Date of approval.
Date of revision.
Lercanidipine Hydrochloride Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Lercanidipine Hydrochloride Tablets
English name: Lercanidipine Hydrochloride Tablets
Hanyu Pinyin：Yansuan Lekadiping Pian
Ingredients
Chemical Name: Methyl 2-[(3,3-diphenylpropyl)methanamine]-1,1-dimethylethyl-(4RS)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride
Chemical structure formula.
Molecular formula: C36H41N3O6-HCl
Molecular weight: 648.19
Properties
This product is a film-coated tablet, microscopic yellow or yellow after removing the coating.
Indications
For the treatment of mild and moderate essential hypertension.
Specification】10mg
Dosage and Administration
Usage
Take orally once daily, 15 minutes before meals.
Dosage
The recommended dose is 10mg per dose, which can be increased to 20mg per dose according to the individual response of the patient.
[Adverse Reactions].
Adverse reactions occur in approximately 1.8% of patients receiving treatment.
The following table shows the incidence of adverse drug reactions with at least a probable causal relationship according to the MedDRA Systematic Organ Classification System, classified by frequency of occurrence (occasional, rare).
According to the table, the most frequent adverse drug reactions reported in controlled clinical trials and occurring in less than 1% of patients were headache, dizziness, peripheral edema, tachycardia, palpitations, and flushing.
MedDRA System Organ Classification Frequency Criteria Terminology Immune system abnormalities are very rare (<1/10,000) Hypersensitivity reactions Psychiatric disorders are rare (≥1/10,000 <1/1000) Drowsiness Neurological abnormalities are occasional (≥1/1,000 <1/100) Headache; vertigo Cardiac disorders are rare (≥1/10,000 <1/ 1000)
Occasional (≥1/1,000 <1/100) angina pectoris
Tachycardia; palpitations vascular abnormalities occasional (≥1/1,000 <1/100)
Very rare (<1/10,000) flushing
Syncope Gastrointestinal system abnormalities rare (≥1/10,000 <1/1000) Nausea; dyspepsia; diarrhea; abdominal pain; vomiting Skin and subcutaneous tissue abnormalities rare (≥1/10,000 <1/1000) Rash Musculoskeletal, connective tissue, and bone abnormalities rare (≥1/10,000 <1/1000) Myalgia Renal and urinary system abnormalities rare (≥1/10,000 <1/1000) Polyuria systemic abnormalities and administration site abnormalities occasional (≥1/1,000 <1/100)
Rare (≥1/10,000 <1/1000) peripheral edema
Weakness; fatigue In post-marketing applications, spontaneous reports of the following adverse reactions are very rare (<1/10,000): gingival hyperplasia, reversible elevation of serum liver transaminases, hypotension, urinary frequency and chest pain.
In some rare cases, some dihydropyridines can cause precordial pain or angina pectoris. Very few patients with pre-existing angina have increased frequency, duration, or severity of anginal episodes. Individual cases of myocardial infarction have also been reported.
Lercanidipine does not adversely affect blood glucose and lipid levels.
Contraindications
Hypersensitivity to the active ingredient “lercanidipine”, any dihydropyridines or any drug excipients
Pregnancy and lactation (see [Pregnancy and Lactation])
Women of childbearing potential, unless an effective form of contraception is used
Left ventricular outflow tract obstruction
Untreated congestive heart failure
Unstable angina pectoris
Severe hepatic or renal impairment
Within one month of myocardial infarction
Concomitant administration of potent inhibitors of CYP3A4, cyclosporine or grapefruit juice (see [Drug Interactions])
[Precautions].
Patients with pathological sinus node syndrome (if no pacemaker is installed in the body) should be closely monitored during the application of Lecardipine. Although controlled hemodynamic studies have not found any impairment of ventricular function, caution is needed when applying this product in patients with left ventricular insufficiency. Evidence suggests that cardiovascular risk may be increased when short-acting dihydropyridines are administered to patients with ischemic heart disease. Although lercanidipine is a long-acting drug, caution should be exercised in its application in these patients as well.
In some rare cases, some dihydropyridines cause precordial pain or angina, and in a very small number of patients with pre-existing angina, the frequency, duration, or severity of angina attacks increases. Individual cases of myocardial infarction have also been reported (see [Adverse Reactions]).
Use in cases of abnormal hepatic or renal function: Caution should be exercised when initiating treatment with this product in patients with mild to moderate abnormal hepatic or renal function. Although the commonly recommended dose may be tolerated in this population, caution is required when increasing the daily dose to 20 mg. Since the antihypertensive effect may be enhanced with impaired hepatic function, dose adjustment needs to be considered.
The use of lercanidipine is not recommended in patients with severe hepatic impairment or severe renal insufficiency (GFR<30 ml/min).
Alcohol or alcoholic beverages should be avoided while taking the drug, as this may increase the vasodilatory effects of the antihypertensive drug (see [Drug Interactions]).
Inducers of CYP3A4 enzymes, such as antiepileptic drugs (phenytoin, carbamazepine, etc.) and rifampin, may reduce the plasma levels of lercanidipine and therefore the effectiveness of lercanidipine may be reduced (see [Drug Interactions]).
Each tablet contains 30 mg of lactose and should not be used in patients with Lapp lactase deficiency, galactosemia, or glucose/galactose malabsorption syndrome.
For Pregnant and Lactating Women】.
Data from animal studies in rats and rabbits indicate that lercanidipine is not teratogenic and fertility was not impaired in rats. However, because there is no clinical experience with the use of lercanidipine during pregnancy and lactation, and because other dihydropyridines have been found to be teratogenic in animals, lercanidipine should not be used in women during pregnancy, and women of childbearing age should use lercanidipine hydrochloride tablets only after using an effective form of contraception. Due to the highly lipophilic nature of lercanidipine, there may be distribution in breast milk. Therefore, lercanidipine hydrochloride tablets should not be taken by nursing mothers.
[For Children].
Not to be taken by patients under 18 years of age
Geriatric use]
No special dose adjustment is generally necessary for elderly patients, but attention should be paid at the beginning of treatment.
Drug Interactions]
Lercanidipine is known to be metabolized by the CYP3A4 enzyme, so concomitant administration of inhibitors and inducers of CYP3A4 enzyme may affect the metabolism and clearance of lercanidipine.
Concomitant prescription of lercanidipine and CYP3A4 enzyme inhibitors (e.g., ketoconazole, itraconazole, ritonavir, erythromycin, diclofenac) should be avoided (see [Contraindications]).
An interaction study with a strong blocker of CYP3A4 enzyme – ketoconazole – showed a significant increase in plasma lercanidipine concentration levels (a 15-fold increase in the area under the curve (AUC) and an 8-fold increase in peak drug concentration Cmax for the preferred isomer S-lercanidipine).
Cyclosporine and lercanidipine should not be used together (see [Contraindications]).
Plasma concentrations of both lercanidipine and cyclosporine have been found to increase when the two are applied together.
In a study in young healthy volunteers, when cyclosporine was administered 3 hours after lercanidipine, the plasma concentration of lercanidipine did not change, while the AUC of cyclosporine increased by 27%. However, if lercanidipine and cyclosporine were taken together, the blood concentration of lercanidipine increased 3-fold and the AUC of cyclosporine increased by 21%.
Lercanidipine should not be taken with grapefruit juice (see [Contraindications]).
As with other dihydropyridines, lercanidipine is sensitive to the metabolic inhibition of grapefruit juice, resulting in increased systemic utilization and thus increased antihypertensive effect.
When 20 mg of lercanidipine is administered orally with midazolam in elderly volunteers, absorption of lercanidipine increases (by approximately 40%) and the rate of absorption decreases (tmax is prolonged from 1.75 to 3 hours). There is no change in midazolam concentration.
Caution should be exercised when simultaneously administering lercanidipine with other CYP3A4 enzyme substrates, such as terfenadine, astemizole, and class III antiarrhythmic drugs such as amiodarone and quinidine.
Caution should be taken when concurrently applying lercanidipine and inducers of CYP3A4 enzymes such as antiepileptic drugs (phenytoin, carbamazepine, etc.) and rifampin, as the antihypertensive effect may be reduced and the patient’s blood pressure should be monitored more frequently than usual.
When lercanidipine and metoprolol (a beta-adrenergic receptor blocker cleared mainly by the liver) were applied together, there was no significant change in the bioavailability of metoprolol, but the bioavailability of lercanidipine decreased by 50%. This effect may be due to the fact that β-adrenoceptor blockers reduce blood flow to the liver and thus may also have similar effects on other drugs in this class. Therefore, lercanidipine can be safely taken concomitantly with beta-adrenergic receptor blockers, but dose adjustment may be required.
An interaction study with fluoxetine, an inhibitor of CYP2D6 and CYP3A4 enzymes, in volunteers aged 65 ± 7 years (mean age ± standard deviation) showed no clinically relevant changes in the pharmacokinetics of lercanidipine.
Concomitant administration of cimetidine at a daily dose of 800 mg does not cause significant changes in blood levels of lercanidipine, but caution should be exercised if higher doses are administered, as the bioavailability and antihypertensive effects of lercanidipine may be increased.
No pharmacokinetic interactions were observed between the two drugs in patients taking long-term beta-methyl digoxin with 20 mg of lercanidipine. Healthy volunteers taking digoxin followed by 20 mg of lercanidipine on an empty stomach showed a 33% increase in Cmax of digoxin, but no significant change in AUC or renal clearance. Patients taking digoxin concomitantly should be closely monitored for clinical signs of digoxin toxicity.
When 20 mg of lecadipine and 40 mg of simvastatin were combined multiple times, the AUC of lecadipine was not significantly altered, but the AUC of simvastatin was increased by 56% and its active product, β-hydroxamic acid, was increased by 28%, although these changes are unlikely to be clinically relevant. This interaction would not have occurred if lercanidipine had been taken orally in the morning and simvastatin in the evening, as the drug was administered.
Concomitant administration of 20 mg of lercanidipine and warfarin on an empty stomach in healthy volunteers does not alter the pharmacokinetics of warfarin.
Lercanidipine can be safely administered concomitantly with diuretics and angiotensin-converting enzyme inhibitors.
Alcohol or alcoholic beverages should be avoided while taking the drug, as this may increase the vasodilatory effects of the antihypertensive drug (see [Precautions]).
[Drug overdose].
Three cases of drug overdose have been reported in post-marketing applications (150 mg, 280 mg and 800 mg of lercanidipine in each case to attempt suicide).
Dose level signs/symptoms management method results 150mg + intake of unknown amount of alcohol drowsiness gastric lavage
Activated charcoal recovery 280mg + 5.6mg moxonidine cardiogenic shock
Severe myocardial ischemia
Mild renal failure high dose catecholamines
Furosemide
Digitalis
Peripheral intravenous volume expansion therapy recovery 800mg vomiting
Hypotension activated charcoal
Laxative
Dopamine IV recovery
As with other dihydropyridines, drug overdose is expected to produce significant hypotension and reflex tachycardia due to peripheral vasodilation. In cases of severe hypotension, bradycardia, and loss of consciousness, cardiovascular support would be helpful, and intravenous atropine may be applied in cases of bradycardia.
Given the longer pharmacologic effects of lercanidipine, cardiovascular monitoring of patients who have overdosed is required for at least 24 hours. There is no information available to evaluate the effects of dialysis. Because of the high pro-fingerprinting nature of the drug, plasma levels of the drug are not indicative of the duration of the overdose risk period and dialysis may not be effective.
Pharmacology and Toxicology
Pharmacological effects
Lercanidipine is a new generation dihydropyridine calcium channel blocker that inhibits the inward transmembrane flow of calcium ions into the myocardium and smooth muscle. Lercanidipine exerts its antihypertensive effect mainly by its S-enantiomer, which can lower blood pressure by directly relaxing vascular smooth muscle and reducing peripheral resistance.
Toxicological studies
Genotoxicity and carcinogenicity of lercanidipine have not been observed.
Reproductive toxicity: No effect of lercanidipine on fertility in rats and no teratogenicity in pregnant rats or pregnant rabbits was observed. Lercanidipine may cause embryonic loss before and after implantation and delayed fetal development in rats. Lercanidipine hydrochloride caused obstructed labor at high doses (12 mg/kg/day).
Pharmacokinetics]
After oral administration of 10~20mg of Lercanidipine, the drug was completely absorbed. The peak blood levels were 3.30ng/ml±2.09s.d. and 7.66ng/ml±5.90s.d., and the time to peak was generally 1.5~3 hours after dosing.
The blood levels of the two isomers of lercanidipine were similar: the plasma time to peak was the same, and the peak level and area under the curve were on average 1.2 times higher for the S-isomer. The clearance half-lives of the two isomers were essentially the same, and no interconversion of the two isomers in vivo was observed.
The absolute bioavailability of lercanidipine in patients administered after feeding was approximately 10% due to higher first-pass metabolism, however, the absolute bioavailability in healthy volunteers administered in the fasted state decreased to 1/3 of the former.
Oral administration of lercanidipine within 2 hours after a high-fat meal would increase its bioavailability fourfold. Therefore, lercanidipine should be administered before a meal.
The distribution of lercanidipine from plasma to tissues and organs is rapid and widespread.
The binding of lercanidipine to serum proteins is over 98%. Since plasma protein levels are decreased in patients with severe hepatic and renal abnormalities, the free form drug levels of lercanidipine are increased in these patients.
Lercanidipine is metabolized exclusively by the CYP3A4 enzyme; no prototype component of the drug was found in urine or feces. The drug is converted mainly to inactive metabolites, about 50% of which are excreted in the urine.
In vitro studies on human liver microsomes showed some degree of inhibition of both CYP3A4 and CYP2D6 at concentrations higher than 160 and 40 times the peak plasma concentration of 20 mg of oral lercanidipine, respectively.
In addition, drug interaction studies in humans have shown that lercanidipine does not alter plasma levels of midazolam, a typical CYP3A4 substrate, and metoprolol, a typical CYP2D6 substrate. Therefore, lercanidipine at therapeutic doses does not inhibit the biotransformation of drugs metabolized by CYP3A4 and CYP2D6.
Lercanidipine is primarily cleared by biotransformation.
The terminal elimination half-life of lercanidipine is 8 to 10 hours and the therapeutic effect lasts for 24 hours due to its high binding to lipid membranes. No accumulation has been observed with repeated dosing.
The dose at oral administration is not proportional to the plasma concentration of lercanidipine (non-linear kinetics). For oral administration of 10 mg, 20 mg and 40 mg of lercanidipine, peak plasma concentration ratios of 1:3:8 and area under the plasma concentration one-time curve ratios of 1:4:18 were observed. suggesting that first-pass metabolism is progressively saturated. Thus, utilization increases with increasing dose.
In elderly patients and in patients with mild to moderate hepatic and renal impairment, the pharmacokinetics of lercanidipine behaved similarly to that observed in the general population. Patients with severe renal insufficiency or who are dependent on dialysis show higher drug levels (approximately 70%). The systemic bioavailability of lercanidipine may be increased in patients with moderate to severe hepatic impairment because the drug is metabolized primarily by the liver.
Storage】Storage at room temperature (10~30℃) in a dry place
Package】Polyvinyl chloride solid pharmaceutical hard tablets and pharmaceutical aluminum foil package, 7 tablets/plate, 2 plates/box.
Expiration date
12 months
【Execution standard
Approval number】
【Marketing license holder
Company Name: Shenzhen Xinlitai Pharmaceutical Co.
Address
Address: 37th Floor, Main Building, Chegongmiao Greenview Plaza, No. 6009 Shennan Avenue, Futian District, Shenzhen
Manufacturer
Company Name: Shenzhen Xinlitai Pharmaceutical Co.
Address: No. 1, Planning Road 5, Longtian Street Industrial Zone, Pingshan District, Shenzhen
Postal code: 518118
Telephone number: 0755-83867888
Fax number: 0755-83867338
Website: http//:www.salubris.com