NIKP-Bisoprolol

NIKP-Bisoprolol

bisoprolol

Manufacturer:

Nichi-Iko

Distributor:

DKSH
Full Prescribing Info
Contents
Bisoprolol fumarate.
Description
NIKP-Bisoprolol tablet 2.5mg contains 2.5mg of bisoprolol fumarate in each tablet.
NIKP-Bisoprolol tablet 5mg contains 5mg of bisoprolol fumarate in each tablet.
This product is a "Japanese Pharmacopeia Bisoprolol Fumarate Tablet".
Bisoprolol Fumarate occurs as white crystals or a white crystalline powder.
It is very soluble in water and in methanol, and freely soluble in ethanol (99.5) and in acetic acid (100).
A solution of Bisoprolol Fumarate (1 in 10) shows no optical rotation.
Nonproprietary name: Bisoprolol Fumarate.
Chemical name: (2RS)-1-(4-{[2(1-Methylethoxy)ethoxy]methyl}phenoxy)-3-[(1-methylethyl)amino]propan-2-ol hemifumarate.
Molecular formula: (C18H31NO4)2·C4H4O4.
Molecular weight: 766.96.
Melting point: 101-105°C.
Excipients/Inactive Ingredients: This product contains lactose, hydroxypropyl cellulose, and magnesium stearate as inactive ingredients.
Action
Pharmacology: Pharmacokinetics: Bioequivalence Study: When a single dose of two tablets of NIKP-Bisoprolol tablet 2.5mg or two tablets of the reference product (both tablets contain 5 mg of bisoprolol fumarate) were given to healthy male adults during fasting with a cross-over method, the plasma concentrations of bisoprolol fumarate were measured. In a statistical analysis for the obtained pharmacokinetic parameters (AUC and Cmax), calculation results of 90% confidence intervals for the parameters were within a range between log (0.8) and log (1.25), demonstrating the bioequivalence of the two formulations.
Additionally, when one tablet of NIKP-Bisoprolol tablet 2.5mg or one tablet of the reference product (both tablets contain 5mg of bisoprolol fumarate) was administered, similar bioequivalence results of both formations were observed. (See Tables 1 and 2 and Figures 1 and 2.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image


Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Plasma concentration and pharmacokinetic parameters such as AUC and Cmax may vary depending on study conditions including selection of subjects, body fluid sampling frequency/sampling time, etc.
Dissolution profile:
NIKP-Bisoprolol tablet 2.5mg and NIKP-Bisoprolol tablet 5mg have been confirmed to meet the dissolution specification for Bisoprolol Fumarate Tablet stipulated in the Official Monographs of the Japanese Pharmacopeia.
Indications/Uses
Hypertension; Angina pectoris; Adjunct to standard therapy in chronic heart failure.
Dosage/Direction for Use
Hypertension and angina pectoris: The usual adult oral dose is 5mg to 10mg of bisoprolol fumarate once daily. This may be adjusted depending on patient age or symptoms.
Adjunct to standard therapy in chronic heart failure: The initial oral dose of bisoprolol fumarate is 1.25*mg once daily. If tolerated, the dose should be doubled after 1 week, and then increased gradually at 1 to 4 weeks intervals to the maximum dose tolerated. The maximum dose should not be exceeding 10mg once daily.
*Other product needs to be chosen for the given strength.
Overdosage
Symptoms: Overdosage may result in bradycardia, complete atrioventricular block, heart failure, hypotension, bronchial spasms, etc. These symptoms, however, have also been reported as adverse reactions.
Treatment: If overdose occurs, administration of the drug should be discontinued and the drug should be eliminated using stomach pump, etc., as necessary while appropriate measures, such as the following, are performed: Bradycardia, complete atrioventricular block: Atropine sulfate hydrate, isoprenaline hydrochloride, etc., should be administered or cardiac pacing should be performed.
Rapid worsening of heart failure: Diuretics, cardiac stimulants, or vasodilators should be administered intravenously.
Hypotension: Cardiac stimulants, vasopressors, transfusion, etc., should be administered or assisted circulation should be performed.
Bronchial spasms: Bronchodilators such as isoprenaline hydrochloride, β2 stimulants, or aminophylline hydrate, etc., should be administered.
Contraindications
Patients with severe bradycardia (significant sinus bradycardia), atrioventricular block (second or third degree), sinoatrial block, sick sinus syndrome [May lead to worsening of symptoms.].
Patients with diabetic ketoacidosis and metabolic acidosis [May lead to strengthened suppression of cardiac contractility due to acidosis.].
Patients with cardiogenic shock [May suppress heart function and lead to worsening of symptoms.].
Patients with right heart failure due to pulmonary hypertension [May suppress heart function and lead to worsening of symptoms.].
Patients with heart failure that require intravenous administration of cardiac stimulants or vasodilators [May lead to worsening of symptoms due to the suppressive effect against cardiac contractility.].
Patients with decompensated heart failure [May lead to worsening of heart failure due to the suppressive effect against cardiac contractility.].
Patients with severe peripheral circulatory failure (e.g. gangrene) [May suppress dilation of peripheral blood vessels, leading to worsening of symptoms.]
Patients with untreated pheochromocytoma (refer to Precautions Regarding Dosage and Administration under Precautions).
Pregnant women or women who may be pregnant (refer to Use in Pregnancy & Lactation).
Patients who have a history of sensitivity to any of the ingredients of this product.
Warnings
For patients with chronic heart failure, use only under the direction of a physician with adequate experience treating chronic heart failure.
For patients with chronic heart failure, attention should be paid to worsening of symptoms at the initial administration or when dose amount is increased, and any dosage adjustments should be made with caution. (Refer to Precautions Regarding Dosage and Administration, Important Precautions and Other Precautions under Precautions.)
Special Precautions
Precautions Regarding Dosage and Administration: For Patients with pheochromocytoma, administration of this drug in a single dose may lead to a sudden rise in blood pressure. This drug should be administered after initial treatment with alpha blockers and should be used in combination with alpha blockers.
Patients with essential hypertension or angina pectoralis combined with chronic heart failure should refer to Dosage & Administration regarding chronic heart failure.
Adjunct to standard therapy for chronic heart failure: For administration to patients with chronic heart failure, the initial dosage must start at 1.25*mg or less once daily, and the maintenance dosage must be set individually for each patient based on tolerability. (Refer to Other Precautions as follows.)
*Other products need to be chosen for the given strength.
When initial administration or increase in dose of this product are conducted, close monitoring must be performed and tolerability should be checked because worsening of heart failure, edema, weight gain, dizziness, hypotension, bradycardia, fluctuations in blood sugar, and worsened kidney function may occur.
In order to avoid worsening of heart failure or retention of fluid (edema, weight gain, etc.) during initial administration or when increasing the dose amount of this drug, adequate treatment for fluid retention should be performed before administering this drug. If heart failure or worsening of fluid retention (edema, weight gain, etc.) occurred and improvement is not seen with increased doses of diuretics, dosage amount of this drug is to be decreased or discontinued. If symptoms such as hypotension, dizziness, etc., are observed and improvement is not seen by decreasing dose amount of angiotensin-converting enzyme inhibitors or diuretics, the dosage amount of this drug is to be decreased. If severe bradycardia occurs, the dosage amount of this drug is to be decreased. Furthermore, the dosage amount of this drug should not be increased until these symptoms have stabilized.
When administration of this drug is discontinued abruptly, heart failure may worsen. Discontinuation of this drug should not be performed suddenly; in principle, the dose amount should be gradually decreased and then administration should be discontinued.
When readministering the drug after a drug withdrawal of 2 weeks or longer, in accordance with Dosage & Administration, administration should start from a low dose and gradually increased in dosage.
Careful administration (NIKP-Bisoprolol tablet 2.5mg and NIKP-Bisoprolol tablet 5mg should be administered with care in the following patients.): Patients at risk of bronchial asthma and bronchial spasms [May constrict bronchial tubes and cause onset of symptoms.].
Patients with idiopathic hypoglycemia, poorly controlled diabetes, long-term fasting [Attention should be paid to blood sugar levels because may mask sympathetic system responses, such as tachycardia, etc., which are prodromal symptoms of low blood sugar.].
Patients with thyrotoxicosis [May mask symptoms of poisoning, such as tachycardia, etc. (refer to Important Precautions as follows)].
Patients with severe hepatic or renal dysfunction [May delay metabolism/excretion of the drug and increase the effects.].
Patients with peripheral circulatory failure (Raynaud's syndrome, intermittent claudication, etc.) [May suppress dilation of peripheral blood vessels and cause symptoms to worsen.].
Patients with bradycardia, atrioventricular block (first degree) [May suppress cardiac conduction system of the heart and cause symptoms to worsen.].
Patients with extremely low blood pressure [May risk an even lower drop in blood pressure.].
Patients with variant angina [May cause symptoms to worsen.].
Patients with psoriasis or a history of psoriasis [May trigger or worsen symptoms.].
Elderly patients (refer to Use in Elderly as follows).
Important Precautions: For long-term administration, heart function tests (pulse rate, blood pressure, ECG, X-ray, etc.) should be performed regularly. If symptoms of bradycardia or hypotension occur, administration should be discontinued or the dosage amount decreased. Further, atropine should be used when necessary. Attention should be paid to hepatic and renal function, hemogram, etc.
When abruptly discontinuing administration to patients with angina pectoris who are currently using similar compounds (propranolol hydrochloride), there are cases that have been reported where symptoms worsened or there was onset of myocardial infarction when withdrawal from the drug is necessary, it should be done gradually and with careful monitoring. The patient should be warned not to stop taking the drug without the instruction of a doctor. For applications other than angina pectoris, such as irregular pulse, and especially with elderly patients, an equivalent amount of care should be taken.
When abruptly discontinuing administration to patients with thyrotoxicosis, symptoms may worsen, and as such, when withdrawal from the drug is necessary, it should be done gradually and with careful monitoring.
No administration within 48 hours prior to surgery is advisable.
Dizziness or light-headedness may occur, patients who are administered this drug (especially in early stages) should be aware of the dangers inherent in operating machinery, such as when driving a vehicle.
For chronic heart failure: For administration to patients with chronic heart failure, it is advisable to have the patient hospitalized when starting administration or increasing the dose; For patients with severe chronic heart failure who administrate the drug, careful management is necessary because the patient should be hospitalized when starting administration or increasing dose amount.
Precautions Concerning Usage: Precautions for dispensing: Patients should be instructed to remove the tablets from the blister package prior to use. (It has been reported that, if the blister is swallowed, its sharp corners may puncture the esophageal mucosa, and resulting in serious complications such as mediastinitis.)
Other Precautions: For patients taking β blockers, anaphylactic reactions caused by other drugs may become more severe and treatment with normal amounts of adrenalin may not be effective.
In a placebo-controlled double-blind comparative study on Japanese patients with chronic heart failure using a different dosage adjustment method from the approved method (increasing/decreasing daily doses once daily at levels of 0.625, 1.25, 2.5, or 5mg), for the primary endpoint "death due to cardiovascular trouble or hospitalization due to worsening of heart failure," there were no predominance for bisoprolol fumarate over the placebo [event occurrence rates: bisoprolol fumarate group 13/100 cases, placebo group 14/100 cases, hazard ratio (95% confidence interval) 0.93 (0.44-1.97)]. Among these, there were 12 cases for bisoprolol fumarate and 9 cases for placebo under "hospitalization due to worsening of heart failure," and there was 1 case for bisoprolol fumarate and 5 cases for placebo under "death due to cardiovascular trouble."
Use in Elderly: For elderly patients, attention should be paid to the following, and the drug should be administered carefully while monitoring the patient's condition, e.g., starting from a small dose when beginning administration.
In general, excessive drops in blood pressure are not advisable for elderly patients. [May lead to cerebral infarction, etc.]
Because pulse rate and heart rhythm trouble, such as bradycardia, etc., occur more easily in elderly patients, dosage should be decreased or administration should be discontinued if such symptoms occur.
If withdrawal from the drug is necessary, the dosage should be decreased gradually. (Refer to Important Precautions as previously mentioned.)
Use in Children: The safety of NIKP-Bisoprolol tablet 2.5mg and NIKP-Bisoprolol tablet 5mg in children has not been established (no clinical experience).
Use In Pregnancy & Lactation
The drug should not be administered to pregnant women or women who may be pregnant. [Animal studies (rat) reported fetal toxicity (lethal, growth inhibition) and neonatal toxicity (developmental toxicity, etc.).]
Nursing should be avoided during administration. [Animal studies (rat) reported that bisoprolol fumarate transmitted through.]
Adverse Reactions
Surveys or studies that demonstrate frequency of adverse reaction have not been conducted.
Clinically significant adverse reactions (Frequency unknown): Heart failure, complete atrioventricular block, severe bradycardia, sick sinus syndrome: As heart failure, complete atrioventricular block, severe bradycardia, or sick sinus syndrome may occur, heart function should be examined regularly, and if any of these adverse reactions occur, appropriate measures should be taken, such as decreasing the dose or discontinuing administration.
Other adverse reactions: If an adverse reaction occurs, appropriate measures, such as discontinuing administration, should be taken. (See Table 3.)

Click on icon to see table/diagram/image
Drug Interactions
Precautions for coadministration (NIKP-Bisoprolol tablet 2.5mg and NIKP-Bisoprolol tablet 5mg should be administered with care when coadministered with the following drugs.): See Table 4.

Click on icon to see table/diagram/image
Storage
Store below 30°C.
Shelf-life: 3 years.
MIMS Class
ATC Classification
C07AB07 - bisoprolol ; Belongs to the class of selective beta-blocking agents. Used in the treatment of cardiovascular diseases.
Presentation/Packing
Tab 2.5 mg (white uncoated, unscored, weighing 90 mg, 6.0 mm in diameter, 2.9 mm thick, with identification code
Click on icon to see table/diagram/image
) x 10 x 10's. 5 mg (white uncoated, scored, weighing 100 mg, 6.5 mm in diameter, 3.0 mm thick, with identification code
Click on icon to see table/diagram/image
) x 10 x 10's.
Exclusive offer for doctors
Register for a MIMS account and receive free medical publications worth $768 a year.
Sign up for free
Already a member? Sign in