Pr
Dom-MIRTAZAPINE
(Mirtazapine Tablets) 15 mg and 30 mg
6111 Royalmount Ave., Suite 100 June 12, 2006 Montreal, Quebec H4P 2T4
PART I: HEALTH PROFESSIONAL INFORMATION 3 SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 9 DRUG INTERACTIONS 13 DOSAGE AND ADMINISTRATION 14 OVERDOSAGE 16 ACTION AND CLINICAL PHARMACOLOGY 16 STORAGE AND STABILITY 19 DOSAGE FORMS, COMPOSITION AND PACKAGING 19 PART II: SCIENTIFIC INFORMATION 21 PHARMACEUTICAL INFORMATION 21 DETAILED PHARMACOLOGY 22 TOXICOLOGY 25 REFERENCES 29 PART III: CONSUMER INFORMATION 31
Pr
Dom-MIRTAZAPINE
(Mirtazapine) 15 mg and 30 mg Tablets Antidepressant
| Route of Administration | Dosage Form/ Strength | Clinically Relevant Nonmedicinal Ingredients |
| Oral | tablet 15 mg, 30 mg | None. For a complete listing see Dosage Forms, Composition and Packaging section. |
Dom-MIRTAZAPINE (Mirtazapine) is indicated for the symptomatic relief of depressive illness. The efficacy of mirtazapine 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 mirtazapine for extended periods should periodically evaluate the long-term response of the individual patient to the drug.
Geriatrics (> 65 years of age):
Pharmacokinetic studies revealed a decreased clearance in the elderly, especially 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 CLINICAL PHARMACOLOGY, DOSAGE and ADMINISTRATION and WARNINGS AND PRECAUTIONS (Somnolence)].
In elderly patients, and patients with moderate to severe renal or hepatic impairment, limited pharmacokinetic data (see PHARMACOLOGY) demonstrates increased serum concentration and/or reduced clearance of mirtazapine. Mirtazapine should thus be dosed with care in these populations (See Pharmacokinetics Subsection of CLINICAL PHARMACOLOGY).
Pediatrics (0 to 18 years of age):
No data is available.
Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.
Pediatrics: Placebo-Controlled Clinical Trial Data
Adults and Pediatrics: Additional data
Discontinuation Symptoms
General
In U.S. short-term controlled studies the use of mirtazapine 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 $ 7% occurred in 7.5% of the patients taking mirtazapine compared to 0% in patients taking placebo. The average weight gain in the US long-term controlled trials was 8 lbs. over 28 weeks.
Carcinogenesis and mutagenesis
Carcinogenicity studies were conducted with mirtazapine given in the diet at doses of 2, 20, and 200 mg/kg/day to mice and 2, 20, and 60 mg/kg/day to rats. The highest doses used are approximately 20 and 12 times the maximum recommended human dose (MRHD) of 45 mg/day on a mg/m2 basis in mice and rats, respectively. There was an increased incidence of hepatocellular adenoma and carcinoma in male mice at the high dose. In rats, there was an increase in hepatocellular adenoma in females at the mid and high doses and in hepatocellular tumors and thyroid follicular adenoma/cystadenoma and carcinoma in males at the high dose. The data suggest that the above effects could possibly be mediated by non-genotoxic mechanisms, the relevance of which to humans is not known. The doses used in the mouse study may not have been enough to fully characterize the carcinogenic potential of mirtazapine tablets.
Mirtazapine was not mutagenic or clastogenic and did not induce general DNA damage as determined in several genotoxicity tests: Ames test, in vitro gene mutation assay in Chinese hamster V 79 cells, in vitro sister chromatid exchange assay in cultured rabbit lymphocytes, in vivo bone marrow micronucleus test in rats, and unscheduled DNA synthesis assay in HeLa cells.
Cardiovascular
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 mirtazapine compared to 7 % for placebo. In these same studies, non-fasting triglycerides increased to > 500 mg/dL in 6 % of patients taking mirtazapine compared to 3 % for placebo.
Clinical experience with mirtazapine in patients with concomitant systemic illness is limited. Accordingly, care is advisable in prescribing mirtazapine 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. Mirtazapine 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 ischernic stroke) and conditions that would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medication).
Dependence/Tolerance
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 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 mirtazapine misuse or abuse (e.g., development of tolerance, incrementations of dose, drug-seeking behavior).
When discontinuing treatment, patients should be monitored for symptoms which may be associated with discontinuation e.g. dizziness, abnormal dreams, sensory disturbances (including paresthesias and electric shock sensation), 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).
Hematologic
In premarketing clinical trials, two (one with Sjogren's Syndrome) out of 2,796 patients treated with 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. If a patient develops a sore throat, fever, stomatitis or other signs of infection, along with a low WBC count, treatment with mirtazapine should be discontinued and the patient should be closely monitored.
Hepatic/biliary/Pancreatic
In U.S. short-term controlled studies, clinically significant ALT (SGPT) elevations (3 times the normal range) were noted in 2%, respectively, of patients treated with mirtazapine and in 0% of patients treated with placebo. Most patients did not develop signs or symptoms associated with compromised liver function. While some patients were discontinued due to ALT increases, others 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).
Neurologic
In pre-marketing clinical trials, only one seizure was reported in the 2,796 U.S. and non-U.S. patients treated with mirtazapine. However, no controlled studies have been carried out in patients with a history of seizures. Therefore, care should be exercised when mirtazapine is used in these patients.
The use of 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 discontinuation of 10% of mirtazapine-treated patients compared to 2% of placebo-treated patients. Mirtazapine 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 mirtazapine therapy does not adversely affect their ability to engage in such activities.
In U.S. short-term controlled studies, the use of mirtazapine was associated with dizziness in 7% of patients compared to 3% for placebo.
Psychiatric
Mania/hypomania occurred in approximately 0.2% (3/1,299 patients) of mirtazapine treated patients in all U.S. studies (controlled and non-controlled). Although the incidence of mania/hypomania was very low during treatment with mirtazapine, it should be used carefully in patients with a history of mania/hypomania.
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 mirtazapine should be written for the smallest quantity consistent with good patient management, in order to reduce the risk of overdose (see WARNINGS AND PRECAUTIONS: POTENTIAL ASSOCIATION WITH BEHAVIORAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM).
Renal
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 Pharmacokinetic Subsection of CLINICAL PHARMACOLOGY). In such patients, upward dose titration should be carefully monitored (see DOSAGE and ADMINISTRATION).
Sexual Function/Reproduction
In a fertility study in rats, mirtazapine was given at doses up to 100 mg/kg (20 times the maximum recommended human dose (MRHD) on a mg/m2 basis). Mating and conception were not affected by the drug, but estrous cycling was disrupted at doses that were 3 or more times the MRHD and pre-implantation losses occurred at 20 times the MRHD.
Special Population
Safe use of mirtazapine during pregnancy has not been established. Therefore, it should not be administered to women of childbearing potential unless, in the opinion of the treating physician, the expected benefits to the patient outweighs the possible hazards to the fetus. Post-marketing reports indicate that some neonates exposed to SSRIs (Selective Serotonin Reuptake Inhibitors), or other newer antidepressants, such as MIRTAZAPINE, 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, hyperreflexia, tremor jitteriness, irritability and constant crying. 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-MAO Inhibitors). When treating a pregnant woman with MIRTAZAPINE during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. (See DOSAGE AND ADMINISTRATION).
Safe use of mirtazapine during lactation has not been established. Therefore, it should not be administered to nursing mothers unless, in the opinion of the treating physician, the expected benefits to the patient outweighs the possible hazards to the child.
Safety and effectiveness in children under 18 years of age have not been established.
Pharmacokinetic studies revealed a decreased clearance in the elderly, especially 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 CLINICAL PHARMACOLOGY, DOSAGE and ADMINISTRATION and WARNINGS AND PRECAUTIONS (Somnolence)].
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Adverse events leading to discontinuation of treatment
Sixteen percent of patients treated with mirtazapine tablets in U.S. short-term controlled studies discontinued treatment due to an adverse event compared to 7% of patients treated with placebo. Adverse events that accounted for more than 5% of discontinuations with mirtazapine were somnolence (10%).
Commonly Observed Adverse Events in US Short-Term Controlled Clinical Trials
The most commonly observed adverse events related to the use of mirtazapine (5% or greater drug related incidence for mirtazapine 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%).
Adverse Events Occurring at an Incidence of 1% or More Among Mirtazapine-Treated
Patients
The table that follows enumerates adverse events that occurred at an incidence of 1% or more among mirtazapine-treated patients (and greater than the incidence in placebo-treated patients) who participated in U.S. short-term placebo-controlled trials in which patients were dosed in a range of 5 to 60 mg per day. The investigator reported adverse clinical experiences using terms of their own choice. Reported adverse events were then classified using the 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.
TABLE 1
INCIDENCE OF ADVERSE CLINICAL EXPERIENCES ($ 1% for mirtazapine)
IN U.S. SHORT-TERM PLACEBO-CONTROLLED STUDIES 1,2,3
Body System U.S. Studies
Adverse Clinical Experience
N = Number of Patients
Body as a Whole
Mirtazapine Placebo
N = 453 N = 361
Asthenia 34 (8%) 17 (5%)
Flu Syndrome 22 (5%) 9 (3%)
Back Pain 9 (2%) 3 (1%)
Digestive System
| Dry Mouth | 112 (25%) | 54 (15%) |
| Increased Appetite | 76 (17%) | 7 (2%) |
| Constipation | 57 (13%) | 24 (7%) |
Metabolic and Nutritional Disorders
| Weight Gain | 54 (12%) | 6 (2%) |
| Peripheral Edema | 11 (2%) | 4 (1%) |
| Edema | 6 (1%) | 1 (0%) |
Musculoskeletal System
Myalgia 9 (2%) 3 (1%) | ||
|---|---|---|
| Nervous System | ||
| Somnolence | 243 (54%) | 65(18%) |
| Dizziness | 33 (7%) | 12(3%) |
| Abnormal Dreams | 19 (4%) | 5 (1%) |
| Thinking Abnormal | 15 (3%) | 4 (1%) |
| Tremor | 7 (2%) | 2(1%) |
| Confusion | 9 (2%) | 1(0%) |
Respiratory System
Dyspnea 5 (1%) 1 (0%)
Urogenital System
Urinary Frequency 8 (2%) 5 (1%)
% rounded off to the nearest whole integer
Events which had an incidence on placebo> Mirtazapine: Infection, pain, headache, nausea, diarrhea and insomnia.
Events which had an incidence of Mirtazapine comparable to placebo: Chest pain, palpitation, tachycardia, postural
hypotension, dyspepsia, flatulence, libido decreased, hypertonia, nervousness, rhinitis, pharyngitis, sweating, amblyopia, tinnitus and taste perversion.
There was evidence of adaptation to some adverse events with continued therapy (e.g. increased appetite, dizziness and somnolence).
ECG Changes
The electrocardiograms for 338 patients who received mirtazapine 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.
Abnormal Laboratory Findings
Elevated cholesterol, serum glucose, and triglycerides were the most common blood chemistry parameters observed in US studies. The plasma samples were drawn from non-fasting patients, and these parameters are affected by diet. Patients taking mirtazapine 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 mirtazapine 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 mirtazapine 1.7% and placebo 1. 1 %. The incidence of neutropenias in all clinical studies for mirtazapine was 1.5%. Most of the observed cases of neutropenia were mild isolated and nonprogressive (Please see WARNINGS AND PRECAUTIONS). Other Adverse Events Observed During the Premarketing Evaluation of Mirtazapine During worldwide controlled and uncontrolled clinical trials, mirtazapine was administered to 2,796 patients. The listing of events which follows are 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 mirtazapine, they were not necessarily drug related. Following the adverse experiences 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 the WARNING AND PRECAUTIONS section.
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, 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.
Respiratory Systems
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.
Adverse Reactions following Discontinuation of Treatment (or Dose Reduction)
There have been reports of adverse reactions upon the discontinuation of mirtazapine (particularly when abrupt), including but not limited to the following: dizziness, abnormal
dreams, sensory disturbances (including paresthesias 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 the 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).
Post-Market Adverse Drug Reaction
Adverse events reported since market introduction, which were temporally (but not necessary 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-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).
The metabolism and pharmacokinetics of mirtazapine may be affected by the induction or inhibition of drug-metabolizing enzymes.
Many drugs are metabolized by and/or inhibit various cytochrome P450 isoenzymes 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 also shown that mirtazapine is not a potent inhibitor of any of these enzymes, the concomitant use of mirtazapine with other drugs metabolized by these enzymes has not been formally evaluated. Therefore, it is not possible to make any definite statements about the risks of co-administration of mirtazapine with such drugs.
Because mirtazapine is bound to plasma proteins (85%), care should be exercised when mirtazapine is co-administered to a patient who may be receiving another drug which is highly protein bound.
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 mirtazapine.
Drug-Food Interactions
The impairment of mental and motor skills produced by mirtazapine have been shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking mirtazapine.
Drug-Herb Interactions
In common with SSRI's and SNRI, pharmacodynamic interactions between mirtazapine and the herbal remedy St. John's Wort may occur and may result in an increase in undesirable effects. Dose adjustment of mirtazapine should be considered if clinically indicated.
There are no known interactions of mirtazapine with commonly used laboratory tests.
Dosing Considerations
Adult patients
Discontinuation of mirtazapine treatment
Children
Initial Treatment: Dom-MIRTAZAPINE (mirtazapine) 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 mirtazapine in the range of 15 to 45 mg per 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 per day, (See ACTIONS and CLINICAL PHARMACOLOGY, Clinical Trials Showing Efficacy sub-section). Mirtazapine has an elimination half-life of approximately 20 to 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. Longer-Term Treatment: 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 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 15 - 45 mg/day (See ACTIONS AND CLINICAL PHARMACOLOGY). Based on these limited data, it is unknown whether or not the dose of mirtazapine 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.
Symptoms associated with the discontinuation or dosage reduction of Dom-MIRTAZAPINE have been reported. Patients should be monitored for these and other symptoms when discontinuing treatment or during dosage reduction (See WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS). A gradual reduction in the dose 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 WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS).
Post-marketing reports indicate that some neonates exposed to MIRTAZAPINE, SSRIs, or other newer antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating a pregnant woman with MIRTAZAPINE during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering MIRTAZAPINE in the third trimester.
Elderly and Patients with Moderate to Severe Renal or Hepatic Impairment
: In elderly patients, and patients with moderate to severe renal or hepatic impairment, limited pharmacokinetic data (see PHARMACOLOGY) demonstrates increased serum concentration and/or reduced clearance of mirtazapine. Mirtazapine should thus be dosed with care in these populations (See Pharmacokinetics Subsection of CLINICAL PHARMACOLOGY).
Children
(see WARNINGS AND PRECAUTIONS: POTENTIAL ASSOCIATION WITH BEHAVIORAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM).
In clinical trials, the only drug overdose death reported while taking mirtazapine tablets was in combination with amitriptyline and chlorprohixene in a non-U.S clinical study. Based on plasma levels, the mirtazapine dose taken was 30 to 45 mg, while plasma levels of amitriptyline and chlorprohixene were found to be at toxic levels. In other premarketing overdose cases with mirtazapine 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 mirtazapine alone.
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 center for additional information on the treatment of any overdose.
Mirtazapine has a tetracyclic structure unrelated to selective serotonin reuptake inhibitors, tricyclic, or monoamine oxidase inhibitors. Mirtazapine enhances noradrenergic and specific serotonergic transmission.
Mirtazapine acts as an antagonist at central presynaptic "2 adrenergic inhibitory autoreceptors and heteroreceptors which result in an increase in central noradrenergic and serotonergic activity. This action may explain its antidepressant activity. Mirtazapine is a potent antagonist of 5-HT2 and 5-HT3 receptors. 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-HT1A and 5-HT1B receptors. Both enantiomers of mirtazapine appear to contribute to its pharmacological activity. The (+) enantiomer blocks 5-HT2 receptors as well as "2 receptors and the (-) enantiomer blocks 5-HT3 receptors. Mirtazapine is a potent histamine(Hl) receptor antagonist which may contribute to its sedative effect and possibly to weight gain due to increased appetite. Mirtazapine is a moderate peripheral "1 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.
Pharmacokinetics
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 to 40 hours.
Mirtazapine is extensively metabolized and quantitatively eliminated via urine (75%) and feces (15%); approximately 90% of this elimination occurs within the first 72 to 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-desmethyl 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.
Protein Binding
: Mirtazapine is approximately 85% bound to plasma proteins over a concentration range of 10 to 1000 ng/mL. Binding appears to be both nonspecific and reversible. The binding affinity of mirtazapine to human liver proteins is 2.8 times greater than to human plasma proteins. As with all drugs that are protein bound, care should be exercised when
co-administering medications that may interact with mirtazapine at protein binding sites (See WARNINGS AND PRECAUTIONS).
Special Populations and Conditions
Following administration of mirtazapine 20 mg per day for 7 days, females of all-ages (range 25 to 74) exhibited significantly longer elimination half-lives than males (mean half-life 37 hours for females vs 26 hours for males) (see Table 2). 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). In this same study oral clearance was reduced in older subjects (mean age 65; range 55 to 75) compared to younger subjects. The difference was greatest in males, with a 40% lower clearance for mirtazapine in the older vs younger group. Caution is indicated in administering mirtazapine in the elderly (see WARNINGS AND PRECAUTIONS, and DOSAGE and ADMINISTRATION).
| Group Adult male | Single Dose 21.7 +- 4.2 | Multiple Dose 22.1 +- 3.7 |
| N=9 | ||
| Adult female | 37.7 +- 13.3 | 35.4 +- 13.7 |
| N=9 Elderly # male | 32.2 +- 15.4 | 31.1 +- 15.1 |
| N=8 Elderly # female | 40.6 +- 12.8 | 39.0 +- 10.8 |
| N=8 | ||
| * # expressed in hours. The 'elderly' group consisted of subjects 55 and older (55 to 75; mean age 6 | ||
5)
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 the 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 mirtazapine to patients who may have compromised renal function.
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.
Clinical Trials Showing Efficacy
The efficacy of mirtazapine in the treatment of depression was demonstrated in four US placebo-controlled trials (6 week duration) in adult outpatients meeting DSM III criteria for major depression. Patients were titrated with mirtazapine starting at a dose of 5 mg per day up to a dose of 35 mg per day (by the beginning of week 3). Outcome measures included the Hamilton Depression Rating Scale (21-item), and the Montgomery and Asberg Depression Rating Scale. The mean mirtazapine dose for patients completing the four studies ranged from 21 to 32 mg per day. Additional supportive studies used higher doses up to 50 mg per day. In the U.S. short-term flexible-dose controlled trials (Mirtazapine, N = 323), 70% and 54% of the patients received final doses $ 20 mg and $ 25 mg, respectively. In a longer-term study, patients meeting DSM-IV criteria for a major depressive disorder who had responded during an initial 8 to 12 weeks of acute treatment on mirtazapine tablets were randomized to continuation of mirtazapine tablets or placebo for up to 40 weeks of observation for relapse. Response during the open phase was defined as having achieved a HAMD-17 total score of #8 and 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 mirtazapine tablets 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.
Dom-MIRTAZAPINE tablets should be stored at controlled room temperature, 15o - 30o C, in a tightly closed, light-resistant container.
Availability of Dosage Forms
Dom-MIRTAZAPINE (mirtazapine) Tablets are supplied as: 15 mg Tablets - Yellow, oval, scored, coated tablet imprinted with "P" logo on one side of the scored and with "15" on the other side of the tablet. Available in white HDPE bottles containing 100 tablets. 30 mg Tablets - Red-brown, oval coated tablets printed with a "P" logo above a score line on one side and printed "30" on the other side of the tablet. Available in white HDPE bottles containing 100 tablets and blister packs of 30 tablets.
Composition
Each film coated tablet contains 15 mg of mirtazapine . Non medicinal ingredients (alphabetical): colloidal silicon dioxide, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, synthetic yellow iron oxide and titanium dioxide.
Each film coated tablet contains 30 mg of mirtazapine . Non medicinal ingredients (alphabetical): colloidal silicon dioxide, iron oxide yellow, iron oxide red, lactose monohydrate, macrogol/PEG 3350, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol-part. hydrolyzed, sodium starch glycolate, talc and titanium dioxide.
Product Monograph available upon request. Dominion Pharmacal Montreal, Quebec H4P 2T4