Date of approval.
Date of revision.
Pulucapride Succinate Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name
Generic name: Prucalopride Succinate Tablets
English name: Prucalopride Succinate Tablets
Hanyu Pinyin: Huposuan Pulukabili Pian
Ingredients
Active ingredient: Pulukabili Succinate
Chemical name: 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl]-7-benzofurancarboxamide butanedioate.
Chemical structure formula.
Molecular formula: C18H26ClN3O3.C4H6O4
Molecular weight: 485.96
【Properties】.
This product is a film-coated tablet, which appears white or off-white after removing the coating.
Indications
It is used for the treatment of chronic constipation in adult female patients whose symptoms are not adequately relieved by light laxatives.
Specification
(1) 1mg (in the form of Prilucapride)
(2) 2mg (in prucalopride)
Dosage and Administration
Usage: Take orally. It can be taken before and after meals.
Dosage.
Adults: 2mg once daily.
Geriatric patients (> 65 years of age): The starting dose is 1 mg once daily and may be increased to 2 mg once daily if needed.
Children and adolescents: This product is not recommended for use in children and adolescents younger than 18 years of age.
Patients with renal dysfunction: The dose for patients with severe renal dysfunction (GFR < 30ml/min/1.73m2) is 1mg once daily. no dose adjustment is required for patients with mild to moderate renal dysfunction.
Patients with hepatic dysfunction: The recommended starting dose for patients with severe hepatic dysfunction (Child-Pugh class C) is 1 mg once daily. no dose adjustment is required for patients with mild to moderate hepatic dysfunction.
Clinical studies have shown no increase in efficacy at a daily dose of 4 mg.
If this product is ineffective after 4 weeks of treatment, the patient should be re-evaluated and reconsidered whether continued treatment would be beneficial.
This product has demonstrated good efficacy in double-blind placebo-controlled studies of up to 3 months. If the course of treatment is extended, patients should be evaluated periodically for benefit.
[Adverse Reactions].
In a comprehensive analysis of 17 double-blind placebo-controlled studies, approximately 3,300 patients with chronic constipation were administered this product orally. Of these patients, more than 1,500 received the recommended dose of 2 mg per day and approximately 1,360 patients received 4 mg per day.
At the 2 mg daily dose, the most frequently reported adverse reactions associated with drug therapy were headache (17.8%) and gastrointestinal symptoms (abdominal pain (13.7%), nausea (13.7%) and diarrhea (12.0%)). Most of these adverse reactions occurred at the beginning of treatment and usually resolved after a few days of continued use. Other adverse reactions were occasionally reported. Most of the adverse reactions were mild to moderate.
A total of 564 elderly patients (≥ 65 years of age) with chronic constipation were treated with this product in all double-blind studies. Similar to the younger age group, the most common adverse reactions in elderly patients treated with this product were gastrointestinal symptoms (diarrhea, abdominal pain, or nausea) and headache. No clinically meaningful increase in the incidence of adverse events was observed in the drug-treated group compared to the placebo group.
The following adverse reactions were reported in the control clinical study with the recommended dose of 2 mg, corresponding to the following frequencies: very common (≥ 1/10), common (≥ 1/100 to < 1/10), and occasional (≥ 1/1,000 to < 1/100). Within each frequency grouping, adverse reactions are listed in strict decreasing order. Frequency calculations are based on data from placebo-controlled clinical studies.
Nutritional and Metabolic Disorders
Common: Loss of appetite
Neurological Disorders
Very common: Headache
Common: Dizziness
Occasional: tremor, migraine
Cardiovascular disorders
Occasional: palpitations
Ear and vagus disorders
Occasional: vertigo
Gastrointestinal disorders
Very common: nausea, diarrhea, abdominal pain
Common: vomiting, indigestion, flatulence, abnormal bowel sounds
Occasionally: rectal bleeding
Kidney and urinary tract disorders
Occasionally: urinary frequency
Systemic and dosing site conditions
Common: fatigue
Occasionally: fever, malaise
After the first day of treatment, nausea and diarrhea occurred more frequently during treatment in the drug group, but were not significantly different (the difference in incidence between the drug and placebo groups ranged from 1% to 3%), and most other common adverse reactions occurred at similar rates in the drug and placebo groups (the difference between the two groups was less than 1%).
Palpitations were reported in 0.7%, 0.9%, 0.9%, and 1.9% of patients treated with placebo, 1 mg of this product, 2 mg of this product, and 4 mg of this product, respectively, with most patients not discontinuing this product. As with any new onset of symptoms, patients should promptly report new episodes of palpitations to their physician.
Contraindications]
-Patients who are hypersensitive to the active ingredient or any of the excipients of this product.
-Patients with renal dysfunction requiring dialysis.
-Patients with intestinal perforation or obstruction due to structural or functional abnormalities of the intestinal wall, mechanical intestinal obstruction, severe intestinal inflammatory diseases such as Crohn’s disease, ulcerative colitis and toxic megacolon/megorectum.
-Patients who have recently undergone bowel surgery.
[Precautions].
1. Prior to treatment with this product, a thorough patient history and examination is required to rule out secondary causes of constipation and to determine that the patient has been on light laxatives for at least 6 months without achieving adequate relief.
2. The safety and efficacy of this product in combination with laxatives has not been evaluated, although laxatives have been used as temporary emergency relief medication in pivotal clinical trials.
3. The efficacy and safety of this product has only been demonstrated in the treatment of chronic functional constipation. The efficacy and safety of this product has not been evaluated in patients with secondary causes of constipation, including endocrine, metabolic, and neurological disorders, and therefore it is not recommended for use in these patients. The efficacy and safety of this product has not been demonstrated in patients with drug-related constipation, including constipation with secondary causes due to opioids, and therefore it is not recommended for use in such patients.
4. Renal excretion is the primary route of clearance of this product. It is recommended that the dose administered to patients with severe renal dysfunction be reduced to 1 mg.
5. The safety and efficacy of this product in patients with severe and clinically unstable disease (e.g., hepatic, cardiovascular or pulmonary disease, neurological or psychiatric disease, cancer or AIDS and other endocrine diseases) have not been conclusively demonstrated in controlled clinical trials. Caution should be exercised when prescribing this product to these patients. It should be used with particular caution in patients with a history of cardiac arrhythmia or ischemic cardiovascular disease.
6. Patients should consult a physician if they experience palpitations during administration.
7. If severe diarrhea occurs while using this product, the effectiveness of oral contraceptives may be reduced and alternative methods of contraception are recommended to prevent possible oral contraceptive failure.
8. Hepatic dysfunction is unlikely to have a clinically meaningful effect on the metabolism and exposure of this product. The recommended starting dose for administration to patients with severe hepatic dysfunction is 1 mg.
9. The tablets contain lactose monohydrate. Patients with rare genetic disorders such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this product.
10. This product should be used with caution in patients taking drug therapy known to cause QTc prolongation.
11. No studies have been conducted on the effects of this product on driving and the ability to operate machinery. The use of this product, especially on the first day, may cause dizziness and fatigue, which may affect driving and the ability to operate machinery.
12. No interaction with food has been observed.
13. Keep out of the reach of children.
Pregnant women and nursing mothers
Clinical experience with the use of this product during pregnancy is limited. Although cases of spontaneous abortion have been identified in clinical studies, the correlation between this product and spontaneous abortion cannot be determined due to the presence of other risk factors. In animal studies, no direct or indirect deleterious effects on pregnancy, embryo/fetal development, delivery, or postnatal development have been observed. The use of this product during pregnancy is not recommended. Women of childbearing potential should use an effective method of contraception during the use of this product.
Prilucapride is secreted in breast milk. Breastfeeding is not expected to have an effect on the newborn/infant when this product is administered at therapeutic doses. However, due to the lack of human data on breastfeeding women receiving this product, its use during breastfeeding is not recommended.
Animal studies have shown no effect of this product on fertility in females or males.
[Pediatric Use].
There is a paucity of clinical data in this area; therefore, the use of this product in children and adolescents younger than 18 years of age is not recommended.
Geriatric Use
The starting dose for elderly patients older than 65 years of age is 1 mg, which can be increased to 2 mg if needed.
Drug Interactions]
The potential for pharmacokinetic interactions with prucalopride is low. It is mostly excreted in the urine as a prototype drug (about 60% of the dose) and is metabolized very slowly in vitro.
In an in vitro study in human liver microsomes, prucalopride at therapeutically relevant concentrations did not inhibit specific CYP450 activity.
Prilucapride may be a weak substrate for P-glycoprotein (P-gp), but is not an inhibitor of P-gp at clinically relevant concentrations.
Ketoconazole is a potent inhibitor of CYP3A4 and P-glycoprotein, and 200 mg of ketoconazole twice daily increased the AUC of this product by approximately 40%. This weak effect may be attributed to inhibition of P-glycoprotein-mediated renal transport and is not clinically significant. A similar degree of interaction may be observed when combined with other P-glycoprotein inhibitors such as verapamil, cyclosporine A, quinidine, and ketoconazole. This product may also be secreted via another renal transporter protein. Inhibition of all transporter proteins associated with active secretion of prilucapride (including P-gp) may theoretically increase exposure to this product by 75%.
Studies in healthy subjects have shown no clinically meaningful effects on the pharmacokinetics of warfarin, digoxin, ethanol, paroxetine, or oral contraceptives. During concomitant administration with this product, a 40% increase in Cmax and a 28% increase in AUC24h was found for erythromycin, the mechanism of action of which was not fully defined and the increase was not clinically meaningful. Therapeutic doses of probenecid, cimetidine, erythromycin and paroxetine did not affect the pharmacokinetics of this product.
Due to its mechanism of action, the use of atropine analogues may reduce the mediating effect of this product on 5-HT4 receptors.
Drug overdose]
In a study of healthy subjects, this product was well tolerated when treated with 20 mg once daily (10 times the recommended therapeutic dose). Overdose may result in symptoms caused by amplification of the known effects of the drug, including headache, nausea, and diarrhea. There is no specific treatment for drug overdose of this product. If an overdose occurs, patients should receive symptomatic treatment or use supportive medical measures, if necessary. If needed, electrolyte disturbances caused by large fluid loss due to diarrhea or vomiting can be treated.
Pharmacology and Toxicology
Pharmacological effects
Prilucapride is a dihydrobenzofurancarboxamide, a selective, high-affinity pentraxin (5-HT4) receptor agonist with pro-intestinal motility. In vitro and in vivo studies have shown that prucalopride enhances peristaltic reflexes and propulsive motility patterns in the gastrointestinal tract through 5-HT4 receptor activation.
Toxicological studies
Safety Pharmacology
A slight increase in heart rate and blood pressure was observed after intravenous administration in anesthetized pigs and in awake dogs, but no similar phenomenon was observed in anesthetized or awake dogs when similar blood concentrations were achieved orally.
Proscapride concentrations up to 1 μM (49 times the human therapeutic dose of 7.5 ng/mL) did not affect IKr currents in hERG-transfected HEK293 or COS-7 cells, and the EC50 values for IKr current inhibition ranged from 4.1 to 22 μM (200 to 1100 times the human therapeutic blood concentration). In ex vivo tests in rabbit and canine Purkinje fibers, rabbit heart and guinea pig papillary muscle, no effect on action potential timing was seen at concentrations up to 1 μM of prucalopride. Intravenous prilucapride caused an increase in systolic and diastolic blood pressure in conscious dogs and anesthetized pigs, but no other relevant cardiovascular effects were observed at prilucapride concentrations equivalent to human therapeutic blood concentrations.
Genotoxicity
Prilucapride had positive results in the Ames test, positive results in the in vitro rat hepatocyte in vitro DNA synthesis (UDS) test, and negative results in the mouse lymphoma cell test, human peripheral blood lymphocyte chromosome aberration test, mouse micronucleus test, in vivo UDS test, and in vivo transgenic Big Blue test.
Reproductive toxicity
No significant adverse effects were observed in the fertility and early embryotoxicity test and the perinatal toxicity test in rats given prilucapride orally at doses up to 20 mg/kg. A slight decrease in gestational uterine weight and a small decrease in the number of corpus luteum were seen in the perinatal toxicity test at 80 mg/kg. No teratogenic effects or other embryotoxicity were seen in the embryo-fetal development toxicity test with 80 mg/kg given orally to rats and rabbits, with exposures (based on Cmax) equivalent to 938-fold in humans and 38-fold in rabbits (based on AUC0-24h). Neonatal/juvenile animal toxicity tests were conducted in rats and dogs administered for one week and one month, with a no toxic effect dose (NOAEL) of 5 mg/kg in dogs; however, effects including decreased body weight gain were seen at all doses (5 to 80 mg/kg).
Carcinogenicity
In a two-year carcinogenicity test in mice and rats, doses up to 80 mg/kg/day were observed in mice and 40 (females) and 80 (males) mg/kg/day in rats. Increased incidence of mammary adenocarcinoma was seen in mice at a dose of 80 mg/kg/day (approximately 200 times the exposure at the maximum clinically recommended daily dose (MRHD) in humans in terms of AUC); the no-effect dose was 20 mg/kg/day (approximately 27 times the MRHD in terms of AUC). In rats, an increased incidence of benign adenoid pheochromocytomas, pituitary adenomas, pancreatic adenomas, hepatocellular adenomas (medium and high doses), and thyroid follicular tumors was seen at high doses (approximately 45 times the MRHD in terms of AUC); the no-effect dose was 5 mg/kg/day (approximately 7 times the MRHD in terms of AUC).
Mechanistic studies have shown that D2 receptor antagonism at high concentrations of prucalopride induces hyperprolactinemia, which may contribute to the increased incidence of mammary, pituitary, pancreatic, and adrenal tumors in mice and rats. Prilucapride and its rat-specific metabolism at high doses have hepatic enzyme-inducing effects, which may be responsible for the increased incidence of liver and thyroid tumors in rats. Since no increase in plasma prolactin levels was observed in clinical studies and the metabolism of prucalopride in humans differs greatly from that in rats, these tumor findings are considered to be of low clinical relevance.
[Pharmacokinetics].
Absorption: 2 mg of prucalopride is rapidly absorbed after a single oral dose, reaching peak blood concentration (Cmax) within 2 to 3 hours. Absolute oral bioavailability>90%. Simultaneous ingestion of food does not affect the oral bioavailability of this product.
Distribution: The product is widely distributed with a steady-state volume of distribution (Vdss) of 567 liters. The plasma protein binding rate of this product is approximately 30%.
Metabolism: Metabolism is not the major route of clearance of this product. In vitro, metabolism through the human liver is very slow and only small amounts of metabolites have been observed. In an oral dosing study in men using radiolabeled prucalopride, small amounts of seven metabolites were recovered in urine and feces. Metabolite R107504 was most abundant in urine and feces, accounting for 3.2% and 3.1% of the dose, respectively. Other metabolites found and quantified in urine and feces were R084536 (formed by N-dealkylation, 3% of the dose) as well as hydroxylation products (3% of the dose) and N-oxidation products (2% of the dose). The prototype active ingredient accounted for 92% to 94% of the total radioactivity in plasma. r107504, r084536 and r104065 (formed by O-demethylation) were identified as trace metabolites in plasma.
Excretion: Most of the drug is excreted in healthy subjects as a prototype (approximately 60-65% of the administered amount in the urine and approximately 5% in the feces), and renal excretion of the prototype involves passive filtration and active secretion. The mean plasma clearance of this product is 317 ml/min and its terminal half-life is approximately 1 day. Steady state is reached within 3 to 4 days. The trough and peak steady-state plasma concentrations were 2.5 ng/ml and 7 ng/ml, respectively, when treated with 2 mg of this product once daily. the cumulative ratio after once-daily administration ranged from 1.9 to 2.3. The pharmacokinetics of prucalopride were dose-related over the therapeutic dose to overdose (up to 20 mg) range. At extended treatment, once-daily administration of this product showed non-time-dependent kinetics.
Special Populations
Population Pharmacokinetics: Pooled population pharmacokinetic analyses in Phases I, II, and III showed that overall apparent clearance correlated with creatinine clearance, but that age, weight, gender, or race had no effect on overall apparent clearance.
Elderly patients: Following once-daily administration of 1 mg, the peak concentration and AUC of this product were 26% to 28% higher in elderly subjects than in younger adults. This effect can be attributed to diminished renal function in the elderly.
Renal dysfunction: Compared to normal subjects, blood concentrations of this product were 25% and 51% higher in subjects with mild (ClCR 50 ~ ≤ 79 mL/min/1.73 m2) and moderate (ClCR 25 ~ ≤ 49 mL/min/1.73 m2) renal dysfunction after a single dose of 2 mg, respectively. In subjects with severe renal dysfunction (ClCR ≤ 24 mL/min/1.73 m2), blood concentrations were 2.3 times higher than in healthy subjects.
Hepatic dysfunction: Non-renal elimination accounts for approximately 35% of the total elimination pathway, and Cmax and AUC after a single dose of 2 mg of this product were on average 10% to 20% higher in patients with moderate to severe hepatic dysfunction compared to normal subjects.
Pediatric patients
After a single oral dose of 0.03 mg/kg in pediatric patients between the ages of 4 and 12 years, the peak blood concentration of this product was similar to that of adults after a single dose of 2 mg, while the AUC of the free drug was 30-40% lower than that of adults. Free drug exposure was similar throughout the age range (4 to 12 years). In pediatric patients, the mean terminal half-life of this product is approximately 19 hours (range 11.6 to 26.8 hours).
[Storage].
Seal and store in a dry place below 30℃.
Package
Aluminum-plastic blister package, 7 tablets/plate/box, 12 tablets/plate/box, 14 tablets/plate/box.
Expiration date】 24 months
【Execution standard
Marketing license holder】 Hebei Renhe Yikang Pharmaceutical Co.
Approval number】
Manufacturer
Company Name: Hebei Renhe Yikang Pharmaceutical Co.
Production Address: Qingliangdian Town, Wuyi County, Hengshui City, Hebei Province
Postal Code: 053400
Telephone number: 0318-5813777
Fax number: 0318-5813777