Blocadren Information
Blocadren () Description
Blocadren () (Timolol Maleate) is a non-selective beta-adrenergic
receptor blocking agent. The chemical name for timolol maleate is ()-1-[(1,1-dimethylethyl)amino]-3-[[4-(4-morpholinyl)-1,2,5-thiadiazol-3-yl]oxy]-2-propanol
()-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 CHNOS•CHO and
its structural formula is:
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.
Blocadren () Clinical Pharmacology
Blocadren () is a beta and beta (non-selective)
adrenergic receptor blocking agent that does not have significant intrinsic
sympathomimetic, direct myocardial depressant, or local anesthetic activity.
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, 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%).
Blocadren () Contraindications
Blocadren () is contraindicated in patients with bronchial asthma
or with a history of bronchial asthma, or severe chronic obstructive pulmonary
disease (see sinus bradycardia;
second and third degree atrioventricular block; overt cardiac failure (see ); cardiogenic shock; hypersensitivity
to this product.
Blocadren () Warnings
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
Exacerbation of Ischemic Heart
Disease Following Abrupt Withdrawal
abrupt
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 ).
Blocadren () Precautions
Muscle
Weakness:
Cerebrovascular Insufficiency:
Catecholamine-depleting drugs:
Non-steroidal
anti-inflammatory drugs:
Calcium antagonists:
Intravenous
calcium antagonists should be used with caution in patients receiving beta-adrenergic
blocking agents.
Digitalis
and either diltiazem or verapamil:
Quinidine:
Clonidine:
Risk from Anaphylactic Reaction:
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 daily human oral dosage, there were no clinically
meaningful changes in serum prolactin.
Timolol maleate
was devoid of mutagenic potential when evaluated (mouse) in the micronucleus test and cytogenetic assay (doses
up to 800 mg/kg) and in a
neoplastic cell transformation assay (up to 100 μg/mL). In Ames tests
the highest concentrations of timolol employed, 5000 or 10,000 μg/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.
Pregnancy Category C.
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.
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 ).
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 and .)
Blocadren () 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:
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 ),
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: anaphylaxis,extremity
pain, decreased exercise tolerance, weight loss, fever; cardiac arrest, cardiac failure, cerebral vascular accident, worsening
of angina pectoris, worsening of arterial insufficiency, Raynaud's phenomenon,
palpitations, vasodilatation; gastrointestinal
pain, hepatomegaly, vomiting, diarrhea, dyspepsia; nonthrombocytopenic purpura; hyperglycemia, hypoglycemia; rash, skin irritation, increased pigmentation, sweating, alopecia; arthralgia; local weakness, increase in signs and symptoms of myasthenia
gravis; depression, nightmares,
somnolence, insomnia, nervousness, diminished concentration, hallucinations; cough; visual disturbances, diplopia, ptosis, dry eyes; 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.
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 () .
Blocadren () 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 LDof
the drug is 1190 and 900 mg/kg in female mice and female rats, respectively.
An hemodialysis study, using C
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:
Blocadren () Dosage And Administration
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.
Blocadren () How Supplied
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:
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:
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:
