Date of approval: 01/14/2015
Date of revision: 01 December 2015
December 07, 2015
April 01, 2016
Year Month Day
Instructions for Flupirtine Melitrexin Tablets
Please read the instructions carefully and use under the guidance of a physician
Warnings
Antidepressants and suicide in children and adolescents
Short-term studies in children and adolescents with depression and other psychiatric disorders suggest that antidepressants increase the risk of suicidal ideation and suicidal behavior (suicide), and this risk must be weighed against the clinical need if haloperidol melitrexin Tablets or any other antidepressant is considered in children and adolescents. Patients who have already started treatment should be closely monitored for worsening clinical symptoms, suicidality, or unusual behavioral changes. Family members and caregivers should be advised to increase close observation of the patient and to improve communication with the primary care physician. Flupirtine melitrexin tablets are not approved for use in pediatric patients (see [Precautions] and [Pediatric Dosage]).
A comprehensive analysis of placebo-controlled trials in the acute phase (a total of 24 trials including 4400 patients) of 9 antidepressants (SSRIs and other antidepressants) for the treatment of depression, obsessive-compulsive disorder, or other psychiatric disorders in children and adolescents showed that these children and adolescents treated with antidepressants had a significantly increased risk of adverse events of suicidal ideation and suicidal behavior (suicide) during the first few months of treatment. The risk was significantly increased. The average risk of these adverse events was 4% in patients treated with antidepressants, twice the risk of placebo-treated patients (2%). No suicidal events occurred in these trials.
Drug Name]
Generic name: Flupentixol Melitrexin Tablets
English name: Flupentixol and Melitracen Tablets
Hanyu Pinyin: Fupaisaidun Meiliquxin Pian
Ingredients
This product is a compound preparation, its main components are: Flupentixol and Melitracen Hydrochloride. Excipients: anhydrous lactose, microcrystalline cellulose, low substituted hydroxypropyl cellulose, stearic acid, silicon dioxide, film-coated premix (gastric soluble type).
Properties
This product is a film-coated tablet, which appears white or off-white after removing the coating.
Indications
Mild to moderate depression and anxiety.
Neurosis, psychogenic depression, depressive neurosis, insidious depression, psychosomatic disease with anxiety and emotional indifference, menopausal depression, restlessness and depression in alcohol and drug addicts.
Specification
Each tablet contains haloperidol 0.5mg and melitrexin 10mg.
Dosage
Adults: Usually 2 tablets per day, 1 in the morning and 1 at noon; in severe cases, the dose may be increased to 2 in the morning. The maximum daily dosage is 4 tablets.
Elderly patients: 1 tablet in the morning is sufficient.
Maintenance dose: Usually 1 tablet per day, taken orally in the morning.
In cases of insomnia or severe restlessness, it is recommended to reduce the dose or add a mild sedative during the acute phase.
Adverse reactions]
Insomnia is the most common adverse effect of this product.
MedDRA
System Organ
Classification common
(>1%, <10%) Occasionally
(>0.1%, <1%) Rare
(>0.01%, <0.1%) Very rare
(<0.01%) Unknown Blood and lymphatic system disorders Thrombocytopenia, leukopenia, granulocyte deficiency Venous embolism Psychiatric disorders Insomnia, restlessness, agitation Nightmares, anxiety, confusion of mental status Suicidal ideation, suicidal behavior Neurological disorders Drowsiness, tremor, dizziness Extrapyramidal symptoms (e.g., tardive dyskinesia, dyskinesia), Parkinson’s disease, malignant syndromes Eye disorders Dysregulation Cardiac disorders Tachycardia, arrhythmias Gastrointestinal disorders Dry mouth, constipation Nausea, dyspepsia Hepatobiliary disorders Abnormal liver function tests Cholestasis/jaundice, liver disorders Skin and subcutaneous tissue disorders Rash, alopecia Musculoskeletal and connective tissue disorders Myalgia Systemic disorders and drug administration site conditions Fatigue weakness Pregnancy, puerperium and perinatal conditions Neonatal extrapyramidal symptoms and/or withdrawal symptoms Physical examination Prolonged QT interval on ECG Cases of withdrawal syndrome have been observed.
The psychiatric adverse effects described above may also be symptoms of depression itself. In any case, these symptoms may be alleviated when the depression improves.
Post-marketing situation: There are reports of cholestatic hepatitis in some cases.
Contraindications
1. Contraindicated in patients with hypersensitivity to melitrexin, haloperidol, or any of the inactive ingredients of this product. 2.
2. Contraindicated in circulatory failure, central nervous system depression from any cause (e.g., acute alcohol, barbiturate, or opioid intoxication), comatose state, adrenal pheochromocytoma, hemopoietic malignancy, untreated angle-closure glaucoma. Not recommended in patients with early recovery from myocardial infarction, various degrees of heart block or arrhythmias and coronary ischemia.
3. Concomitant use with monoamine oxidase inhibitors is prohibited. The combination of melitrexin with monoamine oxidase inhibitors, including non-selective inhibitors, selective monoamine oxidase-A inhibitors (e.g., moclobemide) and monoamine oxidase-B inhibitors (e.g., stiglitazone), may result in symptoms of pentraxin syndrome, including fever, myoclonus, rigidity, tremor, euphoria, panic, confusion, and autonomic nervous system dysfunction (i.e., circulatory disturbances).
4. Like other tricyclic antidepressants, melitrexin should not be used in patients who are taking monoamine oxidase inhibitors. Treatment with this product should not be initiated until 14 days after discontinuation of non-selective monoamine oxidase inhibitors and sellegrin, and at least 1 day after discontinuation of moriclofenamide. Similarly, treatment with monoamine oxidase inhibitors should be started after 14 days of discontinuation of this product for observation.
Precautions]
This product should be administered with caution in patients with organic brain injury, convulsive seizures, urinary retention, hyperthyroidism, Parkinson’s syndrome, myasthenia gravis, advanced hepatic disease, cardiovascular and other circulatory disorders.
Due to its excitatory properties, this product is not recommended for agitated and overly hyperactive patients. If the patient has been previously treated with tranquilizers, they should be tapered off.
Patients with depression are still at risk of suicide if there is no significant reduction in depressive symptoms.
Suicidal patients should not be given large amounts of medication during treatment.
Based on the fact that other psychotropic drugs have been reported, this product may alter insulin and glucose tolerance, which requires that the dose of glucose-lowering medication be adjusted when using this product in diabetic patients.
In patients with closed-angle glaucoma and shallow anterior chamber, the use of this product may stimulate pupil dilation and lead to acute glaucoma attacks. Concurrent use of tricyclic and tetracyclic antidepressants during local anesthesia increases the risk of arrhythmias and hypotension. If possible, discontinue this product several days before a surgical procedure, and if emergency surgery is performed in unavoidable circumstances, be sure to inform the anesthesiologist of a history of prior antidepressant treatment.
As with other antipsychotics, haloperidol may cause a prolonged QT interval. A persistently prolonged QT interval may increase the risk of malignant arrhythmias. Therefore, haloperidol should be used with caution in susceptible individuals (hypokalemia, hypomagnesemia, or genetic qualities) and in patients with a history of cardiovascular disease (e.g., prolonged QT interval, significant bradycardia (<50 beats/min), recent acute myocardial infarction episodes, decompensated heart failure, or arrhythmias). Combination therapy with other antipsychotics that may cause prolongation of the QT interval should be avoided (see [Drug Interactions]).
This product contains anhydrous lactose in the excipients. Patients with rare genetic galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption are advised not to take this product. As with all neuroleptics, malignant syndromes (potentially fatal) occur rarely with administration of this product.
Very rarely, especially at the beginning of haloperidol treatment, extrapyramidal symptoms may occur. Irreversible delayed dyskinesia may occur when neuroleptics such as haloperidol are used for long-term treatment.
Patients on long-term haloperidol need to have their mental and neurological status, blood counts, and liver function checked regularly.
Cases of venous thromboembolism (VTE) have been reported with the use of antipsychotic medications. Because risk factors for VTE are frequently present in patients receiving antipsychotic medications, all possible risk factors for VTE should be identified and precautions taken prior to and during treatment with this product.
Patients taking this product should not drive or operate dangerous machinery due to the impairment of concentration and responsiveness associated with both the condition and the use of this product.
Adverse events have been reported in human applications that may have adverse effects on sexual function and fertility in women and/or men. In the event of clinically significant hyperprolactinemia, breast leakage, amenorrhea, or sexual dysfunction, dose reduction (if possible) or discontinuation should be considered. After discontinuation, the drug has produced reversible effects.
[For pregnant and lactating women].
It is best not to take this product during pregnancy and lactation.
Reproductive toxicity studies in animals have shown that the combination of the two active ingredients, haloperidol and melitrexin, has no harmful effects on embryonic development, but no controlled studies have been conducted in pregnant women.
Non-teratogenic effects: Female patients using antipsychotics (including haloperidol) in the last trimester of pregnancy have a risk of extrapyramidal symptoms and/or withdrawal symptoms in their neonates after delivery. Newborns may present with symptoms such as agitation, abnormal muscle rigidity or weakness, tremors, lethargy, respiratory distress, or feeding problems. There may be differences in the severity of these complications. In some cases, the newborn presents with only self-limiting symptoms, while in other cases, the newborn requires monitoring in an intensive care unit or an extended hospital stay.
Flupirtide should not be used during pregnancy unless the need is clear. If discontinuation is required during pregnancy, it should probably not be done abruptly. Small amounts of haloperidol are secreted through breast milk. Animal and human studies have not been conducted on the secretion of melitrexin in breast milk.
Pediatric Dosage]
There is a lack of data on the safety and efficacy of this product in children.
Geriatric use
See [Dosage and Administration] for more information.
Several randomized, placebo-controlled clinical trials have shown an approximately 3-fold increase in the risk of cerebrovascular adverse events in elderly patients with dementia in certain atypical antipsychotic trial groups. The mechanism for this increased risk is unknown. An increased risk of cerebrovascular events cannot be ruled out for other antipsychotics as well as for other patient populations.
Data from two large observational studies showed a slightly increased risk of death in elderly patients with dementia treated with antipsychotics compared with those not receiving treatment. There is insufficient information to make a definitive assessment of the magnitude of this risk, and the reason for the increased risk is unknown.
This product is not approved for the treatment of dementia-related behavioral disorders.
Drug Interactions]
Contraindications to Compounding.
Concomitant use with monoamine oxidase inhibitors (including non-selective inhibitors, selective monoamine oxidase-A inhibitors (e.g., moclobemide), and monoamine oxidase-B inhibitors (e.g., sregiline)) is contraindicated and carries a risk of malignant syndrome (see [Contraindications] for details).
Non-recommended combinations.
Sympathomimetics: Melitrexin may potentiate the cardiovascular effects of the following drugs, including epinephrine, ephedrine, isoprenaline, norepinephrine, phenylephrine, and phenylpropanolamine (ingredients contained in local anesthetics, general anesthetics, and nasal decongestants).
Adrenergic nerve blockers: This product reduces the antihypertensive effects of guanethidine, betanidine, reserpine, colistin, and methyldopa. Review of all antihypertensive therapy is recommended during treatment with tricyclic antidepressants.
Anticholinergics: tricyclic antidepressants enhance the effects of such drugs in the eye, central nervous system, intestine, and bladder, and may increase the risk of paralytic intestinal obstruction and hyperthermia, and should be avoided in combination.
Drugs that may prolong the QT interval: Combination with other drugs known to significantly prolong the QT interval may cause worsening of the prolonged QT interval associated with antipsychotic treatment. Coadministration with the following drugs should be avoided.
-Class Ia and III antiarrhythmics (e.g., quinidine, amiodarone, sotalol, dofetilide)
-Some antipsychotics (e.g., haloperidol, quetiapine)
-Some macrolides (e.g. erythromycin)
-Some antihistamines (e.g., terfenadine, astemizole)
-Some quinolone antibiotics (e.g., gatifloxacin, moxifloxacin)
The above list is not exhaustive and other drugs known to significantly prolong the QT interval (e.g., cisapride, lithium) should be avoided in combination with this product.
Drugs known to cause electrolyte disturbances (e.g., hypokalemia) and drugs known to increase flupirtine plasma concentrations should be used with caution because of the possible increased risk of QT interval prolongation and malignant arrhythmias (see [Precautions]).
Pair with caution.
CNS sedatives: This product potentiates the effects of alcohol, barbiturates, and other CNS sedative drugs (e.g., hypnotics, anxiolytics, antihistamines, opioids, and narcotics). The combination of a nerve blocker (haloperidol) with lithium increases the risk of neurotoxicity. It decreases the effect of levodopa and increases its risk of cardiac adverse effects.
[Drug overdose].
The earliest occurrence of drug overdose is the severe anticholinergic symptoms caused by melitrexin, and the extrapyramidal motor symptoms caused by haloperidol overdose are rarely seen.
Symptoms: drowsiness, excitement, restlessness, hallucinations. Anticholinergic effects: pupil dilation, tachycardia, urinary retention, mucosal dryness, decreased bowel movements, convulsions, fever, sudden central depression, coma, respiratory depression. Cardiac symptoms: arrhythmias (ventricular tachyarrhythmia, tip-twisting ventricular tachycardia, ventricular fibrillation), heart failure, hypotension, cardiogenic shock. Metabolic acidosis. Hypokalemia.
Therapeutic measures: hospitalization (intensive care unit), symptomatic and supportive treatment. Gastric lavage is given, and activated charcoal treatment should be used even in the later stages of drug administration. Take measures to maintain respiratory and cardiovascular system function. monitor cardiac function with ECG continuously for 3 to 5 days. To avoid further decrease in blood pressure, epinephrine should not be used. Valium can be used to treat convulsions and Biperiden can be used to treat extrapyramidal symptoms.
Pharmacology and Toxicology
Pharmacological effects
Haloperidol Melitrexin Tablets is a compound preparation consisting of haloperidol and melitrexin. Flupirtide is a thiazide nerve blocker with anxiolytic and antidepressant effects in small doses. Melitrexin is a tricyclic biphasic antidepressant with euphoric properties when applied at low doses. The combination of the two ingredients has antidepressant, anxiolytic and euphoric properties.
Toxicological studies
Reproductive toxicity.
In the rat fertility test, haloperidol and melitrexin administered alone produced a slight effect on fertility, with haloperidol slightly affecting pregnancy rates in female rats and melitrexin slightly inhibiting fertility in males, at doses well above the clinically applied dose.
In rats and rabbits, the combination of haloperidol and melitrexin did not induce embryonic malformations and did not affect embryonic development. In mice, melitrexin resulted in reduced litter weight and increased late embryonic uptake, but embryonic malformations were observed only at toxic doses in parental animals. In mice and rats, no significant effects of melitrexin on postnatal development were observed.
[Pharmacokinetics].
The combination of flupirtide and melitrexin does not affect the pharmacokinetic properties of each.
Flupirtide.
Flupirtide is a mixture of two geometric isomers, cis (Z)-flupirtide with activity and trans (E)-flupirtide, in a ratio of approximately 1:1. The following data are for cis (Z)-flupirtide with activity.
Absorption: For oral administration, the time to peak blood concentration of haloperidol is about 4-5 h. The bioavailability of oral administration is about 40%.
Distribution: The apparent volume of distribution is about 14.1 L/kg, and the plasma protein binding rate is about 99%.
Biotransformation: cis-(Z)-flupirtine is metabolized in vivo by three main pathways-sulfonation oxidation, side chain N-dehydroxylation, and glucuronide binding. The metabolites have no psychopharmacological activity. The concentration of haloperidol in brain and other tissues is higher than that of its metabolites.
Clearance: The elimination half-life of haloperidol is approximately 35 hours, and the mean plasma clearance is approximately 0.29 L/min. Haloperidol is excreted primarily in the feces, but also partially in the urine. The human consumption of tritium-labeled haloperidol suggests that its main excretion route in humans is fecal, which is about four times the amount excreted in urine. Breast milk also contains small amounts of haloperidol, with an average milk/plasma concentration ratio of 1:3.
Linearity: Flupirtide has linear kinetics. It takes 7 days for plasma concentrations to reach steady state. If 5 mg of haloperidol is administered orally once daily, the minimum steady-state blood concentration is 1.7 ng/ml (3.9 nmol/L).
Geriatric patients: Pharmacokinetic tests have not been performed in elderly patients. However, other drugs in the thiotron class, such as zuclopenthixol, have been shown to have pharmacokinetic parameters that do not correlate with patient age.
Patients with decompensated liver function: no relevant data are available.
Patients with decompensated renal function: Presumably, from the nature of drug excretion, decompensated renal function may have little effect on the plasma concentration of the prodrug.
Melitrexin.
Absorption: The time to peak blood concentration for oral administration is approximately 4 h. Oral bioavailability is unknown.
Distribution: Apparent volume of distribution is unknown. The plasma protein binding rate in rats is approximately 89%.
Biotransformation: Melitrexin is metabolized mainly through two pathways: demethylation and hydroxylation. The main active metabolite is seconal rituxin.
Clearance: The elimination half-life of melitrexin is approximately 19 hours (range 12 to 24 hours). The plasma clearance (Cls) is unknown. In rats, melitrexin is excreted primarily in the feces, but also partially in the urine. Excretion models suggest that fecal excretion of melitrexin is approximately 2.5 times greater than urinary excretion, and it is unknown whether melitrexin is secreted through breast milk.
Geriatric patients: no data available.
Patients with hepatic decompensation: no data available.
Patients with reduced renal function: No data available.
Storage】 Keep below 25℃.
Package】 Double aluminum package. 7 tablets/plate x 2 plates/box; 7 tablets/plate x 3 plates/box; 7 tablets/plate x 4 plates/box.
Expiration date】 18 months.
【Execution standard
【Approval Number】 State Drug Administration H20153014
【Manufacturing enterprise
Enterprise name: Sichuan Hesco Pharmaceutical Co.
Production Address: No. 53, Shunjiang Avenue South, East District, Meishan Economic Development Zone, Sichuan Province
Postal code: 620000
Telephone number: 028-38787378
Fax number: 028-38787272
Website: www.haisco.com