Blocadren Information
Blocadren (Timolol maleate) 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 (Timolol maleate) 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 (Timolol maleate) Clinical Pharmacology
Blocadren (Timolol maleate) 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 (Timolol maleate) 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 (Timolol maleate) 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 (Timolol maleate) at a dosage of 20-60 mg/day reduces blood pressure without causing postural hypotension in most patients with essential hypertension. Administration of Blocadren (Timolol maleate) 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 (Timolol maleate) , 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 (Timolol maleate) . In the majority of patients with hypertension Blocadren (Timolol maleate) also decreases plasma renin activity. Dosage adjustment to achieve optimal antihypertensive effect may require a few weeks. When therapy with Blocadren (Timolol maleate) is discontinued, the blood pressure tends to return to pretreatment levels gradually. In most patients the antihypertensive activity of Blocadren (Timolol maleate) 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 (
Blocadren (Timolol maleate) 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 (Timolol maleate) 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 (Timolol maleate) Contraindications
Blocadren (Timolol maleate) 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 (Timolol maleate) 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 (Timolol maleate) 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 (Timolol maleate) 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 (Timolol maleate) 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 (Timolol maleate) 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 (Timolol maleate) Adverse Reactions
Blocadren (Timolol maleate) 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 (Timolol maleate) , 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 (Timolol maleate) .
Blocadren (Timolol maleate) Overdosage
Overdosage has been reported with Tablets Blocadren (Timolol maleate) . A 30-year-old female ingested 650 mg of Blocadren (Timolol maleate) (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 (Timolol maleate) should be discontinued and the patient observed closely. The following additional therapeutic measures should be considered:
Blocadren (Timolol maleate) Dosage And Administration
The usual initial dosage of Blocadren (Timolol maleate) 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 (Timolol maleate) may be used with a thiazide diuretic or with other antihypertensive agents. Patients should be observed carefully during initiation of such concomitant therapy.
Blocadren (Timolol maleate) How Supplied
No. 3343 — Tablets Blocadren (Timolol maleate) , 5 mg, are light blue, round, compressed tablets, with code MSD 59 on one side and Blocadren (Timolol maleate) on the other. They are supplied as follows:
No. 3344 — Tablets Blocadren (Timolol maleate) , 10 mg, are light blue, round, scored, compressed tablets, with code MSD 136 on one side and Blocadren (Timolol maleate) on theother. They are supplied as follows:
No. 3371 — Tablets Blocadren (Timolol maleate) , 20 mg, are light blue, capsule shaped, scored, compressed tablets, with code MSD 437 on one side and Blocadren (Timolol maleate) on the other. They are supplied as follows:
