ization and diuretic therapy, timolol should be withdrawn. 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of ischemic heart disease following abrupt withdrawal hypersensitivity to catecholamines has been observed in patients withdrawn from beta-blocker therapy; exacerbation of angina and, in some cases, myocardial infarction have occurred after abrupt discontinuation of such therapy.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 timolol maleate is contraindicated, see contraindications), should in general not receive beta-blockers, including timolol. however, if timolol 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 norepinephrine (see overdosage). diabetes mellitus timolol 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.

tered 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 to 8 weeks use of the maximum daily dosage, therapy with timolol should be discontinued.

olol 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 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: adverse reaction* withdrawal† timolol (n=945) % placebo (n=939) % timolol (n=945) % placebo (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 * 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: 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 timolol maleate, but reported with other beta-adrenergic blocking agents, should be considered potential adverse effects of timolol. 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 timolol. clinical laboratory test findings clinically important changes in standard laboratory parameters were rarely associated with the administration of timolol. 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.

ard 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 timolol maleate at a dosage of 20 to 60 mg/day reduces blood pressure without causing postural hypotension in most patients with essential hypertension. administration of timolol 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 timolol, 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 timolol. in the majority of patients with hypertension timolol also decreases plasma renin activity. dosage adjustment to achieve optimal antihypertensive effect may require a few weeks. when therapy with timolol is discontinued, the blood pressure tends to return to pretreatment levels gradually. in most patients the antihypertensive activity of timolol 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 timolol, begun 7 to 28 days following infarction, was shown to reduce overall mortality; this was primarily attributable to a reduction in cardiovascular mortality. timolol 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 timolol 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 timolol also reduced the incidence of nonfatal reinfarction. the mechanism of the protective effect of timolol is unknown. timolol 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 timolol 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 timolol maleate 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.

s 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.