Beova

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

Pharmacology: Pharmacodynamics: Mechanism of Action: Vibegron is a selective human beta-3 adrenergic receptor agonist. Activation of the beta-3 adrenergic receptor increases bladder capacity by relaxing the detrusor smooth muscle during bladder filling. 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 removed bladder tissues: Vibegron suppressed contraction in a concentration-dependent manner in removed human bladder tissues contracted by electrical stimulation. (In vitro.)
Effects on bladder functions: Vibegron increased the bladder capacity in rhesus monkeys under anesthesia in a dose-dependent manner. This drug increased the bladder capacity in crab-eating monkeys without anesthesia in a dose-dependent manner.
Clinical Studies: Clinical Studies for Efficacy and Safety: Domestic phase III double-blind placebo-controlled study: 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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Domestic phase III long-term study: 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 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_1/2 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_1/2. (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. (Japanese and non-Japanese data.)
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. (Non-Japanese data.)
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) renal impairment patients, respectively. (Non-Japanese data.)
Patients with hepatic impairment: After single oral administration of 100 mg 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. (Non-Japanese data.) [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.)
Drug-Drug Interaction: 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. (Non-Japanese data.)
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. (Non-Japanese data.) [See Interactions.]
Diltiazem: Co-administration 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. (Non-Japanese data.)
Note): Approved dose of this drug is 50 mg.

Treatment of symptoms associated with overactive bladder (OAB): urinary urgency, urinary frequency and urge incontinence.

Usual adult dose is 50 mg of Vibegron orally once daily after a meal.

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

This drug is contraindicated to patients with a history of hypersensitivity to any of the components of this 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 prioritized.
Precautions Concerning Patients with Specific Backgrounds: Patients with Complications or History of Diseases, etc.: Patients with severe cardiac disease: Symptoms may be aggravated due to heart rate increased, etc.
Patients with Hepatic Impairment: Patients with advanced hepatic impairment: Blood concentration of Vibegron may increase. (See Pharmacology: Pharmacokinetics under Actions.)
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.
Use in Pregnancy & Lactation: See USE IN PREGNANCY & LACTATION section for further information.
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. When a drug is present in animal milk, it is likely that the drug will be present in human milk.

The following adverse reactions may occur. Therefore, patients should be carefully monitored. If any abnormality is noted appropriate measures should be taken including discontinuation of this drug.
Clinically Significant Adverse Reaction: Urinary retention (incidence unknown).
Other Adverse Reactions: See Table 10.

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Vibegron is suggested to be a substrate for CYP3A4 or P-glycoprotein (P-gp).
This drug should be administered with caution when co-administered with the following: See Table 11.

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Store at temperatures not exceeding 30°C.
Shelf Life: 24 Months.

Drugs for Bladder & Prostate Disorders

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

Rx