Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1707
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BLOCADREN (Tablet)
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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.<br/>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 .<br/>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 BLOCADRENshould
be discontinued.
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BLOCADREN is a betaand beta(non-selective)
adrenergic receptor blocking agent that does not have significant intrinsic
sympathomimetic, direct myocardial depressant, or local anesthetic activity.<br/>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 returnto 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, which included patients 20 to 75 years of age, 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%).<br/>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, usingC
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.
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No. 3343���Tablets BLOCADREN, 5 mg, are light
blue, round, compressed tablets, with code MSD 59 on one side and BLOCADREN
on the other. They are supplied as follows: NDC 0006-0059-68 bottles of 100. No.
3344���Tablets BLOCADREN, 10 mg, are light blue, round, scored,
compressed tablets, with code MSD 136 on one side and BLOCADREN on theother. They are supplied as follows: NDC 0006-0136-68 bottles of 100 No. 3371���Tablets BLOCADREN, 20 mg, are light blue, capsule shaped, scored, compressed
tablets, with code MSD 437 on one side and BLOCADREN on the other. They
are supplied as follows: NDC 0006-0437-68 bottles of 100 Storage Store at controlled
room temperature, 15-30��C (59-86��F). Keep container tightly closed.
Protect from light. MERCK&CO., INC., Whitehouse
Station, NJ 08889, USA Issued March 2002 Printed
in USA 7901233
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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.
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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.<br/>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 several 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.<br/>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 timesthe maximum recommended human dose).
Similar differences were not observed in rats administered doses equivalent
to approximately 20 or 80 timesthe 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 timesthe
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 daily 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��g/mL). In Ames tests
the highest concentrations of timolol employed, 5000 or 10,000��g/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 timesthe maximum recommended human dose.<br/>Pregnancy: Pregnancy Category C. Teratogenicity
studies with timolol in mice, rats and rabbits at doses up to 50 mg/kg/day
(approximately 40 timesthe 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 timesthe 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 timesthe
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.<br/>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.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been
established.<br/>Geriatric Use: Clinical studies of BLOCADREN for the treatment of hypertension
or migraine did not include sufficient numbers of subjects aged 65 and over
to determine whether they respond differently from younger subjects. In
a clinical study of BLOCADREN in patients who had survived the acute phase
of a myocardial infarction, approximately 350 patients (37%) were 65-75 years
of age. Safety and efficacy were not different between these patients and
younger patients (see CLINICAL PHARMACOLOGY,
Pharmacodynamics). Other reported clinical
experience has not identified differences in responses between the elderly
and younger patients. In general, dose selection for an elderly patient should
be cautious, usually starting at the low end of the dosing range, reflecting
the greater frequency of decreased hepatic, renal or cardiac function, and
of concomitant disease or other drug therapy. This drug
is known to be substantially excreted by the kidney, and the risk of toxic
reactions to this drug may be greater in patients with impaired renal function.
Because elderly patients are more likely to have decreased renal function,
care should be taken in dose selection, and it may be useful to monitor renal
function. (See PRECAUTIONS, Impaired
Hepatic or Renal Function andDosing
in the Presence of Marked Renal Failure.)
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timolol maleate
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BLOCADREN (Tablet)
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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: 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 ,
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: The following additional adverse effects have been reported
in clinical experience with the drug: Body as
a Whole: anaphylaxis,extremity
pain, decreased exercise tolerance, weight loss, fever; Cardiovascular: cardiac arrest, cardiac failure, cerebral vascular 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 ; 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.
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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.<br/>Myocardial Infarction: BLOCADREN is indicated in patients who have survived the
acute phase of myocardial infarction, and are clinically stable, to reduce
cardiovascular mortality and the risk of reinfarction.<br/>Migraine: BLOCADREN is indicated for the prophylaxis of migraine headache.
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BLOCADREN
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