Approval Date.
Mirtazapine Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Warnings
Suicidal ideation and antidepressants
Results of short-term clinical trials of depression (MDD) and other psychiatric disorders have shown that antidepressants increase the risk of suicidal thoughts and committing suicidal acts (suicidal ideation) in children, adolescents, and young adults (<24 years of age) compared with placebo. Anyone considering the use of this or other antidepressants in children, adolescents, or young adults (<24 years of age) must weigh their risks against their clinical needs. Short-term clinical trials have not shown an increased risk of suicidal ideation with antidepressant use compared with placebo in adults older than 24 years of age; and in adults aged 65 years and older, the risk of suicidal ideation was reduced with antidepressant use. Depression and certain psychiatric disorders are themselves associated with an increased risk of suicide, and patients of all ages must be closely monitored for worsening clinical symptoms, suicidal ideation, and abnormal changes in behavior after initiation of treatment with antidepressants. Families and caregivers should be advised that they must closely observe and communicate with their physicians. This product is not approved for use in pediatric patients (see [Precautions] and [Pediatric Dosage]).
Drug Name]
Generic name: Mirtazapine tablets
Trade name: Mirtazapine®
English Name: Mirtazapine Tablets
Hanyu Pinyin：Midanping Pian
Ingredients】 The main ingredient of this product is Mirtazapine.
Chemical name: 1,2,3,4,10,14b-hexahydro-2-methylpyrazinyl[2,1-a]pyrido[2,3-c][2]benzazepine
Chemical structure formula.
Molecular formula: C17H19N3
Molecular weight: 265.35
Characteristic】 This product is a blue film-coated tablet, which appears white or off-white after removing the film coating.
Indications】For the treatment of depression.
Specification】15mg.
Dosage]
Oral administration. It should be swallowed with water and should not be chewed.
Adults.
The effective dose is usually 15 to 45 mg per day. the starting dose of treatment is 15 mg or 30 mg. it usually takes effect after one to two weeks of administration. When the right amount of drug is taken, there should be an effect within two to four weeks. If the effect is not obvious enough, the dose can be increased to the maximum dose. If there is no effect after two to four weeks of dose increase, the product should be discontinued.
Patients with renal impairment.
The clearance of mirtazapine is decreased in patients with moderate to severe renal impairment (creatinine clearance <40 ml/min). Dosage should be carefully selected for use in patients with moderate to severe renal impairment (see [Precautions]).
Patients with hepatic impairment.
Clearance of mirtazapine is decreased in patients with hepatic impairment. Dose selection should be made with caution in patients with hepatic impairment. Particular caution should be exercised when using this product in patients with severe hepatic impairment as no studies have been conducted in this population (see [Precautions]).
The clearance half-life of mirtazapine is 20 to 40 hours, so it should be taken once daily (preferably at bedtime). It can also be taken in divided doses (e.g., once in the morning and once in the evening, with a higher dose at night).
Patients should take the drug continuously for at least 6 months for adequate treatment to maintain efficacy.
Gradual discontinuation of the drug is recommended to prevent withdrawal symptoms (see [Precautions]).
[Adverse Reactions].
Because patients with depression often exhibit symptoms that are caused by the illness itself, it is sometimes difficult to distinguish which symptoms are due to the illness itself and which are due to mirtazapine treatment.
In randomized, placebo-controlled clinical trials of mirtazapine tablets, the most common adverse reactions reported with an incidence of more than 5% included drowsiness, sedation, dry mouth, weight gain, increased appetite, dizziness, and fatigue. In addition, based on the results of controlled clinical trials conducted in the United States, the most common adverse events associated with mirtazapine use (incidence of 5% or more) and differing from the incidence in patients in the placebo group (at least twice the incidence with mirtazapine treatment) were: drowsiness, increased appetite, weight gain, and dizziness.
All randomized, placebo-controlled trials conducted in patients (including non-depressed patients) evaluated the adverse effects of mirtazapine. The meta-analysis (meta) included 20 clinical trials with planned treatment durations of up to 12 weeks, with 1501 patients (134 person-years) treated with up to 60 mg/day doses of mirtazapine and 850 patients (79 person-years) treated with placebo. The extension period of these trials was excluded to maintain comparability with placebo treatment.
Table 1 shows the categorized incidence of adverse reactions, which were higher and statistically significant in the mirtazapine tablet-treated group compared with the placebo group in the clinical trials, with the addition of spontaneously reported adverse reactions. The frequency of adverse reactions in spontaneous reports was based on the rate at which these events were reported in the clinical trials. The frequency of spontaneously reported adverse reactions that were not observed in randomized, placebo-controlled trials of mirtazapine was categorized as “frequency unknown”.
Table 1 Adverse reactions to mirtazapine tablets
Systemic organ classification very common
(≥1/10) Common
(≥1/100 to <1/10) Occasional
(≥1/1,000 to <1/100) Rare
(≥1/10,000 to <1/1,000) Frequency unknown Blood and lymphatic system abnormalities Bone marrow suppression (granulocytopenia, granulocyte deficiency, aplastic anemia, and thrombocytopenia)
Eosinophilia Endocrine disorders Disorders of antidiuretic hormone secretion Metabolic and nutritional abnormalities Weight gain1
Increased appetite1 Hyponatremia Mental disorders Dream abnormalities
Confusion of consciousness
Anxiety2, 5
Insomnia3, 5 Nightmares2
Mania
Agitation2
Hallucinations
Psychomotor fidgeting (including inability to sit still, hyperkinesia) Aggressive suicidal ideation6
Suicidal behavior6 Neurological disorders drowsiness1, 4
Sedation1, 4
Headache2 Drowsiness1
Dizziness
Tremor sensory abnormalities2
Restless legs symptoms
Syncope myoclonic convulsions (seizures)
5-hydroxytryptamine syndrome
Oral sensory abnormalities
Dysarthria vascular disorders Postural hypotension hypotension2 Gastrointestinal disorders Dry mouth nausea3
Diarrhea2
Vomiting2
Constipation1 Decreased oral sensation Oral lip edema
Increased salivation Abnormalities of the hepatobiliary system Increased serum transaminase activity Skin and subcutaneous tissue abnormalities Drug rash2 Stevens-Johnson syndrome
Dermatitis herpetiformis
Erythema multiforme
Toxic epidermal necrolysis Musculoskeletal and connective tissue abnormalities Arthralgia
Myalgia
Back pain1 Transverse myelolysis7 Renal and urinary abnormalities Urinary retention Systemic and administration site symptoms Peripheral edema1
Fatigue Sleepwalking disorder
Generalized edema
Local edema Research Increased creatine kinase1 These events in clinical trials occurred more frequently during mirtazapine treatment than placebo, which was statistically significant.
2 These events in clinical trials occurred more frequently during placebo treatment than mirtazapine, but were not statistically significant.
3 These events occurred more frequently than mirtazapine during placebo treatment in clinical trials and were statistically significant.
4 Note: Dose reductions generally do not result in a reduction in drowsiness/sedation, but impair antidepressant efficacy.
5 Anxiety and insomnia (which may be a symptom of depression) can commonly occur or be exacerbated when receiving antidepressant therapy. Symptoms of anxiety and insomnia have been reported to occur or worsen with mirtazapine treatment.
6 Cases of suicidal intent and suicidal behavior have been reported during mirtazapine treatment or early after treatment interruption (see [Caution]).
7 Case reports of transverse rhabdomyolysis associated with 5-hydroxytryptamine syndrome and multiple drug overdose, the latter of which could not be determined to be related to mirtazapine.
Transient elevations in transaminases and gamma-glutamyl transferase were observed in laboratory evaluations of clinical trials (but associated adverse event reports showed no statistical difference compared with placebo).
Pediatric Population
The following adverse events have been frequently observed in clinical trials conducted in children: weight gain, urticaria, and hypertriglyceridemia.
In short-term placebo-controlled trials of mirtazapine tablets at doses of 5 to 60 mg per day conducted in the United States, adverse events that occurred at an incidence of ≥1% and were higher than those in the placebo group are shown in Table 2.
Table 2 Clinical experiences with an incidence of ≥1% in short-term controlled trials in the United Statesa
Body system
Adverse clinical reactions Mirtazapine tablets
(n=453) Placebo
(n=361) Generalized weakness 8% 5% Flu symptoms 5% 3% Back pain 2% 1% Digestive system Dry mouth 25% 15% Increased appetite 17% 2% Constipation 13% 7% Metabolic and nutritional abnormalities Weight gain 12% 2% Peripheral edema 2% 1% Edema 1% 0% Musculoskeletal system Myalgia 2% 1% Nervous system Drowsiness 54% 18% Dizziness 7% 3% Dream abnormalities 4% 1% Abnormal thinking 3% 1% Tremor 2% 1% Confusion 2% 0% Respiratory system dyspnea 1% 0% Genitourinary system urinary frequency 2% 1% Includes events reported by at least 1% of patients treated with mirtazapine tablets, except for the following events, which were more frequent in the placebo group than or equal to the mirtazapine tablet group: headache, infection, pain, chest pain, palpitations, tachycardia, postural hypotension, nausea, dyspepsia, diarrhea, gastrointestinal flatulence, insomnia, nervousness, decreased libido, hypertonia, pharyngitis, rhinitis, sweating, amblyopia, tinnitus, and taste inversions.
Results of a short-term placebo-controlled trial conducted in the United States
Adverse effects leading to discontinuation of treatment
In a 6-week controlled clinical trial conducted in the United States, approximately 16% of 453 patients taking mirtazapine tablets discontinued treatment due to adverse events, and approximately 7% of 361 placebo-treated patients discontinued treatment due to adverse reactions. The most common (≥1%) adverse events associated with treatment interruption and considered drug-related (i.e., events that resulted in at least twice the rate of patient shedding as the placebo group) included
In a 6-week trial of mirtazapine tablets conducted in the United States, resulting in interruption of
Common adverse events that interrupted treatment Adverse events Percentage of patients who interrupted treatment due to adverse events Mirtazapine tablets (n=453) Placebo (n=361) Drowsiness 10.4% 2.2% Nausea 1.5% 0%
Electrocardiogram (ECG) changes
The ECGs of 338 patients treated with mirtazapine and 261 patients treated with placebo in a 6-week placebo-controlled trial were analyzed. A mean change in QTc of + 1.6 msec was observed in patients in the mirtazapine-treated group and -3.1 msec in patients in the placebo-treated group. a mean increase in heart rate of 3.4 beats per minute was observed in patients in the mirtazapine-treated group and 0.8 beats per minute in patients on placebo. The clinical significance of these changes is unknown.
The effect of mirtazapine on the QTc interval was assessed using exposure response analysis in a randomized, placebo, moxifloxacin-positive controlled clinical trial with 54 healthy subjects. The trial showed a positive correlation between mirtazapine concentration and QTc interval prolongation; however, neither the 45 mg dose (therapeutic dose) nor the 75 mg dose (supratherapeutic dose) of mirtazapine had a clinically meaningful effect on the QTc interval.
Other adverse events observed in the premarketing evaluation of mirtazapine.
A total of 2,796 patients took mirtazapine tablets multiple times and had highly variable treatment status as well as treatment duration in premarketing clinical trials, including open and double-blind trials, uncontrolled and controlled trials, inpatient and outpatient trials, fixed-dose and dose-adjustment trials. Clinical investigators report adverse events associated with this treatment using terms of their own choosing. Therefore, it will not be possible to provide a meaningful assessment of the proportion of individuals presenting with adverse events without first grouping similar types of adverse events into a much smaller number of standardized event categories.
In the following, adverse events are categorized using the Standardized Coding of Standard Adverse Reaction Vocabulary (COSTART) terminology, the incidence of which represents the proportion of 2796 patients who experienced at least one adverse event during treatment. It should be emphasized that although the reported events occurred during mirtazapine treatment, they were not necessarily caused by mirtazapine. The incidence of adverse events: commonly ≥1%, occasionally 1% to 1‰, and rarely <1‰.
Adverse events not listed in the above table are listed below. Events of clinical importance are also described in [Precautions].
Systemic: common: discomfort, abdominal pain, acute abdomen; occasional: chills, fever, facial edema, ulcers, photosensitivity reactions, neck stiffness, neck pain, abdominal distention; rare: cellulitis, chest pain (subxiphoid).
Cardiovascular system: common: hypertension, vasodilation; occasional: angina pectoris, myocardial infarction, bradycardia, ventricular extrasystole, syncope, migraine, hypotension; rare: atrial arrhythmia, diastolic rhythm, vascular headache, pulmonary embolism, cerebral ischemia, cardiac enlargement, phlebitis, left heart failure.
Digestive system: common: vomiting, anorexia; occasional: belching, tongue inflammation, cholecystitis, nausea and vomiting, bleeding gums, stomatitis, colitis, abnormal liver function tests; rare: tongue discoloration, ulcerative stomatitis, salivary gland hypertrophy, increased salivation, intestinal obstruction, pancreatitis, stomatitis with mouth sores, cirrhosis, gastritis, gastroenteritis, oral candidiasis, tongue swelling.
Endocrine system: rare: goiter, hypothyroidism.
Hematologic and lymphatic system: rare: lymphadenopathy, leukopenia, petechiae, anemia, thrombocytopenia, lymphocytosis, allohemocytopenia
Metabolic and nutritional abnormalities: common: thirst; occasional: dehydration, weight loss; rare: gout, elevated aspartate aminotransferase (AST), abnormal wound healing, elevated acid phosphatase, elevated aminotransferase (ALT), diabetes mellitus, hyponatremia.
Musculoskeletal system: common: muscle weakness, arthralgia; occasional: arthritis, tenosynovitis; rare: pathological fracture, osteoporotic fracture, bone pain, myositis, tendon rupture, arthrosis, bursitis.
Neurological: common: hyperalgesia, apathy, depression, hyperkinesia, vertigo, convulsions, agitation, anxiety, amnesia, hyperkinesia, sensory abnormalities; occasional: ataxia, delirium, delusion, depersonalization, dyskinesia, extrapyramidal syndrome, increased libido, abnormal coordination, dysarthria, hallucinations, manic reactions, neurosis, dystonia, hostile behavior enhanced reflexes, mood instability, euphoria, paranoia-like reactions; rare: aphasia, nystagmus, inability to sit still (psychomotor fidgeting), xylopathy, dementia, diplopia, drug dependence, paresthesia, grand mal seizures, hypotonia, myoclonus, psychotic depression, withdrawal syndrome, 5-hydroxytryptamine syndrome.
Respiratory: common: increased cough, sinusitis; occasional: epistaxis, bronchitis, asthma, pneumonia; rare: asphyxia, laryngitis, pneumothorax, eruption.
Skin: common: pruritus, rash; occasional: acne, exfoliative dermatitis, dry skin, herpes simplex, hair loss; rare: urticaria, herpes zoster, skin hyperplasia, seborrheic dermatitis, skin ulcers.
Special senses: Occasional: ocular pain, abnormal regulation, conjunctivitis, deafness, keratoconjunctivitis, tearing disorder, glaucoma, auditory hypersensitivity, otalgia; Rare: blepharitis, partial temporary deafness, otitis media, loss of taste, olfactory inversion.
Genitourinary system: common: urinary tract infection; occasional: kidney stones, cystitis, dysuria, urinary incontinence, urinary retention, vaginitis, hematuria, breast pain, amenorrhea, dysmenorrhea, leucorrhea, impotence; rare: polyuria, urethritis, irregular uterine bleeding, menorrhagia, abnormal ejaculation, breast engorgement, breast enlargement, urinary urgency.
Other adverse events observed in the post-marketing evaluation of mirtazapine.
Adverse events reported since marketing that were temporally related to mirtazapine treatment (not necessarily causally related) include cases of tip-twisting ventricular tachycardia and, in some cases, a combination of medications.
Serious skin reactions have been reported, including Stevens-Johnson syndrome, dermatitis herpetiformis, erythema multiforme, and toxic epidermal necrolysis.
[Contraindications
Hypersensitivity.
Hypersensitivity reactions to mirtazapine or any of the excipient components of this product are contraindicated.
Monoamine oxidase inhibitors.
The use of monoamine oxidase inhibitors (MAOIs) intended for the treatment of psychiatric disorders in combination with mirtazapine or within 14 days of discontinuation of mirtazapine is prohibited because of the increased risk of 5-hydroxytryptamine syndrome. Mirtazapine is also contraindicated for 14 days after discontinuation of MAOIs intended for the treatment of psychiatric disorders (see [Precautions]).
Mirtazapine is contraindicated in patients receiving MAOIs such as linezolid or intravenous methylene blue because of the increased risk of 5-hydroxytryptamine syndrome (see [Precautions]).
[Caution].
Warning.
Worsening of clinical symptoms and risk of suicide
Adult and pediatric patients with depression, with or without antidepressants, are at risk for worsening of depression and for suicidal ideation and suicidal behavior and abnormal changes in behavior that will persist until such time as significant remission occurs. Depression and certain psychiatric disorders are known to be associated with suicide risk, and these psychiatric disorders themselves are the strongest predictors of suicide. However, there are long-standing concerns that antidepressants may play a role in inducing worsening depressive symptoms and suicidal ideation and behavior in some patients early in treatment. A pooled analysis of short-term placebo-controlled studies of antidepressants (SSRIs (5-hydroxytryptamine reuptake inhibitors) and others) showed that in children, adolescents and young adults (18-24 years of age) with depression and other psychiatric disorders, antidepressants increased the risk of suicidal ideation and behavior compared with placebo. However, short-term clinical trials did not show an increased risk of suicidal ideation and behavior with antidepressants compared with placebo in adults aged >24 years; in adults aged 65 years and older, the risk of suicidal ideation and behavior was reduced with antidepressant use.
In placebo-controlled trials in children and adolescents with depression, OCD, or other psychiatric disorders (total of 24 short-term clinical trials, 9 antidepressants, more than 4400 patients) and in adult patients with depression or other psychiatric disorders (total of 295 short-term clinical trials [median duration of 2 months], 11 antidepressants. more than 77,000 patients), the risk of drug-induced suicidal ideation and behavior varied considerably among drugs, but most of the drug studies showed a trend toward increased risk of suicidal ideation and behavior in younger patients. The absolute risk of suicidal ideation and behavior varied across indications, with the highest absolute risk in depression. Although the absolute risk differed across indications (drug versus placebo), the risk was relatively stable across age groups for different indications. Table 3 below provides the risk differences (number of cases per 1000 patients with differences in risk of suicidal ideation and behavior from drug and placebo treatment).
Table 3 Age range Number of cases of difference in risk of suicidal ideation and behavior from drug and placebo treatment per 1000 patients Number of cases of increase in drug versus placebo<18 14 cases of increase 18-24 5 cases of decrease in drug versus placebo 25-64 1 case of decrease ≥65 6 cases of decrease in drug versus placebo There were no suicidal events in the pediatric clinical trials. There were suicidal events in adult clinical trials, but the number of occurrences was not sufficient to draw conclusions about the effect of the drug in suicide.
It is unknown whether the risk of suicidal ideation and behavior is perpetuated over the course of long-term medication use (e.g., after several months). However, evidence from placebo-controlled maintenance treatment clinical trials conducted in adults with depression strongly suggests that the use of antidepressants delays the recurrence of depression.
Regardless of the indication for treatment, all patients treated with antidepressants should be closely observed and monitored for worsening clinical symptoms, suicidal ideation and behavior, and abnormal changes in behavior. This is especially true during the initial months of drug treatment and when increasing or decreasing the dose.
The following symptoms can occur in adult and pediatric patients with depression, other psychotic or non-psychotic disorders treated with antidepressants: anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggression, impulsivity, inability to sit still (psychomotor agitation), and light mania and hypomania. Although a causal relationship between the presence of these symptoms and the worsening of depression and/or the development of suicidal ideation and behavior has not been established, it is noted that the presence of these symptoms may be a precursor to the development of suicidal ideation and behavior.
When a patient’s depressive symptoms continue to worsen, suicidal ideation and behaviors develop, or symptoms occur that may be precursors to worsening depressive symptoms or suicidal ideation and behaviors, adjustments to the treatment regimen including discontinuation of medication should be carefully considered. This is especially true if these symptoms are severe, sudden, or inconsistent with the patient’s current symptoms.
If a decision is made to discontinue treatment, the dose should be reduced as soon as possible, but be aware that abrupt discontinuation may cause some symptoms (see [Precautions] and [Dosage]).
When treating patients with depression or other psychotic or non-psychotic disorders with antidepressants, family members and caregivers should be reminded of the need to monitor the patient for agitation, irritability, abnormal changes in behavior, other symptoms mentioned above, and suicidal ideation and behavior, and to report these symptoms to a health care professional as soon as they occur. Family members and caregivers should monitor the patient daily for these symptoms. Prescriptions for the use of Mirtazapine should start with the smallest amount and be accompanied by good patient management to reduce the risk of overdose.
Screening of patients with bipolar disorder
Depressive episodes may be the initial manifestation of bipolar disorder. It is generally believed (although not clarified by controlled trials) that treatment of such episodes with antidepressants alone may increase the likelihood of mixed/manic episodes in patients at risk for bipolar disorder. It is not clear whether the symptoms mentioned above imply that such a transition may occur. However, patients with depressive symptoms should be adequately screened for risk of bipolar disorder prior to initiating treatment with antidepressants; this screening should include a detailed psychiatric history including a family history of suicide and a family history of bipolar disorder and depression. Mirtazapine is not approved for the treatment of bipolar disorder.
5-hydroxytryptamine syndrome
Similar to other 5-hydroxytryptaminergic drugs, 5-hydroxytryptamine syndrome (a potentially life-threatening condition) may occur with mirtazapine treatment, especially when combined with other drugs that may act on the 5-hydroxytryptamine transmitter system (e.g., tretinoin, SSRIs, SNRIs (norepinephrine reuptake inhibitors), lithium salts, sibutramine, amphetamines, St. John’s wort [Hypericum perforatum plant extract], fentanyl and its analogs, tramadol, methamphetamine, tapentadol, pethidine, methadone, pentazocine, tricyclic antidepressants, tryptophan, and buspirone), when combined with drugs that impair 5-hydroxytryptamine metabolism (e.g., methylene blue for MAOIs), when combined with 5-hydroxytryptamine precursor substances (e.g., tryptophan supplements), when combined with antipsychotics or with other dopamine antagonists.
The 5-hydroxytryptamine syndrome may include altered mental status (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, blood pressure instability, hyperthermia, sweating, flushing, and dizziness), neuromuscular disorders (e.g., tremor, tonicity, myoclonus, hyperreflexia, movement disorders), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The most severe form of 5-hydroxytryptamine syndrome is similar to the manifestations of antipsychotic malignant syndrome and includes hyperthermia, muscle tonicity, autonomic instability possibly accompanied by rapid fluctuations in vital signs, and altered mental status. (See [Drug Interactions]).
Combination of mirtazapine with MAOIs is contraindicated. Mirtazapine should also not be used in patients being treated with MAOIs such as linezolid or intravenous methylene blue. The route of administration of methylene blue in all reports was intravenous in the dose range of 1 mg/kg to 8 mg/kg. No other routes (e.g., oral tablet or local tissue injection) or lower doses of methylene blue were reported. In some cases, patients taking mirtazapine may have to be treated with MAOIs such as linezolid or intravenous methylene blue. Mirtazapine should be discontinued prior to initiating treatment with MAOIs (see [Contraindications]).
If there is a reasonable clinical need to combine mirtazapine with an SSRI, SNRI, or other 5-hydroxytryptaminergic drug (e.g., traptans, tricyclic antidepressants, fentanyl, lithium salts, tramadol, buspirone, tryptophan, and St. John’s wort), close patient monitoring is recommended, especially at the beginning of treatment and at increasing doses (see [Drug Interactions]).
Combined use of mirtazapine and 5-hydroxytryptamine precursor substances (e.g., tryptophan supplements) is not recommended.
When these events occur, mirtazapine and any combined 5-hydroxytryptaminergic drugs must be discontinued immediately and symptomatic supportive therapy initiated.
Closed-angle glaucoma
In patients with narrowed atrial angles in the anatomy who have not undergone definitive iridectomy, pupil dilation following the use of multiple antidepressants (including mirtazapine) may cause glaucomatous episodes due to atrial angle closure.
Bone marrow suppression, granulocyte deficiency.
Bone marrow suppression has been reported during mirtazapine treatment, which usually manifests as granulocytopenia or granulocyte deficiency. Reversible granulocyte deficiency has been rare in mirtazapine clinical trials. In pre-marketing clinical trials, two of 2796 patients treated with mirtazapine developed granulocyte deficiency [absolute neutrophil count (ANC) <500/mm3 with signs and symptoms, such as fever and infection], one of whom had Sjögren's syndrome, and one patient developed severe neutropenia (ANC <500/mm3 without associated symptoms). These three patients developed severe neutropenia on days 61, 9 and 14 of treatment, respectively, and all recovered after discontinuation of mirtazapine. Based on these three cases, the incidence of severe neutropenia (with or without associated infection) is approximately 1.1/1000 with a very wide 95% confidence interval of 2.2/10,000 to 3.1/1000. If a patient develops sore throat, fever, stomatitis, or other signs of infection with a decreased white blood cell (WBC) count, mirtazapine therapy should be interrupted and the patient closely monitored. Close monitoring should be performed.
Reports of granulocyte deficiency with post-marketing mirtazapine are rare and mostly reversible, but a few cases have been fatal. The majority of the fatal cases were in patients aged 65 years or older. Therefore, physicians should be careful during treatment and should discontinue the drug and perform a blood count as soon as they notice fever, sore throat, stomatitis or other signs of infection in patients.
General precautions.
Symptoms of interrupted treatment.
Adverse reactions have been reported immediately following interruption (especially abrupt interruption) of mirtazapine tablets, including but not limited to the following reactions: dizziness, dream abnormalities, sensory disturbances (including sensory abnormalities and electroconvulsive sensations), agitation, anxiety, fatigue, confusion, headache, tremor, nausea, vomiting, sweating, or other symptoms that may be clinically significant. The majority of reported cases are mild and self-limiting. Nevertheless, these are reported as adverse reactions, but it should be clear that these symptoms may be related to the underlying disease.
Given the risk of treatment discontinuation symptoms, patients currently taking mirtazapine should not abruptly discontinue treatment. When interruption of mirtazapine therapy is warranted for medical reasons, gradual dose reduction is recommended rather than abrupt discontinuation.
Sedentary inability/psychomotor fidgeting.
Antidepressant use is associated with the onset of sedentary inability, manifested by subjective displeasure or agitation, the need to walk frequently, and the inability to sit still or stand still, most likely within the first few weeks of treatment. Dose escalation can be detrimental to patients who develop these symptoms.
Hyponatremia.
Reports of hyponatremia due to the use of mirtazapine are very rare. Caution should be exercised in patients at risk, such as elderly patients or patients with other drugs known to cause hyponatremia.
Drowsiness.
In controlled trials conducted in the United States, drowsiness occurred in 54% of patients treated with mirtazapine, compared with 18% in the placebo group and 60% in the amitriptyline group. In these trials, drowsiness caused treatment discontinuation in 10.4% of patients treated with mirtazapine, compared with 2.2% in the placebo group. It is not clear whether tolerance to the drowsy effects of mirtazapine will develop. Because mirtazapine may significantly impair behavior, patients should exercise caution when engaging in activities that require alertness until they can assess the effect of the drug on their psychomotor abilities.
Dizziness.
In controlled trials conducted in the United States, 7% of patients treated with mirtazapine reported dizziness, compared to 3% in the placebo group and 14% in the amitriptyline group. It is not known whether dizziness associated with mirtazapine use will be tolerated.
Appetite/weight gain.
In controlled trials conducted in the United States, 17% of patients treated with mirtazapine reported increased appetite, compared with 2% in the placebo group and 6% in the amitriptyline group. In these same trials, 7.5% of mirtazapine-treated patients gained ≥7% body weight, compared to 0% in the placebo group and 5.9% in the amitriptyline group. In pre-marketing clinical trials conducted in the United States, including many patients on long-term, open-label therapy, 8% of patients treated with mirtazapine discontinued the drug due to weight gain. In an 8-week clinical trial in children and adolescents administered at doses of 15 to 45 mg daily, 49% of patients treated with mirtazapine gained at least 7% of their body weight, compared to 5.7% of placebo-treated patients.
Cholesterol/triglycerides.
In controlled trials conducted in the United States, a ≥20% increase in non-fasting cholesterol above the upper limit of normal was observed in 15% of patients treated with mirtazapine , 7% in the placebo group, and 8% in the amitriptyline group. In these same trials, non-fasting triglycerides were elevated to ≥500 mg/dL in 6% of patients treated with mirtazapine, 3% in the placebo group, and 3% in the amitriptyline group.
Elevated transaminases.
In short-term controlled trials conducted in the United States, clinically significant transaminase (ALT) elevations (≥3 times the upper limit of the normal range) were observed in 2.0% of patients (8/424) treated with mirtazapine, 0.3% of placebo-treated patients (1/328), and 2.0% of amitriptyline treated patients (3/181). Most of these ALT-elevated patients did not present with signs or symptoms associated with impaired liver function. Some patients discontinued the drug due to ALT elevation, while others returned to normal liver enzyme levels despite continued mirtazapine therapy. Mirtazapine should be used with caution in patients with impaired hepatic function.
Jaundice.
The drug should be discontinued once jaundice develops.
Induction of mania/ mild mania.
In studies conducted in the United States, approximately 0.2% of patients treated with mirtazapine (3/1299 patients) developed mania/ mild mania. Although the incidence of mania/mild mania was very low during mirtazapine treatment, it should be used with caution in patients with a history of mania/mild mania.
Seizures.
In premarketing clinical trials, only 1 seizure was reported in 2796 U.S. and non-U.S. patients treated with mirtazapine. However, controlled trials have not been conducted in patients with a history of seizures. Caution should therefore be exercised with the use of mirtazapine in these patients.
Use in patients with concomitant disease.
Clinical experience with the use of mirtazapine in patients with concomitant systemic disease is limited. Therefore, caution should be exercised in prescribing mirtazapine to patients with concomitant diseases or conditions that affect metabolic or hemodynamic responses.
Systematic evaluation of mirtazapine has not been performed in patients with a recent history of myocardial infarction or other significant cardiac disease or mirtazapine has not been administered to an assessable dose. Mirtazapine dosing was associated with significant postural hypotension in an early clinical pharmacology trial in healthy volunteers. Postural hypotension was rarely seen in clinical trials in depressed patients. Mirtazapine should be used with caution in patients with cardiovascular or cerebrovascular disease (history of myocardial infarction, angina pectoris, or ischemic stroke episodes) who are known to be at risk of worsening symptoms in the setting of hypotension, and in patients who are prone to hypotensive conditions (dehydration, hypovolemia, and hypotensive drug therapy).
Patients with moderate [glomerular filtration rate (GFR) = 11 to 39 ml/min/1.73 m2] and severe [GFR <10 ml/min/1.73 m2] renal impairment have reduced clearance of mirtazapine, as do patients with hepatic impairment. Mirtazapine should be used with caution in these patients (see [DOSAGE AND ADMINISTRATION]).
Conditions Requiring Monitoring.
The dose of the drug should be monitored and carefully examined periodically in patients with the following conditions.
Epilepsy and organic brain syndrome. Although clinical experience has shown that, as with other antidepressants, seizures are rare with mirtazapine, caution should be exercised in the use of mirtazapine in patients with a history of seizures. It should be discontinued when the patient develops seizures or when the frequency of seizures increases.
Patients with hepatic impairment: After a single oral dose of 15 mg mirtazapine, the clearance of mirtazapine in patients with mild to moderate hepatic impairment decreased by approximately 35% compared to subjects with normal hepatic function. The mean plasma concentration of mirtazapine was increased by approximately 55%.
Patients with renal impairment: After a single oral dose of 15 mg mirtazapine, mirtazapine clearance decreased by 30% and 50% in patients with moderate (creatinine clearance <40 ml/min) and severe (creatinine clearance ≤10 ml/min) renal impairment, respectively, compared to normal subjects. Mean plasma concentrations of mirtazapine were increased by approximately 55% and 115%, respectively. There was no significant difference in patients with mild renal impairment (creatinine clearance <80 ml/min) compared to controls.
Cardiac conditions such as conduction disturbances, angina pectoris and recent episodes of myocardial infarction. Routine precautions and caution with other medications should be taken for these conditions.
Hypotension.
Diabetes: In patients with diabetes, antidepressants may alter the level of glycemic control. Dose adjustment of insulin and/or oral hypoglycemic agents may be required and close monitoring is recommended.
As with other antidepressants, care should be taken with mirtazapine in patients who
Patients with schizophrenia and other psychiatric disorders may experience worsening of psychotic symptoms and possible worsening of delusions after taking antidepressants.
Patients with bipolar disorder in the depressive phase are at risk of transforming into the manic phase with the use of antidepressants. Patients with a history of mania/mild hypomania should be closely monitored. Mirtazapine should be discontinued in any patient who enters the manic phase.
Although mirtazapine is not addictive, post-marketing dosing experience has shown that abrupt discontinuation of treatment after prolonged administration can sometimes cause withdrawal symptoms. Most discontinuation reactions are weak and self-limiting. Among the various reported discontinuation symptoms, dizziness, anxiety, agitation, headache, and nausea are the most common. Although these have been reported as discontinuation symptoms, it is important to note that these symptoms may be related to the underlying disease. As with [dosage], it is recommended that mirtazapine be discontinued gradually.
Patients with urinary difficulties (e.g., patients with prostatic hypertrophy), acute narrow-angle glaucoma, and increased intraocular pressure need to be monitored while taking the drug (although mirtazapine has only a weak anticholinergic effect and its chance of being problematic is small).
The effect of mirtazapine on the QTc interval was evaluated in a randomized, placebo, moxifloxacin-controlled clinical trial in 54 healthy subjects using an exposure response analysis. The results of the trial showed that neither the 45 mg dose (treatment) nor the 75 mg dose (supra-treatment) of mirtazapine had a clinically meaningful effect on the QTc interval. Cases of QT prolongation, tip-twist ventricular tachycardia, ventricular tachycardia, and sudden death have been reported during post-marketing use of mirtazapine. Most reports have been associated with overdose or occurred in patients with other risk factors for QT prolongation, including concomitant use of drugs that prolong QTc. Caution should be exercised when prescribing mirtazapine in patients with a known family history of cardiovascular disease or QT prolongation and when concomitantly administered with other medications that prolong the QTc interval.
Alcohol.
Mirtazapine is known to superimpose alcohol to cause impairment of cognitive or motor skills. Therefore, patients should not consume alcohol while taking mirtazapine.
Lactose.
This drug contains lactose and should not be taken by patients with rare hereditary galactose intolerance, lactase deficiency, or impaired glucose-galactose absorption.
Interference with cognitive and motor behavior.
Because of its significant sedative effects, mirtazapine may cause impairment of judgment, thinking, and especially motor skills. The drowsiness caused by mirtazapine use may impair the patient’s ability to drive, operate machinery, or perform tasks requiring alertness. Therefore, patients should exercise caution when participating in hazardous activities until they are reasonably certain that mirtazapine treatment will not adversely affect their ability to participate in these activities.
Patient Medication Information.
Prescribers or other health practitioners should inform patients, their families, and their caregivers about the risks and benefits of mirtazapine therapy and should provide counseling on the appropriate use of the medication.
Prescription medication, keep out of reach of children.
Children and adolescents under 18 years of age.
This product should not be used in children and adolescent patients under 18 years of age.
In clinical trials of antidepressants in children and adolescents, suicide-related behaviors (suicide attempts and suicidal thoughts) and hostile behaviors (primarily aggression, oppositional behavior, and anger) were more common than in those taking placebo. In addition, there is a lack of long-term safety data on the development of growth, development, cognition, and behavior in children and adolescents taking this medication.
Completion of treatment course.
In cases where patients may show improvement with mirtazapine treatment for 1 to 4 weeks, it is recommended that they should continue treatment as prescribed.
Concomitant medications.
Patients should inform their physician if they are taking or planning to take any prescription or over-the-counter medications, as mirtazapine may interact with other drugs.
Pregnant women and nursing mothers
Patients should inform their doctor if they are pregnant or planning to become pregnant during mirtazapine treatment.
Data on the use of mirtazapine in pregnant women are limited and do not show an increased risk of congenital malformations. Animal studies have not shown any clinically relevant teratogenic effects, but developmental toxicity has been observed (see [Pharmacologic Toxicology]).
Epidemiological data suggest that the use of SSRIs during pregnancy, especially late in gestation, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). Although the relationship between PPHN and mirtazapine treatment has not been studied, this potential risk cannot be excluded considering the mechanism of action involved (increased 5-hydroxytryptamine concentration).
Caution should be exercised when prescribing mirtazapine to pregnant women, and mirtazapine should not be used during pregnancy unless clearly needed. If mirtazapine is not discontinued until delivery or shortly before delivery, monitoring of the newborn for possible discontinuation effects after birth is recommended.
Patients should inform their physician if they are breastfeeding their infants.
Mirtazapine should be used with caution in nursing women because of the potential for partial secretion of mirtazapine into breast milk.
Animal studies and limited clinical data suggest that only a very small amount of mirtazapine is secreted through breast milk. The decision to interrupt breast-feeding or to interrupt mirtazapine treatment should be made by weighing the benefits of breast-feeding for the young child against the benefits of mirtazapine for the mother’s treatment.
Pediatric Use]
The safety and efficacy of the drug in children and adolescents under 18 years of age have not been established. (See [Precautions]).
Geriatric Use]
Use this product with caution in elderly patients.
Approximately 190 elderly patients (age ≥65 years) were enrolled in clinical trials of mirtazapine. Mirtazapine is known to be excreted primarily through the kidneys (75%), and there is an increased risk of decreased clearance of mirtazapine in patients with impaired renal function. Because older adults are more likely to have decreased renal function, dose selection should be done with caution. Sedative drugs may cause confusion and excessive sedation in the elderly. No unusual age-related adverse events were observed in this cohort. Pharmacokinetic tests have shown decreased drug clearance in the elderly.
[Drug Interactions].
Pharmacodynamic Interactions.
Mirtazapine should not be used in combination with monoamine oxidase (MAO) inhibitors or within two weeks of discontinuing treatment with MAO inhibitors. Conversely, patients receiving mirtazapine who require treatment with an MAO inhibitor should be separated by approximately two weeks (see [Contraindications]). In addition, as with SSRIs, co-administration of mirtazapine with other 5-hydroxytryptamine-active substances (L-tryptophan, tritans, tramadol, linezolid, methylene blue, SSRIs, venlafaxine, lithium, and Hypericum perforatum preparations) may result in the development of 5-hydroxytryptamine-related reactions (5-hydroxytryptamine syndrome, see [Precautions]) .
Mirtazapine may exacerbate the sedative effects of benzodiazepines and other sedatives (especially most antipsychotics, histamine H1 antagonists, and opioids). The combination of diazepam (15 mg) in 12 healthy subjects had little effect on the plasma concentration levels of mirtazapine (15 mg). However, the motor skill impairment produced by mirtazapine had a superimposed effect on the effects produced by diazepam. Therefore, patients should be advised to avoid the use of diazepam and other similar drugs while taking mirtazapine.
Mirtazapine can increase the CNS depressant effect of alcohol, therefore, patients should be advised not to consume alcoholic beverages during treatment.
A small but statistically significant increase in the International Normalized Ratio (INR) was induced by 30 mg of mirtazapine daily in subjects taking concomitant warfarin. A more significant effect cannot be ruled out when increasing the dose of mirtazapine taken, and it is recommended that INR levels be monitored when mirtazapine and warfarin are used together.
The risk of QT prolongation and/or ventricular arrhythmias (e.g., tip-twist ventricular tachycardia) may increase with concomitant medications that prolong the QTc interval (e.g., certain antipsychotics and antibiotics) and mirtazapine overdose.
Pharmacokinetic interactions.
Drugs affecting hepatic metabolism.
The metabolism and pharmacokinetics of mirtazapine may be affected by inducers or inhibitors of drug metabolizing enzymes.
Drugs metabolized by and/or inhibiting cytochrome enzyme P450.
CYP enzyme inducers (all of the following were studied in steady-state conditions)
Phenytoin: In healthy male subjects (n=18), phenytoin (200 mg/day) increased the clearance of mirtazapine (30 mg/day) approximately 2-fold, resulting in a 45% decrease in the mean plasma concentration of mirtazapine. The pharmacokinetic effect of mirtazapine on phenytoin was not significant.
Carbamazepine: In healthy male subjects (n=24), carbamazepine (400 mg, 2 doses/day) increased the clearance of mirtazapine (15 mg, 2 doses/day) approximately 2-fold, resulting in a 60% decrease in mean plasma concentrations of mirtazapine. When phenytoin, carbamazepine, or other inducers of hepatic metabolism (e.g., rifampin) are used with mirtazapine, the dose of mirtazapine may need to be increased. If such drugs are discontinued, the dose of mirtazapine may need to be decreased.
CYPase inhibitors.
Cimetidine: Healthy male subjects (n=12) received cimetidine, a weak CYP1A2, CYP2D6, and CYP3A4 inhibitor (800 mg, 2 doses/day), which was combined with mirtazapine (30 mg/day) at steady state after reaching steady state, and the area under the curve (AUC) of mirtazapine increased by more than 50%. Mirtazapine does not alter the pharmacokinetic profile of cimetidine. Mirtazapine may require dose reduction when cimetidine is started in combination and should be increased when cimetidine is discontinued.
Ketoconazole: The combination of the strong CYP3A4 inhibitor ketoconazole (200 mg twice/day for 6.5 days) in healthy male Caucasians (n=24) increased the peak plasma concentration and AUC of a single dose of 30 mg mirtazapine by approximately 40% and 50%, respectively.
Caution should be exercised when combining mirtazapine with strong CYP3A4 inhibitors, HIV protease inhibitors, azole antifungals, erythromycin, or nefazodone.
Paroxetine: An in vivo interaction study in healthy, strongly CYP2D6 metabolizing subjects (n=24) showed that mirtazapine at steady state (30 mg/day) did not alter the pharmacokinetic profile of paroxetine at steady state (40 mg/day), a CYP2D6 inhibitor.
Other Drug-Drug Interactions.
Amitriptyline: In healthy, strongly CYP2D6 metabolizing subjects (n=32), steady-state amitriptyline (75 mg/day) did not alter the pharmacokinetic profile of steady-state mirtazapine (30 mg/day); mirtazapine also did not alter the pharmacokinetic profile of amitriptyline.
Lithium: No clinical effect or significant pharmacokinetic alteration of a single dose of 30 mg mirtazapine was observed in healthy male subjects at steady-state subtherapeutic doses of lithium (600 mg/day for 10 days). The effect of higher doses of lithium on the pharmacokinetics of mirtazapine is not known.
Risperidone: A non-randomized, interaction in vivo study in subjects (n=6) requiring antipsychotic and antidepressant therapy showed that mirtazapine (30 mg/day) at steady state did not affect the pharmacokinetics of risperidone (up to 3 mg, 2 doses/day).
[Drug overdose].
Available experience suggests that symptoms of overdose with mirtazapine alone are usually mild. Central nervous system depression with disorientation and prolonged sedation has been reported, as well as tachycardia, mild hypertension or hypotension. However, very serious (even fatal) consequences may result if the dose is much higher than the therapeutic dose, especially if overdosed with other drugs. QT prolongation and tip-twisting ventricular tachycardia have also been reported in these cases. Patients with drug overdose should be promptly treated with appropriate symptomatic and supportive therapy, ECG monitoring should be performed, and there is no known specific mirtazapine antidote; activated charcoal or gastric lavage may be considered.
Pharmacology and Toxicology
Pharmacological effects
Mirtazapine has a tetracyclic structure and belongs to the piperazine-azepine class of compounds. The mechanism of action of mirtazapine in the treatment of major depression is unknown. Preclinical trials have shown that mirtazapine enhances central norepinephrine and 5-hydroxytryptamine activity, which may be related to the fact that mirtazapine is a central presynaptic inhibitory a2-adrenoceptor antagonist.
Mirtazapine is a strong antagonist of 5-HT2 and 5-HT3 receptors, but has no significant affinity for 5-HT1A and 5-HT1B receptors. Also, mirtazapine is a strong antagonist of H1 receptors, an attribute that explains its apparent sedative effect; mirtazapine has a moderately strong antagonistic effect on a1-adrenoceptors, an attribute that explains the episodic postural hypotension reported in its use; and mirtazapine has a moderately strong antagonistic effect on M receptors, an attribute that explains its relatively low incidence of anticholinergic side effects.
Toxicological studies
Genotoxicity: The Ames test, in vitro Chinese hamster V79 cell gene mutation test, in vitro cultured rabbit lymphocyte sister chromatid exchange test, rat bone marrow micronucleus test and HeLa cell programmed in vitro DNA synthesis test all yielded negative results.
Reproductive toxicity: No effect on mating or pregnancy was observed in rats given mirtazapine up to a dose of 100 mg/kg (20 times the maximum recommended human dose in mg/m2), but the animals’ motility phase was interrupted at doses 3 times or more than the maximum recommended human dose, and pre-laying loss occurred at 20 times the dose.
No teratogenic effects were found in pregnant rats and rabbits at doses of 100 mg/kg and 40 mg/kg (20 and 17 times the maximum recommended human dose in mg/m2, respectively). However, increased post-arrival loss in pregnant rats given mirtazapine, increased pup mortality during the first 3 days of lactation (the cause of death is unknown), and reduced pup birth weight occurred at doses 20 times the maximum recommended human dose, and not at 3 times the recommended human dose.
Carcinogenicity: Carcinogenicity studies were conducted using the adulteration method in rats administered at 2, 20 and 60 mg/kg/day and in mice at 2, 20 and 200 mg/kg/day (in mg/m2, the maximum dose in rats and mice was approximately 12 and 20 times the recommended maximum human dose, respectively). The results showed an increased incidence of hepatocellular adenoma and carcinoma in male mice in the high dose group; hepatocellular adenoma in female rats in the medium and high dose groups, and hepatocellular adenoma and thyroid follicular adenoma/cystic adenoma and carcinoma in male rats in the high dose group. These data suggest that the above effects may be mediated by non-genotoxic mechanisms, and their relevance to humans is unclear.
The dose administered in the mouse study may not be high enough to adequately reflect the potential carcinogenicity profile of mirtazapine.
Pharmacokinetics]
The active ingredient mirtazapine is quickly absorbed after oral administration of mirtazapine tablets (bioavailability is about 50%). The peak plasma concentration is reached after about two hours. About 85% of mirtazapine is bound to plasma proteins. The average half-life is 20-40 hours; half-lives of up to 65 hours are occasionally seen; shorter half-lives are occasionally seen in young people. The size of the clearance half-life is appropriate for a once-daily dosing regimen. Blood levels reach steady state after 3 to 4 days of dosing, after which there will be no accumulation in the body. Mirtazapine has linear pharmacokinetics over the recommended dose range. The pharmacokinetic profile of mirtazapine is not affected by coadministration with food.
Mirtazapine is mostly metabolized and excreted in the urine and feces within a few days after administration. The main biotransformation mode is demethylation and oxidation, followed by binding reactions. In vitro studies on human liver microsomal organisms have shown that the cytochrome P450 enzymes CYP2D6 and CYP1A2 are involved in the formation of 8-hydroxy metabolites of mirtazapine. CYP3A4 is thought to be responsible for the formation of N-demethyl and N-oxide metabolites. The metabolites after demethylation remain pharmacologically active and have the same pharmacokinetic properties as the original compound.
Renal insufficiency.
The clearance of mirtazapine correlates with creatinine clearance. Compared to normal subjects, the overall clearance of mirtazapine decreases by approximately 30% in patients with moderate renal impairment (creatinine clearance (Clcr) = 11 to 39 ml/min/1.73 m2) and by approximately 50% in patients with severe renal impairment (Clcr = <10 ml/min/1.73 m2). Mirtazapine should be used with caution in patients with renal impairment (see [Precautions] and [Dosage]).
Hepatic insufficiency.
Mirtazapine clearance is decreased by approximately 30% in patients with hepatic impairment following a single oral dose of 15 mg mirtazapine tablets compared to subjects with normal liver function. Mirtazapine should be used with caution in patients with hepatic impairment (see [Precautions] and [Dosage]).
Storage】 Keep away from light and dry place.
Package】 Aluminum-plastic package, 10 tablets/plate, 2 plates/box.
Expiration date】 24 months
Execution standard
Approval Number】 State Drug Administration H20060702
Manufacturer
Company Name: Harbin Sanlian Pharmaceutical Co.
Production Address: Beijing Road, Harbin Limin Economic Development Zone
Postal Code: 150025
Telephone number: 0451-57355668
Fax number: 0451-57354698
Web address: www.medisan.com.cn