Approval Date.
Levocetirizine Hydrochloride Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic Name: Levocetirizine Dihydrochloride Tablets
English name: Levocetirizine Dihydrochloride Tablets
Hanyu Pinyin: Yansuan Zuoxitiliqin Pian
Ingredients
The main ingredient of this product is levocetirizine hydrochloride.
Chemical name: (+)-2-[2-[4-(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid dihydrochloride.
Chemical structure formula.
Molecular formula: C21H25ClN2O3-2HCl
Molecular weight: 461.8
【Properties】.
This product is a film-coated tablet, which appears white after removing the coating.
Indications
This product is used for the treatment of allergy-related symptoms of the following diseases: allergic rhinitis (including seasonal persistent allergic rhinitis and perennial persistent allergic rhinitis) and chronic idiopathic urticaria.
Specification
5mg.
Dosage and Administration
(1) Route of administration: Oral.
2）Dose and method of administration
Adults, children aged 6 years and above: 1 tablet (5mg) daily by mouth, either on an empty stomach or during or after a meal.
Patients with renal impairment: No dose adjustment is required for patients with mild renal impairment. The dosage for patients with moderate to severe renal impairment is adjusted according to the following table.
Patient renal function status creatinine clearance (ml/min)a Dose and number of doses moderate renal impairment 30-49 every 2 days, 5mg severe renal impairment<30 every 3 days, 5mg patients with advanced renal disease – using dialysis therapy<10 contraindications [140 – age (years)] x body weight (kg)
a serum creatinine clearance (CLcr ml/min ) = × {0.85 (coefficient for female patients)} 72 × serum creatinine (mg/dl)
Patients with hepatic impairment: For patients with hepatic impairment only, no dosage adjustment is required; for patients with renal impairment, please refer to the dosage for “patients with renal impairment”.
Geriatric patients: For elderly patients with moderate or severe renal impairment, dose adjustment is recommended, please refer to “Patients with renal impairment”.
Adverse Reactions
Refer to clinical studies of the original product.
Pediatric patients.
Two placebo-controlled studies were completed in pediatric patients 6-11 months of age and 1-6 years of age, in which 159 subjects were exposed to levocetirizine at a dose of 1.25 mg twice daily for 2 weeks.
Systemic organ classification and preferred terminology Placebo (n=83) Levocetirizine (n=159) Gastrointestinal disorders Diarrhea 03 (1.9%) Vomiting 1 (1.2%) 1 (0.6%) Constipation 02 (1.3%) Neurological disorders Somnolence 2 (2.4%) 3 (1.9%) Psychiatric disorders Sleep disorders 02 (1.3%) A double-blind study completed with the original investigational product in children 6-12 years of age placebo-controlled study with 243 children exposed to 5 mg of levocetirizine for varying durations of administration (1 week to 13 weeks). The incidence of the following adverse drug reactions was 1% or more in the placebo-controlled or levocetirizine treatment groups
Preferred term placebo (n=240) 5 mg levocetirizine (n=243) Headache 5 (2.1%) 2 (0.8%) Sleepiness 1 (0.4%) 7 (2.9%)
Adults and children 12 years of age and older.
In the therapeutic study 5 mg levocetirizine treatment group and placebo control group completed by the original investigational product in patients of both sexes aged 12 to 71 years, 15.1% of patients and 11.3% of patients experienced at least 1 case of adverse drug reaction, respectively. 91.6% of adverse drug reactions were mild to moderate in severity. In the therapeutic study 5 mg levocetirizine treatment group and the placebo control group, the rate of shedding due to adverse events was 1.0% (9/935) and 1.8% (14/771), respectively.
The clinical therapeutic study of levocetirizine included 935 subjects exposed to 5 mg of this product daily. After pooled analysis, adverse drug reactions with an incidence of 1% or more (common: ≥1/100, <1/10) in the 5 mg levocetirizine treatment group or the placebo control group were reported as follows.
Preferred term (WHOART) Placebo (n = 771) 5 mg levocetirizine (n = 935) Headache 25 (3.2 %) 24 (2.6 %) Drowsiness 11 (1.4 %) 49 (5.2 %) Dry mouth 12 (1.6 %) 24 (2.6 %) Fatigue 9 (1.2 %) 23 (2.5 %) Further uncommon adverse reactions were observed to occur (uncommon: ≥1 /1000, <1/100) (e.g., malaise or abdominal pain).
The following sedative adverse drug reactions occurred more frequently in the 5 mg levocetirizine treatment group (8.1%) compared to the placebo control group (3.1%): drowsiness, fatigue, and malaise.
Post-marketing experience with the original product
In addition to the adverse reactions reported during the clinical study and those described above, the following adverse drug reactions have been reported in post-marketing experience with the original product. Due to insufficient data, it is not possible to predict the incidence of these adverse reactions in the treated population.
Immune system disorders: hypersensitivity reactions, including anaphylactic reactions
Metabolic and nutritional disorders: increased appetite
Psychiatric disorders: anxiety, aggression, agitation, hallucinations, depression, insomnia, suicidal ideation, nightmares
Neurological disorders: convulsions, venous sinus thrombosis, sensory abnormalities, dizziness, syncope, tremors, taste disturbances
Ear and vagus disorders: vertigo
Visual system.
Inflammation, visual disturbances, blurred vision
Cardiac disorders.
Angina pectoris, palpitations, tachycardia
Vascular disease: jugular vein embolism
Respiratory, thoracic and mediastinal disorders: exacerbation of rhinitis,
dyspnea
Gastrointestinal disorders.
Nausea, vomiting
Hepatobiliary diseases: hepatitis
Renal and urological disorders: difficulty urinating, urinary retention
Diseases of the skin and subcutaneous tissues.
Angioneurotic edema, hair thinning, fixed drug rash, pruritus, rash, chancroid, urticaria, photosensitivity reaction/toxicity
Systemic discomfort: ineffective drug therapy, drug interactions, dry mucous membranes
Skeletal muscle, connective tissue and bone disorders: myalgia, arthralgia
Systemic disorders and administration sites: edema
Interference detection methods: cross-reactivity
Physical examination: weight gain, abnormal liver function test results
Description of selected adverse reactions.
Pruritus has been reported in a few patients after discontinuation of this product.
[Contraindication].
Contraindicated in persons with hypersensitivity to any component of this product or to piperazine derivatives.
Contraindicated in patients with advanced renal disease with a creatinine clearance <10 ml/min.
Contraindicated in patients with specific genetic disorders including rare galactose intolerance, primary lactase deficiency (lapp lactase) or glucose-galactose malabsorption.
[Precautions].
1. As this product cannot be used in half at present, it is not recommended for children under 6 years of age.
2. It is recommended to use with caution after drinking alcohol.
3. Patients with predisposing factors for urinary retention (e.g., spinal cord injury, prostatic hyperplasia) should use caution because levocetirizine may increase the risk of urinary retention.
4. Effects on the ability to drive and operate machinery: Levocetirizine may cause increased drowsiness. Therefore, this product can affect the ability to drive a vehicle and operate machinery. Combined administration of alcohol or other central nervous system depressants may result in decreased alertness and impaired ability to operate them.
5. Patients at risk for seizures and convulsions should use caution as levocetirizine may cause exacerbation of seizures.
Pregnant women and nursing mothers
Pregnant women
Only limited study data (prospectively collected from 300 pregnancy outcome study cases) are available for the original product, and these results all indicate no clear causal relationship with malformations or fetal/neonatal toxicity of levocetirizine. Animal studies have not demonstrated direct or indirect deleterious effects in pregnancy, embryo/fetus development, delivery, or postpartum development. Use with caution in pregnant women.
Lactation
Although data are not available on whether levocetirizine is secreted into breast milk, it is expected that the former will also be secreted into breast milk given that cetirizine is secreted into breast milk. Levocetirizine should not be used during lactation.
Fertility
Clinical data on the effect of levocetirizine on fertility have not been obtained and animal data on the effect of fertility do not exist.
Pediatric use]
See [Dosage and Administration] item. In pediatric patients with impaired renal function, the dose should be individually adjusted based on the patient’s renal clearance and body weight.
Geriatric use
See [DOSAGE AND ADMINISTRATION].
Drug Interactions
There are no studies of drug interactions with levocetirizine (including studies without CYP3A4 inducers); previous studies of cetirizine racemization have shown no clinically relevant interdrug adverse reactions (with antipyrine, pseudoephedrine, cimetidine, ketoconazole, erythromycin, azithromycin, glipizide, diazepam). In a study of multiple doses of cetirizine combined with theophylline (400 mg/day), a 16% decrease in cetirizine clearance was found, while theophylline clearance was not altered by the combination of cetirizine. In a multiple dosing study of ritonavir (600 mg twice daily) with cetirizine (10 mg daily), cetirizine exposure was increased by approximately 40%, and ritonavir distribution was also slightly altered (-11%) with the combination. Although studies have shown that the racemic cetirizine does not potentiate the effects of alcohol (0.5 g/l blood level), co-administration of cetirizine or levocetirizine with alcohol or other CNS depressants may lead to a further decrease in alertness and affect mental performance. Eating may cause a decrease in the rate of absorption of levocetirizine, the degree of absorption will not be reduced.
[Drug overdose].
Symptoms: Drowsiness in adults, initial euphoria followed by drowsiness in children.
Treatment: No specific antidote is available. Symptomatic and supportive treatment is recommended after an overdose of this product.
Consider gastric lavage if just taken; levocetirizine cannot be completely removed by dialysis.
Pharmacology and Toxicology
Pharmacological effects: This product is an antihistamine agent, without obvious anticholinergic and anti-5-hydroxytryptamine effects, with a small central inhibitory effect.
Toxicological effects: In a repeated toxicity study in dogs, the non-toxic response dose was 75 mg/kg/day, and the toxic target organ was the gastrointestinal tract. Levocetirizine was administered to pregnant rats at a NOAEL of 200 mg/kg and to rabbits at a developmental NOAEL of 120 mg/kg. levocetirizine is excreted through the placenta of rodents and through the milk of lactating women and should be avoided during pregnancy and lactation. It has no mutagenic effect and is not potentially carcinogenic.
Pharmacokinetics]
The pharmacokinetics of levocetirizine is characterized by a linear relationship between plasma concentration levels and the administered dose, with minimal inter-individual variation. The absorption of levocetirizine in the body is rapid and complete. Food intake may cause a decrease in the absorption rate of levocetirizine, but the total absorption does not decrease, and the degree of absorption of levocetirizine is independent of the administered dose. The results of clinical trials showed that the relative bioavailability of 5 mg levocetirizine tablets was nearly 100%, with peak blood concentrations in adults at approximately 0.9 hours after administration; levocetirizine was firmly bound to plasma proteins, with a plasma protein binding rate of approximately 90% and an apparent volume of distribution of 0.4 L/kg; the plasma elimination half-life was 7.9 ± 1.9 hours, and after 2 days of once-daily administration of 5 mg Levocetirizine has no first-pass effect and its metabolism rate in human body is less than 14% of the administered dose, therefore, individual differences in liver enzymes or the combination of liver enzyme inhibitors have little effect on it, and the possibility of interaction with other substances is small. The possibility of interaction with other substances is small. Levocetirizine is excreted on average 85.4% in the urine and 12.9% in the feces as a prototype. Levocetirizine is not converted to dexcetirizine during absorption and clearance.
Ltd. conducted bioequivalence tests in fasting and postprandial states in healthy adult subjects in China. The results of the study are as follows.
1. Fasting pharmacokinetic results
Table 1 Statistical analysis of fasting pharmacokinetic parameters
Parameter
(Unit) Geometric mean and ratio (N=24) Within-subject variation %CV90% confidence interval certainty % Subject formulation (T) Reference formulation (R) (T/R)%/// Cmax
(ng/ml) 212.7192.7110.3613.61(103.19, 118.02)93.2AUC0-t
(h*ng/ml)1550.61493.7103.819.47(99.06, 108.79)>99.9AUC0-∞
(h*ng/ml)1615.51565.4103.208.67(98.86, 107.72)>99.9The above results can indicate that levocetirizine hydrochloride tablets produced by Qilu Pharmaceutical Co., Ltd. and levocetirizine hydrochloride tablets produced by UCB Farchim SA Switzerland are bioequivalent in Chinese healthy subjects under fasting condition.
2. Postprandial pharmacokinetic results
Table 2 Statistical analysis of postprandial pharmacokinetic parameters
Parameter
(Unit) Geometric mean and ratio (N=24) Intra-subject variation %CV90% confidence interval certainty % Subject formulation (T) Reference formulation (R) (T/R)%///Cmax
(ng/ ml) 142.9142.6100.2317.24(92.08, 109.10)99.5AUC0-t
(h*ng/ ml)1465.01435.5102.067.55(98.31, 105.94)>99.9AUC0-∞
(h*ng/ml)1548.31510.9102.476.41(99.27, 105.78)>99.9The above results can indicate that levocetirizine hydrochloride tablets produced by Qilu Pharmaceutical Co., Ltd. and levocetirizine hydrochloride tablets produced by UCB Farchim SA Switzerland were bioequivalent in healthy Chinese subjects in the postprandial state.
Storage
Keep sealed and store in a dry place below 25℃. Keep out of the reach of children.
Package
Aluminum package, 7 tablets/plate; 10 tablets/plate; 14 tablets/plate.
Expiration date
36 months.
Execution Standard
【Approval number】
【Manufacturer】
Enterprise name: Qilu Pharmaceutical Co.
Production Address: No. 317 Xinluo Street, Jinan High-tech Zone
Zip code: 250100
Telephone number: 0531-83126000, 83126111, 83126333, 83126548
Fax number: 0531-83126288, 83126545
Web
Address: http://www.qilu-pharma.com