Uritos

Uritos

Manufacturer:

Eisai

Marketer:

Eisai
Full Prescribing Info
Contents
Imidafenacin.
Description
Chemical name: 4-(2-Methyl-1H-imidazol-1-yl)-2,2-diphenylbutanamide
Molecular formula: C20H21N3O
Molecular weight: 319.40
Melting point: 192 to 196°C
Description: Imidafenacin occurs as a white crystal or crystalline powder. It is freely soluble in acetic acid (100), soluble in N, N-dimethyl formamide (DMF) and methanol, sparingly soluble in ethanol (99.5), slightly soluble in acetonitrile, and practically insoluble in water. (See Table 1 and Table 2.)


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Action
Pharmacology: Pharmacodynamics: Mode of Action: Contraction of the urinary bladder is known to be induced by acetylcholine with mediation of muscarinic acetylcholine receptor subtype M3.
Acetylcholine release from the nerve terminal of the urinary bladder is probably enhanced by a stimulus to muscarinic acetylcholine receptor subtype M1. Imidafenacin antagonizes subtypes M3 and M1 in vitro. In the urinary bladder, imidafenacin inhibits acetylcholine release by antagonizing subtype M1 and contraction of smooth muscles by antagonizing subtype M3. Compared with the inhibitory effect on the salivary gland, imidafenacin shows higher inhibitory effect on the urinary bladder contraction, probably indicating efficacy and safety of this product in the clinical practice.
Pharmacological Activity: Activity in the muscarinic acetylcholine receptor subtypes (in vitro): (1) Antagonistic activity of imidafenacin was investigated on muscarinic acetylcholine receptors in vas deferens (M1), atrium (M2), and ileum (M3) using tissue specimens prepared from rabbits and guinea pigs. Imidafenacin showed higher antagonistic activity in the ileum (M3) and vas deferens (M1), compared with atrium (M2). Major metabolites in humans showed no antagonistic activity in the muscarinic acetylcholine receptor subtypes.
(2) Antagonistic activity of imidafenacin was investigated in recombinant human muscarinic acetylcholine receptor subtypes M1, M2, and M3 in the receptor binding assay. Imidafenacin showed high affinities for subtypes M3 and M1.
(3) Imidafenacin inhibited acetylcholine release and urinary bladder contraction by antagonizing subtypes M3 and M1 in the tissue specimens prepared from rats.
Activity in the urinary bladder (in vivo): (1) Imidafenacin decreased rhythmic contraction of the rat urinary bladder dose-dependently.
(2) Imidafenacin inhibited a carbachol-induced decrease in the capacity of the rat urinary bladder dose dependently.
Selectivity for the urinary bladder: (1) In rats, the activity ratio of inhibition of rhythmic contraction in the urinary bladder to carbachol-induced salivary secretion was about 10 times higher in imidafenacin than in propiverine hydrochloride, demonstrating high selectivity of imidafenacin for the urinary bladder.
(2) Evaluation of rat performance in the Morris water maze task indicated that antagonistic activity of imidafenacin on subtype M1 was unlikely to impair spatial learning and memory.
Pharmacokinetics:
Plasma Concentrations: (1) Single administration: Effect of meal: After single oral administration of 0.1 mg of imidafenacin to healthy adult males (n=12) at the fasting state, plasma concentration reached the peak (Cmax: 471 pg/mL) at 1.5 hours, and decreased with a half-life of 2.9 hours. Cmax and AUC0-12 at the fed state were about 1.3 and 1.2 times higher than those at the fasting state, respectively. (See figure and Table 3.)


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(2) Repeated administration: After repeated oral administration of 0.25 mg of imidafenacin twice daily for 5 days to the healthy adult males (n=5), the time-course of plasma concentration and pharmacokinetic parameters after the final dosing were comparable to those after the initial dosing, indicating no accumulation of imidafenacin after repeated administration.
Note: The dosage in this study is different from the approved dosage and administration of this product (See Dosage & Administration.)
(3) The elderly: After single oral administration of 0.1 mg of imidafenacin to the healthy non-elderly adult males (n=6) and the elderly males aged 65 years or more (n=9) at the fasting state, Cmax in the elderly was about 1.2 times higher than that in the non-elderly, while AUC0-∞ was comparable between the two groups. (See Table 4.)


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(4) Population pharmacokinetic (PPK) analysis: A two-compartment model involving primary absorption with a lag time in absorption was used for the analysis of population pharmacokinetics by NONMEM. Plasma concentration of imidafenacin was determined at a total of 3,168 points in 852 patients with overactive bladder aged 20 to 85 years (including 101 patients with mild hepatic dysfunction, 116 patients with mild renal dysfunction, and 14 patients with moderate renal dysfunction) and 90 healthy adults aged 20 to 75 years in the long-term study and long-term ascending-dose study. The relationship of clearance (CL/F) of imidafenacin to the following covariates was assessed: body weight, age, gender, drinking habit, smoking habit, indices for hepatic function (AST [GOT], ALT [GPT], γ-GTP, ALP, lactate dehydrogenase, and total bilirubin), indices for renal function (serum creatinine, and blood urea nitrogen), and albumin. CL/F in the patients with mild abnormality in ALP was lower than that in the normal patients by 4%. CL/F in the elderly was lower than that in the non-elderly by 14%. The other covariates including indices for renal function (serum creatinine, blood urea nitrogen) did not affect CL/F. (See Table 5.)


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Absorption (for reference: overseas data): In the healthy adult foreign males, imidafenacin was absorbed almost 100% from the gastrointestinal tract, with an absolute bioavailability of 57.8 %.
Metabolism: After oral administration, about 40% of imidafenacin was subjected to first-pass effect in the liver. Major plasma metabolites included M-2 (oxidized metabolite on the imidazole ring of imidafenacin), M-4 (ring-cleaved metabolite of M-2), and M-9 (N­-glucuronide of imidafenacin). Metabolism to M-2 and M-4 was primarily catalyzed by CYP3A4, and that to M-9 was by UGT1A4. In addition, imidafenacin and its major metabolites, M-2, M-4, and M-9, did not inhibit human CYP species in vitro (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4).
Excretion (for reference: overseas data): After single oral administration of 14C-imidafenacin to healthy adult foreign males (n=6) at a dose of 0.25 mg at the fasting state, 95% of the dose was recovered as radioactivity in the urine and feces until 192 hours after administration (65.6% in the urine, and 29.4% in the feces). Less than 10% of the dose was excreted unchanged in the urine, and none of the dose was excreted unchanged in the feces.
Note) The dosage in this study is different from the approved dosage and administration of this product (See Dosage & Administration.)
Protein Binding: The protein binding ratio of imidafenacin ranged from 87.1 to 88.8%. Major binding proteins were albumin and α1-acid glycoprotein.
Drug Interactions: Itraconazole: After 0.1 mg of imidafenacin was orally co-administered to healthy adult males (n=10) treated with 200 mg of itraconazole once daily for 9 days, Cmax and AUC0-∞ of imidafenacin increased to 1.3 and 1.8 times those after imidafenacin was administered alone, respectively.
Digoxin: After 0.1 mg of imidafenacin twice daily and 0.125 mg (0.25 mg as loading dose) of digoxin once daily were co-administered for 8 days to healthy adult males (n=12), Cmax, AUC0-24, and trough concentration of digoxin were comparable to those after digoxin was administered alone.
(For reference) Distribution in animals (in rats): After single oral administration of imidafenacin to rats, concentration in the bladder reached maximum at 1 hour after administration, and decreased with a half-life of 1.8 hours, more slowly than in the serum. Cmax and AUC0-12 in the bladder were 10.7 and 25.4 times higher than those in the serum, respectively.
Clinical Studies: Double-blind Placebo-controlled Study + : Imidafenacin was orally administered at the dose of 0.1 mg twice daily for 12 weeks to patients with overactive bladder. For the primary efficacy outcome, change in total number of urinary incontinence per week from the baseline value, significant improvement was observed in the imidafenacin group compared with the placebo group. In addition, significant improvement was also observed in changes in mean frequency of urination per day and mean frequency of urinary urgency per day from the baseline values in the imidafenacin group compared with the placebo group. (See Table 6.)


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Long-term Study: Imidafenacin was orally administered at the dose of 0.1 mg twice daily for 52 weeks to patients with overactive bladder. Improvement was observed in changes in total number of urinary incontinence per week, mean frequency of urination per day, and mean frequency of urinary urgency per day from the baseline values, with duration for 52 weeks without attenuation. (See Table 7.)


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Indications/Uses
The following symptoms associated with overactive bladder: urinary incontinency, urinary frequency and urinary urgency.
Dosage/Direction for Use
The usual oral dosage for adults is 0.1 mg of imidafenacin twice daily, after breakfast and supper.
Overdosage
Symptoms: Urinary retention, mydriasis, excitement, tachycardia, etc.
Countermeasures: After gastric lavage or administration of activated carbon, the measures similar to those for overdosage of atropine should be taken. Appropriate measures should be taken according to individual symptoms, including urethral catheterization for urinary retention and administration of pilocarpine for mydriasis.
Contraindications
URITOS Tablets are contraindicated in the following patients: Patients with urinary retention [Symptoms may be aggravated due to inhibition of bladder contraction during urination caused by the anticholinergic effect of this product.]
Patients with occluded pyloric region/duodenum/intestine or paralytic ileus [Symptoms may be aggravated due to inhibition of contraction and motility of gastrointestinal smooth muscles caused by the anticholinergic effect of this product.]
Patients with decreased gastrointestinal movements and muscular tension [Symptoms may be aggravated due to inhibition of contraction and motility of gastrointestinal smooth muscles caused by the anticholinergic effect of this product.]
Patients with narrow-angle glaucoma [Symptoms may be aggravated due to an increase in intraocular pressure caused by the anticholinergic effect of this product.]
Patients with myasthenia gravis [Symptoms may be aggravated due to a decrease in muscle tone caused by the anticholinergic effect of this product.]
Patients with severe heart disease [Symptoms may be aggravated since abnormal electrocardiographic findings including extrasystoles have been reported.]
Patients with a history of hypersensitivity to any of the components of this product.
Special Precautions
Prior to use of this product, clinical symptoms of patients should be confirmed with an appropriate interview, and diagnosis by exclusion of some other diseases with similar symptoms, including urinary tract infection, urinary calculus, and lower urinary-tract neoplasm such as bladder cancer and prostate cancer, should be made by performing appropriate examinations such as urinalysis. In addition, special examinations should be considered to conduct, if necessary.
In patients with overactive bladder complicated with lower urinary-tract obstructive disease, including benign prostatic hypertrophy, treatment of the complication should be given priority.
Careful Administration (URITOS Tablets should be administered with care in the following patients.): Patients with dysuria [Symptoms may be aggravated due to the anticholinergic effect of this product.]
Patients with arrhythmia [Symptoms may be aggravated due to the anticholinergic effect of this product.]
Patients with hepatic dysfunction [Adverse reactions may occur since this product are primarily metabolized in the liver. See Pharmacology: Pharmacokinetics under Actions.]
Patients with renal dysfunction [Renal excretion may be delayed.]
Patients with dementia or cognitive dysfunction [Symptoms may be aggravated due to the anticholinergic effect of this product.]
Patients with Parkinsonian symptoms or cerebrovascular disorder [Symptoms may be aggravated or psychoneurotic symptoms may occur.]
Patients with ulcerative colitis [Toxic megacolon may occur.]
Patients with hyperthyroidism [Sympathetic excitation including tachycardia may be aggravated due to the anticholinergic effect of this product.]
Important Precautions: In patients with lower urinary-tract obstructive disease, including benign prostatic hyperplasia, the volume of residual urine should be measured prior to treatment with this product, and special examinations should be performed if necessary. The patients should be monitored carefully throughout the treatment, with attention to increased volume of residual urine.
Since this product may induce eye accommodation disorder including photophobia, blurred vision, and eye abnormality, patients should be instructed to operate potentially hazardous machinery, such as driving a car, with caution.
This product is not indicated for patients with dementia or cognitive dysfunction who cannot clearly recognize symptoms of overactive bladder.
When no satisfactory efficacy is observed, treatment with this product should not be continued chronically, and an alternative appropriate therapy should be considered.
Other Precautions: An increase in hepatocellular adenoma was reported in 300 mg/kg groups of both males and females in the carcinogenicity study in mice for 2 years (at the oral doses of 30, 100, and 300 mg/kg), while increase in hepatocellular adenoma was not reported in the carcinogenicity study in rats for 2 years (at the oral doses of 3, 7, 15, and 30 mg/kg).
Use in the Elderly: Since physiological functions are generally reduced in the elderly, this product should be administered with care.
Pediatric Use: Safety of this product has not been established in low birthweight babies, neonates, nursing infants, infants, or children (no clinical experience).
Use In Pregnancy & Lactation
Administration of this product is not recommended to pregnant women or women suspected of being pregnant. [Safety of this product has not been established during pregnancy. Transfer to fetus was reported in animal studies (in rats).]
Administration of this product is not recommended during breast feeding. When unavoidable, nursing mothers should discontinue breast feeding during treatment of this product. [Transfer to breast milk was reported in animal studies (in rats).]
Adverse Reactions
Adverse reactions to this product including abnormalities in laboratory test values were reported in 533 (45.5%) of 1,172 cases evaluated. Major adverse reactions included thirst in368 cases (31.4%), constipation in 98 cases (8.4%), photophobia in 18 cases (1.5%), blurred vision in 16 cases (1.4%), sleepiness in 16 cases (1.4%), stomach discomfort in 13 cases (1.1%), increased triglyceride in 13 cases (1.1%), and increased γ-GTP in 12 cases (1.0%) (at the time of approval).
In additional clinical studies for dosage and administration, adverse reactions including abnormalities in laboratory test values were reported in 215 (49.4%) of 435 cases evaluated. Major adverse reactions included thirst/dry mouth in 164 cases (37.7%), constipation in 59 cases (13.6%), residual urine in eight cases (1.8%), positive urinary leukocyte in seven cases (1.6%), stomach discomfort in six cases (1.4%), headache in five cases (1.1%), and dysuria in five cases (1.1%) (at the time of additional approval for dosage and administration).
Clinically significant adverse reaction: Acute glaucoma (incidence: 0.06%): Since incidence of acute glaucoma induced by increased intraocular pressure has been reported, patients should be monitored carefully. When such a symptom is observed, administration should be discontinued, and appropriate measures should be taken immediately.
Urinary retention (frequency unknown: based on spontaneous reporting): Since urinary retention may occur, patients should be monitored carefully. When symptoms are observed, administration should be discontinued, and appropriate measures should be taken.
Hepatic dysfunction (frequency unknown: based on spontaneous reporting): Hepatic dysfunction with elevations of aspartate aminotransferase (AST or glutamate oxaloacetate transaminase [GOT]), alanine aminotransferase (ALT or glutamate pyruvate transaminase [GPT]), or bilirubin may occur. Patients should be carefully monitored, and if any abnormalities are observed, administration of this drug should be discontinued and appropriate measures should be taken immediately.
Clinically significant adverse reactions (similar drugs): Ileus paralytic: Since incidence of ileus paralytic has been reported in the similar drugs (other agents for overactive bladder), patients should be monitored carefully. When symptoms including severe constipation and abdominal distention are observed, administration should be discontinued, and appropriate measures should be taken.
Hallucination/delirium: Since incidence of hallucination/delirium has been reported in the similar drugs (other agents for overactive bladder), patients should be monitored carefully. When these symptoms are observed, administration should be discontinued, and appropriate measures should be taken.
QT prolongation, ventricular tachycardia: Since incidence of symptoms including QT prolongation, ventricular tachycardia, atrioventricular block, and bradycardia has been reported in the similar drugs (other agents for overactive bladder), patients should be monitored carefully. When these symptoms are observed, administration should be discontinued, and appropriate measures should be taken.
Other adverse reactions: (see Table 8).


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Inform the doctor in case of any adverse reactions related to drug use.
Drug Interactions
Imidafenacin is primarily metabolized by CYP3A4 and UGT1A4 in the liver. [See Pharmacology: Pharmacokinetics under Actions].
Precaution for co-administration (URITOS Tablets should be administered with care when co-administered with the following drugs) (see Table 9).


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Caution For Usage
At dispensing: For drugs supplied in a press-through package (PTP), patients should be instructed to remove the drugs from the package prior to administration. [It has been reported that, if the PTP sheet is swallowed mistakenly, the sharp edge of the sheet may perforate the esophageal mucosa, resulting in serious complications such as mediastinitis.]
Storage
Store below 30°C.
ATC Classification
G04BD - Drugs for urinary frequency and incontinence ; Used in the treatment of urological problems.
Presentation/Packing
FC tab 0.1 mg x 3 x 10's.
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