TIMOLOL MALEATE
DESCRIPTION:
BLOCADREN* (Timolol Maleate) is a non-selective beta-adrenergic receptor
blocking agent. The chemical name for timolol maleate is (S)-1-((1,1-
dimethylethyl)amino)-3-((4-(4-morpholinyl)-1,2,5- thiadiazol-3-yl)oxy)-2-
propanol (Z)-2-butenedioate (1:1) salt. It possesses an asymmetric carbon atom
in its structure and is provided as the levo isomer. Its empirical formula is
C13H24N4O3S.C4H4O4.
Timolol maleate has a molecular weight of 432.50. It is a white, odorless,
crystalline powder which is soluble in water, methanol, and alcohol.
BLOCADREN is supplied as tablets in three strengths containing 5 mg, 10 mg or 20
mg timolol maleate for oral administration. Inactive ingredients are cellulose,
FD&C Blue 2, magnesium stearate, and starch.
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ACTIONS/CLINICAL PHARMACOLOGY:
BLOCADREN is a beta1 and beta2 (non-selective) adrenergic receptor blocking
agent that does not have significant intrinsic sympathomimetic, direct
myocardial depressant, or local anesthetic activity.
Pharmacodynamics
Clinical pharmacology studies have confirmed the beta-adrenergic blocking
activity as shown by (1) changes in resting heart rate and response of heart
rate to changes in posture; (2) inhibition of isoproterenol-induced tachycardia;
(3) alteration of the response to the Valsalva maneuver and amyl nitrite
administration; and (4) reduction of heart rate and blood pressure changes on
exercise.
BLOCADREN decreases the positive chronotropic, positive inotropic,
bronchodilator, and vasodilator responses caused by beta-adrenergic receptor
agonists. The magnitude of this decreased response is proportional to the
existing sympathetic tone and the concentration of BLOCADREN at receptor sites.
In normal volunteers, the reduction in heart rate response to a standard
exercise was dose dependent over the test range of 0.5 to 20 mg, with a peak
reduction at 2 hours of approximately 30% at higher doses.
Beta-adrenergic receptor blockade reduces cardiac output in both healthy
subjects and patients with heart disease. In patients with severe impairment of
myocardial function beta-adrenergic receptor blockade may inhibit the
stimulatory effect of the sympathetic nervous system necessary to maintain
adequate cardiac function.
Beta-adrenergic receptor blockade in the bronchi and bronchioles results in
increased airway resistance from unopposed parasympathetic activity. Such an
effect in patients with asthma or other bronchospastic conditions is potentially
dangerous.
Clinical studies indicate that BLOCADREN at a dosage of 20-60 mg/day reduces
blood pressure without causing postural hypotension in most patients with
essential hypertension. Administration of BLOCADREN to patients with
hypertension results initially in a decrease in cardiac output, little immediate
change in blood pressure, and an increase in calculated peripheral resistance.
With continued administration of BLOCADREN, blood pressure decreases within a
few days, cardiac output usually remains reduced, and peripheral resistance
falls toward pretreatment levels. Plasma volume may decrease or remain unchanged
during therapy with BLOCADREN. In the majority of patients with hypertension
BLOCADREN also decreases plasma renin activity. Dosage adjustment to achieve
optimal antihypertensive effect may require a few weeks. When therapy with
BLOCADREN is discontinued, the blood pressure tends to return to pretreatment
levels gradually. In most patients the antihypertensive activity of BLOCADREN is
maintained with long-term therapy and is well tolerated.
The mechanism of the antihypertensive effects of beta-adrenergic receptor
blocking agents is not established at this time. Possible mechanisms of action
include reduction in cardiac output, reduction in plasma renin activity, and a
central nervous system sympatholytic action.
A Norwegian multi-center, double-blind study compared the effects of timolol
maleate with placebo in 1,884 patients who had survived the acute phase of a
myocardial infarction. Patients with systolic blood pressure below 100 mm Hg,
sick sinus syndrome and contraindications to beta blockers, including
uncontrolled heart failure, second or third degree AV block and bradycardia (<50
beats per minute), were excluded from the multi-center trial. Therapy with
BLOCADREN, begun 7 to 28 days following infarction, was shown to reduce overall
mortality; this was primarily attributable to a reduction in cardiovascular
mortality. BLOCADREN significantly reduced the incidence of sudden deaths
(deaths occurring without symptoms or within 24 hours of the onset of symptoms),
including those occurring within one hour, and particularly instantaneous deaths
(those occurring without preceding symptoms). The protective effect of BLOCADREN
was consistent regardless of age, sex or site of infarction. The effect was
clearest in patients with a first infarction who were considered at a high risk
of dying, defined as those with one or more of the following characteristics
during the acute phase: transient left ventricular failure, cardiomegaly, newly
appearing atrial fibrillation or flutter, systolic hypotension, or SGOT (ASAT)
levels greater than four times the upper limit of normal. Therapy with BLOCADREN
also reduced the incidence of non-fatal reinfarction. The mechanism of the
protective effect of BLOCADREN is unknown.
BLOCADREN was studied for the prophylactic treatment of migraine headache in
placebo- controlled clinical trials involving 400 patients, mostly women between
the ages of 18 and 66 years. Common migraine was the most frequent diagnosis.
All patients had at least two headaches per month at baseline. Approximately 50
percent of patients who received BLOCADREN had a reduction in the frequency of
migraine headache of at least 50 percent, compared to a similar decrease in
frequency in 30 percent of patients receiving placebo. The most common
cardiovascular adverse effect was bradycardia (5%).
Pharmacokinetics And Metabolism
BLOCADREN is rapidly and nearly completely absorbed (about 90%) following oral
ingestion. Detectable plasma levels of timolol occur within one-half hour and
peak plasma levels occur in about one to two hours. The drug half-life in plasma
is approximately 4 hours and this is essentially unchanged in patients with
moderate renal insufficiency. Timolol is partially metabolized by the liver and
timolol and its metabolites are excreted by the kidney. Timolol is not
extensively bound to plasma proteins; i.e., <10% by equilibrium dialysis and
approximately 60% by ultrafiltration. An In Vitro hemodialysis study, using 14C
timolol added to human plasma or whole blood, showed that timolol was readily
dialyzed from these fluids; however, a study of patients with renal failure
showed that timolol did not dialyze readily. Plasma levels following oral
administration are about half those following intravenous administration
indicating approximately 50% first pass metabolism. The level of beta
sympathetic activity varies widely among individuals, and no simple correlation
exists between the dose or plasma level of timolol maleate and its therapeutic
activity. Therefore, objective clinical measurements such as reduction of heart
rate and/or blood pressure should be used as guides in determining the optimal
dosage for each patient.
INDICATIONS AND USAGE:
Hypertension
BLOCADREN is indicated for the treatment of hypertension. It may be used alone
or in combination with other antihypertensive agents, especially thiazide-type
diuretics.
Myocardial Infarction
BLOCADREN is indicated in patients who have survived the acute phase of a
myocardial infarction, and are clinically stable, to reduce cardiovascular
mortality and the risk of reinfarction.
Migraine
BLOCADREN is indicated for the prophylaxis of migraine headache.
CONTRAINDICATIONS:
BLOCADREN is contraindicated in patients with bronchial asthma or with a history
of bronchial asthma, or severe chronic obstructive pulmonary disease (see
WARNINGS); sinus bradycardia; second and third degree atrioventricular block;
overt cardiac failure (see WARNINGS); cardiogenic shock; hypersensitivity to
this product.
WARNINGS:
Cardiac Failure
Sympathetic stimulation may be essential for support of the circulation in
individuals with diminished myocardial contractility, and its inhibition by
beta-adrenergic receptor blockade may precipitate more severe failure. Although
beta blockers should be avoided in overt congestive heart failure, they can be
used, if necessary, with caution in patients with a history of failure who are
well-compensated, usually with digitalis and diuretics. Both digitalis and
timolol maleate slow AV conduction. If cardiac failure persists, therapy with
BLOCADREN should be withdrawn.
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. At the first sign or symptom of cardiac failure,
patients receiving BLOCADREN should be digitalized and/or be given a diuretic,
and the response observed closely. If cardiac failure continues, despite
adequate digitalization and diuretic therapy, BLOCADREN should be withdrawn.
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* *
* Exacerbation Of Ischemic Heart Disease *
* Following Abrupt Withdrawal- *
* -Hypersensitivity to catecholamines has *
* been observed in patients withdrawn from *
* beta blocker therapy; exacerbation of *
* angina and, in some cases, myocardial *
* infarction have occurred after Abrupt *
* discontinuation of such therapy. When *
* discontinuing chronically administered *
* timolol maleate, particularly in patients *
* with ischemic heart disease, the dosage *
* should be gradually reduced over a period *
* of one to two weeks and the patient should *
* be carefully monitored. If angina markedly *
* worsens or acute coronary insufficiency *
* develops, timolol maleate administration *
* should be reinstituted promptly, at least *
* temporarily, and other measures appropriate *
* for the management of unstable angina *
* should be taken. Patients should be warned *
* against interruption or discontinuation of *
* therapy without the physician's advice. *
* Because coronary artery disease is common *
* and may be unrecognized, it may be prudent *
* not to discontinue timolol maleate therapy *
* abruptly even in patients treated only for *
* hypertension. *
* *
*************************************************
Obstructive Pulmonary Disease
PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (e.g., CHRONIC BRONCHITIS,
EMPHYSEMA) OF MILD OR MODERATE SEVERITY, BRONCHOSPASTIC DISEASE OR A HISTORY OF
BRONCHOSPASTIC DISEASE (OTHER THAN BRONCHIAL ASTHMA OR A HISTORY OF BRONCHIAL
ASTHMA, IN WHICH "BLOCADREN" IS CONTRAINDICATED, see CONTRAINDICATIONS), SHOULD
IN GENERAL NOT RECEIVE BETA BLOCKERS, INCLUDING "BLOCADREN". However, if
BLOCADREN is necessary in such patients, then the drug should be administered
with caution since it may block bronchodilation produced by endogenous and
exogenous catecholamine stimulation of beta2 receptors.
Major Surgery
The necessity or desirability of withdrawal of 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.
This may augment the risk of general anesthesia in surgical procedures. Some
patients receiving beta-adrenergic receptor blocking agents have been subject to
protracted severe hypotension during anesthesia. Difficulty in restarting and
maintaining the heartbeat has also been reported. For these reasons, in patients
undergoing elective surgery, some authorities recommend gradual withdrawal of
beta-adrenergic receptor blocking agents.
If necessary during surgery, the effects of beta- adrenergic blocking agents may
be reversed by sufficient doses of such agonists as isoproterenol, dopamine,
dobutamine or levarterenol (see OVERDOSAGE).
Diabetes Mellitus
BLOCADREN should be administered with caution in patients subject to spontaneous
hypoglycemia or to diabetic patients (especially those with labile diabetes) who
are receiving insulin or oral hypoglycemic agents. Beta-adrenergic receptor
blocking agents may mask the signs and symptoms of acute hypoglycemia.
Thyrotoxicosis
Beta-adrenergic blockade may mask certain clinical signs (e.g., tachycardia) of
hyperthyroidism. Patients suspected of developing thyrotoxicosis should be
managed carefully to avoid abrupt withdrawal of beta blockade which might
precipitate a thyroid storm.
PRECAUTIONS:
General
Impaired Hepatic Or Renal Function: Since BLOCADREN is partially metabolized in
the liver and excreted mainly by the kidneys, dosage reductions may be necessary
when hepatic and/or renal insufficiency is present.
Dosing In The Presence Of Marked Renal Failure: Although the pharmacokinetics of
BLOCADREN are not greatly altered by renal impairment, marked hypotensive
responses have been seen in patients with marked renal impairment undergoing
dialysis after 20 mg doses. Dosing in such patients should therefore be
especially cautious.
Muscle Weakness: Beta-adrenergic blockade has been reported to potentiate muscle
weakness consistent with certain myasthenic symptoms (e.g., diplopia, ptosis,
and generalized weakness). Timolol has been reported rarely to increase muscle
weakness in some patients with myasthenia gravis or myasthenic symptoms.
Cerebrovascular Insufficiency: Because of potential effects of beta-adrenergic
blocking agents relative to blood pressure and pulse, these agents should be
used with caution in patients with cerebrovascular insufficiency. If signs or
symptoms suggesting reduced cerebral blood flow are observed, consideration
should be given to discontinuing these agents.
Drug Interactions
Catecholamine-Depleting Drugs:
Close observation of the patient is recommended when BLOCADREN is administered
to patients receiving catecholamine-depleting drugs such as reserpine, because
of possible additive effects and the production of hypotension and/or marked
bradycardia, which may produce vertigo, syncope, or postural hypotension.
Non-Steroidal Anti-Inflammatory Drugs:
Blunting of the antihypertensive effect of beta- adrenoceptor blocking agents by
non-steroidal anti-inflammatory drugs has been reported. When using these agents
concomitantly, patients should be observed carefully to confirm that the desired
therapeutic effect has been obtained.
Calcium Antagonists:
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, e.g.
nifedipine, while left ventricular failure and AV conduction disturbances were
more likely to occur with either verapamil or diltiazem.
Intravenous calcium antagonists should be used with caution in patients
receiving beta- adrenergic blocking agents.
Digitalis And Either Diltiazem or Verapamil:
The concomitant use of beta-adrenergic blocking agents with digitalis and either
diltiazem or verapamil may have additive effects in prolonging AV conduction
time.
Quinidine: Potentiated systemic beta-blockade (e.g., decreased heart rate) has
been reported during combined treatment with quinidine and timolol, possibly
because quinidine inhibits the metabolism of timolol via the P-450 enzyme,
CYP2D6.
Clonidine: Beta adrenergic blocking agents may exacerbate the rebound
hypertension which can follow the withdrawal of clonidine. If the two drugs are
coadministered, the beta adrenergic blocking agent should be withdrawn several
days before the gradual withdrawal of clonidine. If replacing clonidine by beta-
blocker therapy, the introduction of beta adrenergic blocking agents should be
delayed for serveral days after clonidine administration has stopped.
Risk From Anaphylactic Reaction: While taking beta-blockers, patients with a
history of atopy or a history of severe anaphylactic reaction to a variety of
allergens may be more reactive to repeated accidental, diagnostic, or
therapeutic challenge with such allergens. Such patients may be unresponsive to
the usual doses of epinephrine used to treat anaphylactic reactions.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
In a two-year study of timolol maleate in rats, there was a statistically
significant increase in the incidence of adrenal pheochromocytomas in male rats
administered 300 mg/kg/day (250 times* the maximum recommended human dose).
Similar differences were not observed in rats administered doses equivalent to
approximately 20 or 80 times* the maximum recommended human dose.
In a lifetime study in mice, there were statistically significant increases in
the incidence of benign and malignant pulmonary tumors, benign uterine polyps
and mammary adenocarcinoma in female mice at 500 mg/kg/day (approximately 400
times* the maximum recommended human dose), but not at 5 or 50 mg/kg/day. In a
subsequent study in female mice, in which post- mortem examinations were limited
to uterus and lungs, a statistically significant increase in the incidence of
pulmonary tumors was again observed at 500 mg/kg/day.
The increased occurrence of mammary adenocarcinoma was associated with
elevations in serum prolactin that occurred in female mice administered timolol
at 500 mg/kg/day, but not at doses of 5 or 50 mg/kg/day. An increased incidence
of mammary adenocarcinomas in rodents has been associated with administration of
several other therapeutic agents which elevate serum prolactin, but no
correlation between serum prolactin levels and mammary tumors has been
established in man. Furthermore, in adult human female subjects who received
oral dosages of up to 60 mg of timolol maleate, the maximum recommended human
oral dosage, there were no clinically meaningful changes in serum prolactin.
Timolol maleate was devoid of mutagenic potential when evaluated In Vivo (mouse)
in the micronucleus test and cytogenetic assay (doses up to 800 mg/kg) and In
Vitro in a neoplastic cell transformation assay (up to 100 mcgm/mL). In Ames
tests the highest concentrations of timolol employed, 5000 or 10,000 mcgm/plate,
were associated with statistically significant elevations of revertants observed
with tester strain TA100 (in seven replicate assays), but not in three
additional strains. In the assays with tester strain TA100, no consistent dose
response relationship was observed, nor did the ratio of test to control
revertants reach 2. A ratio of 2 is usually considered the criterion for a
positive Ames test.
Reproduction and fertility studies in rats showed no adverse effect on male or
female fertility at doses up to 125 times* the maximum recommended human dose.
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* Based on patient weight of 50 kg
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Pregnancy
Pregnancy Category C. Teratogenicity studies with timolol in mice, rats and
rabbits at doses up to 50 mg/kg/day (approximately 40 times* the maximum
recommended daily human dose) showed no evidence of fetal malformations.
Although delayed fetal ossification was observed at this dose in rats, there
were no adverse effects on postnatal development of offspring. Doses of 1000
mg/kg/day (approximately 830 times* the maximum recommended daily human dose)
were maternotoxic in mice and resulted in an increased number of fetal
resorptions. Increased fetal resorptions were also seen in rabbits at doses of
approximately 40 times* the maximum recommended daily human dose, in this case
without apparent maternotoxicity. There are no adequate and well-controlled
studies in pregnant women. BLOCADREN should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
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*Based on patient weight of 50 kg
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Nursing Mothers
Timolol maleate has been detected in human milk. Because of the potential for
serious adverse reactions from timolol in nursing infants, a decision should be
made whether to discontinue nursing or to discontinue the drug, taking into
account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
DRUG INTERACTIONS:
Close observation of the patient is recommended when BLOCADREN is administered
to patients receiving catecholamine-depleting drugs such as reserpine, because
of possible additive effects and the production of hypotension and/or marked
bradycardia, which may produce vertigo, syncope, or postural hypotension.
Blunting of the antihypertensive effect of beta- adrenoceptor blocking agents by
non-steroidal anti-inflammatory drugs has been reported. When using these agents
concomitantly, patients should be observed carefully to confirm that the desired
therapeutic effect has been obtained.
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, e.g.
nifedipine, while left ventricular failure and AV conduction disturbances were
more likely to occur with either verapamil or diltiazem.
Intravenous calcium antagonists should be used with caution in patients
receiving beta- adrenergic blocking agents.
The concomitant use of beta-adrenergic blocking agents with digitalis and either
diltiazem or verapamil may have additive effects in prolonging AV conduction
time.
Risk From Anaphylactic Reaction: While taking beta-blockers, patients with a
history of atopy or a history of severe anaphylactic reaction to a variety of
allergens may be more reactive to repeated accidental, diagnostic, or
therapeutic challenge with such allergens. Such patients may be unresponsive to
the usual doses of epinephrine used to treat anaphylactic reactions.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
BLOCADREN is usually well tolerated in properly selected patients. Most adverse
effects have been mild and transient.
In a multicenter (12-week) clinical trial comparing timolol maleate and placebo
in hypertensive patients, the following adverse reactions were reported
spontaneously and considered to be causally related to timolol maleate:
Timolol
Maleate Placebo
(n = 176) (n = 168)
% %
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BODY AS A WHOLE
fatigue/tiredness 3.4 0.6
headache 1.7 1.8
chest pain 0.6 0
asthenia 0.6 0
CARDIOVASCULAR
bradycardia 9.1 0
arrhythmia 1.1 0.6
syncope 0.6 0
edema 0.6 1.2
DIGESTIVE
dyspepsia 0.6 0.6
nausea 0.6 0
SKIN
pruritus 1.1 0
NERVOUS SYSTEM
dizziness 2.3 1.2
vertigo 0.6 0
paresthesia 0.6 0
PSYCHIATRIC
decreased libido 0.6 0
RESPIRATORY
dyspnea 1.7 0.6
bronchial spasm 0.6 0
rales 0.6 0
SPECIAL SENSES
eye irritation 1.1 0.6
tinnitus 0.6 0
These data are representative of the incidence of adverse effects that may be
observed in properly selected patients treated with BLOCADREN, i.e., excluding
patients with bronchospastic disease, congestive heart failure or other
contraindications to beta blocker therapy.
In patients with migraine the incidence of bradycardia was 5 percent.
In a coronary artery disease population studied in the Norwegian multi-center
trial (see ACTIONS/CLINICAL PHARMACOLOGY), the frequency of the principal
adverse reactions and the frequency with which these resulted in discontinuation
of therapy in the timolol and placebo groups were:
BLOCADREN Adverse Reaction* Withdrawal**
-------------------------------------------------------------------------------------------
Timolol Placebo Timolol Placebo
(n = 945) (n = 939) (n = 945) (n = 939)
% % % %
---------- ---------- ---------- ----------
Asthenia or Fatigue 5 1 <1 <1
Heart Rate <40 beats/minute 5 <1 4 <1
Cardiac Failure--Nonfatal 8 7 3 2
Hypotension 3 2 3 1
Pulmonary Edema--Nonfatal 2 <1 <1 <1
Claudication 3 3 1 <1
AV Block 2nd or 3rd degree <1 <1 <1 <1
Sinoatrial Block <1 <1 <1 <1
Cold Hands and Feet 8 <1 <1 0
Nausea or Digestive Disorders 8 6 1 <1
Dizziness 6 4 1 0
Bronchial Obstruction 2 <1 1 <1
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* When an adverse reaction recurred in a patient, it is listed only once.
** Only principal reason for withdrawal in each patient is listed.
These adverse reactions can also occur in patients treated for hypertension.
The following additional adverse effects have been reported in clinical
experience with the drug: Body As A Whole: extremity pain, decreased exercise
tolerance, weight loss, fever; Cardiovascular: cardiac arrest, cardiac failure,
cerebrovascular accident, worsening of angina pectoris, worsening of arterial
insufficiency, Raynaud's phenomenon, palpitations, vasodilatation; Digestive:
gastrointestinal pain, hepatomegaly, vomiting, diarrhea, dyspepsia; Hematologic:
nonthrombocytopenic purpura; Endocrine: hyperglycemia, hypoglycemia; Skin: rash,
skin irritation, increased pigmentation, sweating, alopecia; Musculoskeletal:
arthralgia; Nervous System: local weakness, increase in signs and symptoms of
myasthenia gravis; Psychiatric: depression, nightmares, somnolence, insomnia,
nervousness, diminished concentration, hallucinations; Respiratory: cough;
Special Senses: visual disturbances, diplopia, ptosis, dry eyes; Urogenital:
impotence, urination difficulties.
There have been reports of retroperitoneal fibrosis in patients receiving
timolol maleate and in patients receiving other beta-adrenergic blocking agents.
A causal relationship between this condition and therapy with beta-adrenergic
blocking agents has not been established.
Potential Adverse Effects: In addition, a variety of adverse effects not
observed in clinical trials with BLOCADREN, but reported with other beta-
adrenergic blocking agents, should be considered potential adverse effects of
BLOCADREN: 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, slightly clouded
sensorium, and decreased performance on neuropsychometrics; Cardiovascular:
Intensification of AV block (see CONTRAINDICATIONS); Digestive: Mesenteric
arterial thrombosis, ischemic colitis; Hematologic: Agranulocytosis,
thrombocytopenic purpura; Allergic: Erythematous rash, fever combined with
aching and sore throat, laryngospasm with respiratory distress; Miscellaneous:
Peyronie's disease.
There have been reports of a syndrome comprising psoriasiform skin rash,
conjunctivitis sicca, otitis, and sclerosing serositis attributed to the beta-
adrenergic receptor blocking agent, practolol. This syndrome has not been
reported with BLOCADREN.
Clinical Laboratory Test Findings: Clinically important changes in standard
laboratory parameters were rarely associated with the administration of
BLOCADREN. Slight increases in blood urea nitrogen, serum potassium, uric acid,
and triglycerides, and slight decreases in hemoglobin, hematocrit and HDL
cholesterol occurred, but were not progressive or associated with clinical
manifestations. Increases in liver function tests have been reported.
OVERDOSAGE:
Overdosage has been reported with Tablets BLOCADREN. A 30-year-old female
ingested 650 mg of BLOCADREN (maximum recommended daily dose- -60 mg) and
experienced second and third degree heart block. She recovered without treatment
but approximately two months later developed irregular heartbeat, hypertension,
dizziness, tinnitus, faintness, increased pulse rate and borderline first degree
heart block.
The oral LD50 of the drug is 1190 and 900 mg/kg in female mice and female rats,
respectively.
An In Vitro hemodialysis study, using 14C timolol added to human plasma or whole
blood, showed that timolol was readily dialyzed from these fluids; however, a
study of patients with renal failure showed that timolol did not dialyze
readily.
The most common signs and symptoms to be expected with overdosage with a beta-
adrenergic receptor blocking agent are symptomatic bradycardia, hypotension,
bronchospasm, and acute cardiac failure. Therapy with BLOCADREN should be
discontinued and the patient observed closely. The following additional
therapeutic measures should be considered:
(1) Gastric Lavage
(2) Symptomatic Bradycardia: Use atropine sulfate intravenously in a dosage of
0.25 mg to 2 mg to induce vagal blockade. If bradycardia persists, intravenous
isoproterenol hydrochloride should be administered cautiously. In refractory
cases the use of a transvenous cardiac pacemaker may be considered.
(3) Hypotension: Use sympathomimetic pressor drug therapy, such as dopamine,
dobutamine or levarterenol. In refractory cases the use of glucagon
hydrochloride has been reported to be useful.
(4) Bronchospasm: Use isoproterenol hydrochloride. Additional therapy with
aminophylline may be considered.
(5) Acute Cardiac Failure: Conventional therapy with digitalis, diuretics, and
oxygen should be instituted immediately. In refractory cases the use of
intravenous aminophylline is suggested. This may be followed if necessary by
glucagon hydrochloride which has been reported to be useful.
(6) Heart Block (Second Or Third Degree): Use isoproterenol hydrochloride or a
transvenous cardiac pacemaker.
DOSAGE AND ADMINISTRATION:
Hypertension
The usual initial dosage of BLOCADREN is 10 mg twice a day, whether used alone
or added to diuretic therapy. Dosage may be increased or decreased depending on
heart rate and blood pressure response. The usual total maintenance dosage is
20-40 mg per day. Increases in dosage to a maximum of 60 mg per day divided into
two doses may be necessary. There should be an interval of at least seven days
between increases in dosages.
BLOCADREN may be used with a thiazide diuretic or with other antihypertensive
agents. Patients should be observed carefully during initiation of such
concomitant therapy.
Myocardial Infarction
The recommended dosage for long-term prophylactic use in patients who have
survived the acute phase of a myocardial infarction is 10 mg given twice daily
(see ACTIONS/CLINICAL PHARMACOLOGY).
Migraine
The usual initial dosage of BLOCADREN is 10 mg twice a day. During maintenance
therapy the 20 mg daily dosage may be administered as a single dose. Total daily
dosage may be increased to a maximum of 30 mg, given in divided doses, or
decreased to 10 mg once per day, depending on clinical response and
tolerability. If a satisfactory response is not obtained after 6-8 weeks use of
the maximum daily dosage, therapy with BLOCADREN should be discontinued.