Date of approval.
Date of revision.
Olopatadine Hydrochloride Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Olopatadine Hydrochloride Tablets
English name: Olopatadine Hydrochloride Tablets
Hanyu Pinyin：Yansuan Aoluotading Pian
Ingredients
The active ingredient of this product is Olopatadine Hydrochloride.
Chemical name: 11-[(Z)-3-(dimethylamino)propylidene]-6-11-dihydrodibenzo[b,e] oxaheptane-2-acetic acid hydrochloride.
Chemical structure formula.
Molecular formula: C21H23NO3﹒HCl
Molecular weight: 373.87
Properties
This product is a light pink film-coated tablet, which appears white or off-white after removing the coating.
Indications
Allergic rhinitis, urticaria, pruritic skin diseases (eczema, dermatitis, itchy rash, pruritus, psoriasis vulgaris, exudative erythema multiforme).
Specification
5mg
Dosage]
Take orally. The dosage for adults is usually 5mg twice a day, once in the morning and once at night before bedtime.
Increase or decrease according to age and symptoms.
Use with caution in patients with hepatic or renal insufficiency (see [Precautions]).
Adverse reactions]
Among 9620 patients in foreign registration trials and post-marketing surveys (including long-term use surveys), 1056 cases (incidence rate 11.0%) had adverse reactions or abnormal laboratory test values, totaling 1402 cases.
The main adverse reactions were drowsiness in 674 cases (7.0%), increase in alanine aminotransferase (ALT/GPT) in 68 cases (0.7%), tiredness in 53 cases (0.6%), increase in aspartate aminotransferase (AST/GOT) in 46 cases (0.5%), and thirst in 36 cases (0.4%), etc.
1) Serious adverse reactions
Fulminant hepatitis, liver function impairment, jaundice (incidence unknown): Fulminant hepatitis, liver function impairment accompanied by rise in AST (GOT), ALT (GPT), γ-glutamyl transpeptidase (γ-GTP), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), etc., and jaundice may occur, so attention should be paid to observation. If abnormalities occur, the drug should be discontinued and disposed of appropriately.
(2) Other adverse reactions
The following adverse reactions may occur, so attention should be paid to observation and appropriate disposition such as dose reduction or discontinuation should be carried out if abnormalities are found.
(≥5%≥0.1% and <5%<0.1% incidence of unknown allergiesNote) Erythema and other rash swelling (face/extremities, etc.), pruritus, dyspnea Nervous system drowsiness and tiredness, thirst
Headache/heaviness, dizziness, low attention span, numbness, involuntary movements (face/extremities, etc.) Digestive system
Dysentery, nausea and constipation, endostomia/corns of the mouth/tongue pain, burning sensation in the stomach, hyperphagia and vomiting Liver Liver function abnormalities [ALT (GPT), AST (GOT), LDH
AST (GOT), LDH, γ-GTP
ALP, increased total bilirubin] Blood Leukocytosis, eosinophilia, lymphopenia Leukopenia, thrombocytopenia Kidney
Urinary system Increased urine occult blood BUN, positive urine protein, increased blood creatinine, frequent urination, difficulty in urination Circulatory system Palpitations, increased blood pressure Others Increased serum cholesterol Positive urine sugar, chest discomfort, abnormal taste, weight gain, hot flashes Abnormal menstruation, muscle
(Flesh pain, arthralgia Note) When such symptoms occur, stop taking the drug.
Contraindications
Patients with a history of hypersensitivity to the ingredients of this product are prohibited.
Precautions
1. Administer with caution (the following patients should take the drug with caution)
(1) Patients with low renal function: there is a possibility of persistently high blood concentration, refer to [Pharmacokinetics] section.
2) Patients of advanced age: refer to the section of [Geriatric Use] and [Pharmacokinetics].
(3) Patients with hepatic impairment: there is a possibility of worsening hepatic impairment.
2.Important basic precautions
(1) Because drowsiness can be produced by taking this product, patients taking the drug should avoid dangerous mechanical operations such as driving a motor vehicle.
(2) Patients receiving long-term steroid therapy should gradually reduce the amount of steroids under strict management if they need to reduce the amount of steroids due to taking this product.
(3) When seasonal patients take this product, they should consider starting the drug when the season is approaching and continue it until the end of the season.
(4) If the use of this product is ineffective, be careful not to take the drug blindly for a long time.
3.Notice of medication use
1） When dispensing medication
For drugs packed in PTP, please instruct the patient to take the drug after removing it from the PTP plate. (There are reports of serious complications such as perforation and mediastinitis caused by hard edges piercing the esophageal mucosa due to accidental administration of PTP plates.)
2）.When divided and used
It should be stored away from light after division.
4.Other precautions.
(1) Although the causal relationship is not clear, there have been reports of myocardial infarction during the administration of this product.
(2) Do not take this product before the intradermal reaction test because it will inhibit the allergic intradermal reaction and affect the confirmation of allergy.
Pregnant women and nursing mothers
1. For pregnant women or women who may be pregnant, take the drug only when the efficacy is higher than the risk. ［The safety of the drug in pregnant women has not been established.]
2. Nursing mothers should avoid taking this product, and should stop breastfeeding if they must take it. ［Migration to breast milk and inhibition of neonatal weight gain have been reported in animal studies (rats).
[Pediatric use].
The safety of use in low birth weight neonates, newborns, nursing infants, and young children has not been established. (Little experience with its use).
Geriatric use]
Since most elderly patients have lower physiological functions and are more prone to adverse reactions, the drug should be administered with caution while observing the patient’s condition, starting with a low dose, etc.
Drug Interactions
Not yet known.
Drug overdose]
In a phase I clinical trial, six healthy adult men received 80 mg of this product orally in a single dose, four cases developed drowsiness, one case developed lethargy (complicated by drowsiness), and one case developed symptoms of decreased concentration.
Pharmacology and Toxicology]
Pharmacological effects
This product mainly has selective antagonistic effect on histamine H1 receptor, and inhibits the production and freeing of chemical transmitters (leukotrienes, coagulation oxane, PAF, etc.), and inhibits the freeing of neurotransmitter tachykinin.
1. Antihistamine effect
In the receptor binding test, it has a strong antagonistic effect on histamine H1 receptor (Ki value: 16 nmol/L), while it shows little affinity for muscarinic M1 receptor, and its effect is selective. In addition, it can show inhibitory effect in the histamine-induced tracheal constriction response in guinea pigs.
2. Experimental anti-allergic effect
In allergic rhinitis model (guinea pig, rat) test, it has inhibitory effect on antigen-induced vascular hyperpermeability and nasal congestion. It has a strong inhibitory effect on passive skin sensitization and allergic tracheal constriction in rats and guinea pigs.
In addition, it has an inhibitory effect on platelet-activating factor (PAF)-induced allergic tracheal hyperactivity in guinea pigs.
3. Inhibitory effect on the production and free process of transmitters
It has inhibitory effects on the freeing of histamine released from rat abdominal mast cells (IC30 values, 72μmol/L: ovalbumin stimulation; 110μmol/L: dinitrophenyl bovine serum albumin stimulation; 26μmol/L: A-23187 stimulation; 270μmol/L: mixture 48/80 stimulation), and also acts on the arachidonic acid metabolic system to inhibit The production and freeing of lipid mediators such as leukotrienes (IC30 value, 1.8 μmol/L), thromboxane (IC30 value, 0.77 μmol/L) and PAF (production: 52.8% inhibition at 10 μmol/L; free: 26.7% inhibition at 10 μmol/L) released by human neutrophils.
4. Inhibitory effect on tachykinin free
The free neurotransmitter tachykinin from sensory nerve endings is involved in the occurrence and deterioration of allergic diseases. In the test of major bronchial muscle specimens from guinea pigs, the product inhibited the contractile response involving tachykinin during electrical stimulation (IC30 value, 5.0 μmol/L) by inhibiting the freeing of tachykinin through K+ channel activity (SKCa channel: small conductance Ca2+-activatdeK+ channel).
Toxicological studies
1. Single oral administration toxicity tests were conducted in mice, rats and dogs, and the LD50 was above 1000mg/kg.
2. The non-toxic dose for rats was 10mg/kg when administered orally for 52 weeks.
3. No teratogenicity was observed in rats at 400mg/kg administered orally.
4. No antigenicity, mutagenicity or carcinogenicity was observed in the test with mice.
Pharmacokinetics
Absorption
(1) Single dose in healthy adults
The changes in blood concentration and pharmacokinetic parameters of olopatadine hydrochloride 5mg and 10mg were administered orally to healthy adult males under fasting conditions in a single dose as shown below. The concentrations of the primary drug were determined by radioimmunoassay (RIA method).
Pharmacokinetic parameters
Parameters
Dose Cmax
(ng/ml) Tmax
(hr)T1/2
(hr) AUC0-∞
(ng-hr /ml) 5mg107.66±22.011.00±0.328.75±4.63*326±63*10mg191.78±42.990.92±0.477.13±2.21**638±136**mean±standard deviation,*: n=4;**n=10
2) Multiple dosing in healthy adults
Eight healthy adult males received oral olopatadine hydrochloride 10 mg/dose twice/day for 6 days, with one dose on day 7, for a total of 13 doses. The blood concentration reached steady state on day 4, and the Cmax was 1.14 times that of the single dose. (Measurement method: RIA method).
(3) Single dosing in patients with renal hypofunction (before hemodialysis)
Patients with low renal function with creatinine clearance of 2.3 to 34.4 ml/min were given a single oral dose of 10 mg of this product after breakfast. the changes in blood concentration are shown in the graph below. Compared with healthy adults, the Cmax in patients with hyporenal function was 2.3 times higher and the AUC was about 8 times higher. (Measurement method: RIA method).
(4) Single dose in elderly patients
The changes of blood concentration after a single oral dose of 10mg of this product in elderly patients (over 70 years old) are shown in the figure below. The blood concentration is higher than that of healthy adults, with Cmax about 1.3 times and AUC about 1.8 times. T1/2 is basically the same, 10 to 11 hours. (Measurement method: RIA method).
Distribution
● Intra-tissue distribution (reference: data from rat test)
When 14C-Olopatadine hydrochloride 1mg/kg was given orally to rats, most tissues reached the highest radioenergetic concentration 30 minutes after administration. The radioactive energy concentrations in the digestive tract and in the liver, kidney and bladder were higher than those in the plasma.
●Permeability, migration (reference: data from rat test)
The permeability of the blood-brain barrier was the lowest among all measured tissues in rats after oral administration of 14C-olodadine hydrochloride at 1 mg/kg, and the Cmax was about 1/25 of the Cmax in plasma. The concentration of radioactive energy in fetal plasma and tissues was about 0.07-0.38 times higher than that in maternal plasma. After oral administration of 14C-Olopatadine hydrochloride 1mg/kg to lactating rats, the AUC0-∞ of radioactive energy in milk was about 1.5 times of that in plasma. ●Protein binding rate (in vitro ultrafiltration method)
Added concentration (ng/ml) 0.1101000 Serum protein binding rate (%) 54.755.254.7 Metabolism
The metabolites in the plasma of a single oral dose of 80mg of this product in healthy adults are: N-oxide about 7%, N-monodemethylate about 1% (AUC ratio to prodrug), and urinary metabolites about 3% and 1%, respectively (cumulative urinary excretion rate at 48 hours). (Measurement method: LC/MS/MS method).
Urinary excretion
The cumulative urinary excretion rate of the drug in its original form at 48 hours for single oral doses of 5 mg and 10 mg in healthy adults ranged from 63.0 to 71.8% of the dose administered.
In addition, multiple doses of 10 mg/dose, 2 doses/day for 6 days and 1 dose on the 7th day, for a total of 13 doses, showed essentially the same urinary excretion rate as for the single dose. (Measurement method: LC/MS/MS method).
Storage
Store below 25℃.
Package】
Aluminum foil for drug packaging; polyvinyl chloride solid pharmaceutical hard tablets.
12 tablets/plate×1 plate/box, 12 tablets/plate×2 plate/box, 12 tablets/plate×3 plate/box, 12 tablets/plate×4 plate/box, 12 tablets/plate×5 plate/box.
[Expiration date
24 months
【Execution standard】
××××××
【Approval number】
State Drug Certificate: ××××××
【Manufacturer】
Company Name: Beijing Allegra Pharmaceutical Technology Co.
Address: Room 0816, 8/F, Building 1, 59 Gaoliangqiao Xiejie, Haidian District, Beijing
Manufacturer: Jiangsu Wangao Pharmaceutical Co.
Address: No. 688 Dinghai Road, Haimen Economic and Technological Development Zone, Jiangsu Province
Postal Code: 100044
Telephone number: 010-62110220
Fax number: 010-62110220