Corbis
Bisoprolol
Oral use
Film-coated tablets
Formulae
Corbis 2.5 Film-coated tablets: Each film-coated tablet contains Bisoprolol
fumarate 2.5 mg. Excipients: Pregelatinized corn starch; Crospovidone; Colloidal
silicon dioxide; Microcr ystalline cellulose; Magnesium stearate; Hydroxypropyl
methylcellulose; Titanium dioxide; Triacetin.
Corbis 5 Film-coated tablets: Each film-coated tablet contains Bisoprolol
fumarate 5 mg. Excipients: Pregelatinized corn starch; Crospovidone; Colloidal
silicon dioxide; Microcr ystalline cellulose; Magnesium stearate; Hydroxypropyl
methylcellulose; Titanium dioxide; Triacetin; Red ferric oxide; Yellow ferric oxide.
Corbis 10 Film-coated tablets: Each film-coated tablet contains Bisoprolol
fumarate 10 mg. Excipients: Pregelatinized corn starch; Crospovidone; Colloidal
silicon dioxide; Microcr ystalline cellulose; Magnesium stearate; Hydroxypropyl
methylcellulose; Titanium dioxide; Triacetin.
Therapeutic Action
ß 1-selective adrenergic blocking agent.
Ing.10410
Indications
Treatment of hypertension. Prevention of angina pectoris. Treatment of moderate
to severe stable congestive heart failure associated to decrease in ventricular
systolic function, in combination with angiotensin-conver ting enzyme (ACE)
inhibitors, diuretics and in some cases cardiac glycosides.
Pharmacological Action
Bisoprolol is a potent and highly ß 1 -selective adrenergic blocking agent. It does
not exhibit intrinsic sympathomimetic nor relevant membrane-stabilizing activity.
Due to its poor affinity for ß 2 -adrenergic receptors of bronchial and vascular
smooth muscle and for those involved in metabolic regulation Bisoprolol should
not affect airways resistance nor metabolic effects mediated by these receptors.
Like for other betablockers, the mechanism of action of Bisoprolol in hypertension
was not completely established, although it is known that it reduces cardiac
output, plasma renin activity and tonic sympathetic outflow from the vasomotor
centers in the brain. In patients suffering from angina pectoris, the ß1-adrenergic
receptor blocking effect leads to a decrease in cardiac demand of oxygen due
to a decrease in cardiac activity. In patients with stable congestive heart failure
under treatment with diuretics and ACE-inhibitors treatment with Bisoprolol
was shown to improve left ventricular function, reducing hospitalizations due
to decompensation, to improve the NYHA functional class and to decrease the
incidence of sudden death increasing sur vival rate.
Pharmacokinetics:
Bisoprolol is absorbed almost completely in the gastrointestinal tract. Its first
pass metabolism is ver y low, thus showing a bioavailability of nearly 90%. Its
protein binding is of about 30%. The plasma elimination half-life ranges from
10 to 12 hours, which accounts for a 24-hours activity with a once daily dosing.
Nearly 95% of the dose administered is eliminated in the urine, with about 50%
of this amount appearing as unchanged Bisoprolol. No pharmacologically active
metabolites were found in humans. Dose adjustment is generally not necessar y
in patients with renal or hepatic failure. In patients suffering from chronic stable
heart failure (NYHA class III) higher plasma levels and an extension in plasma
elimination half-life (17 ± 5 hours) were obser ved.
Dosage and Administration
Adults:
Hypertension and angina pectoris:
Usual dose is 10 mg once daily.
In some patients a 2.5 mg or 5 mg dose once daily may be sufficient.
Maximum recommended daily dosage is 20 mg.
Heart failure:
Its use is recommended for patients suffering from chronic stable heart failure who
did not show acute decompensation in the course of the last six weeks and did not
require changes in their basic treatment during the last two weeks. These patients
should be under treatment with optimal doses of ACE-inhibitors (or other vasodilators
in case of intolerance to ACE-inhibitors), diuretics and eventually cardiac glycosides.
Treatment with Corbis should be initiated at minimum doses, tapering it gradually
according to following scheme:
• 1.25 mg once daily during 1 week; in case of good tolerability increase to
• 2.5 mg once daily during another week; in case of good tolerability increase to
• 3.75 mg once daily during another week; in case of good tolerability increase to
• 5 mg once daily during 4 weeks; in case of good tolerability increase to
• 7.5 mg once daily during 4 weeks; in case of good tolerability increase to
• 10 mg once daily for maintenance treatment.
Maximum recommended dose is of 10 mg once daily and it should be achieved
in not less than 12 weeks.
After administration of the first 1.25 mg dose, the patient should be observed
during about 4 hours, specially monitoring blood pressure, hear t rate and
eventual signs of impairment of congestive heart failure or conduction disorders.
At the first signs of adverse events (symptomatic bradycardia, hypotension,
impairment of congestive hear t failure) the administration of the maximum
recommended dosage may not be achieved. If necessary, the maximum dose achieved
should be reduced gradually.
If necessar y, treatment may be discontinued and reinitiated when considered
appropriate. In case of impairment of congestive heart failure, it is recommended
to adjust the doses of the basic treatment (ACE-inhibitors, diuretics).
It is recommended not to discontinue treatment with Bisoprolol in an abrupt
manner as a transient impairment in congestive heart failure may occur. In case
discontinuation of Bisoprolol treatment turns necessar y, it is recommended to
taper therapy by halves at weekly inter vals.
Treatment of chronic stable heart failure with Bisoprolol usually is of long-term
duration.
Patients with renal or hepatic impairment: In patients with severe renal failure
(creatinine clearance < 20 ml/minute) or severe hepatic failure, maximum daily
dose should not exceed 10 mg. There are no evidences suggesting that dosage
should be altered in patients undergoing hemodialysis. Treatment of congestive heart
failure in patients with renal or hepatic failure, requires a cautious dose-adjustment.
Geriatric patients:
Usually no dose-adjustment is required, but in some patients 5 mg once a day may
be sufficient.
Contraindications
Known hypersensitivity to Bisoprolol or to any components of the product.
A s w i t h o t h e r ß 1- a d r e n e r g i c b l o c k i n g a g e n t s , B i s o p r o l o l s h o u l d n o t b e
administered to patients with untreated congestive hear t failure, cardiogenic
s h o c k , s in u s b lo c k , s in u s n o d e d is e a s e , s e c o n d o r t h ir d d e gr e e AV b lo c k
(without pacemaker), bradycardia with a hear t rate of <60 beats/minute prior
to treatment, hypotension (systolic blood pressure <100 mm/Hg), advanced
peripheral ar terial occlusive disease, Raynaud’s syndrome, severe asthma
or severe obstructive airways disease, untreated pheochromocytoma and
metabolic acidosis.
Warnings
Although Bisoprolol is a highly ß 1-selective adrenergic blocking agent it should
be administered with caution to patients with chronic obstructive air ways
disease or familiar histor y of bronchial asthma. In some patients suffering
f r o m a s t h m a o c c a s i o n a l l y a n i n c r e a s e i n a i r w a y s r e s i s t a n c e m a y o c c u r.
Usually this type of bronchospasm shows a good response to bronchodilators
w i t h ß 2- a d r e n e r g i c r e c e p t o r a g o n i s t e f f e c t l i k e s a l b u t a m o l . L i k e o t h e r
betablocking agents, Bisoprolol may increase allergen sensitivity and severity
of allergic reactions and may modif y results of adrenaline treatment.
Bisoprolol may mask clinical signs of hyperthyroidism (thyrotoxicosis).
There is no clinical experience in the treatment of congestive hear t failure
in patients with diabetes mellitus type I (insulin-dependent patients), renal
failure (serum creatinine ≥ 3.4 mg/dl) or hepatic failure.
Precautions
Use with caution in patients with first degree AV block or extended PR inter val,
Prinzmetal’s angina, bronchospasms (bronchial asthma or obstructive air ways
disease), diabetes mellitus with impor tant fluctuations in glycemia (clinical
signs of hypoglycemia may be masked), metabolic acidosis, prolonged fasting,
ongoing desensitization treatment and peripheral circulator y disorders like
occlusive ar terial disease or Raynaud’s syndrome.
In patients with ischemic hear t disease treatment should not be discontinued
abruptly.
Corbis should be administered with caution in diabetic patients as hypoglycemia
symptoms (specially tachycardia) may be masked.
In patients with histor y of psoriasis, administration of betablocking agents
should be cautiously evaluated based upon risk/benefit ratio.
Based upon individual differences in the response to Bisoprolol, it should be
administered with caution in patients operating automobiles and hazardous
machiner y or engaging in other tasks requiring aler tness, especially when
initiating treatment, when switching to other doses and in patients drinking
alcoholic beverages.
Pregnancy: Betablocking agents may develop certain pharmacological effects
affecting gestation and the fetus. Administration of betablocking agents during
the last stage of pregnancy may produce bradycardia or hypotension in the
fetus or the newborn. As with other betablocking agents, Corbis should only
be administered during pregnancy if strictly necessar y and if the potential
benefit for the mother justifies the potential risk to the mother and the
fetus. In case of administration, fetal growth and uteroplacental blood flow
should be closely monitored. The newborn must also be closely monitored, as
bradycardia or hypoglycemia may appear in the course of the first 3 days of life.
Nursing: There are no adequate and well-controlled studies regarding excretion
of Bisoprolol in human milk. Af ter evaluating the risk/benefit ratio of the
administration of Corbis to nursing mothers and if the potential benefit justifies
its use, discontinuation of nursing should be considered.
Pediatric use: Since safety and effectiveness of Bisoprolol in pediatric patients
have not been established, its administration is not recommended.
Use in the elderly: There are no adequate and well-controlled studies in the
treatment of congestive hear t failure in patients over 80 years.
Overdosage
The most common signs expected with overdosage of a betablocking agent are:
Bradycardia, hypotension, congestive heart failure, bronchospasm and hypoglycemia.
The few cases of overdosage (up to 2000 mg) with Bisoprolol reported were
characterized by bradycardia and hypotension. Limited data suggest that Bisoprolol
is not dialyzable. In case of overdosage cessation of treatment is recommended,
providing symptomatic and supportive treatment.
Bradycardia: Administer intravenous atropine. If the response is inadequate,
isoproterenol or another agent with positive chronotropic properties may be given
cautiously. Under some circumstances, transvenous pacemaker insertion may be
necessary. Hypotension: Intravenous fluids or vasopressors should be administered.
Intravenous glucagon may be useful. Second or third degree atrioventricular block:
Patients should be carefully monitored and treated with isoproterenol infusion or
transvenous cardiac pacemaker insertion, as appropriate. Congestive heart failure:
Initiate conventional therapy (digitalis glycosides, diuretics, inotropic agents,
vasodilators). Bronchospasm: Administer bronchodilator therapy (isoproterenol,
ß 2 -adrenergic agonists and / or aminophylline). Hypoglycemia: Administer
intravenous glucose.
In the event of overdosage attend the nearest hospital or contact the Toxicology
Centers: Children’s Hospital Ricardo Gutiérrez: (011) 4962-6666 / 2247,
Hospital A. Posadas: (011) 4654-6648 / 4658-7777.
Sold under prescription
Made in Argentina
Product authorized by the Ministry of Health
Certificate Nº 48,411
Technical Director: Mirta Beatriz Fariña, Pharmacist
Manufactured at José E. Rodó 6424,
C1440AKJ Autonomous City of Buenos Aires
Last revised: September 2001
Medicinal product
Keep out of the reach of children
Keep in a dry place at temperature below 30°C
Information to Health Care Professionals and Patients:
Roemmers S.A.I.C.F.
Fray Justo Sarmiento 2350,
B1636AKJ Olivos,
Pcia. de Buenos Aires
www.roemmers.com.ar
How Supplied
Corbis 2,5 Film-coated tablets:
Packages containing 30 film-coated tablets.
White, round film-coated tablets, scored and coded BP 2.5 on one
side of the tablet, and marked with Roemmers’ identification isologue
on the other side.
Corbis 5 Film-coated tablets:
Packages containing 30 film-coated tablets.
Salmon colored, round film-coated tablets, scored and coded BP 5
on one side of the tablet, and marked with Roemmers’ identification
isologue on the other side.
Corbis 10 Film-coated tablets:
Packages containing 30 film-coated tablets.
White, round film-coated tablets, scored and coded BP 10 on one
side of the tablet, and marked with Roemmers’ identification isologue
on the other side.
Instructions for breaking scored tablets:
I f du e t o m e dic al r e c o mm e n datio n, t able t br e ak ing is n e c e s s ar y, p r o c e e d
a s f o llow s:
Place the tablet on an even and rigid sur face.
Press with the tip of the fingers of both hands, simultaneously, on both sides of
the score until breaking the film- coated tablet.
49
Adverse Reactions
Corbis is usually well tolerated. Adverse events reported are normally attributed
to its pharmacological action. They generally appear when starting treatment,
are mild and resume within 1-2 weeks of treatment.
C e n t r a l n e r v o u s s y s t e m : O c c a s io n a l l y, w h e n s t a r t i n g t r e a t m e n t, as t he n i a ,
fatigue, vertigo and mild headache. Ver y rarely: Sleep disturbances, depression.
S p e c i a l s e n s e s : Ve r y r a r e l y: Re d u c e d l a c r i m a t i o n, h e a r i n g d i s t u r b a n c e s .
C a r d i o v a s c u l a r : O c c a s i o n a l l y: Pa r e s t h e s i a a n d c o l d e x t r e m i t i e s . R a r e l y:
Bradycardia, atrioventricular conduction disturbances, congestive heart failure
impairment, abrupt fall in blood pressure, orthostatic hypotension.
Respirator y: Rarely: Bronchospasm in patients with histor y of bronchial asthma
or obstructive airways disease.
Digestive: Occasionally: Nausea, vomiting, diarrhea and constipation.
Musculoskeletal: Rarely: Muscle weakness, myalgia, muscle twitching.
B 1109303872
Ing.10410 0411
Drug Interactions
Bisoprolol may potentiate the effects of concomitantly administered
antihypertensive agents. Concomitant administration of reserpine,
guanethidine, alfa methyldopa and clonidine may produce excessive reduction
of sympathetic activity and hear t rate. In patients receiving concurrent therapy
with clonidine (not recommended combination) there is an increased risk of
rebound hyper tension. If therapy with clonidine is to be discontinued, it is
suggested that Corbis be discontinued for several days before the withdrawal
of clonidine.
Bisoprolol should be used with care when myocardial depressants or inhibitors
of AV conduction, such as cer tain calcium antagonists (par ticularly of the
phenylalkylamine [verapamil] and benzothiazepine [diltiazem] classes)
(not recommended combination) or class I antiarrhythmic agents, such as
disopyramide, or class III antiarrhythmic agents, such as amiodarone, are
used concurrently.
Concurrent administration with digitalis glycosides may decrease hear t rate
and slow atrioventricular conduction.
It is recommended not to administer intravenous calcium antagonists or
antiarrhythmics during treatment with Bisoprolol.
Concomitant administration of parasympathomimetics, even tacrine, may slow
atrioventricular conduction.
Ergotamine derivatives may exacerbate peripheral circulator y disorders.
Prostaglandin synthesis inhibitors may decrease the hypotensive effect of
Bisoprolol.
Concurrent use of rifampicin may shor ten the plasma elimination half-life of
Bisoprolol, however usually no dose adjustment is required.
Phamacokinetic studies document no clinically relevant interactions with
other agents given concomitantly, including thiazide diuretics, and cimetidine.
There was no effect of Bisoprolol on prothrombin in patients on stable doses
of war farin.
Bisoprolol may potentiate the effects of insulin and oral hypoglycemic agents.
In case anesthesia is needed, the anesthesiologist must be informed beforehand
that the patient is treated with Bisoprolol. In patients with severe ischemic
cardiopathy the convenience of continuing treatment with Bisoprolol should
be evaluated. Caution should be exer ted when administering cyclopropane or
trichloroethylene.
Tr i c y c l i c a n t i d e p r e s s a n t s , b a r b i t u r a t e s , p h e n o t h i a z i n e s a n d o t h e r
antihyper tensive agents may increase the hypotensive effect of Bisoprolol.
Since monoamine A oxidase inhibitors may increase the hypotensive effect of
betablocking agents as well as generate the risk of a hyper tensive crisis, their
association with Bisoprolol is not recommended.
Mefloquine may enhance the risk of bradycardia in patients under treatment
with Bisoprolol.
Concomitant use of Bisoprolol and sympathomimetic agents may reduce the
effect of both medications. Higher doses of epinephrine might be required
when treating allergic reactions.
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