Date of approval.
Date of modification.
Solifenacin Succinate Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name
Generic Name: Solifenacin Succinate Tablets
English Name: Solifenacin Succinate Tablets
Hanyu Pinyin: Huposuan Suolinaxin Pian
Ingredients
Chemical Name: Solifenacin Succinate
(3R)-1-azabicyclo[2.2.2]oct-3-yl(1S)-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate monosuccinate
Chemical structure formula.
Molecular formula: C23H26N2O2-C4H6O4
Molecular weight: 480.55
Properties
This product is a light yellow round film-coated tablet, which appears white after removing the film coating.
Indications
It is used for the treatment of urinary incontinence and/or urinary frequency and urgency in patients with overactive bladder.
Specification
5mg
Dosage
The recommended dose of this product is one tablet (5mg) once daily, or two tablets (10mg) once daily if necessary. This product must be taken with water, before or after meals.
Patients with renal dysfunction
No dose adjustment is required in patients with mild to moderate renal dysfunction (creatinine clearance > 30 ml/min). Patients with severe renal dysfunction (creatinine clearance ≤ 30 ml/min) should be administered with caution at doses not exceeding 5 mg daily.
Patients with hepatic dysfunction
No dose adjustment is required for patients with mild hepatic dysfunction. Patients with moderate hepatic dysfunction (Child-Pugh score 7 to 9) should be dosed with caution at a dose not to exceed 5 mg once daily.
Potent cytochrome P450 3A4 inhibitors
When administered concomitantly with ketoconazole or therapeutic doses of other potent CYP3A4 inhibitors such as ritonavir, nelfinavir and itraconazole, the maximum dose of this product should not exceed 5 mg.
Adverse reactions]
Due to the pharmacological effects of solifenacin, this product may cause anticholinergic side effects, which are usually mild or moderate and their frequency is dose dependent.
The most common adverse reaction reported was dry mouth, which occurred in 11% of patients treated with 5 mg once daily, 22% with 10 mg once daily, and 4% with placebo. Dry mouth was usually mild and occasionally patients required interruption of treatment. Overall, compliance with drug therapy was very high (approximately 99%), with approximately 90% of patients treated with this product completing the 12-week study.
MedDRA system organ classification is common
≥1/10 common
≥1/100,<1/10 rare
≥1/1,000, <1/100 rare
≥1/10,000, <1/1000 very rare
<1/10000, unknown
(not speculative from available data) Infectious and infectious diseases Urinary tract infections, cystitis Immune system diseases Allergic reactions* Metabolic and nutritional diseases Decreased appetite*, hyperkalemia* Psychiatric disorders Hallucinations*, confusional states* Delirium* Neurological disorders Drowsiness, taste disturbances Dizziness*, headache* Ocular disorders Blurred vision Dry eyes Glaucoma* Cardiac disorders Ventricular tachycardia of the tip-twist type* ECG QT Prolonged intervals*, atrial fibrillation*, palpitations*, tachycardia* Respiratory, thoracic and mediastinal disorders Nasal dryness Vocal difficulties* Gastrointestinal system disorders Dry mouth Constipation, nausea, dyspepsia, abdominal pain Gastro-oesophageal reflux disease, dry throat Colonic obstruction, fecal impaction, vomiting* Intestinal obstruction*, abdominal discomfort* Hepatobiliary system disorders Liver disorders*, abnormal liver function tests* Skin and subcutaneous tissue disorders Dry pruritus*, skin Rash*, erythema multiforme*, urticaria*, angioedema*, exfoliative dermatitis*, musculoskeletal and connective tissue disorders, muscle weakness*, renal and urinary disorders, difficulty urinating, urinary retention, renal impairment*, systemic disorders and administration site reactions, fatigue, peripheral edema*, adverse reactions observed after marketing.
Contraindications
This product is contraindicated in patients with urinary retention, severe gastrointestinal disease (including toxic megacolon), myasthenia gravis or narrow-angle glaucoma, or in patients at risk for the following conditions
Patients with hypersensitivity to the active ingredient or excipients of the product.
Patients undergoing hemodialysis.
Patients with severe hepatic dysfunction.
Patients with severe renal dysfunction or moderate hepatic dysfunction who are using potent CYP3A4 inhibitors such as ketoconazole.
[Caution].
Other causes of urinary frequency (heart failure or kidney disease) should be confirmed before treatment with this product. If a urinary tract infection is present, appropriate antibacterial therapy should be initiated.
It should be used with caution in patients with
Clinically significant lower urinary tract obstruction with risk of urinary retention.
Gastrointestinal obstructive disease.
At risk of diminished gastrointestinal motility.
Severe renal dysfunction (creatinine clearance ≤ 30 ml/min; see [Dosage] and [Pharmacokinetics]) in these patients at doses not exceeding 5 mg once daily.
Moderate hepatic dysfunction (Child-Pugh score of 7 to 9; see [Dosage] and [Pharmacokinetics]), in these patients at a dose of no more than 5 mg once daily.
Concomitant use of a potent cytochrome P450 3A4 inhibitor such as ketoconazole; see [DOSAGE] and [DRUG INTERACTIONS].
Esophageal hiatal hernia/gastroesophageal reflux and/or are taking medications that can cause or exacerbate esophagitis (e.g., diphosphonate compounds).
Autonomic disease.
Prolonged QT interval and tip-twisting ventricular tachycardia have been observed in patients with risk factors (e.g., preexisting long QT syndrome and hypokalemia).
The safety and efficacy of the drug in patients with neurogenic detrusor overactivity have not been established.
It should not be used in patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
Angioedema with airway obstruction has been reported in some patients following the use of this product. If angioedema develops, the product should be discontinued and appropriate treatment and/or measures should be taken.
Anaphylactic reactions have been reported in some patients following the use of solifenacin succinate. In patients who develop anaphylactic reactions, solifenacin succinate should be discontinued and appropriate treatment and/or measures taken.
Maximum efficacy of this product may be determined as early as 4 weeks after administration.
Effects on Driving and Operation of Machinery: Like other anticholinergic drugs, solifenacin may cause blurred vision, drowsiness, and fatigue (rare) (see [ADVERSE REACTIONS]) and may have a negative effect on driving and operation of machinery.
Pregnant women and nursing mothers
Pregnancy
There are no clinical data on the use of Solifenacin in women during pregnancy. Animal studies have not shown direct harmful effects on fertility, embryo/fetal development or delivery. The potential risk to humans is unknown and caution should be exercised when prescribing to women during pregnancy.
Lactation
There are no data on the secretion of solifenacin in human milk. Solifenacin and/or its metabolites have been detected in the milk of mice, causing a dose-dependent developmental arrest of newborn pups. Therefore, this product should be avoided in nursing mothers.
Pediatric Use]
The safety and efficacy of the drug for use in children have not been established. Therefore, this product should not be used in children.
[Geriatric Use].
Dose adjustment according to age is not required. A multi-dose study of this product in elderly volunteers (65-80 years of age) and a population pharmacokinetic analysis in a randomized, double-blind, placebo-controlled study showed no clinically significant changes in the pharmacokinetics of solifenacin succinate due to age. In placebo-controlled clinical studies, there was little overall difference in safety between older and younger patients treated with solifenacin succinate 5 mg or 10 mg for 4 weeks to 12 weeks.
Drug Interactions]
Pharmacological interactions: Combination with other drugs with anticholinergic properties may cause more pronounced therapeutic effects and side effects. An interval of approximately one week should be set before discontinuing treatment with other anticholinergic drugs. Concomitant use of cholinergic agonists may reduce the efficacy of solifenacin.
Solifenacin reduces the effects of drugs that stimulate gastrointestinal motility such as metoclopramide and cisapride.
Pharmacokinetic interactions: In vitro studies have demonstrated that solifenacin does not inhibit CYP 1A1/2, 2C9, 2C19, 2D6, or 3A4 from human liver microsomes at therapeutic concentrations; therefore, solifenacin is unlikely to affect the clearance of drugs metabolized by these CYP isoenzymes.
Effect of other drugs on the pharmacokinetics of solifenacin: Solifenacin is metabolized by CYP3A4. Concomitant administration of the potent CYP3A4 inhibitor ketoconazole 200 mg/day increased solifenacin AUC twofold; increasing the ketoconazole dose to 400 mg/day increased solifenacin AUC threefold. Therefore, the maximum dose of this product should be limited to 5 mg when concurrently administering ketoconazole or therapeutic doses of other potent CYP3A4 inhibitors such as ritonavir, nelfinavir and itraconazole (see [Dosage]).
Concomitant treatment with solifenacin and potent CYP3A4 inhibitors is contraindicated in patients with severe renal dysfunction or moderate hepatic dysfunction.
The role of enzyme induction on the pharmacokinetics of solifenacin and its metabolites, as well as the role of high-affinity CYP3A4 substrates on solifenacin exposure, has not been studied. Because solifenacin is metabolized by CYP3A4, pharmacokinetic interactions may occur with other high-affinity CYP3A4 substrates (e.g., verapamil, diltiazem) and CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine).
Effect of solifenacin on the pharmacokinetics of other drugs
Oral contraceptives: No pharmacokinetic interactions have been shown with oral administration of Solifenacin on concomitant oral administration of contraceptives (ethinylestradiol/levonorgestrel).
Warfarin: The pharmacokinetics of R-warfarin or S-warfarin and their effects on prothrombin time were not altered when this product was administered orally.
Digoxin: No effect on the pharmacokinetics of digoxin was shown when this product was administered orally.
[Drug Overdose].
Symptoms: Overdose of solifenacin succinate may result in severe anticholinergic effects. The highest dose of solifenacin succinate taken incidentally by a single patient was 280 mg over a 5-hour period, resulting in altered mental status, but did not require hospitalization.
Treatment: If an overdose of solifenacin succinate occurs, the patient should be treated with activated charcoal. Gastric lavage within 1 hour is effective, but do not induce vomiting.
As for other anticholinergic symptoms, they may be treated as follows.
Severe central anticholinergic effects such as hallucinations or significant euphoria: treat with toxic lentil or carbachol.
convulsions or significant euphoria: treatment with benzodiazepines
respiratory insufficiency: treatment with artificial respiration
tachycardia: treatment with beta-blockers
urinary retention: catheterization.
Dilated pupils: eye drops with trichothecene and/or sending the patient to a dark room for rest.
As with other anticholinergics, extra care should be taken in case of overdose in patients with known QT-interval prolongation (e.g., hypokalemia, bradycardia, and taking drugs that prolong the QT-interval), patients with preexisting cardiac disease (myocardial ischemia, arrhythmias, congestive heart failure).
Pharmacology and Toxicology]
Pharmacological effects: Solifenacin is a competitive muscarinic receptor antagonist with higher selectivity for the bladder than for the salivary glands. Muscarinic M3 receptors play an important role in a number of functions that are primarily cholinergic mediated, including contraction of bladder smooth muscle and stimulation of salivary secretion. Solifenacin succinate inhibits overactivity of the detrusor muscle by blocking muscarinic M3 receptors in bladder smooth muscle, thereby relieving the symptoms of urge incontinence, urgency and frequency that accompany overactive bladder disorder.
Toxicological studies: Preclinical safety data obtained from routine safety pharmacology studies, repeated dosing toxicity studies, genotoxicity studies, fertility studies, embryonic development studies, carcinogenicity studies, and reproductive toxicity studies indicate no specific risk for the use of solifenacin in humans. In prenatal and postnatal developmental studies in mice, the administration of solifenacin to lactating females caused a dose-dependent reduction in postnatal survival, lower pup weights, and slowed physiological development at clinically relevant levels. Doses that achieved pharmacological effects were given after day 10 or day 21 of life in pups, and dose-related increases in mortality were seen, with higher mortality in both groups than in adult mice, but no significant growth and developmental toxicity was seen. Plasma exposure was higher in young mice given from postnatal day 10 than in adult mice; systemic exposure was comparable to adult mice given from postnatal day 21. The clinical significance of the increased mortality in young mice is not known.
Pharmacokinetics
General characteristics
Absorption: After oral administration, the maximum plasma concentration (Cmax) of solifenacin is reached after 3 to 8 hours, and tmax is independent of the dose administered. Between 5 and 40 mg doses, Cmax and area under the curve (AUC) increase proportionally to the administered dose. Absolute bioavailability was approximately 90%.
Feeding did not affect the Cmax and AUC of solifenacin.
Distribution: The apparent volume of distribution of solifenacin after intravenous administration is approximately 600 L. Solifenacin is largely bound to plasma proteins (approximately 98%), primarily α1-acidic glycoproteins.
Metabolism: Solifenacin is extensively metabolized in the liver, the main metabolizing enzyme being cytochrome P450 3A4 (CYP3A4). However, another metabolic pathway also exists that may aid in the metabolism of solifenacin. The systemic clearance of solifenacin is approximately 9.5 L per hour, with a terminal half-life of approximately 45 to 68 hours. In addition to solifenacin, one pharmacologically active metabolite (4R-hydroxy solifenacin) and three inactive metabolites (N-glucosidic acid conjugate, solifenacin N-oxide, and 4R-hydroxy solifenacin-N-oxide) are detected in plasma after oral administration.
Excretion: After a single dose of 14C-labeled solifenacin 10 mg, approximately 70% radioactivity was detected in urine and approximately 23% in feces within 26 days. Approximately 11% of the radioactivity recovered in urine was from unchanged prodrug, approximately 18% was from N-oxidized metabolites, 9% was from 4R-hydroxy-N-oxidized metabolites, and 8% was from 4R-hydroxy metabolites (active metabolites).
Dose ratio: pharmacokinetics were linear over the therapeutic dose range.
Patient characteristics
Age: No dose adjustment based on age is required. Studies conducted in the elderly population have shown that solifenacin exposure, expressed as AUC, in healthy elderly subjects (age 65-80 years) after solifenacin succinate (5 mg and 10 mg once daily) administration was similar to that in healthy younger subjects (age 55 years or less). In the elderly population, this was demonstrated by a slightly slower mean absorption of tmax and a terminal half-life approximately 20% longer. These modest differences were not considered clinically significant.
The pharmacokinetics of solifenacin in children and adolescents have not been established.
Gender: The pharmacokinetics of solifenacin are not affected by gender.
Race: The pharmacokinetics of solifenacin are not influenced by race.
Renal Dysfunction: The AUC and Cmax of solifenacin in patients with mild to moderate renal dysfunction were not significantly different compared to healthy volunteers. In patients with severe renal dysfunction (creatinine clearance ≤30 ml/min), solifenacin exposure was significantly increased compared to controls, as evidenced by an increase in Cmax of approximately 30%, an increase in AUC of more than 100%, and an increase in t1/2 of more than 60%. A statistically significant relationship was seen between creatinine clearance and solifenacin clearance.
The pharmacokinetics of solifenacin in patients undergoing hemodialysis were not studied.
Hepatic Dysfunction: In patients with moderate hepatic dysfunction (Child-Pugh score 7 to 9), Cmax was unaffected, AUC was increased by 60%, and t1/2 was doubled. The pharmacokinetics of solifenacin in patients with severe hepatic dysfunction have not been studied.
Storage】Sealed and stored at room temperature (10~30℃).
Package】Polytrifluoroethylene/Polyvinyl chloride solid pharmaceutical compound hard tablets/pharmaceutical aluminum foil, 10 tablets/plate/box.
Expiration date】 24 months
Execution Standard
Approval number
Drug marketing license holder
Name: Hangzhou Huadong Pharmaceutical Group Zhejiang Huayi Pharmaceutical Co.
Registered Address: No. 15, Shuangfeng Road, Fotang Town, Yiwu City, Zhejiang Province
Postal code: 322002
Contact: 0579-89948265
Fax: 0579-89948300
Inquiry：0571-88056711
Web address: http://www.huayipharm.com
【Manufacturing enterprise
Company name: Hangzhou Huadong Pharmaceutical Group Zhejiang Huayi Pharmaceutical Co.
Production Address: No. 15 Shuangfeng Road, Futang Town, Yiwu City
Postal code: 322002
Contact：0579-89948265
Fax: 0579-89948300
Inquiry：0571-88056711
Web address: http://www.huayipharm.com