Overdose
No specific information on emergency treatment of overdosage with Kerlone (betaxolol hydrochloride) is available. The most common effects expected are bradycardia, congestive heart failure, hypotension, bronchospasm, and hypoglycemia. In one acute overdosage of betaxolol, a 16-year-old female recovered fully after ingesting 460 mg.
Oral LD50s are 350 to 400 mg betaxolol/kg in mice and 860 to 980
mg/kg in rats.
In the case of overdosage, treatment with Kerlone (betaxolol hydrochloride) should be stopped and the patient carefully observed. Hemodialysis or peritoneal dialysis does not remove substantial amounts of the drug. In addition to gastric lavage, the following therapeutic measures are suggested if warranted:
Hypotension: Use sympathomimetic pressor drug therapy, such as
dopamine, dobutamine, or norepinephrine. In refractory cases of overdosage of
other beta-blockers, the use of glucagon hydrochloride has been reported to
be useful.
Bradycardia:Atropine should be administered. If there is no
response to vagal blockade, isoproterenol should be administered cautiously.
(see WARNINGS: Anesthesia and major surgery).
In refractory cases the use of a transvenous cardiac pacemaker may be considered.
Acute cardiac failure: Conventional therapy including digitalis,
diuretics, and oxygen should be instituted immediately.
Bronchospasm: Use a β2- agonist. Additional therapy
with aminophylline may be considered.
Heart block (2nd- or 3rd-degree): Use isoproterenol or a transvenous
cardiac pacemaker.
Contraindications
Kerlone (betaxolol hydrochloride) is contraindicated in patients with known hypersensitivity to the drug.
Kerlone (betaxolol hydrochloride) is contraindicated in patients with sinus bradycardia, heart block greater
than first degree, cardiogenic shock, and overt cardiac failure. (see WARNINGS).
Undesirable effects
Most adverse reactions have been mild and transient and are typical of beta-adrenergic blocking agents, eg, bradycardia, fatigue, dyspnea, and lethargy. Withdrawal of therapy in U.S. and European controlled clinical trials has been necessary in about 3.5% of patients, principally because of bradycardia, fatigue, dizziness, headache, and impotence.
Frequency estimates of adverse events were derived from controlled studies in which adverse reactions were volunteered and elicited in U.S studies and volunteered and/or elicited in European studies.
In the U.S., the placebo-controlled hypertension studies lasted for 4 weeks, while the active-controlled hypertension studies had a 22- to 24- week double-blind phase. The following doses were studied: betaxolol-5, 10, 20, and 40 mg once daily; atenolol-25, 50, and 100 mg once daily; and propranolol-40, 80, and 160 mg b.i.d.
Kerlone (betaxolol hydrochloride) , like other beta-blockers, has been associated with the development of antinuclear antibodies (ANA) (e.g., lupus erythematosus). In controlled clinical studies, conversion of ANA from negative to positive occurred in 5.3% of the patients treated with betaxolol, 6.3% of the patients treated with atenolol, 4.9% of the patients treated with propranolol, and 3.2% of the patients treated with placebo.
Betaxolol adverse events reported with a 2% or greater frequency, and selected events with lower frequency, in U.S. controlled studies are:
| Dose Range |
Betaxolol
(N=509)
5-40 mg q.d.* |
Propranolol
(N=73)
40-160 mg b.i.d. |
Atenolol
(N=75)
25-100 mg q.d. |
Placebo
(N=109) |
| Body System/Adverse Reaction |
(%) |
(%) |
(%) |
(%) |
| Cardiovascular |
| Bradycardia (heart rate < 50 BPM) |
8.1 |
4.1 |
12.0 |
0 |
| Symptomatic bradycardia |
0.8 |
1.4 |
0 |
0 |
| Edema |
1.8 |
0 |
0 |
1.8 |
| Central Nervous System |
| Headache |
6.5 |
4.1 |
5.3 |
15.6 |
| Dizziness |
4.5 |
11.0 |
2.7 |
5.5 |
| Fatigue |
2.9 |
9.6 |
4.0 |
0 |
| Lethargy |
2.8 |
4.1 |
2.7 |
0.9 |
| Psychiatric |
| Insomnia |
1.2 |
8.2 |
2.7 |
0 |
| Nervousness |
0.8 |
1.4 |
2.7 |
0 |
| Bizarre dreams |
1.0 |
2.7 |
1.3 |
0 |
| Depression |
0.8 |
2.7 |
4.0 |
0 |
| Autonomic |
| Impotence |
1.2† |
0 |
0 |
0 |
| Respiratory |
| Dyspnea |
2.4 |
2.7 |
1.3 |
0.9 |
| Pharyngitis |
2.0 |
0 |
4.0 |
0.9 |
| Rhinitis |
1.4 |
0 |
4.0 |
0.9 |
| Upper respiratory infection |
2.6 |
0 |
0 |
5.5 |
| Gastrointestinal |
| Dyspepsia |
4.7 |
6.8 |
2.7 |
0.9 |
| Nausea |
1.6 |
1.4 |
4.0 |
0 |
| Diarrhea |
2.0 |
6.8 |
8.0 |
0.9 |
| Musculoskeletal |
| Chest pain |
2.4 |
1.4 |
2.7 |
0.9 |
| Arthralgia |
3.1 |
0 |
4.0 |
1.8 |
| Skin |
| Rash |
1.2 |
0 |
0 |
0 |
*Five patients received 80 mg q.d.
†N=336 males; impotence is a known possible adverse effect of this pharmacological
class.
|
Of the above adverse reactions associated with the use of betaxolol, only bradycardia was clearly dose related, but there was a suggestion of dose relatedness for fatigue, lethargy, and dyspepsia.
In Europe, the placebo-controlled study lasted for 4 weeks, while the comparative studies had a 4- to 52-week double-blind phase. The following doses were studied: betaxolol 20 and 40 mg once daily and atenolol 100 mg once daily.
From European controlled hypertension clinical trials, the following adverse events reported by 2% or more patients and selected events with lower frequency are presented:
| Dose range |
Betaxolol
(N=155)
20-40 mg q.d. |
Atenolol
(N=81)
100 mg q.d. |
Placebo
(N=60) |
| Body System/Adverse Reaction |
(%) |
(%) |
(%) |
| Cardiovascular |
| Bradycardia (heartrate < 50 BPM) |
5.8 |
5.0 |
0 |
| Symptomatic bradycardia |
1.9 |
2.5 |
0 |
| Palpitation |
1.9 |
3.7 |
1.7 |
| Edema |
1.3 |
1.2 |
0 |
| Cold extremities |
1.9 |
0 |
0 |
| Central Nervous System |
| Headache |
14.8 |
9.9 |
23.3 |
| Dizziness |
14.8 |
17.3 |
15.0 |
| Fatigue |
9.7 |
18.5 |
0 |
| Asthenia |
7.1 |
0 |
16.7 |
| Insomnia |
5.0 |
3.7 |
3.3 |
| Paresthesia |
1.9 |
2.5 |
0 |
| Gastrointestinal |
| Nausea |
5.8 |
1.2 |
0 |
| Dyspepsia |
3.9 |
7.4 |
3.3 |
| Diarrhea |
1.9 |
3.7 |
0 |
| Musculoskeletal |
| Chest pain |
7.1 |
6.2 |
5.0 |
| Joint pain |
5.2 |
4.9 |
1.7 |
| Myalgia |
3.2 |
3.7 |
3.3 |
The only adverse event whose frequency clearly rose with increasing dose was
bradycardia. Elderly patients were especially susceptible to bradycardia, which
in some cases responded to dose-reduction (see PRECAUTIONS).
The following selected (potentially important) adverse events have been reported at an incidence of less than 2% in U.S. controlled and open, long-term clinical studies, European controlled clinical trials, or in marketing experience. It is not known whether a causal relationship exists between betaxolol and these events; they are listed to alert the physician to a possible relationship:
Autonomic: flushing, salivation, sweating.
Body as a whole: allergy, fever, malaise, pain, rigors.
Cardiovascular: angina pectoris, arrhythmia, atrioventricular
block, heart failure, hypertension, hypotension, myocardial infarction, thrombosis,
syncope.
Central and peripheral nervous system: ataxia, neuralgia, neuropathy,
numbness, speech disorder, stupor, tremor, twitching.
Gastrointestinal: anorexia, constipation, dry mouth, increased
appetite, mouth ulceration, rectal disorders, vomiting, dysphagia.
Hearing and Vestibular: earache, labyrinth disorders, tinnitus,
deafness.
Hematologic: anemia, leucocytosis, lymphadenopathy, purpura,
thrombocytopenia.
Liver and biliary: increased AST, increased ALT.
Metabolic and nutritional: acidosis, diabetes, hypercholesterolemia,
hyperglycemia, hyperkalemia, hyperlipemia, hyperuricemia, hypokalemia, weight
gain, weight loss, thirst, increased LDH.
Musculoskeletal: arthropathy, neck pain, muscle cramps, tendonitis.
Psychiatric:abnormal thinking, amnesia, impaired concentration,
confusion, emotional lability, hallucinations, decreased libido.
Reproductive disorders: Female: breast pain, breast fibroadenosis,
menstrual disorder; Male: Peyronie's disease, prostatitis.
Respiratory: bronchitis, bronchospasm, cough, epistaxis, flu,
pneumonia, sinusitis.
Skin: alopecia, eczema, erythematous rash, hypertrichosis, pruritus,
skin disorders.
Special senses: abnormal taste, taste loss.
Urinary system: cystitis, dysuria, micturition disorder, oliguria,
proteinuria, abnormal renal function, renal pain.
Vascular:cerebrovascular disorder, intermittent claudication,
leg cramps, peripheral ischemia, thrombophlebitis.
Vision: abnormal lacrimation, abnormal vision, blepharitis, ocular
hemorrhage, conjunctivitis, dry eyes, iritis, cataract, scotoma.
Potential adverse effects: Although not reported in clinical studies
with betaxolol, a variety of adverse effects have been reported with other beta-adrenergic
blocking agents and may be considered potential adverse effects of betaxolol:
Central nervous system: Reversible mental depression progressing
to catatonia, an acute reversible syndrome characterized by disorientation for
time and place, short-term memory loss, emotional lability with slightly clouded
sensorium, and decreased performance on neuropsychometric tests.
Allergic: Fever combined with aching and sore throat, laryngospasm,
respiratory distress.
Hematologic: Agranulocytosis, thrombocytopenic purpura, and nonthrombocytopenic
purpura.
Gastrointestinal: Mesenteric arterial thrombosis, ischemic colitis.
Metabolic: Hypoglycemia.
Miscellaneous: Raynaud's phenomena. There have been reports of
skin rashes and/or dry eyes associated with the use of beta-adrenergic blocking
drugs. The reported incidence is small, and in most cases, the symptoms have
cleared when treatment was withdrawn. Discontinuation of the drug should be
considered if any such reaction is not otherwise explicable. Patients should
be closely monitored following cessation of therapy.
The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with Kerlone (betaxolol hydrochloride) during investigational use and extensive foreign experience. However, dry eyes have been reported.
Therapeutic indications
Kerlone (betaxolol hydrochloride) is indicated in the management of hypertension. It may be used alone or concomitantly with other antihypertensive agents, particularly thiazide-type diuretics.
Name of the medicinal product
Kerlone
Fertility, pregnancy and lactation
Pregnancy Category C. In a study in which pregnant rats received
betaxolol at doses of 4, 40, or 400 mg/kg/day, the highest dose (600 x MRHD)
was associated with increased postimplantation loss, reduced litter size and
weight, and an increased incidence of skeletal and visceral abnormalities, which
may have been a consequence of drug-related maternal toxicity. Other than a
possible increased incidence of incomplete descent of testes and sternebral
reductions, betaxolol at 4 mg/kg/day and 40 mg/kg/day (6 x MRHD and 60 x MRHD)
caused no fetal abnormalities. In a second study with a different strain of
rat, 200 mg betaxolol/kg/day (300 x MRHD) was associated with maternal toxicity
and an increase in resorptions, but no teratogenicity. In a study in which pregnant
rabbits received doses of 1, 4, 12, or 36 mg betaxolol/kg/day (54 x MRHD), a
marked increase in post-implantation loss occurred at the highest dose, but
no drug-related teratogenicity was observed. The rabbit is more sensitive to
betaxolol than other species because of higher bioavailability resulting from
saturation of the first-pass effect. In a peri- and postnatal study in rats
at doses of 4, 32, and 256 mg betaxolol/kg/day (380 x MRHD), the highest dose
was associated with a marked increase in total litter loss within 4 days postpartum.
In surviving offspring, growth and development were also affected.
There are no adequate and well-controlled studies in pregnant women. Kerlone (betaxolol hydrochloride) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Beta-blockers reduce placental perfusion, which may result in intrauterine fetal death, immature and premature deliveries. In addition, adverse effects (especially hypoglycemia and bradycardia) may occur in the fetus.
Qualitative and quantitative composition
Kerlone (betaxolol hydrochloride) 10-mg tablets are round, white, film coated, with KERLONE (betaxolol hydrochloride) 10 debossed on one side and scored on the other, supplied as:
| NDC Number |
Size |
| 0025-5101-31 |
bottle of 100 |
Kerlone (betaxolol hydrochloride) 20-mg tablets are round, white, film coated, with KERLONE (betaxolol hydrochloride) 20 debossed on one side and β on the other, supplied as:
| NDC Number |
Size |
| 0025-5201-31 |
bottle of 100 |
Store at controlled room temperature 15° - 25°C (59° - 77°F)
Manufactured for: sanofi-aventis U.S. LLC Bridgewater, NJ 08807.
Revised September 2008.
Special warnings and precautions for use
WARNINGS
Cardiac failure
Sympathetic stimulation may be a vital component supporting circulatory function
in congestive heart failure, and beta-adrenergic receptor blockade carries the
potential hazard of further depressing myocardial contractility and precipitating
more severe heart failure. In hypertensive patients who have congestive heart
failure controlled by digitalis and diuretics, beta-blockers should be administered
cautiously. Both digitalis and beta-adrenergic receptor blocking agents slow
AV conduction.
In patients without a history of cardiac failure
Continued depression of the myocardium with beta-blocking agents over a period
of time can, in some cases, lead to cardiac failure. Therefore at the first
sign or symptom of cardiac failure, discontinuation of Kerlone (betaxolol hydrochloride) should be considered.
In some cases beta-blocker therapy can be continued while cardiac failure is
treated with cardiac glycosides, diuretics, and other agents, as appropriate.
Exacerbation of angina pectoris upon withdrawal
Abrupt cessation of therapy with certain beta-blocking agents in patients
with coronary artery disease has been followed by exacerbations of angina pectoris
and, in some cases, myocardial infarction has been reported. Therefore, such
patients should be warned against interruption of therapy without the physician's
advice. Even in the absence of overt angina pectoris, when discontinuation of
Kerlone (betaxolol hydrochloride) is planned, the patient should be carefully observed and therapy should
be reinstituted, at least temporarily, if withdrawal symptoms occur.
Bronchospastic diseases
PATIENTS WITH BRONCHOSPASTIC DISEASE SHOULD NOT IN GENERAL RECEIVE BETA-BLOCKERS.
Because of its relative β1 selectivity (cardioselectivity),
low doses of Kerlone (betaxolol hydrochloride) may be used with caution in patients with bronchospastic
disease who do not respond to or cannot tolerate alternative treatment. Since
β1 selectivity is not absolute and is inversely related to dose,
the lowest possible dose of Kerlone (betaxolol hydrochloride) should be used (5 to 10 mg once daily) and
a bronchodilator should be made available. If dosage must be increased, divided
dosage should be considered to avoid the higher peak blood levels associated
with once-daily dosing.
Anesthesia and major surgery
The necessity, or desirability, of withdrawal of a beta-blocking therapy prior
to major surgery is controversial. Beta-adrenergic receptor blockade impairs
the ability of the heart to respond to beta-adrenergically mediated reflex stimuli.
While this might be of benefit in preventing arrhythmic response, the risk of
excessive myocardial depression during general anesthesia may be increased and
difficulty in restarting and maintaining the heart beat has been reported with
beta-blockers. If treatment is continued, particular care should be taken when
using anesthetic agents which depress the myocardium, such as ether, cyclopropane,
and trichloroethylene, and it is prudent to use the lowest possible dose of
Kerlone (betaxolol hydrochloride). Kerlone (betaxolol hydrochloride) , like other beta-blockers, is a competitive inhibitor of beta-receptor
agonists and its effect on the heart can be reversed by cautious administration
of such agents (eg, dobutamine or isoproterenol-see OVERDOSAGE).
Manifestations of excessive vagal tone (eg, profound bradycardia, hypotension)
may be corrected with atropine 1 to 3 mg IV in divided doses.
Diabetes and hypoglycemia
Beta-blockers should be used with caution in diabetic patients. Beta-blockers
may mask tachycardia occurring with hypoglycemia (patients should be warned
of this), although other manifestations such as dizziness and sweating may not
be significantly affected. Unlike nonselective beta-blockers, Kerlone (betaxolol hydrochloride) does not
prolong insulin-induced hypoglycemia.
Thyrotoxicosis
Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism
(eg, tachycardia). Abrupt withdrawal of beta-blockade might precipitate a thyroid
storm; therefore, patients known or suspected of being thyrotoxic from whom
Kerlone (betaxolol hydrochloride) is to be withdrawn should be monitored closely (see DOSAGE
AND ADMINISTRATION: Cessation of therapy).
Kerlone (betaxolol hydrochloride) should not be given to patients with untreated pheochromocytoma.
PRECAUTIONS
General
Beta-adrenoceptor blockade can cause reduction of intraocular pressure. Since
betaxolol hydrochloride is marketed as an ophthalmic solution for treatment
of glaucoma, patients should be told that Kerlone (betaxolol hydrochloride) may interfere with the glaucoma-screening
test. Withdrawal may lead to a return of increased intraocular pressure. Patients
receiving beta-adrenergic blocking agents orally and beta-blocking ophthalmic
solutions should be observed for potential additive effects either on the intraocular
pressure or on the known systemic effects of beta-blockade.
The value of using beta-blockers in psoriatic patients should be carefully weighed since they have been reported to cause an aggravation in psoriasis.
Impaired hepatic or renal function
Kerlone (betaxolol hydrochloride) is primarily metabolized in the liver to metabolites that are inactive
and then excreted by the kidneys; clearance is somewhat reduced in patients
with renal failure but little changed in patients with hepatic disease. Dosage
reductions have not routinely been necessary when hepatic insufficiency is present
(see DOSAGE AND ADMINISTRATION) but patients
should be observed. Patients with severe renal impairment and those on dialysis
require a reduced dose. (See DOSAGE AND ADMINISTRATION).
Carcinogenesis, mutagenesis, impairment of fertility
Lifetime studies with betaxolol HCl in mice at oral dosages of 6, 20, and
60 mg/kg/day (up to 90 x the maximum recommended human dose [MRHD] based on
60-kg body weight) and in rats at 3, 12, or 48 mg/kg/day (up to 72 x MRHD) showed
no evidence of a carcinogenic effect. In a variety of in vitro and in
vivobacterial and mammalian cell assays, betaxolol HCl was nonmutagenic.
Betaxolol did not adversely affect fertility or mating performance of male or
female rats at doses up to 256 mg/kg/day (380 x MRHD).
Pregnancy
Pregnancy Category C. In a study in which pregnant rats received
betaxolol at doses of 4, 40, or 400 mg/kg/day, the highest dose (600 x MRHD)
was associated with increased postimplantation loss, reduced litter size and
weight, and an increased incidence of skeletal and visceral abnormalities, which
may have been a consequence of drug-related maternal toxicity. Other than a
possible increased incidence of incomplete descent of testes and sternebral
reductions, betaxolol at 4 mg/kg/day and 40 mg/kg/day (6 x MRHD and 60 x MRHD)
caused no fetal abnormalities. In a second study with a different strain of
rat, 200 mg betaxolol/kg/day (300 x MRHD) was associated with maternal toxicity
and an increase in resorptions, but no teratogenicity. In a study in which pregnant
rabbits received doses of 1, 4, 12, or 36 mg betaxolol/kg/day (54 x MRHD), a
marked increase in post-implantation loss occurred at the highest dose, but
no drug-related teratogenicity was observed. The rabbit is more sensitive to
betaxolol than other species because of higher bioavailability resulting from
saturation of the first-pass effect. In a peri- and postnatal study in rats
at doses of 4, 32, and 256 mg betaxolol/kg/day (380 x MRHD), the highest dose
was associated with a marked increase in total litter loss within 4 days postpartum.
In surviving offspring, growth and development were also affected.
There are no adequate and well-controlled studies in pregnant women. Kerlone (betaxolol hydrochloride) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Beta-blockers reduce placental perfusion, which may result in intrauterine fetal death, immature and premature deliveries. In addition, adverse effects (especially hypoglycemia and bradycardia) may occur in the fetus.
Neonatal period
The beta-blocker action persists in the neonate for several days after birth
to a treated mother: there is an increased risk of cardiac and pulmonary complications
in the neonate in the postnatal period. Bradycardia, respiratory distress and
hypoglycemia have also been reported. Accordingly, attentive surveillance of
the neonate (heart rate and blood glucose for the first 3 to 5 days of life)
in a specialized setting is recommended.
Nursing mothers
Since Kerlone (betaxolol hydrochloride) is excreted in human milk in sufficient amounts to have pharmacological
effects in the infant, caution should be exercised when Kerlone (betaxolol hydrochloride) is administered
to a nursing mother.
Pediatric use
Safety and effectiveness in pediatric patients have not been established.
Elderly patients
Kerlone (betaxolol hydrochloride) may produce bradycardia more frequently in elderly patients. In general,
patients 65 years of age and older had a higher incidence rate of bradycardia
(heart rate < 50 BPM) than younger patients in U.S. clinical trials. In a
double-blind study in Europe, 19 elderly patients (mean age = 82) received betaxolol
20 mg daily. Dosage reduction to 10 mg or discontinuation was required for 6
patients due to bradycardia (See DOSAGE AND ADMINISTRATION).
Dosage (Posology) and method of administration
The initial dose of Kerlone (betaxolol hydrochloride) in hypertension is ordinarily 10 mg once daily
either alone or added to diuretic therapy. The full antihypertensive effect
is usually seen within 7 to 14 days. If the desired response is not achieved
the dose can be doubled after 7 to 14 days. Increasing the dose beyond 20 mg
has not been shown to produce a statistically significant additional antihypertensive
effect; but the 40-mg dose has been studied and is well tolerated. An increased
effect (reduction) on heart rate should be anticipated with increasing dosage.
If monotherapy with Kerlone (betaxolol hydrochloride) does not produce the desired response, the addition
of a diuretic agent or other antihypertensive should be considered (see, DRUG
INTERACTIONS).
Dosage adjustments for specific patients
Patients with renal failure: In patients with renal impairment,
clearance of betaxolol declines with decreasing renal function.
In patients with severe renal impairment and those undergoing dialysis the initial dose of Kerlone (betaxolol hydrochloride) is 5 mg once daily. If the desired response is not achieved, dosage may be increased by 5 mg/day increments every 2 weeks to a maximum dose of 20 mg/day.
Patients with hepatic disease: Patients with hepatic disease
do not have significantly altered clearance. Dosage adjustments are not routinely
needed.
Elderly patients: Consideration should be given to reduction
in the starting dose to 5 mg in elderly patients. These patients are especially
prone to beta-blocker-induced bradycardia, which appears to be dose related
and sometimes responds to reductions in dose.
Cessation of therapy: If withdrawal of Kerlone (betaxolol hydrochloride) therapy is planned,
it should be achieved gradually over a period of about 2 weeks. Patients should
be carefully observed and advised to limit physical activity to a minimum.
Interaction with other medicinal products and other forms of interaction
).
Dosage adjustments for specific patients
Patients with renal failure: In patients with renal impairment,
clearance of betaxolol declines with decreasing renal function.
In patients with severe renal impairment and those undergoing dialysis the initial dose of Kerlone (betaxolol hydrochloride) is 5 mg once daily. If the desired response is not achieved, dosage may be increased by 5 mg/day increments every 2 weeks to a maximum dose of 20 mg/day.
Patients with hepatic disease: Patients with hepatic disease
do not have significantly altered clearance. Dosage adjustments are not routinely
needed.
Elderly patients: Consideration should be given to reduction
in the starting dose to 5 mg in elderly patients. These patients are especially
prone to beta-blocker-induced bradycardia, which appears to be dose related
and sometimes responds to reductions in dose.
Cessation of therapy: If withdrawal of Kerlone (betaxolol hydrochloride) therapy is planned,
it should be achieved gradually over a period of about 2 weeks. Patients should
be carefully observed and advised to limit physical activity to a minimum.
HOW SUPPLIED
Kerlone (betaxolol hydrochloride) 10-mg tablets are round, white, film coated, with KERLONE (betaxolol hydrochloride) 10 debossed on one side and scored on the other, supplied as:
| NDC Number |
Size |
| 0025-5101-31 |
bottle of 100 |
Kerlone (betaxolol hydrochloride) 20-mg tablets are round, white, film coated, with KERLONE (betaxolol hydrochloride) 20 debossed on one side and β on the other, supplied as:
| NDC Number |
Size |
| 0025-5201-31 |
bottle of 100 |
Store at controlled room temperature 15° - 25°C (59° - 77°F)
Manufactured for: sanofi-aventis U.S. LLC Bridgewater, NJ 08807.
Revised September 2008.
Side Effects & Drug Interactions
SIDE EFFECTS
Most adverse reactions have been mild and transient and are typical of beta-adrenergic blocking agents, eg, bradycardia, fatigue, dyspnea, and lethargy. Withdrawal of therapy in U.S. and European controlled clinical trials has been necessary in about 3.5% of patients, principally because of bradycardia, fatigue, dizziness, headache, and impotence.
Frequency estimates of adverse events were derived from controlled studies in which adverse reactions were volunteered and elicited in U.S studies and volunteered and/or elicited in European studies.
In the U.S., the placebo-controlled hypertension studies lasted for 4 weeks, while the active-controlled hypertension studies had a 22- to 24- week double-blind phase. The following doses were studied: betaxolol-5, 10, 20, and 40 mg once daily; atenolol-25, 50, and 100 mg once daily; and propranolol-40, 80, and 160 mg b.i.d.
Kerlone (betaxolol hydrochloride) , like other beta-blockers, has been associated with the development of antinuclear antibodies (ANA) (e.g., lupus erythematosus). In controlled clinical studies, conversion of ANA from negative to positive occurred in 5.3% of the patients treated with betaxolol, 6.3% of the patients treated with atenolol, 4.9% of the patients treated with propranolol, and 3.2% of the patients treated with placebo.
Betaxolol adverse events reported with a 2% or greater frequency, and selected events with lower frequency, in U.S. controlled studies are:
| Dose Range |
Betaxolol
(N=509)
5-40 mg q.d.* |
Propranolol
(N=73)
40-160 mg b.i.d. |
Atenolol
(N=75)
25-100 mg q.d. |
Placebo
(N=109) |
| Body System/Adverse Reaction |
(%) |
(%) |
(%) |
(%) |
| Cardiovascular |
| Bradycardia (heart rate < 50 BPM) |
8.1 |
4.1 |
12.0 |
0 |
| Symptomatic bradycardia |
0.8 |
1.4 |
0 |
0 |
| Edema |
1.8 |
0 |
0 |
1.8 |
| Central Nervous System |
| Headache |
6.5 |
4.1 |
5.3 |
15.6 |
| Dizziness |
4.5 |
11.0 |
2.7 |
5.5 |
| Fatigue |
2.9 |
9.6 |
4.0 |
0 |
| Lethargy |
2.8 |
4.1 |
2.7 |
0.9 |
| Psychiatric |
| Insomnia |
1.2 |
8.2 |
2.7 |
0 |
| Nervousness |
0.8 |
1.4 |
2.7 |
0 |
| Bizarre dreams |
1.0 |
2.7 |
1.3 |
0 |
| Depression |
0.8 |
2.7 |
4.0 |
0 |
| Autonomic |
| Impotence |
1.2† |
0 |
0 |
0 |
| Respiratory |
| Dyspnea |
2.4 |
2.7 |
1.3 |
0.9 |
| Pharyngitis |
2.0 |
0 |
4.0 |
0.9 |
| Rhinitis |
1.4 |
0 |
4.0 |
0.9 |
| Upper respiratory infection |
2.6 |
0 |
0 |
5.5 |
| Gastrointestinal |
| Dyspepsia |
4.7 |
6.8 |
2.7 |
0.9 |
| Nausea |
1.6 |
1.4 |
4.0 |
0 |
| Diarrhea |
2.0 |
6.8 |
8.0 |
0.9 |
| Musculoskeletal |
| Chest pain |
2.4 |
1.4 |
2.7 |
0.9 |
| Arthralgia |
3.1 |
0 |
4.0 |
1.8 |
| Skin |
| Rash |
1.2 |
0 |
0 |
0 |
*Five patients received 80 mg q.d.
†N=336 males; impotence is a known possible adverse effect of this pharmacological
class.
|
Of the above adverse reactions associated with the use of betaxolol, only bradycardia was clearly dose related, but there was a suggestion of dose relatedness for fatigue, lethargy, and dyspepsia.
In Europe, the placebo-controlled study lasted for 4 weeks, while the comparative studies had a 4- to 52-week double-blind phase. The following doses were studied: betaxolol 20 and 40 mg once daily and atenolol 100 mg once daily.
From European controlled hypertension clinical trials, the following adverse events reported by 2% or more patients and selected events with lower frequency are presented:
| Dose range |
Betaxolol
(N=155)
20-40 mg q.d. |
Atenolol
(N=81)
100 mg q.d. |
Placebo
(N=60) |
| Body System/Adverse Reaction |
(%) |
(%) |
(%) |
| Cardiovascular |
| Bradycardia (heartrate < 50 BPM) |
5.8 |
5.0 |
0 |
| Symptomatic bradycardia |
1.9 |
2.5 |
0 |
| Palpitation |
1.9 |
3.7 |
1.7 |
| Edema |
1.3 |
1.2 |
0 |
| Cold extremities |
1.9 |
0 |
0 |
| Central Nervous System |
| Headache |
14.8 |
9.9 |
23.3 |
| Dizziness |
14.8 |
17.3 |
15.0 |
| Fatigue |
9.7 |
18.5 |
0 |
| Asthenia |
7.1 |
0 |
16.7 |
| Insomnia |
5.0 |
3.7 |
3.3 |
| Paresthesia |
1.9 |
2.5 |
0 |
| Gastrointestinal |
| Nausea |
5.8 |
1.2 |
0 |
| Dyspepsia |
3.9 |
7.4 |
3.3 |
| Diarrhea |
1.9 |
3.7 |
0 |
| Musculoskeletal |
| Chest pain |
7.1 |
6.2 |
5.0 |
| Joint pain |
5.2 |
4.9 |
1.7 |
| Myalgia |
3.2 |
3.7 |
3.3 |
The only adverse event whose frequency clearly rose with increasing dose was
bradycardia. Elderly patients were especially susceptible to bradycardia, which
in some cases responded to dose-reduction (see PRECAUTIONS).
The following selected (potentially important) adverse events have been reported at an incidence of less than 2% in U.S. controlled and open, long-term clinical studies, European controlled clinical trials, or in marketing experience. It is not known whether a causal relationship exists between betaxolol and these events; they are listed to alert the physician to a possible relationship:
Autonomic: flushing, salivation, sweating.
Body as a whole: allergy, fever, malaise, pain, rigors.
Cardiovascular: angina pectoris, arrhythmia, atrioventricular
block, heart failure, hypertension, hypotension, myocardial infarction, thrombosis,
syncope.
Central and peripheral nervous system: ataxia, neuralgia, neuropathy,
numbness, speech disorder, stupor, tremor, twitching.
Gastrointestinal: anorexia, constipation, dry mouth, increased
appetite, mouth ulceration, rectal disorders, vomiting, dysphagia.
Hearing and Vestibular: earache, labyrinth disorders, tinnitus,
deafness.
Hematologic: anemia, leucocytosis, lymphadenopathy, purpura,
thrombocytopenia.
Liver and biliary: increased AST, increased ALT.
Metabolic and nutritional: acidosis, diabetes, hypercholesterolemia,
hyperglycemia, hyperkalemia, hyperlipemia, hyperuricemia, hypokalemia, weight
gain, weight loss, thirst, increased LDH.
Musculoskeletal: arthropathy, neck pain, muscle cramps, tendonitis.
Psychiatric:abnormal thinking, amnesia, impaired concentration,
confusion, emotional lability, hallucinations, decreased libido.
Reproductive disorders: Female: breast pain, breast fibroadenosis,
menstrual disorder; Male: Peyronie's disease, prostatitis.
Respiratory: bronchitis, bronchospasm, cough, epistaxis, flu,
pneumonia, sinusitis.
Skin: alopecia, eczema, erythematous rash, hypertrichosis, pruritus,
skin disorders.
Special senses: abnormal taste, taste loss.
Urinary system: cystitis, dysuria, micturition disorder, oliguria,
proteinuria, abnormal renal function, renal pain.
Vascular:cerebrovascular disorder, intermittent claudication,
leg cramps, peripheral ischemia, thrombophlebitis.
Vision: abnormal lacrimation, abnormal vision, blepharitis, ocular
hemorrhage, conjunctivitis, dry eyes, iritis, cataract, scotoma.
Potential adverse effects: Although not reported in clinical studies
with betaxolol, a variety of adverse effects have been reported with other beta-adrenergic
blocking agents and may be considered potential adverse effects of betaxolol:
Central nervous system: Reversible mental depression progressing
to catatonia, an acute reversible syndrome characterized by disorientation for
time and place, short-term memory loss, emotional lability with slightly clouded
sensorium, and decreased performance on neuropsychometric tests.
Allergic: Fever combined with aching and sore throat, laryngospasm,
respiratory distress.
Hematologic: Agranulocytosis, thrombocytopenic purpura, and nonthrombocytopenic
purpura.
Gastrointestinal: Mesenteric arterial thrombosis, ischemic colitis.
Metabolic: Hypoglycemia.
Miscellaneous: Raynaud's phenomena. There have been reports of
skin rashes and/or dry eyes associated with the use of beta-adrenergic blocking
drugs. The reported incidence is small, and in most cases, the symptoms have
cleared when treatment was withdrawn. Discontinuation of the drug should be
considered if any such reaction is not otherwise explicable. Patients should
be closely monitored following cessation of therapy.
The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with Kerlone (betaxolol hydrochloride) during investigational use and extensive foreign experience. However, dry eyes have been reported.
DRUG INTERACTIONS
The following drugs have been coadministered with Kerlone (betaxolol hydrochloride) and have not altered
its pharmacokinetics: cimetidine, nifedipine, chlorthalidone, and hydrochlorothiazide.
Concomitant administration of Kerlone (betaxolol hydrochloride) with the oral anticoagulant warfarin has
been shown not to potentiate the anticoagulant effect of warfarin.
Catecholamine-depleting drugs (eg, reserpine) may have an additive effect when given with beta-blocking agents. Patients treated with a beta-adrenergic receptor blocking agent plus a catecholamine depletor should therefore be closely observed for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.
Should it be decided to discontinue therapy in patients receiving beta-blockers and clonidine concurrently, the beta-blocker should be discontinued slowly over several days before the gradual withdrawal of clonidine.
Literature reports suggest that oral calcium antagonists may be used in combination with beta-adrenergic blocking agents when heart function is normal, but should be avoided in patients with impaired cardiac function. Hypotension, AV conduction disturbances, and left ventricular failure have been reported in some patients receiving beta-adrenergic blocking agents when an oral calcium antagonist was added to the treatment regimen. Hypotension was more likely to occur if the calcium antagonist were a dihydropyridine derivative, eg, nifedipine, while left ventricular failure and AV conduction disturbances, including complete heart block, were more likely to occur with either verapamil or diltiazem.
Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.
Amiodarone is an antiarrhythmic agent with negative chronotropic properties that may be additive to those seen with beta blockers.
Disopyramide is a Type I antiarrhythmic drug with potent negative inotropic and chronotropic effects. Disopyramide has been associated with severe bradycardia, asystole and heart failure when administered with beta blockers.
Risk of anaphylactic reaction: Although it is known that patients
on beta-blockers may be refractory to epinephrine in the treatment of anaphylactic
shock, beta-blockers can, in addition, interfere with the modulation of allergic
reaction and lead to an increased severity and/or frequency of attacks. Severe
allergic reactions including anaphylaxis have been reported in patients exposed
to a variety of allergens either by repeated challenge, or accidental contact,
and with diagnostic or therapeutic agents while receiving beta-blockers. Such
patients may be unresponsive to the usual doses of epinephrine used to treat
allergic reaction.
