Timolide (Timolol Maleate)

TIMOLIDE®

Merck Frosst

Timolol Maleate-Hydrochlorothiazide

Antihypertensive

Action and Clinical Uses:

Timolide combines the antihypertensive activity of 2 agents: a beta-adrenergic receptor blocking agent (timolol maleate) and a diuretic (hydrochlorothiazide).

Timolol is a non-selective beta-adrenergic receptor blocking agent that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anesthetic (membrane stabilizing) activity in humans.

The mechanism of the antihypertensive effect of beta-adrenergic receptor blocking agents has not yet been established. Among the factors that may be involved are: (i) competitive ability to antagonize catecholamine-induced tachycardia at the beta-receptor sites in the heart, thus decreasing cardiac output, (ii) inhibition of renin release by the kidneys, (iii) inhibition of the vasomotor centres.

Hydrochlorothiazide increases excretion of sodium and chloride in approximately equivalent amounts, and may cause a simultaneous, usually minimal, loss of bicarbonate. Natriuresis is usually accompanied by some loss of potassium. The mechanism of the antihypertensive effect of thiazides may be related to the excretion and redistribution of body sodium. Hydrochlorothiazide usually does not decrease normal blood pressure.

The combination of timolol with thiazide-like diuretics has been shown to be compatible and generally more effective than timolol alone in reducing elevated blood pressure.

Timolol is rapidly absorbed following oral ingestion. Detectable plasma levels of timolol occur within one-half hour and persist for about 8 to 12 hours. Peak plasma levels occur in about 1 to 2 hours. The drug half-life in plasma is approximately 3 to 4 hours. Timolol and its metabolites are excreted principally by the kidney. Plasma levels following oral administration are about half those following i.v. administration indicating approximately 50% first pass metabolism.

The onset of the diuretic action of hydrochlorothiazide occurs in 2 hours and the peak action in about 4 hours. Diuretic activity lasts about 6 to 12 hours. Hydrochlorothiazide is eliminated rapidly by the kidney.

Indications And Clinical Uses:

This fixed combination is not indicated for initial therapy of hypertension. Hypertension requires therapy titrated to the individual patient. It is always better to adjust the dosage of each antihypertensive drug separately, but when the fixed combination corresponds to the optimum drug and dose requirements of the patient its use may be convenient in patient management. For further adjustment of dosage, however, it is best to use the individual drugs again. The treatment of hypertension is not static, but must be re-evaluated as conditions in each patient warrant.

Timolide is indicated for maintenance therapy of patients with hypertension who require timolol maleate and hydrochlorothiazide as part of their treatment in the dosage and ratio present in Timolide.

Contra-Indications:

Congestive heart failure (see Warnings), right ventricular failure secondary to pulmonary hypertension, significant cardiomegaly, sinus bradycardia, second and third degree AV block, cardiogenic shock, allergic rhinitis, bronchospasm (including bronchial asthma), or severe chronic obstructive pulmonary disease (see Precautions), anesthesia with agents that produce myocardial depression, e.g., ether, anuria, hypersensitivity to timolol maleate, hydrochlorothiazide or to sulfonamide-derived drugs.

Warnings in Clinical States:

Cardiac Failure: Special caution should be exercised when administering Timolide to patients with a history of heart failure. Sympathetic stimulation is a vital component supporting circulatory function in congestive heart failure, and inhibition with beta blockade always carries a potential hazard of further depressing myocardial contractility and precipitating cardiac failure.

In patients without a history of cardiac failure, continued depression of the myocardium over a period of time can, in some cases, lead to cardiac failure. In rare instances this has been observed during timolol maleate therapy. Therefore, at the first sign or symptom of impending cardiac failure occurring during therapy with Timolide, patients should be fully digitalized and/or given additional diuretic therapy, and the response observed closely.

Timolol acts selectively without blocking the inotropic action of digitalis on the heart muscle. However, the positive inotropic action of digitalis may be reduced by the negative inotropic effects of timolol when the 2 drugs are used concomitantly. The effects of timolol maleate and digitalis are additive in depressing AV conduction. If cardiac failure persists, therapy with Timolide should be discontinued (see below).

Abrupt Cessation of Therapy: Patients with angina should be warned against abrupt discontinuation of Timolide. There have been reports of severe exacerbation of angina and of myocardial infarction or ventricular arrhythmias occurring in patients with angina pectoris, following abrupt discontinuation of beta blocker therapy including timolol maleate. The last two complications may occur with or without preceding exacerbation of angina pectoris. Therefore, when discontinuation of Timolide is planned in patients with angina pectoris, the dosage should be gradually reduced over a period of about 2 weeks and the patient should continue to be carefully observed. The same frequency of administration should be maintained. In situations of greater urgency, therapy with Timolide should be discontinued stepwise and under conditions of closer observation. If angina markedly worsens or acute coronary insufficiency develops, it is recommended that treatment with Timolide be reinstituted promptly at least temporarily.

Since ischemic heart disease may be unrecognized, the above advice should be followed in patients considered to be at risk of having asymptomatic ischemic heart disease.

Severe sinus bradycardia due to unopposed vagal activity may result from the administration of timolol; in such cases, consider the use of i.v. atropine, and, if no improvement is seen, i.v. isoproterenol.

Various skin rashes and conjunctival xerosis have been reported with beta blockers including timolol maleate. A severe syndrome (oculo-muco-cutaneous syndrome) whose signs include conjunctivitis sicca and psoriasiform rashes, otitis and sclerosing serositis have occurred with the chronic use of one beta-adrenergic blocking agent. This syndrome has not been observed with timolol. However physicians should be alert to the possibility of such reactions and should discontinue treatment in the event that this occurs.

In patients with thyrotoxicosis, timolol may give a false impression of improvement by diminishing peripheral manifestations of hyperthyroidism without improving thyroid function. Special considerations should be given to the potential of timolol to aggravate congestive heart failure. Timolol does not alter thyroid function tests. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta blockade which might precipitate a thyroid storm. Thiazides may decrease serum PBI levels without signs of thyroid disturbance.

In patients with renal disease, thiazides may precipitate azotemia, and cumulative effects may develop in the presence of impaired renal function. If progressive renal impairment becomes evident, Timolide should be discontinued.

In patients with impaired hepatic function or progressive liver disease, even minor alterations in fluid and electrolyte balance may precipitate hepatic coma. Hepatic encephalopathy, manifested by tremors, confusion, and coma, has been reported in association with diuretic therapy including hydrochlorothiazide.

In patients receiving thiazides, sensitivity reactions may occur with or without a history of allergy or bronchial asthma.

The possible exacerbation or activation of systemic lupus erythematosus has been reported with thiazides.

Precautions:

Timolide should be administered with caution to patients prone to non-allergic bronchospasm (e.g., chronic bronchitis, emphysema) since beta-blockade may block bronchodilatation produced by endogenous and exogenous catecholamine stimulation of beta receptors.:

Elective or emergency surgery: Beta-adrenergic receptor blockade impairs the ability of the heart to respond to beta-adrenergically mediated reflex stimuli. 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 with angina pectoris undergoing elective surgery, some authorities recommend gradual withdrawal of beta-adrenergic receptor blocking agents (see recommendations given under Warnings-Abrupt cessation of therapy).

In emergency surgery, since timolol is a competitive inhibitor of beta-adrenergic receptor agonists its effects may be reversed, if necessary, by sufficient doses of such agonists as isoproterenol or levarterenol.

Beta-adrenergic receptor blocking agents may mask the premonitory signs and symptoms of acute hypoglycemia. Therefore, Timolide should be administered with caution to patients subject to spontaneous hypoglycemia, or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycemic agents. Insulin requirements in diabetic patients may be increased, decreased, or unchanged by thiazides. Diabetes mellitus which has been latent may become manifest during administration of thiazide diuretics.

Since timolol is excreted mainly by the kidneys, dosage reduction may be necessary when renal insufficiency is present. Marked hypotension has been observed in patients with severe renal insufficiency undergoing renal hemodialysis following oral administration of 20 mg of timolol.

Patients receiving thiazides should be carefully observed for clinical signs of fluid or electrolyte imbalance (hyponatremia, hypochloremic alkalosis, and hypokalemia). Periodic determination of serum electrolytes should be performed at appropriate intervals. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance include dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis is present, or during concomitant use of corticosteroids or ACTH. Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability). Hypokalemia may be avoided or treated by use of potassium supplements, potassium sparing agents or foods with a high postassium content.

Any chloride deficit during thiazide therapy is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease). Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction rather than administration of salt except in rare instances when the hyponatremia is life threatening. In actual salt depletion, appropriate replacement is the therapy of choice.

Because calcium excretion is decreased by thiazides, Timolide should be discontinued before carrying out tests for parathyroid function. Pathologic changes in the parathyroid glands, with hypercalcemia and hypophosphatemia, have been observed in a few patients on prolonged thiazide therapy; however, the common complications of hyperparathyroidism such as renal lithiasis, bone resorption, and peptic ulceration have not been seen.

The antihypertensive effects of thiazides may be enhanced in the postsympathectomy patient.

Hyperuricemia may occur or acute gout may be precipitated in certain patients receiving thiazide therapy.

Pregnancy: Thiazides cross the placental barrier and appear in cord blood. Timolol has not been studied in human pregnancy. The use of Timolide in pregnancy or in women of childbearing potential requires that the anticipated benefit be weighed against possible risk to mother and/or fetus. These hazards include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions which have occurred in the adult.

Lactation: Although timolol is excreted in the milk of the rat, it is not known whether it is excreted in human milk. Thiazides appear in human milk. If use of the drug is deemed essential, the patient should stop nursing.

Children: The safety for use of timolol in children has not been established; therefore, Timolide is not recommended in the pediatric age group.

Drug Interactions:

The combination of Timolide with an antihypertensive peripheral vasodilator produces a greater fall in blood pressure than either drug alone. The same degree of blood pressure control can be achieved by lower than usual dosages of each drug. Therefore, when using such combined therapy, careful monitoring of the dosages is required until the patient is stabilized.

Close observation of the patient is recommended when Timolide 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.

Thiazides may decrease arterial responsiveness to norepinephrine. This diminution is not sufficient to preclude the therapeutic effectiveness of the pressor agent in therapy.

Thiazides may increase the responsiveness to tubocurarine.

Lithium generally should not be given with diuretics because they reduce its renal clearance and add a high risk of lithium toxicity. Read Prescribing Information for lithium preparations before use of such preparations with Timolide.

Orthostatic hypotension may occur and may be potentiated by alcohol, barbiturates or narcotics.

The rate of elimination of hydrochlorothiazide is decreased somewhat by the coadministration of probenecid without, however, an accompanying reduction in diuresis.

Adverse Reactions:

In clinical trials of 257 patients treated with Timolide the following incidence of adverse reactions was determined.

Adverse Reactions:

Incidence 3% Incidence >1%-<3% Incidence £ 1%

Respiratory dyspnea (3.5%) bronchial spasm (3.1%) cough rales

CNS dizziness (3.8%) headache insomnia local weakness paresthesia vertigo anxiety depression nervousness confusion decreased libido somnolence

Cardiovascular bradycardia hypotension cardiac failure arrhythmia syncope worsening of angina pectoris

Gastrointestinal diarrhea abdominal pain dyspepsia nausea constipation vomiting

Allergic/ Dermatologic pruritus dry mucous membrane pigmentation rash sweating

Genitourinary renal colic urinary frequency

Others fatigue/ tiredness (4.2%) asthenia back pain chest pain edema extremity pain myalgia

Clinical Laboratory Test Findings: Clinically important changes in standard laboratory parameters were rarely associated with the administration of Timolide. The changes in laboratory parameters were not progressive and usually were not associated with clinical manifestations. The most common changes were increases in serum triglycerides and uric acid and decreases in serum potassium and chloride.

Other adverse reactions that have been reported with the individual components are: Respiratory: laryngospasm, epistaxis; CNS: lightheadedness, drowsiness, vivid dreams, abnormal gait, abnormal sensations, agitation, neurosis; Cardiovascular: hypertension, palpitation, orthostatic hypotension (may be aggravated by alcohol, barbiturates, or narcotics), decreased renal perfusion, lengthening of the PR interval, 2nd and 3rd degree AV block, sinus arrest (if SA node previously diseased), cold extremities, Raynaud’s phenomenon; Gastrointestinal: anorexia, gastric irritation, cramping, intrahepatic cholestatic jaundice, pancreatitis, sialadenitis, fecal incontinence, hepatomegaly; Hematologic: leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia, hemolytic anemia; Urogenital: impotence; Hypersensitivity: purpura, photosensitivity, urticaria, exfoliative dermatitis, necrotizing angiitis (vasculitis, cutaneous vasculitis), fever, respiratory distress including pneumonitis, anaphylactic reactions; Special Senses: visual disturbances, including xanthopsia and transient blurred vision, dry eyes, conjunctivitis, itching eyes, tinnitus, vestibular disorder; Other: hyperglycemia, glycosuria, hyperuricemia, muscle cramps, weakness, restlessness, weight loss.

Symptoms And Treatment Of Overdose:

Symptoms: The timolol component may cause bradycardia, hypotension, bronchospasm or acute cardiac failure.

The hydrochlorothiazide component may cause excessive diuresis with electrolyte depletion and dehydration. Signs are dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, gastrointestinal disturbances, mental confusion, delirium, convulsions, shock and coma.

If digitalis has also been administered, hypokalemia may accentuate myocardial abnormalities (e.g. cardiac arrhythmias).

Hydrochlorothiazide may precipitate hepatic coma in cirrhotics, potentiate other antihypertensive agents and decrease responsiveness to norepinephrine.

Treatment: There is no specific antidote. If ingestion is, or may have been, recent, gastric lavage or emesis may reduce absorption; when ingestion has been earlier, infusions may be helpful to promote urinary excretion.

Symptomatic Bradycardia: Use atropine sulfate i.v. 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 cardiac pacemaker may be considered.

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.

Hypotension: Use sympathomimetic pressor drug therapy, such as levarterenol or epinephrine. In refractory cases the use of glucagon hydrochloride has been reported to be useful.

Bronchospasm: Use isoproterenol hydrochloride. Additional therapy with aminophylline may be considered.

Stupor or Coma: Administer supportive therapy as clinically warranted.

Gastrointestinal Effects: Though usually of short duration, these may require symptomatic treatment.

Abnormalities in BUN and/or Serum Electrolytes: Monitor serum electrolyte levels and renal function; institute supportive measures as required individually to maintain hydration, electrolyte balance, respiration and cardiovascular-renal function.

Dosage And Administration:

Dosage must be determined for individual patients by titration of each component separately. Where the fixed combination in Timolide supplies the dosage so determined, the combination product may be used for maintenance therapy.

One tablet of Timolide given once or twice daily can be used to administer 10 to 20 mg timolol and 25 to 50 mg hydrochlorothiazide/day. Giving the 2 tablets in the morning may be tried provided the patient is carefully monitored to assure that the blood pressure remains controlled.

If higher doses of either ingredient are needed the individual components should be used.

When necessary, another antihypertensive agent may be added gradually, beginning with 50% of the usual recommended starting dose to avoid excessive reduction in blood pressure. If during maintenance therapy dosage adjustment is necessary, it is advisable to use the individual drugs.

Availability And Storage:

Each light blue, bevelled edge, hexagonal shaped tablet, marked Frosst 67, contains: timolol maleate 10 mg and hydrochlorothiazide 25 mg. Gluten-, lactose- and tartrazine-free. Bottles of 100.

TIMOLIDE® Merck Frosst Timolol Maleate-Hydrochlorothiazide Antihypertensive

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