How Do I Choose the Best Mirtazapine Tablets?
Mirtazapine tablets / Mirtazapine orally disintegrating tablets, prescription drugs, suitable for the treatment of depression.
Mirtazapine tablets / Mirtazapine orally disintegrating tablets, prescription drugs, suitable for the treatment of depression.
Mirtazapine has a tetracyclic structure and belongs to the piperazine-azaze compounds.
Mirtazapine's anti-depressant pharmacological mechanism; it can improve the symptoms of depression and the sleep structure of patients, improve sleep quality; less cause sexual dysfunction, improve patient compliance; easy to use, less drug interactions, and well tolerated.
- Drug Name
- Mirtazapine tablets
- Whether prescription drugs
- prescription
- Main indications
- Depression treatment
- Dosage form
- sheet
Mirtazapine Tablets Drug Information
Mirtazapine Tablets Basic Information
[Commodity name] REMERON
[General name] Mirtazapine Tablets / Mirtazapine Orally Disintegrating Tablets
[Chinese Pinyin] Midanping Pian / Midanping Kouqiangbengjiepian
[English Common Name] Mirtazapine Tablets / Mirtazapine Orally Disintegrating Tablets
[Main ingredients] The main ingredient of this product is mirtazapine
specification:
Mirtazapine tablets: 30mg.
Mirtazapine orally disintegrating tablet: 15mg.
package:
Mirtazapine tablets: aluminum-plastic packaging. 10 tablets, 30 tablets / box.
Mirtazapine Orally Disintegrating Tablets: Child-resistant, peelable, single-dose blister packs with hard perforations, pressed from aluminum foil, plastic-coated aluminum foil coated with heat-seal lacquer.
Plastic film contains: PVC (polyvinyl chloride), polyamide and polyester.
15mg: 18 tablets / box.
[Validity] 36 months.
[Executive standards] Mirtazapine tablets: Registration standards for imported drugs: JX20100185.
Mirtazapine Orally Disintegrating Tablets: 15mg Specification: JX20090211; [1]
[Approval number] Mirtazapine tablets: Import drug registration number: H20140031.
Mirtazapine Orally Disintegrating Tablets: 15mg specification import drug registration certificate number: H20110383; [1]
manufacturer
Company Name: NV Organon
Address: Kloosterstraat 6, 5349 AB Oss, the Netherlands
Name of Mirtazapine Tablet Factory: NV Organon
Address: Kloosterstraat 6, 5349 AB Oss, the Netherlands
Mirtazapine Orally Disintegrating Tablets Factory Name: CIMA Labs. Inc.
Address: 10000 Valley View Road, Eden Prairie, MN 55344 USA
Packing factory name: NV Organon
Address: Kloosterstraat 6,5349 AB Oss, the Netherlands [1]
[Main ingredients] The main ingredient of this product is mirtazapine. [2]
Chemical name: 1,2,3,4,10,14b-Hexahydro-2-methylpyrazino [2,1-a] pyrido [2,3-c] [2] Benzazepine.
Structural formula:
[Character]
Mirtazapine tablets: This product is a red-brown oval film-coated tablet. After removing the coating, it turned white to off-white.
Mirtazapine Orally Disintegrating Tablets:
15mg: This product is a white tablet; [2]
Mirtazapine tablets indications
For the treatment of depression. [2]
Dosage of mirtazapine tablets
Oral administration.
Mirtazapine tablets should be swallowed with water and should not be chewed.
Mirtazapine orally disintegrating tablets break down quickly in the mouth and do not need to be swallowed with water.
adult:
The effective dose is usually 15 to 45 mg per day. The starting dose of treatment should be 15 mg or 30 mg. This product works after one to two weeks of administration. When taken in moderation, the effect should be within two to four weeks. If the effect is not obvious, the dose can be increased to the maximum dose. However, if the dose does not work after two to four weeks, the drug should be stopped.
Patients with impaired renal function:
Patients with moderate to severe renal impairment (creatinine clearance <40ml / min) have reduced clearance of mirtazapine. This should be taken into account when prescribing this product to such patients (see [Cautions]).
Patients with impaired liver function:
The clearance rate of mirtazapine decreased in patients with liver impairment. This should be taken into account when prescribing this product to such patients, especially those with severe hepatic impairment, as patients with severe hepatic impairment have not been studied (see [Precautions]).
Mirtazapine has a clearance half-life of 20 to 40 hours, so this product is suitable for taking once a day (preferably before going to bed). The drug can also be taken in divided doses (such as once in the morning and evening, a higher dose should be taken at night).
Patients should take the medication continuously and should be fully treated for at least 6 months to ensure that symptoms disappear.
Withdrawal: It is recommended to gradually withdraw to prevent symptoms of withdrawal (see [Precautions]).
Mirtazapine orally disintegrating tablets should be taken as follows:
1. Do not crush orally disintegrating tablets
To prevent crushing the orally disintegrating tablet, do not squeeze the orally disintegrating tablet blister.
2. Remove the blister of the orally disintegrating tablet
Each plate includes 6 blister, separated by seam holes. Peel the blister along the dotted line
3. Peel off the lidding film
Carefully peel off the lid film from the arrow shown in the corner
4. Take out the orally disintegrating tablet
Remove the orally disintegrating tablet with dry hands and place on the tongue
Orally disintegrating tablets should be used immediately after removal from the blistered eyes. Once removed, it cannot be stored again. [2]
Mirtazapine tablets adverse reactions
Because patients with depression often show some symptoms caused by the disease itself, it is sometimes difficult to distinguish which symptoms are caused by the disease itself and which symptoms are caused by the treatment of this product.
In randomized, placebo-controlled clinical trials of this product, the most common adverse reactions reported with a incidence of more than 5% include: lethargy, sedation, dry mouth, weight gain, increased appetite, dizziness, and fatigue. In addition, according to the results of controlled clinical trials conducted in the United States , the most common is related to the use of this product (incidence rate is 5% or more) and is different from the incidence of patients in the placebo group (the incidence rate of this product is at least placebo) Adverse events): lethargy, increased appetite, weight gain, and dizziness.
All randomized, placebo-controlled trials in patients (including non-depressive patients) evaluated adverse effects of this product. The meta-analysis (meta) included 20 clinical trials with a planned treatment duration of up to 12 weeks, with 1501 patients (134 person-years) receiving up to a 60 mg / day dose of mirtazapine and 850 patients ( 79 years) received placebo. The extension of these trials was excluded to maintain comparability with placebo treatment.
Table 1 shows the classification incidence of adverse reactions. In clinical trials, compared with the placebo group, the adverse reaction rate in the mirtazapine treatment group was higher and statistically significant. Spontaneous reported adverse reactions were added. The frequency of adverse reactions in spontaneous reports is based on the rate at which these events are reported in clinical trials. The frequency of adverse reactions that were not observed in a randomized placebo-controlled trial of mirtazapine was classified as "frequency unknown".
In laboratory evaluations of clinical trials, transient elevations of transaminase and -glutamyltransferase were observed (but related adverse event reports showed no statistical difference compared to placebo).
Children crowd
The following adverse events are frequently observed in clinical trials in children: weight gain, urticaria, and hypertriglyceridemia.
In the short-term placebo-controlled trial of mirtazapine tablets at a dose of 5 to 60 mg per day in the United States , the incidence of adverse events 1% and higher than that of the placebo group is shown in Table 2.
Table 2.Clinical experience with incidence of 1% in short-term controlled trials in the United Statesa |
|---|
Body system Adverse clinical reaction | Mirtazapine tablets (n = 453) | Placebo (n = 361) |
whole body |
weak | 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 disorders |
Gain weight | 12% | 2% |
Peripheral edema | 2% | 1% |
Edema | 1% | 0% |
Musculoskeletal system |
Myalgia | 2% | 1% |
nervous system |
Lethargy | 54% | 18% |
dizziness | 7% | 3% |
Dream abnormal | 4% | 1% |
Abnormal thinking | 3% | 1% |
Tremor | 2% | 1% |
Confusion | 2% | 0% |
Respiratory system |
Difficulty breathing | 1% | 0% |
Genitourinary system |
Frequent urination | 2% | 1% |
a Includes events reported by at least 1% of mirtazapine patients, with the exception of the following events, which have a higher incidence in the placebo group than or equal to the mirtazapine group: headache, infection, pain, chest pain, palpitations, heartbeat Excessive speed, orthostatic hypotension, nausea, indigestion, diarrhea, flatulence, insomnia, nervousness, decreased sexual desire, hypertonicity, pharyngitis, rhinitis, sweating, amblyopia, tinnitus, taste inversion |
Results of short-term placebo-controlled trials in the United States
Adverse reactions leading to discontinuation of treatment
In a six-week controlled clinical trial 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 suffered from adverse events. Response and interrupt treatment. The most common (1%) adverse events related to discontinuation of treatment and considered to be drug-related (i.e., events that caused at least twice as much patient shedding as the placebo group) included:
| Common adverse events leading to discontinuation of treatment in a 6-week mirtazapine tablet trial in the United States |
|---|
Adverse event | Percentage of patients discontinued due to adverse events |
Mirtazapine tablets (n = 453) | Placebo (n = 361) |
Lethargy | 10.4% | 2.2% |
nausea | 1.5% | 0% |
Electrocardiogram (ECG) changes
The electrocardiograms of 338 patients receiving this product and 261 patients receiving placebo were analyzed in a 6-week placebo-controlled trial. In the mirtazapine-treated patients, no QTc 500 msec was observed. The mean change in QTc in the mirtazapine-treated group was + 1.6 msec, and the mean QTc in the placebo-treated group was 3.1 msec. The heart rate of patients in the mirtazapine group increased by an average of 3.4 beats / minute, and the heart rate of the placebo patients increased by an average of 0.8 beats / minute. The clinical significance of these changes is unknown.
Other adverse events observed in the pre-market evaluation of this product:
In the pre-marketing clinical trials, a total of 2796 patients took mirtazapine tablets multiple times, and the treatment status and duration of treatment varied widely, including open and double-blind trials, uncontrolled and controlled trials, inpatient and outpatient trials , Fixed dose and dose adjustment tests. Clinical researchers report adverse events related to this treatment in terms of their choice. Therefore, it is impossible to provide a meaningful assessment of the proportion of individuals with adverse events without first categorizing similar types of adverse events into a smaller number of standardized event categories.
In the following, the standard adverse reaction vocabulary standard coding (COSTART) terminology is used to classify adverse events, and the incidence rate represents the proportion of 2796 patients who had at least one adverse event during treatment. It should be emphasized that although the reported incident occurred during the treatment of this product, it may not be caused by this product. The incidence of adverse events: 1% in common cases, 1% 1 in rare cases, and <1 in rare cases.
The following are adverse events not listed in the above table. Events of clinical importance are also described in [Precautions].
Whole body: common: Discomfort, abdominal pain, acute abdomen; occasionally: Chills, fever, facial edema, ulcers, photosensitivity, neck stiffness, neck pain, abdominal distension; rare: Cellulitis, chest pain (under the sternum).
Cardiovascular system: common: hypertension, vasodilation; occasional: angina pectoris, myocardial infarction, bradycardia, ventricular contraction, syncope, migraine, hypotension; rare: atrial arrhythmia, dual rhythm, blood vessels Headache, pulmonary embolism, cerebral ischemia, enlarged heart, phlebitis, left heart failure.
Digestive system: common: vomiting, anorexia; occasional: belching, glossitis, cholecystitis, nausea and vomiting, bleeding gums, stomatitis, colitis, abnormal liver function tests; rare: discoloration of tongue, ulcerative stomatitis, salivary gland hypertrophy , Increased salivation, intestinal obstruction, pancreatitis, aphthous stomatitis, cirrhosis, gastritis, gastroenteritis, oral candidiasis, swelling of the tongue.
Endocrine system: rare: Goiter, hypothyroidism.
Blood and lymphatic system: Rare: lymphadenopathy, leukocytopenia, petechiae, anemia, thrombocytopenia, lymphocytosis, pancytopenia.
Metabolic and Nutritional Disorders: Common: Thirst; Occasionally: Dehydration, weight loss; rare: gout, elevated aspartate aminotransferase (AST), abnormal wound healing, elevated acid phosphatase, elevated alanine aminotransferase (ALT), diabetes, hyponatremia .
Musculoskeletal system: common: myasthenia gravis, joint pain; occasional: arthritis, tenosynovitis; rare: pathological fracture, osteoporotic fracture, bone pain, myositis, tendon rupture, arthropathy, bursitis.
Nervous system: Common: Hypoesthesia, apathy, depression, reduced motor function, dizziness, twitching, agitation, anxiety, forgetfulness, hyperkinesis, paresthesia; occasional: ataxia, delirium, illusion, disintegration of personality, exercise Disorders, extrapyramidal syndrome, increased libido, abnormal coordination, dysarthria, hallucinations, manic reactions, neurosis, dystonia, hostile behavior, enhanced reflexes, emotional instability, euphoria, paranoia-like Reaction; rare: Aphasia, nystagmus, insomnia (psychomotor restlessness), stiffness, dementia, diplopia, drug dependence, paralysis, seizures, hypotonia, myoclonus, psychotic depression, withdrawal syndrome, 5-serotonin syndrome .
Respiratory system: common: increased cough, sinusitis; occasional: epistaxis, bronchitis, asthma, pneumonia; rare: Asphyxia, laryngitis, pneumothorax, hiccup.
Skin: common: itching, rash; occasional: acne, exfoliative dermatitis, dry skin, herpes simplex, hair loss; rare: Urticaria, shingles, skin hyperplasia, seborrheic dermatitis, skin ulcers.
Special sensations: Occasionally: eye pain, abnormal regulation, conjunctivitis, deafness, keratoconjunctivitis, tearing disorders, glaucoma, auditory allergies, ear pain; rare: blebitis, partial temporary deafness, otitis media, loss of taste, paranoia .
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, urethra Inflammation, irregular uterine bleeding, excessive menstruation, abnormal ejaculation, breast congestion, breast enlargement, urgency.
Other adverse events observed in the post-marketing evaluation of this product:
Report adverse events since listing. These events are related to mirtazapine treatment in time (not necessarily causal), including 4 cases of torsional ventricular tachycardia, but 3 of them had concomitant medication. All patients recovered.
Cases of severe skin reactions have been reported, including Stevens-Johnson syndrome, bullous dermatitis, erythema polymorpha, and toxic epidermal necrosis. [2]
Mirtazapine tablets contraindications
Hypersensitivity:
Those who have hypersensitivity to mirtazapine or any excipient component of this product are prohibited.
Monoamine oxidase inhibitor:
Monoamine oxidase inhibitors (MAOIs) intended for the treatment of mental illness are not allowed to be used in combination with this product or within 14 days of discontinuation of this product because of the increased risk of serotonin syndrome. This product is also banned within 14 days after discontinuation of MAOIs intended for the treatment of mental illness (see [Precautions]).
Similarly, patients who are receiving MAOIs such as linezolid or intravenous methylene blue are prohibited from using this product because of the increased risk of serotonin syndrome (see [Cautions]). [2]
Precautions for Mirtazapine Tablets
caveat:
Worsening clinical symptoms and risk of suicide:
Adults and children with depression, whether taking antidepressants or not, their depression may worsen, and suicidal thoughts and suicidal behaviors and abnormal changes in behavior may occur. This risk will continue until the condition becomes obvious Until remission. Depression and certain mental disorders are known to be associated with the risk of suicide, and these mental disorders themselves are the strongest predictors of suicide. However, there have been long-standing concerns that antidepressants may play a role in inducing worsening depression symptoms, suicidal ideation, and behavior in the early stages of treatment in some patients. Summary analysis of short-term placebo-controlled studies of antidepressants (selective serotonin reuptake inhibitors and other drugs) shows that in children, adolescents, and young people (18-24 years) with depression (MMD) and other mental disorders Compared with placebo, antidepressants increase the risk of suicidal thoughts and suicidal behaviors (suicidal ideation, behavior). Short-term clinical trials have not shown that in adults older than 24 years, the use of antidepressants increases the risk of suicidal ideation and behavior compared to placebo; in adults 65 and older, the use of antidepressants After depression, the risk of suicidal ideation and behavior was reduced.
Placebo-controlled trials in children and adolescents with depression, obsessive-compulsive disorder (OCD), or other mental disorders (a total of 24 short-term clinical trials, 9 antidepressants, including 4,400 patients) and in patients with depression Placebo-controlled trials (advanced short-term clinical trials totaling 295 short-term clinical trials, median duration of 2 months, 11 antidepressants, and approximately 77,000 patients) in adult patients with neurological or other mental disorders. Suicidal ideation and behavioral risks vary widely, but most drug studies have shown a trend toward increased suicidal risk in younger patients. The absolute risk of suicidal ideation and behavior is different in different indications, and the absolute risk is highest in depression. Although the absolute risk varies between indications (drugs versus placebo), the risk is relatively stable across the age groups of the indications. Table 3 provides the risk differences (number of suicide ideas and behavioral risk differences per 1000 patients with drug and placebo).
| table 3 |
|---|
age range | Differences in suicidal ideation and behavioral risk per 1000 patients with drug and placebo |
Increased number of cases compared to placebo |
<18 | 14 more cases |
18 24 | 5 more cases |
Reduced number of cases compared to placebo |
25 64 | Reduced by 1 case |
65 | 6 cases reduced |
No suicides occurred in children's clinical trials. Suicides have occurred in adult clinical trials, but the number has not been sufficient to draw conclusions about the effects of drugs on suicide.
It is unknown whether the risk of suicidal ideation and behavior will continue during long-term medication (such as a few months later). However, evidence from placebo-controlled maintenance treatment clinical trials in adult patients with depression shows that the use of antidepressants can delay the relapse of depression.
Regardless of the indication being treated, all patients receiving antidepressant medication should be properly monitored and closely monitored for worsening clinical symptoms, suicidal tendency, and abnormal behavior changes, especially within the first few months of the drug's initial treatment, and increasing Or reduce the dose.
Adults and children with depression, other psychotic or non-psychiatric disorders can be treated with antidepressants in the following symptoms: anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, meditation Impossible (psychomotor restlessness) and mild mania and mania. Although a causal relationship between the appearance of these symptoms and the exacerbation of depression and / or the generation of suicidal impulses has not been established, it is noted that the appearance of these symptoms may be a precursor to suicidal tendencies.
When the patient's depressive symptoms continue to worsen, suicidal tendency appears, or symptoms that may be aggravated or depressive of suicidal symptoms, careful consideration should be given to adjusting the treatment plan including the possible discontinuation of drug treatment. This is especially true if these symptoms are severe, sudden, or not compatible with the patient's current symptoms.
When using antidepressants to treat patients with depression or other psychotic or non-psychiatric disorders, family members and caregivers should be reminded of the need to monitor patients for irritability, irritability, abnormal behavior changes, and other symptoms mentioned above As well as suicidal tendencies, report these symptoms to health professionals as soon as they occur. Family members and caregivers should perform the above-mentioned inspections on patients daily. When using this product, the prescription should start with the minimum dose and cooperate with good patient management to reduce the risk of overdose.
Screening for patients with bipolar disorder:
Depression episodes may be an early manifestation of bidirectional affective disorder. It is generally accepted (though not clear from controlled trials) that treating 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 above-mentioned symptoms imply that such a change may occur. However, before starting treatment with antidepressants, patients with depressive symptoms should be adequately screened to determine whether they are at risk for bipolar disorder; the screening should include a family history of suicide, bipolar disorder And detailed family history of depression. It should be noted that this product is not approved for the treatment of depression in bipolar disorder.
Myelosuppression, agranulocytosis:
Myelosuppression has been reported during the treatment of this product, and its manifestations are usually granulocytopenia or agranulocytosis. Reversible agranulocytosis is rare in clinical trials of this product. In pre-marketing clinical trials, 2 of 2796 patients treated with this product developed agranulocytosis [ Absolute neutrophil count ( ANC ) < 500 / mm with signs and symptoms such as fever, infection, etc. ] One of them had Sjögren syndrome, and one had severe neutropenia ( ANC < 500 / mm without symptoms ) . These three patients had severe neutropenia on the 61st , 9th, and 14th days of treatment , and all recovered after discontinuation of this product. Based on these three cases, the incidence of severe neutropenia (with or without associated infection) was about 1.1 / 1000 , and the 95% confidence interval was very wide, that is, 2.2 / 10,000 to 3.1 / 1000 . If the patient has sore throat, fever, stomatitis, or other signs of infection, accompanied by a decrease in white blood cell ( WBC ) count, treatment with this product should be discontinued and the patient closely monitored.
There are few reports of agranulocytosis after using this product on the market, most of which are reversible, but there are several cases that are fatal. In fatal cases, most patients are over 65 years of age. Therefore, the doctor should pay attention to the treatment process, once the patient is found to have fever, sore throat, stomatitis or other infection symptoms, the drug should be stopped immediately and a blood count examination should be performed.
Serotonin Syndrome:
It has been reported that serotonin and norepinephrine reuptake inhibitors (SNRIs) and serotonin reuptake inhibitors (SSRIs) have occurred after life-threatening serotonin syndrome, including this product alone, especially with Other serotonin drugs in combination (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's wort), and with serotonin Metabolic drugs (especially MAOIs, whether intended for the treatment of mental illness, or for other purposes, such as linezolid and intravenous methylene blue) are used in combination.
Serotonin syndrome may include altered mental status (such as agitation, hallucinations, delirium, and coma), autonomic instability (such as tachycardia, unstable blood pressure, dizziness, sweating, flushing, high fever), neuromuscular symptoms (such as Tremor, tonicity, myoclonus, hyperreflexia, dyskinesia), seizures and / or gastrointestinal symptoms (eg nausea, vomiting, diarrhea). Patients should be monitored for serotonin syndrome.
It is prohibited to use this product in combination with MAOIs intended to treat mental illness. This product should not be used in patients who are receiving MAOIs such as linezolid or intravenous methylene blue. All reported routes of administration for methylene blue are intravenous, with dosages ranging from 1 to 8 mg / kg. There have been no reports of other routes of use of methylene blue (such as oral tablets or local tissue injection) or lower doses. In some cases, patients who are taking this product may need to receive MAOIs such as linezolid or intravenous methylene blue, and this product should be discontinued before starting MAOI treatment (see Contraindications).
If this product is clinically permitted to be used in combination with other serotonin drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's wort), Be aware of the potential risk of elevated serotonin syndrome, especially at the beginning of treatment and at increased doses.
If this happens, this product and any serotonin drugs should be discontinued immediately and supportive symptomatic treatment should be started.
General considerations:
Symptoms of discontinuation of treatment:
There have been reports of adverse reactions following interruption (especially sudden interruption) of mirtazapine tablets, including but not limited to the following reactions: dizziness, abnormal dreams, sensory disturbances (including paresthesia and electrical shock), agitation, anxiety, fatigue , Confusion, headache, tremor, nausea, vomiting, sweating, or other symptoms that may have clinical significance. Most cases reported were mild and self-limiting. Nonetheless, the above are reported as adverse reactions, but it should be clear that these symptoms may be related to the underlying disease.
In view of the risk of symptoms of discontinuation of treatment, patients currently taking this product cannot abruptly discontinue treatment. When medical treatment is needed to discontinue the treatment of this product, it is recommended to gradually reduce the dose instead of stopping it suddenly.
Inability to meditate / psychomotor restlessness:
The use of antidepressants is related to the occurrence of meditation inability, which is subjective discomfort or anxiety, requires frequent walking, and is accompanied by inability to sit or stand still, most likely in the first few weeks of treatment. Increasing the dose is harmful for patients who develop these symptoms.
Hyponatremia:
Reports of hyponatremia due to mirtazapine are rare. Patients with corresponding risks, such as elderly patients or patients who are concomitant with other drugs known to cause hyponatremia, should be used with caution.
Lethargy:
In controlled trials in the United States , 54% of patients treated with this product developed drowsiness, compared with 18% in the placebo group and 60% in the amitriptyline group. In these trials, drowsiness caused discontinuation of treatment in 10.4% of patients receiving this product, compared with 2.2% in the placebo group. It is unclear whether it will tolerate the lethargy effect of this product. Because this product may significantly impair behavior, patients should be cautious when engaging in activities that require alertness until they can assess the effects of the drug on their psychomotor ability.
dizziness:
In controlled trials in the United States , 7% of patients treated with this product reported dizziness, compared with 3% in the placebo group and 14% in the amitriptyline group. It is unclear whether the dizziness associated with the use of this product will be tolerated.
Appetite / weight gain:
In controlled trials in the United States , 17% of patients treated with this product reported increased appetite, compared with 2% in the placebo group and 6% in the amitriptyline group. In these same trials, 7.5% mirtazapine-treated patients gained 7% in body weight, 0% in the placebo group, and 5.9% in the amitriptyline group. Pre-marketing clinical trials in the United States , including many long-term, open-label patients, 8% of patients receiving this product discontinued due to weight gain. In an 8-week clinical trial for children and adolescents, the daily dose was 15 to 45 mg, 49% of patients receiving this product gained at least 7% in weight, and 5.7% of patients receiving placebo.
Cholesterol / Triglyceride:
In controlled trials conducted in the United States , 15% of patients treated with this product observed non-fasting cholesterol 20% higher than the upper limit of normal, compared with 7% in the placebo group and 8% in the amitriptyline group. In these same trials, 6% of patients treated with mirtazapine increased non-fasting triglycerides to 500 mg / dL, compared with 3% in the placebo group and 3% in the amitriptyline group.
Elevated aminotransferase:
A short-term controlled trial in the United States . 2.0% of patients receiving this product (8/424) observed a clinically significant increase in alanine aminotransferase (ALT) (3 times the upper limit of the normal range). Placebo-treated patients It was 0.3% (1/328) and 2.0% (3/181) in amitriptyline-treated patients. Most of these patients with elevated ALT do not show signs or symptoms associated with impaired liver function. Some patients discontinued due to an increase in ALT. Others continued to treat the product, but liver enzyme levels returned to normal. This product should be used with caution in patients with impaired liver function.
jaundice:
Once jaundice occurs, medication should be discontinued.
Induced mania / mild mania:
In studies conducted in the United States , approximately 0.2% of patients treated with this product (3/1299 patients) developed mania / mild mania. Although the incidence of mania / mild mania is very low during mirtazapine treatment, it should be used with caution in patients with a history of mania / mild mania.
Seizures:
In pre-marketing clinical trials, only 1 seizure was reported in 2796 U.S. and non-U.S. Patients receiving this product. However, no controlled trials have been performed in patients with a history of seizures. Therefore, these patients should be cautious when using mirtazapine.
Use in patients with concomitant diseases:
Clinical experience with this product is limited in patients with concomitant systemic diseases. Therefore, caution should be exercised in prescribing mirtazapine to patients with diseases or conditions that affect metabolic or hemodynamic responses.
Patients with a recent history of myocardial infarction or other significant heart disease have not undergone a systematic review of this product or have not used this product to an evaluable dose. In early clinical pharmacological tests in healthy volunteers, this product was administered with significant orthostatic hypotension. Orthostatic hypotension is rare in clinical trials in patients with depression. For patients with known cardiovascular or cerebrovascular disease that may worsen under hypotension (history of myocardial infarction, angina pectoris, or ischemic stroke), and patients who are prone to hypotension (dehydration, decreased blood volume, and decreased Blood pressure medication), this product should be used with caution.
Moderate [glomerular filtration rate (GFR) = 11 to 39 ml / min / 1.73m] and severe [GFR <10 ml / min / 1.73 m] mirtazapine clearance is reduced and liver function is reduced in patients with renal impairment The same goes for the injured patient. These patients should be used with caution (see [Dosage and Administration]).
Situations requiring supervision:
For patients with the following conditions, pay attention to the dosage and check carefully regularly:
For epilepsy and organic brain syndrome, although clinical experience shows that as with other antidepressants, there are very few seizures when taking this product, it should be used with caution in patients with a history of seizures. Use should be discontinued when patients develop seizures or the frequency of seizures increases.
Patients with liver impairment: After a single dose of 15 mg mirtazapine, mirtazapine clearance in patients with mild to moderate liver impairment decreased by approximately 35% compared with subjects with normal liver function. Mirtazapine increased the average plasma concentration by about 55%.
Patients with impaired renal function: After a single dose of 15 mg mirtazapine, moderate (creatinine clearance <40ml / min) and severe (creatinine clearance 10ml / min) renal function impairment patients with mirtazapine clearance and normal test Compared with the above, it has decreased by 30% and 50% respectively. The average plasma concentration of mirtazapine increased by approximately 55% and 115%, respectively. Patients with mild renal impairment (creatinine clearance <80ml / min) did not differ significantly from the control group.
Heart diseases such as conduction disorders, angina pectoris and recent myocardial infarction. Take regular precautions for such conditions and take other medications with caution.
Hypotension.
Diabetes: For people with diabetes, antidepressants may change blood sugar control levels. It may be necessary to adjust the dosage of insulin and / or oral hypoglycemic agents, and close monitoring is recommended.
As with other antidepressants, the following patients should take care when taking this product:
Patients with schizophrenia and other mental illnesses may experience worsening psychotic symptoms after taking antidepressants, and their delusions may worsen.
Patients with bipolar disorder who are in depression may switch to manic phase after using antidepressants. Patients with a history of mania / mild mania should be closely monitored. Mirtazapine should be discontinued in any patient who has entered the manic phase.
Although this product is not addictive, post-marketing experience has shown that abrupt discontinuation of treatment after long-term administration can sometimes cause withdrawal symptoms. Most withdrawals are weak and self-limiting. Of the various reported withdrawal symptoms, dizziness, anxiety, agitation, headache and nausea were the most common. Although these have been reported as withdrawal symptoms, it should be noted that these symptoms may be related to the underlying disease. Like [Usage and Dosage], it is recommended to gradually stop using mirtazapine.
Patients with difficulty urinating (such as patients with enlarged prostate), acute narrow-angle glaucoma, and patients with increased intraocular pressure should pay attention to observation during taking the drug (although this product has only a weak anticholinergic effect and the chance of its occurrence is small).
alcohol:
This product is known to stack alcohol to cause damage to cognitive or motor skills. Therefore, patients should not drink alcohol while taking mirtazapine.
lactose:
This medicine contains lactose, and patients with rare hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Interfering with cognitive and motor behavior:
Because of the significant sedative effect of this product, it may cause damage to judgment, thinking, and especially motor skills. The drowsiness caused by mirtazapine may impair patients' ability to drive, operate machines, or perform alert tasks. Therefore, patients should be cautious when participating in hazardous activities until they have reason to determine that treatment with this product 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 treatment with this product, and they should provide advice on rational medication use.
Prescription drugs should be kept out of reach of children.
Children and adolescents under 18 years of age:
This product cannot be used in children and adolescents 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 (mainly aggressive, antagonistic, and anger) were more common than those taking placebo. In addition, there is currently no long-term safety data on the growth, development, cognitive and behavioral development of children and adolescents taking this drug.
Complete the course of treatment:
In the case of patients who may improve their condition with this product for 1 to 4 weeks, it is recommended that they continue treatment according to the doctor's advice.
Combination therapy:
If the patient is taking or is planning to take any prescription or over-the-counter medicine, the doctor should be informed as this product may interact with other medicines.
If this product is clinically permitted to be used in combination with other serotonin drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's wort), Be aware of the potential risk of elevated serotonin syndrome, especially at the beginning of treatment and at increased doses.
[Medication for pregnant and lactating women]
If the patient is pregnant or is planning to become pregnant during the treatment of this product, the doctor should be informed.
Data on the use of mirtazapine in pregnant women are limited and do not show an increased risk of congenital malformations. Animal tests have not shown any clinically relevant teratogenic effects, but developmental toxicity has been observed (see [Pharmacology and Toxicology]). Caution should be exercised when prescribing mirtazapine to pregnant women. This product should not be used during pregnancy unless explicitly required. If this product is not discontinued until or shortly before childbirth, it is recommended that newborns be monitored for possible effects of withdrawal after birth.
Tell the doctor if the patient is breastfeeding.
Because this product may be partially secreted into breast milk, lactating women should use this product with caution.
Animal experiments and limited clinical data indicate that only a very small amount of mirtazapine is secreted through milk. Whether to discontinue breastfeeding or the treatment of this product should be fully weighed before deciding whether the benefits of breastfeeding for young children and the benefits of this product for mother treatment.
[Child medication]
This product cannot be used for children and adolescents under 18 years of age (see [Precautions]).
[Medicine for the elderly]
Use this product with caution in elderly patients.
About 190 elderly people (age 65 years) participated in the clinical trial of this product. It is known that this product is mainly excreted by the kidneys (75%), and the risk of decreased clearance of this product is increased in patients with impaired renal function. Because older people are more prone to decline in renal function, care should be taken when choosing a dose. Sedatives can cause confusion and sedation in older people. No abnormal age-related adverse phenomena were found in this group of people. Pharmacokinetic tests show a decline in drug clearance in the elderly. [2]
Mirtazapine tablets drug interactions
Pharmacodynamic Interactions:
Mirtazapine should not be used in combination with monoamine oxidase (MAO) inhibitors or within two weeks of discontinuation of MAO inhibitor therapy. Conversely, if patients receiving mirtazapine need to be treated with MAO inhibitors, they should be separated by about two weeks (see [Contraindications]). In addition, like SSRIs, mirtazapine works with other serotonin active substances (L-tryptophan, triptans, tramadol, linezolid, SSRIs, venlafaxine, lithium and Hypericum perforatum). Preparation) concomitant administration may cause serotonin-related reactions (serotonin syndrome, see [Cautions]).
Mirtazapine may aggravate the sedative effects of benzodiazepines and other sedatives (especially most antipsychotics, histamine H 1 antagonists, opioids). Care should be taken when such drugs are used in combination with mirtazapine. The combined use of diazepam (15 mg) by 12 healthy subjects had little effect on the plasma level of mirtazapine (15 mg). However, the damage of motor skills caused by this product and the effects of diazepam have a superimposed effect. Therefore, patients should be advised to avoid diazepam and other similar drugs while taking this product.
Mirtazapine can increase the inhibitory effect of alcohol on the central nervous system. Therefore, patients should be advised not to drink alcoholic beverages during treatment.
Subjects taking warfarin at the same time taking mirtazapine 30 mg daily caused a small but statistically significant increase in the international normalized ratio (INR). When the dose of mirtazapine is increased, a more significant effect cannot be ruled out. It is recommended to monitor INR levels when mirtazapine and warfarin are used simultaneously.
Pharmacokinetic interactions:
Drugs affecting liver metabolism:
The metabolism and pharmacokinetics of this product may be affected by drug metabolism enzyme inducers or inhibitors.
Drugs metabolized by cytochrome P450 and / or drugs that inhibit cytochrome P450:
CYP enzyme inducers (the following are studies under steady state conditions):
Phenytoin: In healthy male subjects (n = 18), phenytoin (200 mg / day) doubled the clearance of mirtazapine (30 mg / day), resulting in a 45% reduction in mean plasma concentration of mirtazapine . Mirtazapine has no significant effect on the pharmacokinetics of phenytoin.
Carbamazepine: In healthy male subjects (n = 24), carbamazepine (400 mg, 2 times / day) doubled the clearance of mirtazapine (15 mg, 2 times / day), resulting in Mirtazapine reduced the average plasma concentration by 60%. When phenytoin, carbamazepine, or other liver metabolism inducers (such as rifampicin) 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 reduced.
CYP enzyme inhibitor:
Cimetidine: Healthy male subjects (n = 12) received Cimetidine, a weak CYP1A2, CYP2D6, and CYP3A4 inhibitor (800 mg, 2 times / day), after reaching steady state and under steady state Mirtazapine (30 mg / day) combined, the area under the mirtazapine curve (AUC) increased by more than 50%. Mirtazapine does not change the pharmacokinetics of cimetidine. Mirtazapine may need to be reduced when cimetidine is coadministered, and mirtazapine should be increased when cimetidine is discontinued.
Ketoconazole: The strong CYP3A4 inhibitor ketoconazole (200 mg, 2 times / day for 6.5 consecutive days) in healthy male Caucasians (n = 24) can achieve a single plasma peak concentration of mirtazapine 30 mg And AUC increased by about 40% and 50%, respectively.
Caution should be exercised when mirtazapine is used in combination with strong CYP3A4 inhibitors, HIV protease inhibitors, azole antifungals, erythromycin or nefazodone.
Paroxetine: A study of in vivo interactions in healthy, strong CYP2D6 metabolites (n = 24) showed that mirtazapine (30 mg / day) in steady state did not change paroxetine (40 mg / day) ), A pharmacokinetic profile of a CYP2D6 inhibitor.
Other drug-drug interactions:
Amitriptyline: a drug that does not change mirtazapine (30 mg / day) at steady state in healthy, strong CYP2D6 metabolism subjects (n = 32) Generational kinetics; mirtazapine did not change the pharmacokinetics of amitriptyline.
Lithium: No sub-therapeutic dose of lithium (600 mg / day for 10 consecutive days) at steady state in healthy male subjects did not have a clinical effect or significant pharmacokinetic changes on a single dose of 30 mg mirtazapine. The effect of higher doses of lithium on the pharmacokinetics of mirtazapine is unknown.
Risperidone: A non-randomized, interacting in vivo study in subjects in need of antipsychotic and antidepressant treatment (n = 6) showed mirtazapine (30 mg / day) steady state Does not affect the pharmacokinetics of risperidone (up to 3 mg, 2 times / day).
[Drug overdose]
Existing experience shows that the symptoms of overdose of this product alone are usually mild. Central nervous system depression has been reported with loss of orientation and prolonged sedation, as well as tachycardia, mild hypertension or hypotension. However, if the dose is significantly higher than the therapeutic dose, especially when used in excess with other drugs at the same time, it can cause very serious (even fatal) consequences. Patients with overdose should be given appropriate symptomatic and supportive treatment in a timely manner. There is currently no known specific mirtazapine antidote, and activated carbon or gastric lavage can be considered. [2]
Mirtazapine tablets pharmacological action
Mirtazapine has a tetracyclic structure and belongs to the piperazine-azaze compounds. The mechanism of mirtazapine in the treatment of severe depression is unclear. Preclinical trials have shown that this product can enhance the activity of central norepinephrine and serotonin, which may be related to the presynaptic inhibitory 2 Body antagonists.
Mirtazapine is a strong antagonist of 5-HT 2 and 5-HT 3 receptors, but has no obvious affinity for 5-HT 1A and 5-HT 1B receptors. At the same time, mirtazapine is a potent antagonist of the H 1 receptor, this attribute can explain its obvious sedative effect; mirtazapine has a moderate intensity antagonistic effect on the alpha 1 adrenergic receptor, this attribute can explain its Occasional orthostatic hypotension reported in use; mirtazapine has a moderate-intensity antagonistic effect on M receptors, a property that may explain its relatively low incidence of anticholinergic side effects. [3]
Toxicology research
Genotoxicity: Ames test, in vitro Chinese hamster V79 cell gene mutation test, in vitro cultured rabbit lymphocyte sister chromosome exchange test, rat bone marrow micronucleus test, and HeLa cell extraprogrammed DNA synthesis test were all negative.
Reproductive toxicity: Rats were given mirtazapine at a dose of 100 mg / kg (in mg / m, 20 times the maximum recommended dose for humans). No effects on mating and pregnancy were found, but the dose was 3 times or more than the maximum recommended dose for humans. At the dose, the animal's estrus is interrupted, and at 20 times the dose, preimplantation loss occurs.
No teratogenic effects were found when pregnant rats and domestic rabbits dosed 100 mg / kg and 40 mg / kg (in mg / m, 20 and 17 times the maximum recommended human dose, respectively). However, pregnant rats given mirtazapine have increased loss after implantation, increased pup mortality in the first 3 days of lactation (the cause of death is unknown), and reduced birth weight of pups. These effects occur at 20 times the maximum recommended human dose. At the dose, it did not appear at 3 times the dose.
Carcinogenicity: Carcinogenicity studies of 2, 20 and 60 mg / kg / day in rats and 2, 20 and 200 mg / kg / day in mice (in mg / m) (The doses are about 12 and 20 times the maximum recommended human dose, respectively). The results showed that the incidence of hepatocellular adenomas and cancers in male mice in the high-dose group increased; hepatocyte adenomas in female rats in the medium and high-dose groups, and hepatocyte adenomas and thyroid follicular glands in the high-dose group Incidence of tumors / cystadenomas and cancers has increased. These data suggest that the above effects may be mediated by non-genotoxic mechanisms, and its relevance to humans is unclear.
The doses administered in the mouse studies may not be high enough to adequately reflect the potential carcinogenicity of mirtazapine. [2]
Mirtazapine tablets pharmacokinetics
Mirtazapine orally disintegrating tablets and Mirtazapine tablets are bioequivalent.
After taking this product orally, its active ingredient mirtazapine is quickly absorbed (bioavailability is about 50%). The plasma concentration peaked after about two hours. About 85% of mirtazapine binds to plasma proteins. The average half-life is 20 to 40 hours; occasionally a half-life of up to 65 hours; occasionally a shorter half-life is also found in young people. The clearance half-life is sized to be appropriate for daily use. The blood drug concentration reached a steady state after 3 to 4 days of taking the drug, after which there would be no accumulation in the body. Mirtazapine exhibits a linear pharmacokinetic profile over the recommended dose range. Taking it with food does not affect the pharmacokinetics of mirtazapine.
Mirtazapine is mostly metabolized within a few days after taking the drug and excreted through the urine and feces. Its main biological transformation methods are demethylation and oxidation reactions, 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-desmethyl and N-oxide metabolites. The metabolites after disarming still have pharmacological activity and have the same pharmacokinetic properties as the original compound.
Renal insufficiency:
Mirtazapine clearance is associated with creatinine clearance. Compared with normal subjects, the overall clearance rate of mirtazapine decreased by approximately 30% in patients with moderate renal impairment (Cr. (Clcr = <10 ml / min / 1.73 m) decreased by about 50%. Mirtazapine should be used with caution in patients with renal impairment (see [Precautions ] and [Dosage and Administration ] ).
Liver insufficiency:
Compared with subjects with normal liver function, after a single oral administration of 15 mg of this product, mirtazapine clearance in patients with liver impairment decreased by about 30%. Mirtazapine should be used with caution in patients with liver damage (see [Precautions ] and [Dosage and Administration ] ). [2]
Mirtazapine Tablet Guide Recommended
1. The 2010 American Guidelines for the Treatment of Major Depression (APA) recommends mirtazapine as the preferred drug for the acute phase of depression. [4]
2. The 2009 Chinese Guidelines for the Prevention and Treatment of Depressive Disorders states that NassA (mirtazapine) is suitable for all kinds of depressive disorders, especially patients with severe depression and significant anxiety, agitation, and insomnia. [5]
Clinical data of mirtazapine tablets
Comparison of Mirtazapine Orally Disintegrating Tablets and Mirtazapine Tablets:
A clinical trial was conducted in Chinese subjects with the goal of comparing a single dose of this product to marketed mirtazapine tablets (trade name: Ruimeilong) under fasting conditions in the Chinese population. Bioequivalence.
This is an open, randomized, two course (T and R), two cycle, two sequence crossover trial. A single dose of 30 mg of this product was taken orally during course T, and a single dose of 30 mg of mirtazapine tablets was orally taken during course R. A total of 26 Chinese healthy male subjects were enrolled, aged between 18 and 45 years, and the body mass index (BMI) was between 19 and 24 kg / m. They were evenly divided into two sequence groups (13 in each sequence group). Subject). Each subject received a single dose of this product and a single dose of mirtazapine tablets, with a washout period of at least 2 weeks.
All 26 subjects completed the trial.
The following table summarizes the results of bioequivalence studies on Cmax and AUC of this product and mirtazapine tablets, n = 25. The plasma concentration of mirtazapine after taking this product was very low and was considered an abnormal pharmacokinetic value. Therefore, the results of this subject were not included in the bioequivalence test. If the 90% confidence interval of the AUC ratio is completely within the acceptable range of 0.80 to 1.25 and the 90% confidence interval of the Cmax ratio is completely within the acceptable range of 0.70 to 1.43, this product and mirtazapine tablets are considered to be bioequivalence.
parameter | unit | Geometric mean Test drug | Geometric mean Control drug | Point estimate Test drug / control drug | 90% confidence interval | in conclusion |
C max | Ng / ml | 83.1 | 94.3 | 0.88 | 0.74 1.04 | Bioequivalent |
AUC 0- ¥ | Ng * h / ml | 971 | 951 | 1.02 | 0.93 1.13 | Bioequivalent |
AUC 0-tlast | Ng * h / ml | 923 | 903 | 1.02 | 0.93 1.13 | Bioequivalent |
Test drug: This product; Control drug: Mirtazapine tablets on the market (Trade name: Ruimeilong)
Bioequivalence: 90% confidence interval is within the acceptable range (AUC is 0.80 to 1.25, C max is 0.70 to 1.43).
Studies have shown that according to the data of C max , AUC 0-tlast and AUC 0- ¥ , this product is bioequivalence between 30 mg of mirtazapine tablets and 30 mg of marketed mirtazapine tablets. There was no significant therapeutic effect for t max (p> 0.05).
Both therapeutic formulations are well tolerated. No serious adverse events were reported. Mild drowsiness was the only adverse event reported during the trial and the incidence was similar after taking the two treatments. Researchers believe that drowsiness is related to treatment, and all subjects recovered from adverse events. [2]
