URITOS / URITOS OD Tablet Ref.[50721] Active ingredients: Imidafenacin

Adverse reactions to these products including abnormalities in laboratory test values were reported in 533 (45.5%) of 1,172 cases evaluated. Major adverse reactions included thirst in 368 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).

In the post-marketing surveillance (drug-use-surveillance and special drug-use-surveillance), adverse reactions including abnormal laboratory test values were reported in 771 (12.7%) of 6,094 cases evaluated. Major adverse reactions included thirst/dry mouth in 321 cases (5.3%), constipation in 160 cases (2.6%). (At the end of reexamination)

1) Clinically significant adverse reaction

(1) 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.

(2) Urinary retention (incidence: 0.03%†) Since urinary retention may occur, patients should be monitored carefully. When symptoms are observed, administration should be discontinued, and appropriate measures should be taken.

(3) Hepatic dysfunction (incidence: 0.02%†) 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.

†: The incidences of adverse reactions were calculated from the result of post-marketing surveillance (druguse surveillance and special drug-use surveillance).

2) Clinically significant adverse reactions (similar drugs)

(1) 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.

(2) 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.

(3) 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.

3) Other adverse reactions

†: The incidences of adverse reactions were calculated from the result of post-marketing surveillance (drug-use surveillance and special drug-use surveillance).
Note: When any of these symptoms is observed, administration should be discontinued, and appropriate measures should be taken.

1. Careful Administration (URITOS Tablets and OD Tablets should be administered with care in the following patients.)

1. Patients with dysuria [Symptoms may be aggravated due to the anticholinergic effect of these products.]
2. Patients with arrhythmia [Symptoms may be aggravated due to the anticholinergic effect of these products.]
3. Patients with hepatic dysfunction [Adverse reactions may occur since these products are primarily metabolized in the liver. See “PHARMACOKINETICS” 1 (4).]
4. Patients with renal dysfunction [Renal excretion may be delayed.]
5. Patients with dementia or cognitive dysfunction [Symptoms may be aggravated due to the anticholinergic effect of these products.]
6. Patients with Parkinsonian symptoms or cerebrovascular disorder [Symptoms may be aggravated or psychoneurotic symptoms may occur.]
7. Patients with ulcerative colitis [Toxic megacolon may occur.]
8. Patients with hyperthyroidism [Sympathetic excitation including tachycardia may be aggravated due to the anticholinergic effect of these products.]

2. Important Precautions

1. In patients with lower urinary-tract obstructive disease, including benign prostatic hyperplasia, the volume of residual urine should be measured prior to treatment with these products, 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.
2. Since these products 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.
3. These products are not indicated for patients with dementia or cognitive dysfunction who cannot clearly recognize symptoms of overactive bladder.
4. When no satisfactory efficacy is observed, treatment with these products should not be continued chronically, and an alternative appropriate therapy should be considered.
5. OD Tablets (orally disintegrating tablets) are disintegrated in the oral cavity; however, they are not absorbed through the oral mucosa. Thus, OD Tablets should be swallowed with saliva or water. [see “Precautions concerning Use”.]

9. Precautions concerning Use

(1) 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.]

(2) At dosing:

1. OD Tablets (orally disintegrating tablets) can be dosed by swallowing with saliva alone (without water), after the tablets soaked with saliva on the tongue are disintegrated into pieces. OD Tablets can be, naturally, dosed with water.
2. OD Tablets should not be dosed without water at the recumbent position.

10. 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).

Imidafenacin is primarily metabolized by CYP3A4 and UGT1A4 in the liver. [See “PHARMACOKINETICS” 3.] Precaution for co-administration (URITOS Tablets and OD Tablets should be administered with care when co-administered with the following drugs.)

1) 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, C_max and AUC_0-∞ of imidafenacin increased to 1.3 and 1.8 times those after imidafenacin was administered alone, respectively.10)

2) 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), C_max, AUC_0-24, and trough concentration of digoxin were comparable to those after digoxin was administered alone.11)

(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. C_max and AUC_0-12 in the bladder were 10.7 and 25.4 times higher than those in the serum, respectively.

Administration of these products is not recommended to pregnant women or women suspected of being pregnant. [Safety of these products has not been established during pregnancy. Transfer to fetus was reported in animal studies (in rats).]

Administration of these products is not recommended during breast feeding. When unavoidable, nursing mothers should discontinue breast feeding during treatment of these products. [Transfer to breast milk was reported in animal studies (in rats).]

Safety of these products has not been established in lowbirthweight babies, neonates, nursing infants, infants, or children (no clinical experience).

Since physiological functions are generally reduced in the elderly, these products should be administered with care.