ≥1% of patients is presented.

In the tabulations that follow, adverse events as reported by the investigator were classified using a standard COSTART-based Dictionary terminology. 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 Table 1 appear in this listing. Events of major clinical importance are also described in Warnings and Precautions.

REMERON RD is not indicated for use in patients below the age of 18 years (see Warnings and Precautions, General, Potential Association with Behavioural and Emotional Changes, Including Self-Harm; and Dosage and Administration).

Evidence from clinical trials and experience suggests that use in geriatric populations may be associated with differences in safety or effectiveness. A brief discussion can be found in the appropriate sections [see Warnings and Precautions, Neurologic, Somnolence; Special Populations, Geriatrics (>65 years of age); Dosage and Administration; Action and Clinical Pharmacology, Special Populations and Conditions, Geriatrics].

The efficacy of REMERON RD (mirtazapine) Orally Disintegrating Tablets 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 RD for extended periods should periodically evaluate the long-term response of the individual patient to the drug.

REMERON RD (mirtazapine) is indicated for the symptomatic relief of depressive illness.

In clinical trials, the only drug overdose death reported while taking REMERON (mirtazapine) Tablets was in combination with amitriptyline and chlorprohixene in a non-U.S. clinical study. Based on plasma levels, the REMERON dose taken was 30-45 mg, while plasma levels of amitriptyline and chlorprohixene were found to be at toxic levels. In other pre-marketing overdose cases with REMERON Tablets, the following signs and symptoms were reported: disorientation, drowsiness, impaired memory and tachycardia. There were no reports of ECG abnormalities, coma or convulsions following overdose with REMERON Tablets alone.

In post-marketing experience with more than 35 million patients exposed to REMERON (based on average treatment courses of 30 mg/day during 3 months), fatal cases of overdose with REMERON alone have been reported. In many cases details regarding the precise dose are lacking. Fatal acute overdoses with REMERON alone are documented at doses as low as approximately 440 mg, which is estimated from the post-mortem plasma levels, assuming linear pharmacokinetics. However, survival has also been reported with a single REMERON overdose as high as 1350 mg.

Present experience concerning overdose with REMERON alone indicates that symptoms are usually mild. Depression of the central nervous system with disorientation and prolonged sedation have been reported, together with tachycardia and mild hyper- or hypotension. However, there is a possibility of more serious outcomes (including fatalities) at dosages much higher than the therapeutic dose, especially with mixed overdosages.

Treatment should consist of those general measures employed in the management of overdose with any antidepressant.

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.

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 centre for additional information on the treatment of any overdose.

Each white, flat-faced, round, beveled edge, orally disintegrating tablet, coded with TZ2, with a characteristic orange odor, contains: mirtazapine 30 mg. Nonmedicinal ingredients: aspartame (contains phenylalanine), citric acid, crospovidone, hydroxypropyl methylcellulose, magnesium stearate, mannitol, microcrystalline cellulose, natural and artificial orange flavour, polymethyl acrylate, povidone, sodium bicarbonate, starch and sucrose. Boxes of 30 (5×6 unit Dose Blisters).

Each white, flat-faced, round, beveled edge, orally disintegrating tablet, coded with TZ1, with a characteristic orange odor, contains: mirtazapine 15 mg. Nonmedicinal ingredients: aspartame (contains phenylalanine), citric acid, crospovidone, hydroxypropyl methylcellulose, magnesium stearate, mannitol, microcrystalline cellulose, natural and artificial orange flavour, polymethyl acrylate, povidone, sodium bicarbonate, starch and sucrose. Boxes of 30 (5×6 unit Dose Blisters).

Each white, flat-faced, round, beveled edge, orally disintegrating tablet, coded with TZ4, with a characteristic orange odor, contains: mirtazapine 45 mg. Nonmedicinal ingredients: aspartame (contains phenylalanine), citric acid, crospovidone, hydroxypropyl methylcellulose, magnesium stearate, mannitol, microcrystalline cellulose, natural and artificial orange flavour, polymethyl acrylate, povidone, sodium bicarbonate, starch and sucrose. Boxes of 30 (5×6 unit Dose Blisters).

Recent analyses of placebo-controlled clinical trial safety databases from SSRIs (Selective Serotonin Reuptake Inhibitors) and other newer antidepressants suggest that use of these drugs in patients under the age of 18 may be associated with behavioural and emotional changes, including an increased risk of suicidal ideation and behaviour over that of placebo.

In U.S. short-term controlled studies, clinically significant ALT elevations (3 times the normal range) were noted in 2%, respectively, of patients treated with REMERON Tablets and in 0% of patients treated with placebo. Most patients did not develop signs or symptoms associated with compromised liver function. While some patients discontinued treatment due to ALT increases, other patients with elevations continued with enzyme levels returning to normal during ongoing treatment. Mirtazapine should be used with caution in patients with impaired hepatic function (see Dosage and Administration).

On rare occasions serotonin syndrome or neuroleptic malignant syndrome-like events have occurred in association with treatment of REMERON RD, particularly when given in combination with other serotonergic and/or neuroleptic/antipsychotic drugs. As these syndromes may result in potentially life-threatening conditions, treatment with REMERON RD should be discontinued if patients develop a combination of symptoms possibly including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma and supportive symptomatic treatment should be initiated. Due to the risk of serotonergic syndrome or neuroleptic malignant syndrome REMERON RD should not be used in combination with MAO inhibitors or serotonin-precursors (such as L-tryptophan, oxitriptan) and should be used with caution in patients receiving other serotonergic drugs (triptans, lithium, tramadol, St. John’s wort, most tricyclic antidepressants) or neuroleptics/antipsychotics (see Contraindications and Drug Interactions).

The use of REMERON (mirtazapine) Tablets was associated with somnolence in 54% of patients in U.S. short-term controlled studies, compared to 18% with placebo. In these studies, somnolence resulted in of 10% of mirtazapine-treated patients discontinuing treatment compared to 2% of placebo-treated patients. REMERON RD (mirtazapine) Orally Disintegrating Tablets may cause mental or motor impairment because of this prominent sedative effect. Thus, patients should be cautioned about engaging in hazardous activities, such as driving a car or operating dangerous machines, until they are reasonably certain that REMERON RD therapy does not adversely affect their ability to engage in such activities.

Care should be taken in patients with acute narrow-angle glaucoma and increased intra-ocular pressure.

Safe use of REMERON RD during pregnancy has not been established. Therefore, it should not be administered to women of childbearing potential or nursing mothers unless, in the opinion of the treating physician, the expected benefits to the patient outweigh the possible hazards to the child or fetus.

Post-marketing reports indicate that some neonates exposed to SSRIs (Selective Serotonin Reuptake Inhibitors) or other newer antidepressants, such as REMERON RD, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability and constant crying. The frequency of symptoms may vary with each drug. These features are consistent with either a direct toxic effect of SSRIs and other newer antidepressants, or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see Warnings and Precautions, Neurologic, Serotonin Syndrome/Neuroleptic Malignant Syndrome). When treating a pregnant woman with REMERON RD during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see Dosage and Administration).

The Extent of Exposure in Pregnancy During Clinical Trials: None.

In U.S. short-term controlled studies, the use of REMERON Tablets was associated with dizziness in 7% of patients, compared to 3% for placebo.

Pharmacokinetic studies revealed a decreased clearance in the elderly, especially in elderly females. Elderly patients may be more susceptible to adverse events such as sedation, dizziness or confusion. Care should be exercised in dosage and titration to higher doses (see Action and Clinical Pharmacology; Dosage and Administration and Warnings and Precautions, Neurologic, Somnolence).

Care should be taken in patients with micturition disturbances like prostate hypertrophy.

In pre-marketing clinical trials, two (one with Sjögren's Syndrome) out of 2796 patients treated with REMERON (mirtazapine) Tablets and one patient treated with imipramine developed agranulocytosis. In all three cases, the patients recovered after the drug with which they were being treated was stopped. In the post-marketing period with REMERON, very rare cases of agranulocytosis have been reported, mostly reversible, but in some cases fatal. All fatal cases concerned patients with an age above 65. If a patient develops a sore throat, fever, stomatitis or other signs of infection, along with a low WBC count, treatment with REMERON RD (mirtazapine) Orally Disintegrating Tablets should be discontinued and the patient should be closely monitored.

When discontinuing treatment, patients should be monitored for symptoms which may be associated with discontinuation, e.g., dizziness, abnormal dreams, sensory disturbances (including paraesthesia and electric shock sensations), agitation, anxiety, fatigue, confusion, headache, tremor, nausea, vomiting and sweating or other symptoms which may be of clinical significance (see Adverse Reactions). A gradual reduction in the dosage over several weeks, rather than abrupt cessation, is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient’s clinical response (see Adverse Reactions and Dosage and Administration).

The following additional precautions are listed alphabetically.

Care should be taken in patients with diabetes mellitus.

REMERON RD contains aspartame, a source of phenylalanine, therefore, may be harmful for people with phenylketonuria.

Safety and effectiveness in children under 18 years of age have not been established.

REMERON RD contains sucrose, therefore, patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

There are clinical trial and post-marketing reports with SSRIs and other newer antidepressants, in both pediatrics and adults, of severe agitation-type adverse events coupled with self-harm or harm to others. The agitation-type events include: akathisia, agitation, disinhibition, emotional lability, hostility, aggression, and depersonalization. In some cases, the events occurred within several weeks of starting treatment.

Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised in patients of all ages. This includes monitoring for agitation-type emotional and behavioural changes.

Treatment should be discontinued if jaundice occurs.

In U.S. short-term controlled studies the use of REMERON Tablets was associated with increased appetite in 17% and the complaint of weight gain in 12% of patients, compared to 2% for placebo in both cases. In these same trials, weight gain of ≥7% occurred in 7.5% of the patients taking REMERON Tablets compared to 0% in patients taking placebo. The average weight gain in the U.S. long-term controlled trials was 8 lbs. over 28 weeks.

Increased plasma concentrations of mirtazapine occur in patients with moderate and severe hepatic impairment (see Action and Clinical Pharmacology, Special Populations and Conditions). In such patients, upward dose titration should be carefully monitored (see Dosage and Administration).

Mania/hypomania occurred in approximately 0.2% (3/1299 patients) of REMERON-treated patients in all U.S. studies (controlled and non-controlled). Although the incidence of mania/hypomania was very low during treatment with REMERON Tablets, it should be used carefully in patients with a history of mania/hypomania.

Patients currently taking REMERON RD should not discontinue treatment abruptly, due to risk of discontinuation symptoms. At the time that a medical decision is made to discontinue an SSRI or other newer antidepressant drug, a gradual reduction in the dose, rather than an abrupt cessation, is recommended.

Please refer to Warnings and Precautions, General, Agranulocytosis.

Increased plasma concentrations of mirtazapine occur in patients with moderate and severe renal impairment and, to a lesser extent, in patients with hepatic impairment (see Action and Clinical Pharmacology, Special Populations and Conditions). In such patients, upward dose titration should be carefully monitored (see Dosage and Administration).

In pre-marketing clinical trials, only one seizure was reported in the 2796 U.S. and non-U.S. patients treated with REMERON Tablets. However, no controlled studies have been carried out in patients with a history of seizures. Therefore, care should be exercised when REMERON RD is used in these patients.

Suicidal ideation is inherent in depression and may persist until significant remission occurs. As with any patient receiving antidepressants, high-risk patients should be closely supervised during initial drug therapy. Prescriptions of REMERON RD should be written for the smallest quantity consistent with good patient management, in order to reduce the risk of overdose (see Warnings and Precautions, General, Potential Association with Behavioural and Emotional Changes, Including Self-Harm).

In U.S. short-term controlled studies, non-fasting cholesterol increases of >20% above the upper limits of normal were observed in 15% of patients taking REMERON Tablets compared to 7% for placebo. In these same studies, non-fasting triglycerides increased to >500 mg/dl in 6% of patients taking REMERON Tablets compared to 3% for placebo.

Mirtazapine has 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 behaviour, 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 REMERON RD misuse or abuse (e.g., development of tolerance, incrementation of dose, drug-seeking behaviour).

Clinical experience with mirtazapine in patients with concomitant systemic illness is limited. Accordingly, care is advisable in prescribing REMERON RD for patients with diseases or conditions that affect metabolism or hemodynamic responses. Mirtazapine has not been systematically evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or other significant heart disease. Mirtazapine was associated with significant orthostatic hypotension in early clinical pharmacology trials with normal human volunteers. Orthostatic hypotension was infrequently observed in clinical trials with depressed patients. REMERON RD should be used with caution in patients with known cardiovascular or cerebrovascular disease that could be exacerbated by hypotension (history of myocardial infarction, angina or ischemic stroke) and conditions that would predispose patients to hypotension (dehydration, hypovolemia and treatment with antihypertensive medication).

Safe use of REMERON RD during lactation has not been established.

Following administration of mirtazapine 20 mg/day for 7 days, oral clearance was reduced in older subjects (mean age 65; range 55-75) compared to younger subjects (see Table 3). The difference was greatest in males, with a 40% lower clearance for mirtazapine in the older vs. younger group. Caution is indicated in administering REMERON RD (mirtazapine) Orally Disintegrating Tablets in the elderly (see Warnings and Precautions and Dosage and Administration).

Mirtazapine is well absorbed following oral administration and its absolute bioavailability is approximately 50% after either single or multiple doses. Peak plasma concentrations are reached within about 2 hours following an oral dose. The time to peak plasma concentration is independent of dose. The presence of food in the stomach somewhat slows the rate but not the extent of absorption, and thus does not require a dosage adjustment.

Plasma levels are linear over a dose range of 30 to 80 mg. Steady-state plasma levels are attained within about 5 days. The half-life of elimination of mirtazapine after oral administration is approximately 20-40 hours.

REMERON RD (mirtazapine) Orally Disintegrating Tablets have been found to be bioequivalent to REMERON (mirtazapine) Tablets.

The mechanism of action of REMERON RD (mirtazapine) 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. The clinical relevance of this finding is unknown.

In a single-dose study conducted with mirtazapine 15 mg, the elimination half-life of mirtazapine was increased 40% in mild to moderately hepatically impaired subjects as compared to patients with normal hepatic function; this effect on elimination resulted in a 57% increase in AUC and a 33% decrease in clearance.

Mirtazapine is extensively metabolized and quantitatively eliminated via urine (75%) and feces (15%); approximately 90% of this elimination occurs within the first 72-96 hours. Major pathways of biotransformation are demethylation and oxidation followed by 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-demethyl and N-oxide metabolite. The demethyl metabolite is pharmacologically active and appears to have a similar pharmacokinetic profile as that of the parent compound.

The (−)enantiomer has an elimination half-life that is approximately twice as long, and achieves plasma levels that are three times as high as that of the (+)enantiomer.

In a single-dose study conducted with mirtazapine 15 mg, subjects with moderate and severe renal impairment showed a significant decrease in the clearance of ORG 3770 and a consequent increase in AUC (54% and 215% for moderate and severe renal impairment, respectively). Subjects with severe renal impairment had significantly higher peak plasma levels of ORG 3770 (about double that of subjects without renal impairment). These results suggest that caution must be exercised in administering REMERON RD to patients who may have compromised renal function.

In the same study above (see Action and Clinical Pharmacology, Special Populations and Conditions, Geriatrics) females of all ages (range 25-74) exhibited significantly longer elimination half-lives than males (mean half-life of 37 hours for females vs. 26 hours for males) (see Table 3). Although these differences result on average in higher area-under-the-curve (AUC) for females compared to males, there is considerable overlap in individual AUCs between groups. Because of substantial individual variation of AUC and half-life, no specific dosage recommendations based on sex are indicated (see Dosage and Administration).

Mirtazapine acts as an antagonist at central presynaptic α₂ adrenergic inhibitory autoreceptors and heteroreceptors, which results in an increase in central noradrenergic and serotonergic activity. The clinical relevance of this finding is unknown, however, this action may explain its antidepressant activity.

Mirtazapine is a potent antagonist of 5-HT₂ and 5-HT₃ receptors. The clinical relevance of this finding is unclear, however, the 5-HT₂ and 5-HT₃ antagonism by mirtazapine may account for its low rate of nausea, insomnia and anxiety as observed in clinical trials. Mirtazapine has no significant effect on 5-HT_1A and 5-HT_1B receptors.

Both enantiomers of mirtazapine appear to contribute to its pharmacological activity. The (+)enantiomer blocks 5-HT₂ receptors as well as α₂ receptors, and the (−)enantiomer blocks 5-HT₃ receptors. The clinical relevance of this finding is unclear, but this may explain its antidepressant activity and side-effect profile.

Mirtazapine is a potent histamine (H₁) receptor antagonist, which may contribute to its sedative effect and possibly to weight gain due to increased appetite.

Mirtazapine is a moderate peripheral α₁ adrenergic antagonist, a property which 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 occasional occurrence of anticholinergic side effects associated with its use as shown in clinical trials.

REMERON RD is not indicated for use in patients below the age of 18 years (see Warnings and Precautions, General, Potential Association with Behavioural and Emotional Changes, Including Self-Harm; and Dosage and Administration).

REMERON RD is contraindicated in patients who are known to be hypersensitive to the drug or any of its components. For a complete listing, see Dosage Forms, Composition and Packaging.

In patients receiving agents that may affect the serotonergic neurotransmitter systems in combination with a monoamine oxidase (MAO) inhibitor, there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued SSRI treatment and have begun treatment on a MAO inhibitor. Some cases presented with features resembling serotonin syndrome or neuroleptic malignant syndrome (see Warnings and Precautions, Neurologic, Serotonin Syndrome/Neuroleptic Malignant Syndrome). Therefore, REMERON RD should not be used in combination with MAO inhibitors (including linezolid, an antibiotic which is a reversible non-selective MAO inhibitor) or within a minimum of 2 weeks of terminating treatment with MAO inhibitors. Treatment with REMERON RD should then be initiated cautiously and dosage increased gradually until optimal response is reached. MAO inhibitors should not be introduced within 2 weeks of cessation of therapy with REMERON RD.