Trandate
Trandate Medication Information:
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Trandate 100 mg
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Trandate 200 mg
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Pharmacology
Labetalol is an adrenergic receptor blocking agent possessing both alpha1-(post-synaptic) and beta-receptor blocking activity. Its action on beta-receptors is 4 times stronger than that on alpha-receptors. It antagonizes beta1- and beta2-receptors equally.
The mechanism of the antihypertensive action of labetalol has not been fully established. It is considered that labetalol lowers blood pressure by partially blocking the alpha-adrenoreceptors in the peripheral arterioles, thus causing vasodilation and a resulting reduction of peripheral resistance. At the same time, blockade of the beta-adrenoreceptors in the myocardium prevents reflex tachycardia and subsequent elevation of cardiac output. Peripheral vasodilation is achieved with incomplete blockade of alpha-adrenoreceptors in the arterioles and the barostatic reflexes remain sufficiently active to reduce the incidence of postural hypotension.
At rest labetalol slightly reduces the heart rate, increases the stroke volume but does not significantly affect cardiac output. It reduces exercise-induced increases in systolic pressure and heart rate, again without significantly influencing cardiac output.
Following oral administration to hypertensive patients, labetalol decreases plasma renin activity and aldosterone levels, both at rest and during exercise, particularly when these were elevated prior to treatment. It is significantly more efficacious in hypertensive patients with high baseline plasma noradrenaline levels.
Labetalol is well absorbed from the gastrointestinal tract with peak blood levels occurring 1 to 2 hours after oral dosing. A single oral dose of 200 mg produced average peak plasma levels of 360 µg/100 mL. The drug undergoes extensive first pass metabolism following oral administration. The bioavailability of oral compared to i.v. labetalol is approximately 25%. When taken with food, the bioavailability of unchanged drug is increased although peak plasma levels remain the same. The drug is metabolized mostly by conjugation with glucuronic acid; the resulting metabolite is inactive. Rapid and extensive distribution within tissue compartments occurs after i.v. administration. The drug is approximately 50% bound to plasma proteins. Labetalol and its metabolites are rapidly excreted in urine, and via bile into the feces. The plasma half-life of labetalol is approximately 6 to 8 hours following oral administration.
Labetalol produces a significant fall in blood pressure in 1 to 4 hours after the first oral dose. The maximum blood pressure lowering effect at any particular dose level is usually achieved within 24 to 72 hours.
In a clinical pharmacologic study in severe hypertensives, an initial 0.25 mg/kg injection of labetalol administered to patients in the supine position decreased blood pressure by an average of 11/7 mm Hg. Additional injections of 0.5 mg/kg at 15-minute intervals up to a total cumulative dose of 1.75 mg/kg of labetalol caused further dose-related decreases in blood pressure. Some patients required cumulative doses of up to 3.25 mg/kg. The maximal effect of each dose level occurred within 5 minutes. Following discontinuation of i.v. treatment with labetalol, the blood pressure rose gradually and progressively, approaching pretreatment baseline values within an average of 16 to 18 hours in the majority of patients.
Similar results were obtained in the treatment of patients with severe hypertension requiring urgent blood pressure reduction with an initial dose of 20 mg (which corresponds to 0.25 mg/kg for an 80 kg patient) followed by additional doses of either 40 mg or 80 mg at 10-minute intervals to achieve the desired effect or up to a cumulative dose of 300 mg.
Indications
For treatment of hypertension. Labetalol is usually used in combination with other drugs, particularly a thiazide diuretic. However, it may be tried alone as an initial agent in those patients in whom, in the judgement of the physician, treatment should be started with an alpha-beta-blocker rather than with a diuretic. Labetalol may be used in combination with diuretics and/or other antihypertensive agents to treat severe hypertension.
The combination of labetalol with a diuretic has been found to be compatible. Limited experience with other antihypertensive agents has not shown evidence of incompatibility with labetalol.
Precautions
Drug Interactions
When used with diuretics and/or other antihypertensive agents the dose of labetalol must be appropriately adjusted (see Dosage).
Labetalol and halothane have additive hypotensive effects. High doses of halothane (3%) with labetalol predispose the patient to the myocardial depressant effects of halothane and an undesirable reduction in myocardial performance. The anesthesiologist should be informed when a patient is receiving labetalol.
Labetalol blunts the reflex tachycardia produced by nitroglycerin without preventing its hypotensive effect. When labetalol is used with nitroglycerin in patients with angina pectoris, additional antihypertensive effects may occur.
Cimetidine has been shown to increase the oral bioavailability of labetalol. As cimetidine might be given to patients with hypertension also receiving labetalol, special care should be used in establishing the dose required for blood pressure control in such patients.
In one survey, 2.3% of patients taking labetalol in combination with tricyclic antidepressants experienced tremor as compared to 0.7% reported to occur with labetalol alone. The contribution of each of the treatments to this adverse reaction is unknown, but the possibility of a drug interaction cannot be excluded.
Geriatrics
The bioavailability and half-life of labetalol are increased in the elderly. In addition, the hypotensive response is greater in this age group following administration. Therefore, lower doses of labetalol are likely to be required in elderly patients.
Lactation
Labetalol has been found in the breast milk of lactating women. If the use of labetalol is considered essential, then mothers should stop nursing.
Children
Safety and effectiveness in children have not been established.
Pregnancy
Although no teratogenic effects were seen in animal testing, the safety of the use of labetalol during pregnancy has not been established. Labetalol crosses the placental barrier in women and has been found to bind to the eyes of fetal animals. Labetalol should be used in pregnant women only if the expected benefit to the mother justifies the potential risk to the fetus.
Drug/Laboratory Test Interactions
The presence of a metabolite of labetalol in the urine may result in falsely elevated levels of urinary catecholamines when measured by a nonspecific trihydroxyindole (THI) reaction. In screening patients suspected of having a pheochromocytoma and being treated with labetalol, specific radioenzymatic or high performance liquid chromatographic assay techniques should be used to determine levels of catecholamines or their metabolites.
Supplied
200 mg
Each white, capsule-shaped tablet, scored and engraved LAB 200 on one side, PLB on the other side, contains: labetalol HCl 200 mg. Bottles of 100.
100 mg
Each orange, capsule-shaped tablet, scored and engraved LAB 100 on one side, PLB on the other side, contains: labetalol HCl 100 mg. Bottles of 100.
Contraindications
Uncontrolled congestive heart failure (see Warnings); asthma or a history of obstructive lung disease; greater than first degree AV block; cardiogenic shock and states of hypoperfusion; sinus bradycardia; known sensitivity to labetalol.
Warnings
Cardiac failure should be controlled with digitalis and diuretics before labetalol treatment is initiated. Labetalol should not be given to patients with digitalis-resistant heart failure. Sympathetic stimulation is a vital component supporting circulatory function in congestive heart failure and inhibition with beta-blockade always carries the potential hazard of further depressing myocardial contractibility and precipitating cardiac failure. A few patients developed heart failure while on labetalol. Therefore, administration of labetalol to patients with controlled failure or those likely to develop such failure, must be carried out under careful supervision. The drug does not abolish the inotropic action of digitalis on heart muscle.
Patients with angina should be warned against abrupt discontinuation of beta-adrenergic blocking agents. 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 therapy. The last two complications may occur with or without preceeding exacerbation of angina pectoris. Therefore, when discontinuation of labetalol is planned in patients with angina pectoris, the dosage should be gradually reduced over a period of about 2 weeks and the patient should be carefully observed. The same frequency of administration should be maintained. In situations of greater urgency, labetalol therapy 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 the drug be re-instituted promptly, at least temporarily.
Various skin rashes and conjunctival xerosis have been reported with beta-blockers. A severe syndrome (oculomucocutaneous syndrome) whose signs include conjunctivitis sicca and psoriasiform rashes, otitis, and sclerosing serositis has occurred with the chronic use of one beta-adrenergic blocking agent (practolol). This syndrome has not been observed in association with labetalol or any other such agent. However, physicians should be alert to the possibility of such reactions and should discontinue treatment in the event that they occur.
Animal studies have shown that labetalol binds to the melanin of the uveal tract. The significance of this in humans is not known but periodic ophthalmic examinations are advisable while the patient is taking labetalol.
There have been rare reports of severe hepatocellular injury with labetalol therapy. Injury has occurred after both short-term and long-term treatment and may be slowly progressive despite minimal symptomatology. The hepatic injury is usually reversible but rare cases of hepatic necrosis and death have been reported. Appropriate laboratory testing should be performed at regular intervals during labetalol therapy. Tests should also be done at the first sign or symptom of liver dysfunction (e.g., pruritus, dark urine, persistent anorexia, jaundice, right upper quadrant tenderness or unexplained flu-like symptoms). If there is laboratory evidence of liver injury or the patient is jaundiced, labetalol should be stopped and not restarted.
Severe sinus bradycardia may occur with the use of labetalol from unopposed vagal activity remaining after blockade of beta1-adrenergic receptors; in such cases, dosage should be reduced.
In patients with thyrotoxicosis, possible deleterious effects from long-term use of labetalol have not been adequately appraised. Beta-blockade may mask the clinical signs of continuing hyperthyroidism or complications, and give a false impression of improvement. Therefore, abrupt withdrawal of labetalol may be followed by an exacerbation of the symptoms of hyperthyroidism, including thyroid storm.
While labetalol has been shown to be effective in lowering the blood pressure and relieving symptoms in patients with pheochromocytoma, paradoxical hypertensive responses have been reported in a few patients with this tumor. Use caution when administering labetalol to patients with pheochromocytoma.
Adverse Effects
Gastrointestinal
nausea/vomiting (6.1%), dyspepsia (1.9%), constipation (1.6%), dry mouth/sore throat (1.6%).
Musculoskeletal
aches/pains (3.5%), muscle cramps (1.3%).
Urogenital
impotence (2.2%), failure of ejaculation (0.6%), dysuria (0.6%).
Central Nervous System
fatigue/malaise (13.1%), headache (8.0%), depression (2.6%), loss of libido (1.3%), dreaming (1.3%).
Miscellaneous
visual blurring (4.2%), epistaxis (1.6%).
In addition, in the more extensive trials, bronchospasm and severe bradycardia, were reported with the incidence less than 1%. There are rare reports of raised liver function tests, jaundice (both hepatic and cholestatic), and hepatic necrosis (see Warnings).
Other published or unpublished reports describe other rare, isolated adverse events in patients who were taking labetalol (oral or injectable), as follows: bronchospasm and reduction in PEFR, difficulty in micturition including acute urinary retention, ejaculatory failure, Peyronie's disease, toxic myopathy, tremor, taste distortion, hypersensitivity, hypoesthesia, rashes of various types, such as generalized maculopapular, lichenoid, urticarial, bullous lichen planus, psoriasiform, facial erythema and reversible alopecia and very rarely drug fever. A skin lesion resembling disseminated lupus erythematosus occurred in one patient receiving a high dose of labetalol. There are rare reports of patients who developed lupus-like syndromes while on labetalol which cleared upon discontinuation of treatment. Positive antinuclear factor and antimitochondrial antibodies have been reported in patients receiving the drug, but the significance of these findings is not clear. There is a report of hemiparesis following a rapid fall in blood pressure in a patient who was given a single dose of labetalol i.v.
Clinical Laboratory Tests
Occasional elevations of serum transaminases and blood urea have been reported following administration.
Respiratory
dyspnea (3.8%), nasal congestion (1.3%).
Dermatological
drug rash (3.2%), paresthesia (especially “scalp tingling”) (3.8%), pruritus (0.6%) and angioedema.
Cardiovascular
postural hypotension/dizziness (16.9%), angina pectoris (3.2%), Raynaud's phenomenon (3.2%), pedal edema (1.9%), palpitations (1.3%), bradycardia (<1.0%).
Overdose
Symptoms
Excessive hypotension which is posture-sensitive, and sometimes, excessive bradycardia.
Treatment
Patients should be laid supine and their legs raised, if necessary.
Gastric lavage or pharmacologically-induced emesis (using syrup of ipecac) is useful for removal of the drug shortly after ingestion. Hemodialysis removes less than 1% of circulating labetalol, and is therefore not recommended.
The following additional measures should be employed if necessary:
Excessive Bradycardia: Administer atropine to induce vagal blockade. If bradycardia persists, isoproterenol may be administered cautiously. In refractory cases, the use of a cardiac pacemaker may be considered.
Congestive Heart Failure: Conventional therapy with cardiac glycosides and diuretics.
Hypotension: Administer vasopressors, e.g. norepinephrine.
Bronchospasm: Administer a beta2-stimulating agent and/or a theophylline preparation.
Oliguric renal failure has been reported after massive overdosage of labetalol orally. In one case, the use of dopamine to increase blood pressure may have aggravated the renal failure.
Dosage
Geriatrics
Lower doses of labetalol are likely to be required in elderly patients (see Precautions).
Children
Safe and effective use of labetalol in children have not presently been elucidated.
Patients with liver function impairment will likely require lower doses since metabolism of the drug will be diminished.
