Flunarizine Hydrochloride Capsules Instructions
Please read the instructions carefully and use under the guidance of a physician.
Drug Name
Generic Name: Flunarizine Hydrochloride Capsules
English name: Flunarizine Hydrochloride Capsules
Hanyu Pinyin: Yansuan Fuguiliqin Jiaonang
Ingredients
Active ingredient: Flunarizine Hydrochloride
Chemical name: (E)-1-[Bis(4-fluorophenyl)methyl]-4-(2-propenyl-3 -phenyl)-piperazine dihydrochloride
Chemical structure formula.
Molecular Formula: C26H26F2N2 .
2HCl
Molecular weight: 477.42
Properties
The content of this product is white or off-white powder.
Indications
Prophylactic treatment of typical (with aura) or atypical (without aura) migraine.
Symptomatic treatment of vertigo caused by vestibular dysfunction.
Specification
5mg/capsule (based on flunarizine)
Dosage and Administration
Migraine
Headache
headache
of
Prevention
prevention
prevention
Treatment
Treatment
Starting dose: 2 capsules per night may be given at the start of treatment for patients under 65 years of age and 1 capsule per night for patients over 65 years of age. If depression, extrapyramidal reactions and other serious adverse reactions occur during treatment, the drug should be discontinued promptly. If no significant improvement is seen after 2 months of treatment, the patient may be considered unresponsive to flunarizine hydrochloride and the drug may be discontinued.
Maintenance therapy: If the efficacy is satisfactory and the patient requires maintenance therapy, it should be reduced to 5 days of continuous dosing every 7 days (dose as above) and 2 days of discontinuation. Even if prophylactic maintenance therapy is effective and well tolerated, it should be discontinued after 6 months of treatment and observed, and should be reintroduced only in case of relapse.
Vertigo
The daily dose should be the same as above, but should be discontinued promptly after symptom control, usually for an initial course of less than 2 months. If no improvement in symptoms is seen after 1 month of treatment for chronic vertigo or 2 months for sudden onset vertigo, the patient should be considered unresponsive to flunarizine hydrochloride and the drug should be discontinued.
Adverse reactions]
Adverse reactions are adverse events that are considered to be reasonably related to the use of flunarizine based on a thorough evaluation of available adverse events. In individual cases, a causal relationship with flunarizine cannot be fully established. Because clinical trials are conducted under a variety of different conditions, the incidence of adverse reactions observed in clinical trials of one drug cannot be directly compared to the incidence of adverse reactions in clinical trials of another drug and may not reflect the incidence of adverse reactions observed in clinical practice.
Clinical Trial Data
Placebo-controlled, double-blind trial data – adverse reactions reported at a rate of not less than 1%
Two placebo-controlled, parallel double-blind clinical trials evaluated the safety of flunarizine hydrochloride (5 to 10 mg/day) in 500 subjects, 247 patients on flunarizine hydrochloride and 253 patients on placebo. The two trials treated subjects with migraine and vertigo separately.
In these trials, adverse reactions (ADRs) with a reporting rate of not less than 1% in the flunarizine hydrochloride group are shown in Table 1.
Table 1. Adverse reactions reported at a rate of not less than 1% in the flunarizine hydrochloride group in two placebo-controlled, parallel double-blind trials
Classification of organism system/organ
Adverse reaction name Flunarizine hydrochloride (5-10 mg)
(n=247)% Placebo (n=253)% Infectious and invasive disorders Rhinitis 4.01.6 Metabolic and nutritional disorders Increased appetite 4.02.0 Psychiatric disorders Depression 4.50.8 Neurological disorders Drowsiness 9.31.2 Gastrointestinal disorders Constipation 2.40.4 Various musculoskeletal and connective tissue disorders Myalgia 2.40.8 Reproductive and breast disorders Menstrual disorders 2.81.2 Breast pain 1.20.4 Weight gain in various types of examinations 11.32.8
Active drug-controlled trial data-adverse reactions with a reporting rate of not less than 1%
Two double-blind active drug-controlled trials were selected to determine the incidence of adverse reactions. These two trials treated 476 subjects for migraine and vertigo/migraine, respectively, with 10 mg of flunarizine hydrochloride given daily to subjects.
Adverse reactions reported in controlled clinical trials of the active drug at a rate of not less than 1% but not listed in Table 1 are shown in Table 2.
Table 2. Adverse reactions reported at a rate of not less than 1% in the flunarizine hydrochloride group in two double-blind, active drug-controlled trials
Organism system/organ classification
Adverse reactions Flunarizine hydrochloride group (10 mg/day)
(n=476)
% Gastrointestinal system disorders Stomach discomfort 2.3 Systemic disorders and various reactions at the site of administration Fatigue 2.9
Placebo and active controlled trial data – Adverse reactions reported at less than 1%
Other adverse reactions with a reporting rate of less than 1% in the data tables of the two clinical trials mentioned above are shown in Table 3.
Table 3 . Adverse reactions reported at a rate of less than 1% in the flunarizine hydrochloride group in clinical trials with placebo or control drugs
Psychiatric disordersDepressionSleep disturbancesEmotional indifferenceNervous system disordersSquint neckTinnitusDrowsinessSensory abnormalitiesResponse delaysManiaCoordination abnormalitiesOrientation disordersHeart organ disordersPalpitationsGastrointestinal system disordersIntestinal obstructionGastrointestinal dysfunctionDry mouthDermal and subcutaneous tissue disordersHyperhidrosisVarious musculoskeletal and connective tissue disordersMuscle spasmsMuscle twitchingReproductive system and breast disordersMenstrual sparsenessPastorsMenorrheaMenstrual hyperplasiaSexual desire Reduction of systemic diseases and various reactions at the site of administration generalized puffiness weakness peripheral edema
Post-marketing experience
Adverse events first identified as flunarizine adverse reactions after marketing are shown in Table 4.Adverse reactions by spontaneous reporting rate.
Very common
³1/10
Common
³1/100 , and<1/10
Rare
³1/1000, and <1/100
Rare
³1/10,000 and <1/1000
Very rare <1/10,000, including isolated cases.
Based on the spontaneous reporting rate, the following adverse reactions are listed in Table 4 by incidence.
Table 4. Post-marketing adverse reactions of flunarizine hydrochloride by incidence based on spontaneous reporting frequency
Psychiatric disorders very rare insomnia very rare anxiety neurological disorders very rare inability to sit still very rare bradykinesia very rare cogwheel ankylosis very rare dyskinesia very rare primary tremor very rare extrapyramidal reactions very rare Parkinson’s syndrome very rare sedation very rare tremor vascular and lymphovascular disorders very rare hypotension gastrointestinal disorders very rare nausea various muscle Skeletal and connective tissue disorders Very rare muscle ankylosis Skin and subcutaneous tissue disorders Very rare erythema Genital and breast disorders Very rare breast overflow
Contraindications
Flunarizine hydrochloride is contraindicated in patients with a history of depression, Parkinson’s disease or other symptoms of extrapyramidal disease.
It is contraindicated in patients with hypersensitivity to flunarizine or any of the excipients of this product.
Precautions]
In rare patients, weakness may gradually increase during treatment and treatment should be discontinued.
Please use at the recommended dose. The physician should monitor the patient regularly (especially during maintenance therapy) to ensure timely discontinuation of the drug in case of extrapyramidal or depressive symptoms. Treatment should also be discontinued if efficacy decreases during maintenance therapy.
Caution should be taken when driving a vehicle or operating machinery because of the potential for drowsiness (especially during the initial dose).
Flunarizine hydrochloride may cause extrapyramidal symptoms, depression, and Parkinson’s disease, especially in patients with a tendency to develop such conditions such as elderly patients, and should therefore be used with caution in such patients.
Because of the possibility of drowsiness, especially at the beginning of the course of treatment, patients should exercise caution when performing activities such as driving or operating dangerous machinery.
Pregnant women and nursing mothers
Use during pregnancy
Animal studies have not demonstrated direct or indirect effects of flunarizine hydrochloride on reproduction, embryonic development, the course of pregnancy, or the perinatal period. There is no safety information on the use of flunarizine hydrochloride during pregnancy in humans.
Use in Lactating Women
Although there is no information on the secretion of flunarizine hydrochloride in human milk, tests with lactating dogs have shown that flunarizine hydrochloride can be secreted in milk, and its milk concentration is higher than that in blood, so women taking flunarizine hydrochloride should not breastfeed.
Pediatric Dosage]
There is no information on the use in children.
Geriatric use
Use with caution in elderly patients.
Drug Interactions]
Excessive sedation may occur when flunarizine hydrochloride is used in combination with alcohol, hypnotics or sedative drugs.
Flunarizine hydrochloride is not contraindicated in patients using b-blockers.
The pharmacokinetics of flunarizine hydrochloride are not affected by topiramate. A 16% increase in systemic exposure to flunarizine was observed in migraine patients when flunarizine hydrochloride and topiramate (50 mg/12 hr) were administered together at 12-hour intervals during the treatment period; a 14% increase in systemic exposure was observed compared to patients receiving flunarizine hydrochloride alone. The steady-state pharmacokinetics of topiramate were also unaffected.
Long-term administration of flunarizine hydrochloride did not affect the distribution of phenytoin, carbamazepine, valproate, or phenobarbital. Blood concentrations of flunarizine hydrochloride in epileptic patients treated with these antiepileptic drugs were lower than in healthy subjects given similar doses. When flunarizine hydrochloride is combined with carbamazepine, valproate, or phenytoin, the plasma protein binding of carbamazepine, valproate, or phenytoin is not affected.
[Drug overdose].
Based on the pharmacological properties of flunarizine hydrochloride, sedation and weakness may occur in overdose. There have been cases of drowsiness, agitation, and tachycardia in overdosed individuals (up to 600 mg in a single dose). There is no known specific antidote. In appropriate cases, activated charcoal can be used for treatment.
Pharmacology and Toxicology
Pharmacological effects
Pharmacotherapeutic grouping of this product: Anti-vertigo drug. ATC code: N07CA03.
Flunarizine hydrochloride is a selective calcium antagonist, which can block excessive calcium ions from entering the cell across the membrane to prevent intracellular calcium overload, and also prevent large amounts of calcium from entering neurons during ischemia and hypoxia, improve cerebral microcirculation and neuronal metabolism, inhibit cerebral vasospasm, platelet coagulation and increased blood viscosity, etc. In addition, it has cell membrane stabilizing effects. It is highly lipid soluble and can easily cross the blood-brain barrier.
It has no effect on cardiac contraction and conduction.
Toxicological studies
Non-clinical CNS effects (e.g., sedation, salivation, and ataxia) were observed only at exposures well above the maximum human exposure, with little relevance to clinical use.
A comprehensive series of non-clinical studies on the safety of this product have been conducted, including: toxicity from single oral administration (mice, adult and juvenile rats, guinea pigs), intraperitoneal (mice and rats), subcutaneous (mice and rats), intravenous (mice and rats), and intra-arterial (rats) administration; toxicity from repeated oral administration (oral toxicity at multiple doses over 12 months in dogs and 18 months in rats), intravenous toxicity (dogs 3 months and 1 month in rats); reproduction assays for oral administration testing fertility and overall reproductive capacity in rats; teratogenicity and embryotoxicity in rats, rabbits, and pre- and postnatal rats. An extensive series of mutagenicity studies have been conducted on this product, including: in vitro loci and/or gene mutation assays in Salmonella typhimurium, companion recessive lethality assays in Drosophila, chromosomal aberration assays in human lymphocytes, and in vivo micronucleus and dominant lethality assays in mice. The carcinogenicity of this product was assessed using the lifespan of mice and rat models after oral administration.
Toxicity tests with single oral administration (LD50 of approximately 960-1896 mg/kg in mice; LD50 of approximately 343-1935 mg/kg in rats) resulted in a wide range of safety compared to the maximum therapeutic dose in humans (approximately 0.2 mg/kg for a 50 kg patient). Results of toxicity tests in rats and dogs with repeated oral administration suggest that some clinical effects may be associated with excessive pharmacological effects, but all were observed at doses well above the therapeutic dose of the drug (approximately 400 times the maximum therapeutic dose in humans on a mg/kg basis) and have little relevance to clinical use. In reproductive trials, it had no effect on fertility and was not teratogenic. At very high doses (approximately 150-400 times the maximum human therapeutic dose at mg/kg), fetal toxicity was less than maternal toxicity. The product is not mutagenic and is not a major carcinogen. Prolactin-mediated mild mammary hyperplasia and tumorigenesis were observed only in mice at toxic dose levels (approximately 50-100 times the maximum therapeutic dose in humans at mg/kg).
In an in vivo model in anesthetized guinea pigs, flunarizine given intravenously at a total dose of 9.87 mg/kg (approximately 50 times the maximum therapeutic dose in humans based on mg/kg) showed no effect on QTc interval and ECG.
[Pharmacokinetics].
The product is well absorbed, and the blood concentration peaks 2~4 hours after oral administration, and reaches steady state after 5~6 weeks of continuous administration.
Absorption
Flunarizine is well absorbed through the gastrointestinal tract (>80%) and reaches peak blood concentration within 2~4 hours after oral administration. In the presence of reduced gastric acid (increased gastric pH), its bioavailability decreases appropriately.
At multiple doses administered once daily, flunarizine blood concentrations reach steady-state after about 8 weeks and are 3-fold higher than those at the same dose given as a single dose. In the range of 5 ~ 30 mg, the blood concentration of this product is proportional to the administered dose.
Distribution
Flunarizine is bound to plasma proteins >99%. It has a large volume of distribution in both healthy humans and patients with epilepsy, with the former approaching 78 L/kg and the latter approaching 207 L/kg, indicating a wide extravascular distribution of the product. It can rapidly penetrate the blood-brain barrier, and its concentration in the brain is about 10 times higher than that in the plasma.
Metabolism
Flunarizine is metabolized in the liver to at least 15 metabolites. Its main metabolic pathway is the CYP2D6 enzyme.
Elimination
Flunarizine is excreted in the feces, mainly in the form of prodrug and its metabolites, via the bile. Approximately 3-5% of the dose is excreted in the feces as prodrug and metabolites within 24-48 hours after administration, and less than 1% of the dose is excreted in the urine as prodrug. Its terminal elimination half-life is highly variable, ranging from 5 to 15 hours after a single dose in most individuals. Blood concentrations (> 0.5ng/ml) of this drug can be measured in some subjects during an extended period (up to day 30), which may be due to redistribution of the drug in other tissues.
Storage]
Store under shade and seal.
Package】
Aluminum-plastic blister packaging, composed of polyvinyl chloride solid pharmaceutical hard tablets and pharmaceutical aluminum foil, 20 capsules/plate/box; 30 capsules/plate/box; 2×20 capsules/plate/box; 3×20 capsules/plate/box. High density polyethylene bottle for oral solid medicine, 30 capsules/bottle; 60 capsules/bottle.
[Expiration date
24 months
【Execution standard
Approval number】
State Drug Certificate H37023094
Drug Marketing Licensee
Name: Shandong Dongming Pharmaceutical Group Co.
Registered Address: Fangming Section, Huanghe Road, Dongming County, Shandong Province
Manufacturer
Company name: Shandong Dongming Pharmaceutical Group Co.
Production Address: Dongming County, Shandong Province, the Yellow River Road Fangming section
Postal code: 274500
Telephone number: 0530-7201536 7202529
Fax number: 0530-7201536 7202529
Website: www.fangming.com