Approval Date: 12/02/2007
Revision Date: 05/09/2007
December 07, 2007
July 01, 2009
October 01, 2010
March 29, 2011
January 15, 2014
August 21, 2014
December 01, 2015
XX/XX/2019
Bisoprolol Fumarate Tablets Instructions
Please read the instructions carefully and use under the guidance of your physician
[Drug Name].
Generic Name: Bisoprolol Fumarate Tablets
English Name: Bisoprolol Fumarate Tablets
Hanyu Pinyin: Fumasuan Bisuoluo’er Pian
[Ingredients
The main ingredient of this product is Bisoprolol Fumarate.
Chemical name: (±)1-[4-[[2-(1-methylethoxy)ethoxy]methyl]-phenoxy]-3-[(1-methylethyl)amino]-2-propanol fumarate
Chemical structure formula:
Molecular formula: (C18H31NO4)2-C4H4O sub>4
Molecular weight: 766.96
[Properties].
This product is a white single-sided scored tablet.
[Indications
High blood pressure, coronary artery disease (angina pectoris).
Chronic stable heart failure with hyposystolic left ventricular function (ejection fraction ≤ 35%). Use of this product requires adherence to medical advice for ACEinhibitors, diuretics and selective use of cardiac glycoside therapy.
[Specifications
2.5 mg; 5 mg
[Dosage].
For all indications:
This product should be taken in the morning and may be taken with a meal. It should be taken whole with water and should not be chewed.
This product should be used as prescribed by your doctor.
For the treatment of hypertension or angina pectoris.
Usually 5 mg of bisoprolol fumarate once daily. Patients with mild hypertension may start treatment with 2.5 mg of bisoprolol fumarate. If none of the effects are significant, the dose may be increased to 10 mg of bisoprolol fumarate once daily.
The dose of this product should be adjusted on an individual basis, and special attention should be paid to pulse rate and treatment effect.
This product should be used for a long time. The dose of this drug should not be changed without medical advice, and it should not be discontinued. If you need to discontinue the drug, you should do so gradually and not abruptly. This is especially important for patients with coronary artery disease.
Treatment of Chronic Stable Heart Failure (CHF).
Patients must be stable (free of acute failure) at the time of initiation of bisoprolol therapy.
Standard therapy for chronic heart failure includes an ACE inhibitor (or an angiotensin receptor blocker when an ACE inhibitor is not tolerated), a beta-blocker, a diuretic, and, when appropriate, a cardiac glycoside. This product requires specific dose titration for the treatment of chronic stable heart failure.
It is recommended that this product be used under the supervision of a physician experienced in the treatment of chronic heart failure.
Note: A dose titration phase is necessary for the treatment of chronic stable heart failure with this product, which should be started at a low dose and gradually increased according to the following regimen.
1.25 mg once daily for 1 week and, if well tolerated, increase to
2.5mg once daily for 1 week, increasing if well tolerated to
3.75mg once daily, continue for 1 week and if well tolerated, increase to
5mg once daily, continue for 4 weeks and if well tolerated, increase to
7.5mg once daily for 4 weeks, increasing if well tolerated to
10 mg once daily as maintenance therapy
The maximum recommended dose is 10 mg once daily.
Close monitoring of vital signs (blood pressure, heart rate), conduction block, and signs of worsening heart failure after the first dose and during dose escalation is recommended.
Dose adjustment
If temporary worsening of heart failure, hypotension, or bradycardia occurs, it is recommended that the dose of the combined medication be reconsidered. The dose of bisoprolol may be temporarily reduced if necessary, or discontinuation may be considered.
Consider restarting bisoprolol therapy and/or increasing the bisoprolol dose when the condition stabilizes.
The use of this product for the treatment of chronic stable heart failure should be long-term.
No abrupt discontinuation or dose changes should be made without physician guidance, as this may result in temporary worsening of the condition. In particular, patients with ischemic heart disease should not be abruptly discontinued. If discontinuation is necessary, a gradual reduction in dose is recommended.
Special Populations
Hepatic and renal insufficiency
Treatment of hypertension or angina pectoris: Patients with mild to moderate hepatic or renal insufficiency usually do not require dose adjustment. Patients with severe renal failure (creatinine clearance <20 ml/min) and severe hepatic abnormalities should not receive more than 10 mg daily.
There is less experience with bisoprolol in patients on renal dialysis; however, there is also no evidence that dose adjustment is required in this group of patients.
Treatment of chronic stable heart failure: There are no pharmacokinetic data for bisoprolol in patients with chronic heart failure with hepatic and renal insufficiency. Dose escalation in such patients should be done with particular caution.
Elderly patients.
No dose adjustment is required.
[Adverse Reactions].
The incidence of the following adverse reactions, classified by systemic organ, is defined as follows.
very common (≥10%)
Common (≥1%, <10%)
occasional (≥0.1%, <1%)
Rare (≥0.01%, <0.1%)
Very rare (<0.01%)
Nervous system abnormalities
Common: dizziness*, headache*
Laboratory tests
Rare: elevated triglycerides, elevated liver enzymes (ALAT, ASAT)
Eye abnormalities
Rare: decreased tear production (already considering whether the patient uses contact lenses)
Very rare: conjunctivitis
ear and vagal abnormalities
Rare: hearing impairment
Cardiac abnormalities
Very common: bradycardia (in patients with chronic heart failure)
Common: worsening of existing heart failure (in patients with chronic heart failure)
Rare: AV conduction disturbances; bradycardia (in patients with hypertension or angina); worsening of existing heart failure (in patients with hypertension or angina)
Vascular abnormalities
Common: coldness or numbness in extremities; hypotension, especially in patients with heart failure
Sometimes: postural hypotension
Rarely: syncope
Abnormalities of the airway
Rare: bronchospasm in patients with bronchial asthma or a history of airway obstructive disease
Rare: allergic rhinitis
Gastrointestinal abnormalities
Common: complaints of gastrointestinal disorders such as nausea, vomiting, diarrhea, constipation
Musculoskeletal and connective tissue abnormalities
Sometimes: muscle weakness and spasticity
skin abnormalities
Rare: allergic reactions such as itching, flushing, rash.
Very rare: hair loss. beta-blockers may cause or worsen psoriasis, or cause a psoriasis-like rash.
General discomfort
Common: debilitation (in patients with chronic heart failure), fatigue*
Sometimes: debilitation (in patients with hypertension or angina pectoris)
Reproductive system and breast abnormalities
Rare: erectile dysfunction
hepatobiliary abnormalities
Rare: hepatitis
Psychiatric abnormalities
Rarely: depression, sleep disorders
Rarely: nightmares, hallucinations
Only in patients with hypertension or angina pectoris.
* These symptoms occur especially at the start of treatment. They are generally mild in degree and usually disappear after 1-2 weeks.
Tell your physician when any of these adverse reactions or any unintended reactions occur. To avoid serious reactions, inform your physician immediately when an adverse reaction is severe, occurs suddenly, or worsens rapidly.
[Contraindicated].
Bisoprolol is contraindicated in patients who.
Patients with acute heart failure or in the decompensated phase of heart failure requiring treatment with sedative positive inotropic drugs
Patients in cardiogenic shock
Patients with second- or third-degree AV block (without a pacemaker)
Patients with sick sinus syndrome
Patients with sinus block
Patients with symptomatic bradycardia (symptomatic bradycardia)
Symptomatic hypotension
Severe bronchial asthma
Patients with severe peripheral arterial occlusive disease and Raynaud’s syndrome
Patients with untreated pheochromocytoma
Patients with metabolic acidosis
Patients with known hypersensitivity to bisoprolol, its derivatives, or any component of this product
[Precautions
Treatment of chronic stable heart failure with bisoprolol must be started with specific dose titration at regular intervals and should be accompanied by regular monitoring.
Because of the potential for transient worsening of heart disease, the drug should not be stopped abruptly unless clearly indicated, especially in patients with ischemic heart disease.
Bisoprolol should be used with caution in patients with hypertension or angina pectoris with heart failure.
Special care should be taken when using this product in the following situations.
When blood glucose levels fluctuate widely in patients with diabetes; it may mask symptoms of hypoglycemia
Strict fasting
undergoing desensitization therapy
One degree atrioventricular block
Variant angina pectoris
peripheral arterial occlusive disease (symptoms may worsen, especially at the start of treatment)
Although cardioselective (b1)b-blockers may have less effect on lung function than nonselective b-blockers, but as with all b- receptor blockers, use in patients with airway obstructive disease should be avoided unless necessary and, if used in such patients, special caution should be exercised when using this product. In patients with airway obstructive disease, treatment with bisoprolol should be administered starting at the lowest possible dose and closely monitored for symptoms (e.g., dyspnea, decreased activity tolerance, cough).
Patients with bronchial asthma and other chronic obstructive pulmonary disease may have symptoms associated with the use of this product, so bronchodilator therapy should be given concomitantly. Increased airway resistance has occasionally been seen with this product in patients with asthma, so the dose of b2-agonist should be increased.
As with other b-blockers, bisoprolol may increase the body’s sensitivity to allergens and exacerbate allergic reactions, when epinephrine treatment may not produce the desired therapeutic effect.
General anesthesia: When a patient receives general anesthesia, the anesthesiologist must be informed that the patient is on a beta-blocker. If it is deemed necessary to discontinue the drug prior to surgery, the drug must be gradually discontinued and the anesthesia administered 48 hours after complete discontinuation.
Patients with psoriasis or a family history of psoriasis should only be administered b-blockers (e.g., Bisoprolol Fumarate Lolor tablets).
Patients with pheochromocytoma should be treated with bisoprolol only after a-blockers.
Treatment with bisoprolol may mask the symptoms of thyrotoxicosis.
In a study of patients with coronary artery disease, bisoprolol did not affect patients’ ability to drive. However, due to individual differences in response to efficacy, use of this product may affect the ability to drive or maneuver machinery. This is especially important when starting the drug, when increasing the dose, and when taking it with alcohol.
There is no experience with bisoprolol in the treatment of heart failure with the following diseases or conditions.
Insulin-dependent diabetes mellitus (type I)
Severe renal impairment
Severe hepatic impairment
Limited cardiomyopathy
Congenital heart disease
Organic valvular disease with significant hemodynamic changes
myocardial infarction within 3 months
Use with caution in athletes.
[For pregnant and lactating women
Pregnant women.
Bisoprolol may harm pregnant women and/or fetuses/newborns. In general, b-adrenergic receptor antagonists can decrease placental perfusion, which is associated with developmental delay, in utero death, miscarriage, and preterm delivery; in fetuses and neonates, adverse effects such as hypoglycemia and bradycardia may occur. If b-adrenergic receptor blockers must be used, selective b1-adrenergic receptor blockers are preferable.
Bisoprolol should not be used in pregnant women unless it is clear that it is necessary. If bisoprolol must be applied for treatment, the uteroplacental blood flow and fetal growth should be monitored. Once harmful effects on the pregnant woman and fetus are detected, alternative treatment should be chosen. The newborn must be monitored closely and is most susceptible to hypoglycemia and bradycardia in the first 3 days of life.
Lactating women.
It is not known whether this product is excreted through human milk; therefore, bisoprolol is not recommended for treatment in nursing women.
[Pediatric use
There is no experience with bisoprolol in pediatric patients, therefore it is not recommended for use in children.
[Geriatric use
No dose adjustment is required.
[Drug Interactions].
1. Combination of drugs not recommended.
For the treatment of chronic stable heart failure
Class I antiarrhythmic drugs (eg, propyzamide, quinidine): may increase the inhibitory effect of this product on atrioventricular conduction and cardiac contractility.
All indications
Calcium antagonists such as verapamil and diltiazem: Negative effects on contractility, atrioventricular conduction, and blood pressure. Intravenous administration of verapamil in patients treated with b-blockers resulted in significant hypotension and atrioventricular block.
Central antihypertensive drugs (eg, colistin, methyldopa, moxonidine, rimantadine) may result in decreased heart rate and cardiac output as well as vasodilation due to decreased central sympathetic tone. Abrupt discontinuation, especially before discontinuation of b-blockers, may increase the risk of “rebound hypertension.
2. Combination medications to be used with caution
For the treatment of hypertension or angina pectoris.
Class I antiarrhythmic drugs (eg, propyzamide, quinidine): may increase the inhibitory effect of this product on atrioventricular conduction and cardiac contractility.
All indications
Calcium antagonists such as dihydropyridine derivatives (e.g., nifedipine): combination use increases the risk of hypotension and the risk of further deterioration of ventricular pump function in patients in whom heart failure cannot be excluded.
Class III antiarrhythmic drugs (eg, amiodarone): may prolong atrioventricular conduction time.
Parasympathomimetic drugs (including tetrahydroaminoacridine): may prolong atrioventricular conduction time and increase the risk of bradycardia.
Other b-receptor blockers, including eye drops, may potentiate their effects.
Insulin and oral antidiabetic drugs: increase the hypoglycemic effect. Blocking b-adrenergic receptors may mask symptoms of hypoglycemia.
Anesthetics: may cause attenuation of reflex tachycardia and increase the risk of hypotension.
Digitalis toxins: Slows heart rate and prolongs atrioventricular conduction time.
Non-steroidal anti-inflammatory drugs (NSAIDs) may attenuate the hypotensive effects of this product.
β-sympathomimetic drugs (eg, isoproterenol, dobutamine): the effects of these two drugs may be reduced when combined with bisoprolol.
Sympathomimetic application drugs that activate both β- and α-adrenoceptors (e.g., norepinephrine, epinephrine) may exacerbate the α-adrenoceptor-mediated vasoconstriction of these drugs in combination with this product, resulting in increased blood pressure, as well as increased intermittent claudication. The potential for such interactions is generally considered to be greater with the use of nonselective β-blockers.
There is a potential for increased risk of hypotension when combined with antihypertensives and other drugs that have the potential to lower blood pressure (eg, tricyclic antidepressants, barbiturates, phenothiazines).
3. Combination medications to consider
Mefloquine: may increase the risk of bradycardia.
Monoamine oxidase inhibitors (except MAO-B inhibitors): may increase the hypotensive effect of b-blockers and may also increase the risk of hypertensive crisis The risk of hypertension.
[Drug overdose
b- The most common drug overdose reactions to epinephrine receptor blockers are bradycardia, hypotension, bronchial asthma, acute cardiac insufficiency, and hypoglycemia. Individual variability in sensitivity to a single high dose of bisoprolol is substantial, and patients with heart failure may be very sensitive.
Overdose usually occurs and should be discontinued promptly and treated with supportive symptomatic therapy. Limited data suggest that bisoprolol is difficult to remove by dialysis. Based on the expected pharmacologic effects and experience with other b-blockers, the following treatments may be considered when clinically indicated.
Bradycardia: sedation of atropine. If this is not effective, isoproterenol or other positive chronotropic drugs can be given with caution. In some cases, a pacemaker should be implanted through the vein.
Low blood pressure: Supplemental fluids and vasopressor medications should be administered sedately, and sedation of hyperglycemia is beneficial.
Atrioventricular block (second or third degree): The patient should be monitored carefully with appropriate intravenous isoprenaline or intravenous pacemaker implantation.
Exacerbation of acute heart failure: sedation with diuretics, positive inotropic drugs, and vasodilators.
Bronchospasm: treatment with bronchodilators such as isoprenaline, b2-sympathomimetics, and/or aminophylline.
Low blood sugar: sedative glucose.
[Pharmacology and Toxicology
Pharmacological effects
Bisoprolol is a highly selective b1-adrenoceptor blocker (cardioselective) in the No intrinsic sympathomimetic or membrane stabilizing activity was seen in the therapeutic dose range. Bisoprolol fumarate also inhibits b2-adrenoceptors on bronchial and vascular smooth muscle at doses beyond therapeutic doses (≥20 mg). Therefore, it is important to use the lowest effective dose in order to maintain a high selectivity for the heart.
Toxicological studies
Genotoxicity.
The results of the bisoprolol Ames test, the Chinese hamster V79 cell locus mutation test and chromosome aberration test, the DNA damage test, the rat cytogenetic test and the mouse micronucleus test were all negative.
Reproductive toxicity.
No significant effects on fertility and early embryonic development were seen in rats given bisoprolol fumarate orally at doses up to 150 mg/kg/d, which is 77 times the recommended maximum human dose (MRHD) (extrapolated from body surface area).
In the embryo-fetal development toxicity assay, an increased incidence of embryonic resorption was seen in pregnant rats given bisoprolol fumarate 50 mg/kg/d orally, a dose 26 times the MRHD; maternal toxicity (decreased feeding and inhibition of weight gain) was 150 mg/ kg/d, which is 77 times higher than MRHD. Increased early embryonic absorption was seen in pregnant rabbits given bisoprolol fumarate orally at a dose of 12.5 mg/kg/d, and no developmental toxicity was seen in fetuses at a dose 12 times the MRHD.
Carcinogenicity.
No drug-related carcinogenicity was observed in mice given bisoprolol fumarate at doses up to 250 mg/kg/d orally for 20 and 24 months, and in rats given bisoprolol fumarate at doses up to 125 mg/kg/d orally for 26 months. The above doses were 59 and 64 times higher than MRHD, respectively, extrapolated from body surface area.
[Pharmacokinetics
Bisoprolol is almost completely absorbed in the gastrointestinal tract (>90%). Because the first-pass effect is small (<10%), it exhibits a high bioavailability of approximately 90%. Bisoprolol has a plasma protein binding rate of approximately 30%, a volume of distribution of 3.5 L/kg, and a total clearance of approximately 15 L/hour. The plasma half-life after once-daily dosing is 10-12 hours and is maintained in plasma for 24 hours.
Bisoprolol is excreted from the body by two routes. 50% is metabolized by the liver to inactive metabolites and then excreted from the kidneys, and the remaining 50% is excreted from the kidneys as a prodrug. Since the drug is cleared from the kidneys and liver in equal proportions, no dose adjustment is required in patients with mild to moderate hepatic and renal abnormalities. The pharmacokinetics in patients with chronic stable heart failure with impaired hepatic function or renal insufficiency have not been studied.
The kinetics of bisoprolol are linear and independent of age.
Patients with chronic heart failure (NYHA class III) had higher plasma bisoprolol levels and a prolonged half-life compared with healthy volunteers. The maximum plasma concentration at steady state after daily oral dosing of 10 mg was 64± 21 ng/ml with a half-life of 17± 5 hours.
[Storage].
Store below 25C. .
[Packaging
2.5mg
Aluminium-plastic packaging, plus paper/aluminium/polyethylene pharmaceutical laminate film and bag.
10 tablets/plate, 1 plate/bag; 10 tablets/plate, 2 plates/bag.
5mg
Aluminum-plastic packaging, plus paper/aluminum/polyethylene pharmaceutical laminate film and bag.
9 tablets/plate, 2 plates/bag; 10 tablets/plate, 1 plate/bag; 12 tablets/plate, 2 plates/bag.
[Expiration Date].
12 months
[Executive Standard]
[Approval Number].
2.5 mg: State Drug Certificate H20023132
5 mg: GMP H10970082
[Manufacturer].
Company Name: Beijing Huasu Pharmaceutical Co.
Production Address: No.1 Jinguang North Street, Industrial Development Zone, Liangxiang Town, Fangshan District, Beijing
Postal Code: 102488
Tel: 400-650-7799
Fax number: 010-60330583
Website:www. hwellso.com
For questions, please contact the manufacturer directly.