TRANDATE® Roberts Labetalol HCl Antihypertensive
Action and Clinical
Labetalol is an adrenergic receptor blocking agent possessing both alpha 1-(post-synaptic) and beta-receptor blocking activity. Its action on beta-receptors is 4 times stronger than that on alpha-receptors. It antagonizes beta 1- and beta 2-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-adrenoceptors in the peripheral arterioles, thus causing vasodilation and a resulting reduction of peripheral resistance. At the same time, blockade of the beta-adrenoceptors in the myocardium prevents reflex tachycardia and subsequent elevation of cardiac output. Peripheral vasodilation is achieved with incomplete blockade of alpha-adrenoceptors 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 g/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, and 5.5 hours after i.v. 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. Following a bolus i.v. injection, the maximum antihypertensive effect occurs within 5 to 10 minutes in the majority of patients. However, in some patients the peak effect occurs considerably later.
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.
Labetalol administered as a continuous i.v. infusion, with a mean dose of 136 mg (27 to 300 mg) over a period of 2Â to 3 hours (mean of 2 hours and 39 minutes) lowered the blood pressure by an average of 60/35 mm Hg.
Indications And Clinical Uses:
Tablets: For treatment of hypertension. It 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 tablets with a diuretic has been found to be compatible. Limited experience with other antihypertensive agents has not shown evidence of incompatibility with labetalol.
I.V. Injection: For the emergency treatment of severe hypertension when prompt and urgent reduction of blood pressure is essential.
Uncontrolled congestive heart failure (see Warnings); asthma or a history of obstructive airway disease; greater than first degree AV block; cardiogenic shock and states of hypoperfusion; sinus bradycardia; known sensitivity to labetalol.
Warnings in Clinical States:
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 2Â 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 beta 1-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.
During treatment with labetalol injection, signs of cerebral hypoperfusion may occur if blood pressure is reduced too rapidly. Signs include confusion, somnolence, light headedness, dizziness, nausea, vomiting, pallor, sweating, blurred vision, headache, hallucinations and loss of consciousness. Symptoms and signs of myocardial hypoperfusion include chest pain and ischemic changes in the ECG. Although they have not been seen with the use of i.v. labetalol, a number of other adverse reactions including cerebral infarction and optic nerve infarction have been reported with other agents when severely elevated blood pressure was reduced over time- courses or from several hours to as long as 1 or 2 days. The desired blood pressure lowering should therefore be achieved over as long a period of time as is compatible with the patient’s status.
Postural hypotension and syncope may occur in patients treated with labetalol tablets, particularly if the initial dose is too high or if dose titration is too rapid (see Dosage). Treatment should start with small doses without additional alpha- or beta-adrenergic blocking drugs.
Symptomatic postural hypotension (incidence 58%) is likely to occur if patients are tilted or allowed to assume the upright position within 3 hours of receiving labetalol injection. Therefore, the patient’s ability to tolerate the upright position should be established before permitting any ambulation.
Beta-receptor blocking drugs may enhance hypoglycemia in patients prone to this condition. Also, diabetics on insulin or oral hypoglycemic medication may have an increased tendency towards hypoglycemia when treated with these drugs.
Care should be taken if labetalol is used concomitantly with either Class I antiarrhythmic agents or calcium antagonists of the verapamil class since these drugs may potentiate the cardiac depressant activities of labetalol.
In patients with chronic liver disease the oral bioavailability of labetalol is enhanced due to reduced first pass metabolism. Lower doses of labetalol tablets are likely to be required in these patients.
There may be increased difficulty in treating an allergic-type reaction in patients on beta-blockers. In these patients, the reaction may be more severe due to pharmacological effects of beta blockers and problems with fluid changes. Epinephrine should be administered with caution since it may not have its usual effects in the treatment of anaphylaxis. On the one hand, larger doses of epinephrine may be needed to overcome the bronchospasm, while on the other, these doses can be associated with excessive alpha adrenergic stimulation with consequent hypertension, reflex bradycardia and heart block and possible potentiation of bronchospasm. Alternatives to the use of large doses of epinephrine include vigorous supportive care such as fluids and the use of beta agonists including parenteral salbutamol or isoproterenol to overcome bronchospasm and norepinephrine to overcome hypotension.
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 oral or i.v. administration. Therefore, lower doses of labetalol are likely to be required in elderly patients.
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.
Lactation: Labetalol has been found in the breast milk of lactating women. If the use of the drug is considered essential, then mothers should stop nursing.
Children: Safety and effectiveness in children have not been established.
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 anaesthesiologist should be informed when a patient is receiving labetalol.
Labetalol blunts the reflex tachycardia produced by nitroglycerin without preventing its hypotensive effect. When it is used with nitroglycerin in patients with angina pectoris, additional antihypertensive effects may occur.
Cimetidine has been shown to increase the bioavailability of labetalol. As cimetidine might be given to patients with hypertension also receiving labetalol tablets, 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.
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.
The most serious reported adverse effects of labetalol are severe postural hypotension, jaundice and bronchospasm.
Tablets: In well-controlled clinical trials, the most common transient adverse reactions reported at routinely administered therapeutic doses, were postural hypotension and/or dizziness (16.9%), fatigue/malaise (13.1%), and headache (8.0%). Other transient effects include acute retention of urine and difficulty in micturition. The following summarizes the adverse effects reported.
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%).
Gastrointestinal: nausea/vomiting (6.1%), dyspepsia (1.9%), constipation (1.6%), dry mouth/sore throat (1.6%).
Respiratory: dyspnea (3.8%), nasal congestion (1.3%).
Dermatological: drug rash (3.2%), paresthesia (especially “scalp tingling”) (3.8%), pruritus (0.6%) and angioedema.
Urogenital: impotence (2.2%), failure of ejaculation (0.6%), dysuria (0.6%).
Musculoskeletal: aches/pains (3.5%), muscle cramps (1.3%).
CNS: 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, 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).
I.V. Injection: In well controlled clinical trials of 92 patients treated with labetalol injection the most common adverse reactions reported were postural hypotension and/or dizziness (58%), nausea/vomiting (13%), and tingling of the scalp/skin (7%). The following adverse events have been reported with the use of labetalol:
Cardiovascular: postural hypotension/dizziness (58%), ventricular arrhythmia (1%), bradycardia (<1%).
Gastrointestinal: nausea/vomiting (13%), dyspepsia (1%), taste distortion (1%).
Respiratory: dyspnea (1%).
Dermatological: paresthesia (especially “scalp tingling”) (7%), hypoesthesia (1%), pruritus (1%).
CNS: somnolence/yawning (3%), vertigo (1%).
Other published or unpublished reports describe other rare, isolated adverse events in patients who were taking labetalol, as follows: bronchospasm and reduction in PEFR, difficulty in micturition including acute urinary retention, ejaculatory failure, Peyronie’s disease, toxic myopathy, tremor, hypersensitivity, 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 oral administration. Elevations of BUN and serum creatinine following bolus injections were reported in 6.8% of patients.
Symptoms And Treatment Of Overdose :
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 beta 2-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 And Administration:
Tablets: Labetalol should be taken preferably after food. The dosage must always be adjusted in accordance with the individual requirements of the patient. The recommended initial dose is 100 mg twice daily whether used alone or with a diuretic. Thereafter, the dose should be adjusted semi- weekly or weekly according to the response.
The usual maintenance dose is 200 to 400 mg twice daily. Patients may require up to 1 200 mg/day, in 2 divided doses.
Optimal doses are usually lower in patients also receiving a diuretic since an additive antihypertensive effect can be expected.
Geriatrics: Lower doses of labetalol are likely to be required in elderly patients (see Precautions).
Children: Safe and effective use of labetalol tablets in children has not presently been elucidated.
Patients with liver function impairment will likely require lower doses since metabolism of the drug will be diminished.
I.V. Injection: The administration of i.v. labetalol should be restricted to hospitalized patients. Dosage must be individualized according to the severity of the hypertension, to the nature and duration of previous therapy and to the response of the patient during dosing.
Patients should be kept supine during the period of i.v. drug administration because a substantial fall in blood pressure on standing may be anticipated in these patients. The patient’s ability to tolerate the upright position (e.g. use of toilet facilities) should be established, especially during the 3 hours post injection.
The blood pressure should be monitored during and after completion of the infusion or i.v. injections. Rapid or excessive falls in either systolic or diastolic blood pressure during i.v. treatment should be avoided. In patients with excessive systolic hypertension, the decrease in systolic pressure should be used as an indicator of effectiveness in addition to the response of the diastolic pressure.
Lower doses of labetalol are likely to be required in elderly patients (see Precautions).
Either of 2 methods of administration of labetalol injection may be used: repeated i.v. injection or slow continuous infusion.
Repeated i.v. injection: Initially, labetalol injection should be given in a dose ofÂ 20Â mg labetalol (which corresponds to 0.25 mg/kg for an 80 kg patient) by slow i.v. injection over a 2-minute period.
Immediately before the injection and at 5 and 10 minutes after injection, supine blood pressure should be measured to evaluate response. Additional injections of 40 mg can be given at 10-minute intervals until a desired supine blood pressure is achieved or a total of 300 mg labetalol has been injected. The maximum effect usually occurs within 5 to 10 minutes of each injection but may be longer.
Slow continuous infusion: Labetalol is prepared for i.v. continuous infusion by diluting the vial contents with commonly used i.v. fluids (see below). Two methods of preparing the infusion solution: The contents of 2 vials (40mL) are added to 160 mL of a commonly used i.v. fluid such that the resultant 200 mL of solution contains 200 mg of labetalol, 1 mg/mL. The diluted solution should be administered at a rate of 2 mL/min to deliver 2 mg/min. Alternatively, the contents of 2 vials (40 mL) of labetalol injection can be added to 250 mL of a commonly used i.v. fluid. The resultant solution will contain 200 mg of labetalol, approximately 2 mg/3 mL. The diluted solution should be administered at a rate of 3 mL/min to deliver approximately 2 mg/min.
The rate of infusion of the diluted solution may be adjusted downward according to the blood pressure response, at the discretion of the physician. To facilitate a desired rate of infusion, the diluted solution can be infused using a controlled administration mechanism, e.g. graduated burette or mechanically driven infusion pump.
Since the half-life of labetalol is 5 to 8 hours, steady-state blood levels (in the face of a constant rate of infusion) would not be reached during the usual infusion time period. The infusion should be continued until a satisfactory response is obtained and should then be stopped and oral medication started when it has been established that the supine diastolic blood pressure has begun to rise. The effective i.v. dose is usually in the range of 50 to 200 mg. A total dose of up to 300 mg may be required in some patients.
Compatibility with commonly used i.v. fluids: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Labetalol injection was tested for compatibility with commonly used i.v. fluids at final concentrations of 1.25 mg to 3.75 mg labetalol/mL of the mixture. Labetalol injection was found to be compatible with and stable (for 24 hours refrigerated or at room temperature ) in mixtures with the following solutions: Ringer’s Injection USP, Lactated Ringer’s Injection USP, 5% Dextrose and Ringer’s Injection, 5% Lactated Ringer’s and 5% Dextrose Injection, 5% Dextrose Injection USP, 0.9% Sodium Chloride Injection USP, 5% Dextrose and 0.2% Sodium Chloride Injection USP, 2.5% Dextrose and 0.45% Sodium Chloride Injection USP, 5% Dextrose and 0.9% Sodium Chloride Injection USP, and 5% Dextrose and 0.33% Sodium Chloride Injection USP. Labetalol injection was not compatible with 5% Sodium Bicarbonate Injection USP.
Availability And Storage:
Tablets: 100 mg: Each capsule-shaped, orange, film-coated tablet, engraved TRANDATE 100 on one side, scored and engraved RP on the other side, contains: labetalol HCl USP 100 mg. Also contains lactose. Tartrazine-free. Bottles of 100.
200 mg: Each capsule-shaped, white, film-coated tablet, engraved TRANDATE 200 on one side, scored and engraved RP on the other side, contains: labetalol HCl USP 200 mg. Also contains lactose. Tartrazine-free. Bottles of 100.
Injection: Each mL contains: labetalol HCl 5 mg. Also contains methylparaben and propylparaben. Multidose vials of 20 mL, boxes of 6.
TRANDATE® Roberts Labetalol HCl Antihypertensive