Beova

Film-coated tablet.
Light green film-coated tablets with BV50 printed on one side.
Each film-coated tablet contains Vibegron 50 mg.
Excipients/Inactive Ingredient: D-Mannitol, Microcrystalline cellulose, Croscarmellose sodium, Hydroxypropylcellulose, Magnesium stearate, Lactose hydrate, Hypromellose, Titanium oxide, FD&C Blue No.2 Aluminium Lake, Triacetin, Yellow ferric oxide, Carnauba wax.

Pharmacology: Pharmacodynamics: Mechanism of Action: Vibegron selectively stimulates β₃-adrenergic receptors present in bladder smooth muscles, and by relaxing bladders, it promotes urine accumulation function, and improves urinary urgency, urinary frequency and urge incontinence in overactive bladder patients.
Effects on β-adrenergic receptors: In cells stably expressing the human β₃-adrenergic receptors, Vibegron increased concentrations of intracellular cAMP in a concentration-dependent manner, but in cells expressing human β₁- or β₂-adrenergic receptors it hardly increased concentrations of intracellular cAMP (in vitro).
Effects on bladder tissues (in vitro): Vibegron suppressed contraction in a concentration-dependent manner in human bladder tissues contracted by electrical stimulation.
Effects on bladder functions: Vibegron increased the bladder capacity in rhesus monkeys under anesthesia in a dose-dependent manner.
Vibegron increased the bladder capacity in crab-eating monkeys without anesthesia in a dose-dependent manner.
CLINICAL STUDIES: Clinical Studies for Efficacy and Safety: Japan phase III double-blind placebo-controlled study (KRP114V-T301): Vibegron 50 mg, 100 mg^note), or Placebo was orally administered to 1107 patients with overactive bladder once daily after a meal for 12 weeks. Following tables show change in mean urination frequency per day (primary endpoint), change in mean urinary urgency frequency per day and change in mean number of urge incontinence per day (secondary endpoints). Significant improvements were observed in each item evaluated in both treatment groups (Vibegron 50 mg and Vibegron 100 mg) compared with the placebo group.
Adverse reactions occurred in 7.6% (28/370 patients) in the Vibegron 50 mg group, 5.4% (20/369 patients) in the Vibegron 100 mg group and 5.1% (19/369 patients) in the placebo group. Common adverse reactions were constipation in 1.6% (6/370 patients) and dry mouth in 1.4% (5/370 patients) in the 50 mg group. (See Tables 1, 2 and 3.)

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Japan phase III long-term study (KRP114V-T302): Vibegron at the dose of 50 mg was orally administered to 166 patients with overactive bladder once daily after a meal for 52 weeks. After initial administration of Vibegron at the dose of 50 mg for 8 weeks, dosage was increased from 50 mg to 100 mg^note) once daily only in subjects who met the following: insufficient in efficacy, investigator judged no problem in safety, and the subject wished to increase dosage. Following tables show changes at Week 8 and 52 in mean urination frequency per day, mean urinary urgency frequency per day, and mean number of urge incontinence per day. In both the Vibegron 50 mg dose-maintained group and the Vibegron 100 mg dose-increased group, improvement from the baseline (before administration) was observed in every endpoint, which was maintained without attenuation over the duration of 52 weeks.
Adverse reactions occurred in 18.1% (21/116 patients) in the Vibegron 50 mg dose-maintained group, and 11.8% (6/51 patients) in the Vibegron 100 mg dose-increased group. Common adverse reactions were increased residual urine volume in 4.3% (5/116 patients), dry mouth and cystitis both in 2.6% (3/116 patients), and constipation in 1.7% (2/116 patient) in the Vibegron 50 mg dose-maintained group, and constipation and dry mouth both in 3.9% (2/51 patient), and rheumatoid arthritis and pruritus both in 2.0% (1/51 patient) in the Vibegron 100 mg dose-increased group. (See Tables 4, 5 and 6.)

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Note): Approved dose of this drug is 50 mg.
Pharmacokinetics: Blood Level: Single administration: After single oral administration of 10-300 mg^note) of Vibegron to 6 healthy adult males under fasted conditions, C_max and AUC_inf rose more than proportional to dose increase, but t_max and t_½ were constant regardless of the dose. (See figure and Table 7.)

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Repeated administration: After repeated oral administration of 50 mg, 100 mg or 200 mg^note) of Vibegron once daily for 14 days to 6 healthy adult males under fasted conditions, AUC_0-24 was ranging from 1.84 to 2.29 times higher than those on Day 1. The steady state of plasma concentrations of Vibegron was achieved by the 7th day of administration. (See Table 8.)

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Absorption: Effect of meal: After single oral administration of 50 mg of Vibegron to 8 healthy adult males after a meal, pharmacokinetic parameters were as shown as follows. C_max and AUC_inf under fasted conditions were 1.73 and 1.40 times higher, respectively, than those under fed conditions, but there were no effect on T_max and t_½. (See Table 9)

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Distribution: The plasma protein binding rate of Vibegron was approximately 49.6%-51.3%. The blood-to-plasma concentration ratio of Vibegron was measured to be 0.8-1.0 (in-vitro).
Metabolism: Vibegron mostly remains as unchanged form in human plasma after oral administration, and three different glucuronides and two different oxidative metabolites were identified as metabolites.
Excretion: In the mass balance study of single oral administration of 100 mg^note) of ¹⁴C labeled Vibegron to 6 healthy adult males, 20.3% of the dose was recovered as radioactivity in urine and 59.2% in feces by Day 20. Unchanged form accounted for 92.7% of radioactivity in urine and 91.0% in feces.
Patients with Specific Backgrounds: Patients with renal impairment: Among patients with renal impairment, C_max and AUC_inf after single oral administration of 100 mg^note) of Vibegron compared with those of healthy adult subjects were 1.96 and 1.49 times higher in mild (eGFR <90 - ≥60 mL/min/1.73 m²), 1.68 and 2.06 times higher in moderate (eGFR <60 - ≥30 mL/min/1.73 m²), and 1.42 and 1.83 times higher in severe (eGFR less than 30 mL/min/1.73 m², not on dialysis) renal impairment patients, respectively.
Patients with hepatic impairment: After single oral administration of 100 mg^note) of Vibegron in patients with moderate hepatic impairment (Child-Pugh Classification score of 7-9 points), C_max and AUC_inf were 1.35 and 1.27 times higher, respectively, than those of healthy adult subjects [see Precautions].
Geriatric use: After repeated oral administration of 100 mg^note) of Vibegron once daily for 14 days to healthy elderly males (65 to 74 years, 6 cases), C_max and AUC_0-24 was 1.88 and 1.45 times higher, respectively, than those of healthy non-elderly adult males (23 to 39 years, 5 cases) [see Precautions].
Note): Approved dose of this drug is 50 mg.
Toxicology: Preclinical safety data: Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: No carcinogenicity was observed in long-term studies conducted in mice and rats treated with daily oral doses of Vibegron for approximately 2 years. In the mouse carcinogenicity study, CD-1 mice were treated with daily oral doses of Vibegron up to 90 mg/kg/day in males and up to 150 mg/kg/day in females, corresponding to estimated systemic exposures (AUC) 21- and 55-fold higher, respectively, than in humans treated with the recommended daily dose of Vibegron. In the rat carcinogenicity study, Sprague Dawley rats were treated with daily oral doses of Vibegron up to 30 mg/kg/day in males and up to 180 mg/kg/day in females, corresponding to systemic exposures (AUC) 18- and 117-fold higher, respectively, than in humans treated with the recommended daily dose of Vibegron.
Mutagenesis: Vibegron was not mutagenic in in vitro microbial reverse mutation assays, showed no evidence of genotoxic activity in an in vitro human peripheral blood lymphocyte chromosomal aberration assay, and did not increase the frequency of micronucleated polychromatic erythrocytes in an in vivo rat bone marrow micronucleus assay.
Impairment of Fertility: In fertility/general reproductive toxicity studies conducted in rats, females were treated with daily oral doses of 0, 30, 100, 300, or 1000 mg/kg/day Vibegron and males were treated with daily oral doses of 0, 10, 30, or 300 mg/kg/day Vibegron. No effects on fertility were observed in female or male rats at doses up to 300 mg/kg/day, associated with systemic exposure (AUC) at least 274-fold higher than in humans treated with the recommended daily dose of Vibegron. General toxicity, decreased fecundity, and decreased fertility were observed in female rats at 1000 mg/kg/day, associated with estimated systemic exposure 1867-fold higher than in humans treated with the recommended daily dose of Vibegron.

Treatment of overactive bladder with symptoms of urge urinary incontinence, urinary urgency, and urinary frequency.

The recommended adult dosage of Vibegron is one 50 mg tablet orally, once daily after a meal.

There is no experience with inadvertent Vibegron overdosage. In case of suspected overdose, treatment should be symptomatic and supportive.

This product is contraindicated in patients with a history of hypersensitivity to Vibegron or any components of the product.

PRECAUTIONS CONCERNING INDICATIONS: 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.
For patients with lower urinary-tract obstructive disease, including benign prostatic hyperplasia, treatment for these diseases should be prioritised.
PRECAUTIONS CONCERNING PATIENTS WITH SPECIFIC BACKGROUNDS: Patients with Complication or History of Diseases, etc: Patients with severe cardiac disease: Symptoms may be aggravated due to heart rate increased, etc.
Patients with Hepatic Impairment: No dosage adjustment for Vibegron is recommended for patients with mild to moderate hepatic impairment (Child-Pugh A and B). Vibegron has not been studied in patients with severe hepatic impairment (Child-Pugh C) and is not recommended in this patient population.
Urinary Retention: Urinary retention has been reported in patients taking Vibegron. Monitor patients for signs and symptoms of urinary retention, particularly in patients with bladder outlet obstruction and patients taking muscarinic antagonist medications for the treatment of overactive bladder as the risk of urinary retention may be increased. Discontinue Vibegron in patients who develop urinary retention.
Patient with renal impairment: No dosage adjustment for Vibegron is recommended for patients with mild (eGFR ≥60 - <90 mL/min/1.73 m²), moderate (eGFR ≥30 - <60 mL/min/1.73 m²), and severe (<30 mL/min/1.73 m², not on dialysis). Vibegron has not been studied in patient with eGFR <30 mL/min/1.73 m² on dialysis and eGFR <15 mL/min/1.73 m² (with or without hemodialysis) and is not recommended in these patients [see Pharmacology: Pharmacokinetics under Actions].
Precautions for Co-administration (This drug should be administered with caution when co-administered with the following.): See Table 10.

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PRECAUTIONS CONCERNING USE: Precautions Concerning the Dispensing of the Drug: Patients should be instructed to press the tablet out of a press-through package (PTP) before administration. The sharp corner of swallowed PTP sheet may puncture the esophageal mucosa, resulting in serious complications such as mediastinitis.
Effects on ability to drive and use machines: No data available.
Use in Children: No clinical studies in children have been conducted.
Use in the Elderly: Vibegron should be administered with care while monitoring the condition of the patient. The physiological functions are generally reduced in the elderly [see Pharmacology: Pharmacokinetics under Actions].

Pregnant Women: Administration of this product to pregnant women or women who may possibly be pregnant should be allowed only if the expected therapeutic benefits outweigh the possible risks associated with the treatment. Transfer to fetus was reported in animal studies (in rats).
Breast-feeding Women: The continuation or discontinuation of breastfeeding should be considered while taking account of the expected therapeutic benefits and the benefits of maternal feeding. Animal studies (rats) have shown that the drug is excreted into breast milk.

The following adverse reactions may occur. Patients should be carefully monitored. If any abnormality is noted appropriate measures should be taken including discontinuation of this drug.
Clinically Significant Adverse Reactions: Urinary retention (incidence unknown).
Other Adverse Reactions: See Table 11.

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Vibegron is suggested to be a substrate for CYP3A4 or P-glycoprotein (P-gp).
Tolterodine: Coadministration of 100 mg^note) of Vibegron and 4 mg of Tolterodine, a substrate of CYP2D6, to 12 healthy adults resulted in increases in C_max and AUC_0-24 of Vibegron by 1.03-fold and 1.08-fold, respectively, compared with when Vibegron was given alone. Meanwhile, C_max and AUC_0-24 of Tolterodine were increased by 1.12-fold and 1.08-fold, respectively, compared with when Tolterodine was given alone.
Ketoconazole: Coadministration of 100 mg^note) of Vibegron and 200 mg of Ketoconazole a strong CYP3A4/P-gp inhibitor, to 10 healthy adults resulted in increases in C_max and AUC_inf of Vibegron by 2.22-fold and 2.08-fold, respectively [see Precautions].
Diltiazem: Coadministration of 100 mg^note) of Vibegron and 240 mg of Diltiazem, a moderate CYP3A4/P-gp inhibitor, to 12 healthy adults resulted in increases in C_max and AUC_inf of Vibegron by 1.68-fold and 1.63-fold, respectively.
Digoxin: Coadministration of Vibegron increased digoxin C_max and AUC by 21% and 11%, respectively.
Note): Approved dose of this drug is 50 mg.

Incompatibilities: Not applicable.

Do not store above 30°C.

Drugs for Bladder & Prostate Disorders

G04BD15 - vibegron ; Belongs to the class of urinary antispasmodics.