Bisoprolol Fumarate
Bisoprolol Fumarate Prescribing Information
Bisoprolol fumarate is indicated in the management of hypertension. It may be used alone or in combination with other antihypertensive agents.
The dose of Bisoprolol fumarate must be individualized to the needs of the patient. The usual starting dose is 5 mg once daily. In some patients, 2.5 mg may be an appropriate starting dose (see
In patients with hepatic impairment (hepatitis or cirrhosis) or renal dysfunction (creatinine clearance less than 40 mL/min), the initial daily dose should be 2.5 mg and caution should be used in dose-titration. Since limited data suggest that bisoprolol fumarate is not dialyzable, drug replacement is not necessary in patients undergoing dialysis.
It is not necessary to adjust the dose in the elderly, unless there is also significant renal or hepatic dysfunction (see
There is no pediatric experience with Bisoprolol fumarate.
Bisoprolol fumarate is contraindicated in patients with cardiogenic shock, overt cardiac failure, second or third degree AV block, and marked sinus bradycardia.
Safety data are available in more than 30,000 patients or volunteers. Frequency estimates and rates of withdrawal of therapy for adverse events were derived from two U.S. placebo-controlled studies.
In Study A, doses of 5, 10, and 20 mg bisoprolol fumarate were administered for 4 weeks. In Study B, doses of 2.5, 10, and 40 mg of bisoprolol fumarate were administered for 12 weeks. A total of 273 patients were treated with 5 to 20 mg of bisoprolol fumarate; 132 received placebo.
Withdrawal of therapy for adverse events was 3.3% for patients receiving bisoprolol fumarate and 6.8% for patients on placebo. Withdrawals were less than 1% for either bradycardia or fatigue/lack of energy.
The following table presents adverse experiences, whether or not considered drug related, reported in at least 1% of patients in these studies, for all patients studied in placebo-controlled clinical trials (2.5 to 40 mg), as we l as for a subgroup that was treated with doses within the recommended dosage range (5 to 20 mg). Of the adverse events listed in the table, bradycardia, diarrhea, asthenia, fatigue, and sinusitis appear to be dose related.
B o d y Sys te m / Adv er s e Ex p erience | All Adv e r s e E x p e r i e n c e s ( % a) B i s oprolol Fum a r a te | ||
P l a c ebo ( n = 132 ) % | 5 to 20 mg | 2 . 5 to 40 mg | |
( n = 273 ) % | ( n = 404 ) % | ||
S kin | | | |
| increased sweating | 1.5 | 0.7 | 1.0 |
M u s c u l o s k e l e t a l | | | |
| arthralgia | 2.3 | 2.2 | 2.7 |
Central Nervous System | | | |
| dizziness | 3.8 | 2.9 | 3.5 |
| headache | 11.4 | 8.8 | 10.9 |
| hypoesthesia | 0.8 | 1.1 | 1.5 |
Autonomic N er v ou s System | | | |
| dry mouth | 1.5 | 0.7 | 1.3 |
H e a r t Rate / Rhythm | | | |
| bradycardia | 0 | 0.4 | 0.5 |
Psy c h i at ric | | | |
| vivid dreams | 0 | 0 | 0 |
| insomnia | 2.3 | 1.5 | 2.5 |
| depression | 0.8 | 0 | 0.2 |
Gas trointe s tin a l | | | |
| diarrhea | 1.5 | 2.6 | 3.5 |
| nausea | 1.5 | 1.5 | 2.2 |
| vomiting | 0 | 1.1 | 1.5 |
R e s p i r a t o r y | | | |
| Bronchospasm | 0 | 0 | 0 |
| cough | 4.5 | 2.6 | 2.5 |
| dyspnea | 0.8 | 1.1 | 1.5 |
| pharyngitis | 2.3 | 2.2 | 2.2 |
| rhinitis | 3.0 | 2.9 | 4.0 |
| sinusitis | 1.5 | 2.2 | 2.2 |
| URI | 3.8 | 4.8 | 5.0 |
B o d y as a Whole | | | |
| asthenia | 0 | 0.4 | 1.5 |
| chest pain | 0.8 | 1.1 | 1.5 |
| fatigue | 1.5 | 6.6 | 8.2 |
| edema (peripheral) | 3.8 | 3.7 | 3.0 |
| cough | 4.5 | 2.6 | 2.5 |
| dyspnea | 0.8 | 1.1 | 1.5 |
| pharyngitis | 2.3 | 2.2 | 2.2 |
| rhinitis | 3.0 | 2.9 | 4.0 |
| sinusitis | 1.5 | 2.2 | 2.2 |
| URI | 3.8 | 4.8 | 5.0 |
| a percentage of patients with event | | | |
The following is a comprehensive list of adverse experiences reported with bisoprolol fumarate in worldwide studies, or in postmarketing experience (in italics):
Dizziness,
Dry mouth
Bradycardia, palpitations and other rhythm disturbances, cold extremities, claudication, hypotension, orthostatic hypotension, chest pain, congestive heart failure, dyspnea on exertion
Vivid dreams, insomnia, depression.
Gastric/epigastric/abdominal pain, gastritis, dyspepsia, nausea, vomiting, diarrhea, constipation, peptic ulcer
Muscle/joint pain,
Rash, acne, eczema,
Visual disturbances, ocular pain/pressure, abnormal lacrimation, tinnitus, decreased hearing, earache, taste abnormalities.
Gout
Asthma/bronchospasm, bronchitis, coughing, dyspnea, pharyngitis, rhinitis, sinusitis, URI.
Decreased libido/impotence,
Purpura.
Fatigue, asthenia, chest pain, malaise, edema, weight gain, angioedema.
In addition, a variety of adverse effects have been reported with other beta-adrenergic blocking agents and should be considered potential adverse effects of Bisoprolol fumarate:
Reversible mental depression progressing to catatonia, hallucinations, an acute reversible syndrome characterized by disorientation to time and place, emotional lability, slightly clouded sensorium.
Fever, combined with aching and sore throat, laryngospasm, respiratory distress.
Agranulocytosis, thrombocytopenia, thrombocytopenic purpura.
Mesenteric arterial thrombosis, ischemic colitis.
The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with Bisoprolol fumarate during investigational use or extensive foreign marketing experience.
In clinical trials, the most frequently reported laboratory change was an increase in serum triglycerides, but this was not a consistent finding.
Sporadic liver test abnormalities have been reported. In the U.S. controlled trials experience with bisoprolol fumarate treatment for 4-12 weeks, the incidence of concomitant elevations in SGOT and SGPT from 1 to 2 times normal was 3.9%, compared to 2.5% for placebo. No patient had concomitant elevations greater than twice normal.
In the long-term, uncontrolled experience with bisoprolol fumarate treatment for 6-18 months, the incidence of one or more concomitant elevations in SGOT and SGPT from 1 to 2 times normal was 6.2%. The incidence of multiple occurrences was 1.9%. For concomitant elevations in SGOT and SGPT of greater than twice normal, the incidence was 1.5%. The incidence of multiple occurrences was 0.3%. In many cases these elevations were attributed to underlying disorders, or resolved during continued treatment with bisoprolol fumarate.
Other laboratory changes included small increases in uric acid, creatinine, BUN, serum potassium, glucose, and phosphorus and decreases in WBC and platelets. These were generally not of clinical importance and rarely resulted in discontinuation of bisoprolol fumarate.
As with other beta-blockers, ANA conversions have also been reported on bisoprolol fumarate. About 15% of patients in long-term studies converted to a positive titer, although about one-third of these patients subsequently reconverted to a negative titer while on continued therapy.
Bisoprolol fumarate should not be combined with other beta-blocking agents. Patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, should be closely monitored, because the added beta-adrenergic blocking action of Bisoprolol fumarate may produce excessive reduction of sympathetic activity. In patients receiving concurrent therapy with clonidine, if therapy is to be discontinued, it is suggested that Bisoprolol fumarate be discontinued for several days before the withdrawal of clonidine.
Bisoprolol fumarate should be used with care when myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (particularly of the phenylalkylamine [verapamil] and benzothiazepine [diltiazem] classes), or antiarrhythmic agents, such as disopyramide, are used concurrently.
Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.
Concurrent use of rifampin increases the metabolic clearance of Bisoprolol fumarate, resulting in a shortened elimination half-life of Bisoprolol fumarate. However, initial dose modification is generally not necessary. Pharmacokinetic studies document no clinically relevant interactions with other agents given concomitantly, including thiazide diuretics and cimetidine. There was no effect of Bisoprolol fumarate on prothrombin time in patients on stable doses of warfarin.
Risk of Anaphylactic Reaction: While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.
BISOPROLOL FUMARATE USP is a synthetic, beta1-selective (cardioselective) adrenoceptor blocking agent. The chemical name for bisoprolol fumarate is (±)-1-[4-[[2- (1-Methylethoxy)ethoxy]methyl]phenoxy]-3-[(1-methylethyl)amino]-2-propanol (E)-2- butenedioate (2:1) (salt). It possesses an asymmetric carbon atom in its structure and is provided as a racemic mixture. The S(-) enantiomer is responsible for most of the beta- blocking activity. Its molecular formula is (C18H31NO4)2•C4H4O4 and its structure is:
Bisoprolol fumarate has a molecular weight of 766.97. It is a white crystalline powder which is approximately equally hydrophilic and lipophilic, and is readily soluble in water, methanol, ethanol, and chloroform.
Bisoprolol fumarate tablets USP are available as 5 and 10 mg tablets for oral administration.
Inactive ingredients include Colloidal Silicon Dioxide, Corn Starch (Pregelatinized), Crospovidone, Dibasic Calcium Phosphate, Hypromelloses, Magnesium Stearate, Microcrystalline Cellulose, Polyethylene Glycol, Polysorbate 80 and Titanium Dioxide. The 5 mg tablets also contain Red and Yellow Iron Oxide.