labetalol hcl 100 mg tablet

Uses

Labetalol is used for the management of hypertension. The drug is used for hypertension associated with angina or pheochromocytoma and during pregnancy. IV labetalol is used for hypertension associated with myocardial infarction and to control blood pressure in patients with severe hypertension or in hypertensive crises.

In addition, IV labetalol has been used to produce controlled hypotension during anesthesia and to control blood pressure in preeclampsia. The drug also has been used in the management of sympathetic overactivity syndrome with severe tetanus and in angina.

Hypertension

Labetalol hydrochloride is used alone or in combination with other classes of antihypertensive agents in the management of hypertension. Although β-blockers were previously considered a drug of choice for the initial management of hypertension, most current guidelines no longer recommend these drugs as first-line therapy because of the lack of established superiority over other recommended drug classes and at least one study demonstrating that they may be less effective than angiotensin II receptor antagonists in preventing cardiovascular death, myocardial infarction, or stroke. However, β-blockers may still be considered in hypertensive patients who have a compelling indication (e.g., prior myocardial infarction, ischemic heart disease, heart failure) for their use or as add-on therapy in those who do not respond adequately to the preferred drug classes (angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, or thiazide diuretics). (See and )

In general, black hypertensive patients tend to respond better to monotherapy with thiazide diuretics or calcium-channel blocking agents than to monotherapy with β-blockers. Although β-blockers have lowered blood pressure in all races studied, monotherapy with these agents has produced a smaller reduction in blood pressure in black hypertensive patients; however, this population difference in response does not appear to occur during combined therapy with a β-blocker and a thiazide diuretic. (See and in .)

Labetalol is at least as effective as pure β-blockers, thiazide diuretics, methyldopa, or clonidine.

For additional information on the role of β-blockers in the management of hypertension, see Uses in and .

Hypertension Associated with Angina or Myocardial Infarction

Oral labetalol has been used effectively for the management of hypertension in patients with coexisting angina pectoris, and IV labetalol has been used effectively for the management of hypertension associated with acute myocardial infarction. In patients with hypertension and ischemic heart disease, oral labetalol therapy reduced blood pressure and heart rate and was associated with elimination or reduction of anginal pain, improvement in exercise tolerance, and decreased consumption of nitroglycerin. In the management of hypertension associated with acute myocardial infarction, IV infusions of labetalol decreased blood pressure and heart rate and generally decreased cardiac index and pulmonary artery wedge pressure, without producing adverse hemodynamic effects.

Hypertension during Pregnancy

Labetalol has been used for the management of hypertension in pregnant women. The drug has been effective in controlling blood pressure in pregnant women with moderate to severe hypertension, in those with severe pregnancy-induced hypertension, and in those with hypertension and superimposed pregnancy-induced hypertension. In addition, in hypertensive pregnant women with proteinuria, labetalol therapy has resulted in substantially less proteinuria.

The goal of antihypertensive treatment in pregnant women with hypertension is to minimize the acute complications of maternal hypertension while avoiding therapy that would compromise fetal well-being. Antihypertensive therapy is recommended in pregnant women with chronic hypertension who have persistent, severely elevated blood pressure (e.g., systolic blood pressure of 160 mm Hg or higher or diastolic blood pressure of 105 mm Hg or higher); it is less clear whether antihypertensive therapy should be initiated in women with mild to moderate chronic hypertension. If initiation of antihypertensive therapy is considered necessary in a pregnant woman, use of labetalol, nifedipine, or methyldopa is recommended by the American College of Obstetricians and Gynecologists (ACOG) and other experts. In women who are already receiving antihypertensive therapy prior to pregnancy, ACOG states there are insufficient data to make recommendations regarding the continuance or discontinuance of such therapy; treatment decisions should be individualized in these situations. Antihypertensive therapy can reduce the risk of severe hypertension but has not been shown to prevent the development of preeclampsia. Use of labetalol in association with careful prenatal management during pregnancy does not appear to adversely affect the fetus.(See Cautions: Pregnancy, Fertility, and Lactation.)

Labetalol also has been used parenterally in the hospital setting for urgent lowering of blood pressure in severely hypertensive pregnant women, including those with preeclampsia. Recommendations for the management of such patients are based principally on experience in women with preeclampsia or gestational hypertension in the third trimester. Delivery is the preferred method of management for women with severe preeclampsia; however, use of antihypertensive drugs is recommended in such women who have severely elevated blood pressures (sustained systolic blood pressure of at least 160 mm Hg or diastolic blood pressure of at least 110 mm Hg) to prevent potentially life-threatening cardiovascular, renal, and cerebrovascular complications. Results of several randomized clinical trials evaluating antihypertensive therapy in women with severe hypertension during pregnancy suggest that IV labetalol, IV hydralazine, or oral nifedipine are appropriate antihypertensives for urgently lowering blood pressure in such patients; choice of therapy should be based on clinician experience and preference as well as patient-specific factors (e.g., concomitant medical conditions or therapies) and drug-related factors (e.g., route of administration, adverse effects, contraindications, local availability, cost). Although hydralazine historically has been considered the agent of choice for management of hypertensive emergencies associated with pregnancy, some clinicians now prefer IV labetalol for its more rapid onset and shorter duration of action and its more predictable hypotensive effect. If antihypertensive therapy is considered for the management of preeclampsia, it should be recognized that such therapy is employed solely for maternal benefit; it does not improve perinatal outcomes and may adversely affect uteroplacental flow.

Hypertension Associated with Pheochromocytoma

Because of labetalol's α- and β-adrenergic blocking activity, the drug has been used alone to control hypertension and symptoms resulting from excessive β-receptor stimulation in patients with pheochromocytoma. Labetalol generally appears to be effective in these patients; some evidence suggests that the drug may be more effective in patients whose tumors predominantly secrete epinephrine rather than norepinephrine and in patients with sustained rather than paroxysmal hypertension. Since there have been reports that oral labetalol may induce a paradoxical hypertensive crisis in some patients with pheochromocytoma (possibly because the drug's predominant β-adrenergic blockade leaves α-adrenergic stimulation relatively unopposed), the manufacturers recommend that the drug be used with caution in patients with this tumor. Although labetalol has some α-adrenergic blocking activity, some clinicians caution that the drug, like other β-adrenergic blocking agents, should not be used in patients with pheochromocytoma unless they have received pretreatment with an α-adrenergic blocking agent (e.g., IV phentolamine). If labetalol is used in patients with known or suspected pheochromocytoma, appropriate methods for determining urinary catecholamines should be employed.(See Laboratory Test Interferences: Urinary Catecholamines.)

Severe Hypertension and Hypertensive Crises

IV labetalol hydrochloride is used to control blood pressure in patients with severe hypertension or in hypertensive crises for the immediate reduction in blood pressure in patients in whom such reduction is considered an emergency (hypertensive emergencies). Hypertensive emergencies are those rare situations requiring immediate blood pressure reduction (not necessarily to normal ranges) to prevent or limit target organ damage. Such emergency situations include hypertensive encephalopathy, intracerebral hemorrhage, unstable angina pectoris, acute myocardial infarction, pulmonary edema, dissecting aortic aneurysm, and eclampsia, and labetalol generally is suitable for most hypertensive emergencies except when acute cardiac failure is present. Patients with hypertensive emergencies require hospitalization and are treated with an appropriate parenteral agent. Elevated blood pressure alone, in the absence of manifestations or other evidence of target organ damage, rarely requires emergency therapy. The risks of overly aggressive therapy in any hypertensive crisis must always be considered. Excessive falls in blood pressure should be avoided in any hypertensive crisis since they may precipitate renal, cerebral, or coronary ischemia.

Labetalol usually produces a prompt, but gradual reduction of blood pressure without substantial changes in heart rate or cardiac output. IV labetalol appears to adequately reduce blood pressure in about 80-90% of patients with severe hypertension or hypertensive emergencies, irrespective of etiology, and may be useful even when other drugs have failed. The exact effects of previous antihypertensive therapy on the efficacy of IV labetalol have not been fully determined. IV labetalol generally appears to be effective regardless of whether patients have received other hypotensive drugs, including β-blockers; however, in some studies, the drug was reported to be ineffective, usually in patients who received a single IV injection and who were receiving other hypotensive drugs, including β-blockers. The possibility of a diminished response to IV labetalol should be considered in patients receiving α- or β-blockers.

The comparative efficacy and safety of IV labetalol and other currently available parenteral hypotensive agents in the management of severe hypertension and hypertensive emergencies have not been fully evaluated, but IV labetalol is considered one of several parenteral drugs of choice for the management of these forms of hypertension. IV labetalol appears to be as effective as IV diazoxide (parenteral formulation no longer commercially available in the US), but may be less likely to induce excessive hypotension and adverse neurologic or cardiovascular sequelae. Because of its usual lack of substantial changes in heart rate or cardiac output, IV labetalol may be particularly useful in severely hypertensive patients with ischemic heart disease. In addition, IV labetalol has an advantage over most other parenteral hypotensive agents in that oral therapy with the drug may be continued after parenteral therapy when long-term control of blood pressure is necessary. IV labetalol also has been used effectively to control blood pressure and the rate of left ventricular pressure rise (dp/dt) in a few patients with acute dissection of the aorta; the drug produced a gradual reduction in blood pressure without a concomitant increase in heart rate.

Hypertensive urgencies are those situations in which there is a severe elevation in blood pressure without progressive target organ damage. Such urgencies include the upper levels of stage 2 hypertension associated with severe headache, shortness of breath, epistaxis, or severe anxiety. Hypertensive urgencies generally can be managed by intensification or reinstitution (e.g., following noncompliance) of the current antihypertensive regimen or with oral doses of short-acting antihypertensive agents such as labetalol followed by several hours of observation. However, there is no evidence suggesting that failure to aggressively reduce blood pressure in these patients is associated with any short-term risk. In fact, overly aggressive management of severe elevations in blood pressure not associated with impending or progressing organ damage can sometimes lead to cumulative hypotensive effects.

IV labetalol has been used effectively in a small number of patients for the management of hypertensive crises following discontinuance of clonidine, and oral labetalol has been used effectively in a small number of patients to prevent such crises during withdrawal from clonidine therapy. However, since severe rebound hypertension reportedly has occurred in at least one patient during gradual withdrawal of clonidine and concurrent oral administration of labetalol, some clinicians caution that labetalol not be used in such patients unless they have received pretreatment with an α-blocker (e.g., IV phentolamine).

Controlled Hypotension during Anesthesia

IV labetalol hydrochloride has been used effectively to produce controlled hypotension during anesthesia in order to reduce bleeding resulting from surgical procedures. When labetalol and halothane are used concomitantly, a synergistic hypotensive effect results, which may be used to therapeutic advantage.(See Drug Interactions: Halothane.) Labetalol has also been effective in the management of uncontrolled hypertension before anesthesia and during surgery, and for the management and/or prevention of acute hypertensive responses during laryngoscopy.

Chronic Stable Angina

Labetalol has been used in a limited number of patients for the management of chronic stable angina pectoris. Use of the drug has been associated with a reduction in the frequency and severity of anginal attacks, a decrease in nitrate dosage, and an increase in exercise tolerance. β-Blockers are recommended as the anti-ischemic drugs of choice in most patients with chronic stable angina; despite differences in cardioselectivity, intrinsic sympathomimetic activity, and other clinical factors, all β-blockers appear to be equally effective for this indication. For additional information on the role of β-blockers in the management of chronic stable angina, see Uses: Chronic Stable Angina, .

Tetanus

Labetalol has been used with good results for the management of the sympathetic overactivity syndrome associated with severe tetanus. The drug generally has been effective in stabilizing the cardiovascular disturbances, including hypertension, tachycardia, and increased systemic arteriolar resistance, that occur in patients with severe tetanus.

Dosage and Administration

Administration

Labetalol hydrochloride is usually administered orally, but may be administered by slow, direct IV injection or by slow, continuous IV infusion.

Oral Administration

Labetalol hydrochloride is usually administered orally in 2 divided doses daily; however, if adverse effects (e.g., nausea, dizziness) occur and are intolerable (particularly with dosages of 1.2 g daily or higher), administration of the drug in 3 divided doses daily may improve patient tolerance and/or facilitate dosage titration.

IV Administration

To control blood pressure in patients with severe hypertension or hypertensive emergencies, repeated doses of labetalol hydrochloride may be given by slow, direct IV injection over a 2-minute period at intervals of 10 minutes, or a diluted solution of the drug may be administered by slow, continuous IV infusion. For IV infusion, labetalol hydrochloride solutions are prepared by diluting the injection to an appropriate concentration in a compatible IV infusion solution.(See Chemistry and Stability: Stability.) For example, 200 mg of the drug may be added to 160 mL of 5% dextrose injection to provide a solution containing 1 mg/mL. To facilitate a desired rate of infusion, diluted solutions of the drug can be administered via a controlled-infusion device. Labetalol hydrochloride injection and diluted solutions of the drug should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Prefilled syringes of the drug should be destroyed and discarded if damaged in any manner; if the cannula is bent, no attempt should be made to straighten it.

Patients receiving IV labetalol must be kept in a supine position during administration of the drug; a substantial fall in blood pressure on standing should be expected in these patients. Since symptomatic orthostatic hypotension is likely to occur if these patients are tilted upward or allowed to assume an upright position within 3 hours after administration of the drug, they should remain in a supine position during this time period. The patient's ability to tolerate an upright position must be established before any ambulation is permitted.(See Cautions: Precautions and Contraindications.) Blood pressure must be closely monitored during and after completion of IV administration of labetalol. Rapid or excessive reductions in systolic or diastolic blood pressure during IV therapy with the drug should be avoided. In patients with excessive systolic hypertension, the decrease in systolic pressure, as well as the decrease in diastolic pressure, should be used to assess response to the drug. When labetalol is administered by direct IV injection, blood pressure should be monitored before and at 5-minute intervals after each injection; the maximum hypotensive effect usually occurs within 5-15 minutes after each injection. When the drug is administered by continuous IV infusion, the rate of infusion may be adjusted according to the supine blood pressure response. After the desired supine blood pressure is attained or the maximum recommended cumulative dose has been given, IV administration of labetalol should be discontinued. Following discontinuance of IV labetalol, blood pressure is usually monitored at 5-minute intervals for 30 minutes, then at 30-minute intervals for 2 hours, then hourly for about 6 hours, and as necessary thereafter. Oral therapy with the drug may be initiated when it has been established that the supine diastolic blood pressure has begun to increase (usually determined by an increase of 10 mm Hg).

Dosage

Hypertension

Dosage of oral labetalol hydrochloride should be adjusted according to standing blood pressure. Some adverse effects (e.g., nausea, dizziness) of the drug may be minimized or avoided and patient tolerance improved if dosage is adjusted more gradually (e.g., every 2-4 weeks) over a period of 4-12 weeks. The maximum, steady-state blood pressure response with twice-daily dosing occurs within 1-3 days and, with continued dosing, blood pressure can be measured approximately 12 hours after a dose to determine if further dosage titration is necessary. Since the maximum hypotensive effect of the drug is usually evident within 1-4 hours, lack of an excessive hypotensive response to the initial dose or a dose increment can usually be established in an ambulatory clinical setting.

If long-term labetalol therapy is to be discontinued, dosage of the drug should be reduced gradually over a period of 1-2 weeks.(See Cautions: Precautions and Contraindications.)

Usual Dosage

For the management of hypertension in adults, the recommended initial oral dosage of labetalol hydrochloride is 100 mg twice daily, given alone or in combination with a diuretic. Dosage may be adjusted in increments of 100 mg twice daily every 2 or 3 days until the optimum blood pressure response is achieved.

The usual oral maintenance dosage of labetalol hydrochloride recommended by the manufacturers for adults is 200-400 mg twice daily. Some experts recommend a lower usual dosage range of 100-400 mg twice daily; the rationale for this reduced dosage is that it usually is preferable to add another antihypertensive agent to the regimen than to continue increasing labetalol hydrochloride dosage since the patient may not tolerate such continued increases. Because some geriatric individuals eliminate labetalol more slowly than younger adults, a lower maintenance dosage than that recommended for the general population may be adequate to control blood pressure in these older patients. Some manufacturers suggest that a maintenance dosage of 100-200 mg twice daily may be adequate for most geriatric patients. The manufacturers state that some adults with severe hypertension may require labetalol hydrochloride dosages of up to 2.4 g daily given in 2 divided doses, administered alone or in combination with a diuretic; in these patients, dosage titration increments should not exceed 200 mg twice daily.

The panel members appointed to the Eighth Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8 expert panel) state that evidence-based dosing information (i.e., dosages shown in randomized controlled trials to reduce complications of hypertension) should be used when available to determine target dosages of antihypertensive agents. Target dosages generally can be achieved within 2-4 weeks, but it may take up to several months.

When diuretic therapy is initiated in a patient already receiving labetalol hydrochloride, adjustment of labetalol dosage may be necessary. Optimum maintenance dosage of oral labetalol hydrochloride is usually lower in patients also receiving a diuretic.

When patients are transferred from therapy with other antihypertensive agents, oral therapy with labetalol hydrochloride should be initiated in the usual initial dosage and dosage of the existing regimen gradually decreased.

If labetalol hydrochloride is used for the management of hypertension in children, some experts recommend a usual initial oral dosage of 1-3 mg/kg daily given in 2 divided doses. Dosage may be increased as necessary to a maximum dosage of 10-12 mg/kg (up to 1.2 g) daily given in 2 divided doses.

In patients who experience intolerable adverse effects with labetalol, dosage reduction should be considered; if adverse effects worsen or fail to resolve, it may be necessary to discontinue the β-blocker and initiate another class of antihypertensive agent.

Blood Pressure Monitoring and Treatment Goals

Careful monitoring of blood pressure during initial titration or subsequent upward adjustment in dosage of labetalol hydrochloride is recommended.

The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure; specific target levels of blood pressure should be individualized based on consideration of multiple factors, including patient age and comorbidities, and the currently available evidence from clinical studies.

Severe Hypertension and Hypertensive Crises

Dosage of labetalol hydrochloride must be adjusted according to the severity of hypertension and the patient's blood pressure response and tolerance. IV dosage of labetalol hydrochloride should be adjusted according to supine blood pressure. When IV labetalol hydrochloride is used in the management of a hypertensive emergency in adults, the initial goal of such therapy is to reduce mean arterial blood pressure by no more than 25% within minutes to 1 hour, followed by further reduction if stable toward 160/100 to 110 mm Hg within the next 2-6 hours, avoiding excessive declines in pressure that could precipitate renal, cerebral, or coronary ischemia. If this blood pressure is well tolerated and the patient is clinically stable, further gradual reductions toward normal can be implemented in the next 24-48 hours. Patients with aortic dissection should have their systolic pressure reduced to less than 100 mm Hg if tolerated.

To control blood pressure in adults with severe hypertension or hypertensive emergencies, IV labetalol hydrochloride may be given in an initial dose of 20-80 mg by slow, direct IV injection. Higher initial doses (e.g., 1-2 mg/kg) have been administered by direct IV injection, but the 20-mg dose is recommended to minimize adverse effects (e.g., nausea, excessive hypotension) and the risks associated with too rapid reduction in blood pressure. Additional doses, usually 40-80 mg (range: 20-80 mg), may be given at 10-minute intervals until the desired supine blood pressure is achieved or a total cumulative dose of 300 mg has been administered; IV labetalol should then be discontinued and oral therapy with the drug may be initiated when the diastolic blood pressure begins to increase.

As an alternative to direct IV injections, labetalol hydrochloride may be given by continuous IV infusion at an initial rate of 0.5-2 mg/minute, with the rate of infusion adjusted according to the blood pressure response. The usual effective, cumulative dose administered by IV infusion is 50-200 mg, although up to 300 mg may be required in some patients. Because of the elimination half-life of labetalol, steady-state plasma concentrations of the drug are not attained during the usual infusion period. The infusion should be continued until an adequate response is obtained (or the maximum recommended cumulative dose has been given) and then discontinued, and oral therapy with the drug initiated when the supine diastolic blood pressure begins to increase. Some clinicians have used a progressive, incremental IV infusion regimen (i.e., infusing 20, 40, 80, and 160 mg/hour for 1 hour at each dose level, or until the desired blood pressure is achieved) and believe this method may result in a more gradual reduction of blood pressure and minimize adverse effects compared with repeated IV injections of the drug; however, controlled comparisons of the various methods of IV administration are not available. Some clinicians have also used oral regimens for urgent reduction of blood pressure in severely hypertensive patients.

For rapid reduction of blood pressure in pediatric patients (1-17 years of age) with severe hypertension, some experts recommend administration of labetalol hydrochloride as a direct IV injection of 0.2-1 mg/kg per dose, up to 40 mg per dose. As an alternative to direct IV injections, labetalol hydrochloride may be given by continuous IV infusion of 0.25-3 mg/kg per hour.

When oral labetalol therapy is initiated following IV therapy with the drug, the recommended initial oral dose in adults is 200 mg, followed in 6-12 hours by an additional oral dose of 200 or 400 mg, depending on the blood pressure response. Thereafter, while the patient is hospitalized, oral dosage may be increased in usual increments at 1-day intervals, if necessary, to achieve the desired blood pressure control; for subsequent outpatient dosage titration or maintenance dosing, the usual oral dosage recommendations should be followed.

Preeclampsia

To control acute severe hypertension in pregnant women with preeclampsia when delivery is imminent, IV labetalol hydrochloride has been given in an initial dose of 20 mg by slow, direct IV injection, followed by 40 mg IV 10 minutes later and then 80-mg doses at 10-minute intervals for 2 additional doses to a maximum total cumulative dose of 220 mg. Antihypertensive therapy is recommended for women with preeclampsia who have persistent systolic blood pressures of 160 mm Hg or higher or diastolic blood pressures of 110 mm Hg or higher. Blood pressure should be monitored closely.

Controlled Hypotension during Anesthesia

To produce controlled hypotension during halothane anesthesia in adults, IV labetalol hydrochloride has been given in an initial dose of 20 mg (range: 10-25 mg) following induction of anesthesia; if necessary, additional doses of 5-10 mg (range: 2.5-15 mg) were given. When IV labetalol hydrochloride and halothane anesthesia are used concomitantly, the degree and duration of the synergistic hypotensive response can be controlled by adjusting the inspired halothane concentration.(See Drug Interactions: Halothane.) To produce controlled hypotension during anesthesia with other anesthetic agents in adults, IV labetalol hydrochloride has been given in an initial dose of 30 mg, with additional doses of 5-10 mg given if necessary.

Dosage in Renal and Hepatic Impairment

Modification of labetalol hydrochloride dosage does not appear to be necessary in patients with mild to moderate renal impairment. In patients with severe renal impairment (i.e., creatinine clearance less than 10 mL/minute) undergoing dialysis, adequate blood pressure control may be possible with once-daily dosing of the drug.

Although specific data are currently not available, dosage reduction may be necessary in patients with impaired hepatic function since metabolism of the drug may be decreased in these patients.

Cautions

Labetalol hydrochloride shares the toxic potentials of β-adrenergic and postsynaptic α₁-adrenergic blocking agents. Most adverse reactions to labetalol are mild, transient, and occur early in the course of treatment. Adverse effects of labetalol can generally be divided into 3 groups (in decreasing order of frequency): nonspecific effects, effects related to the α-adrenergic blocking activity of the drug, and effects related to its β-adrenergic blocking activity. During controlled clinical studies in patients receiving oral labetalol for 3-4 months, adverse reactions requiring discontinuance of the drug occurred in about 7% of patients; in these same comparative studies, adverse reactions requiring discontinuance of therapy occurred in 8-10% of patients receiving pure β-adrenergic blocking agents (i.e., metoprolol, propranolol) and in 30% of patients receiving a centrally acting adrenergic inhibitor (i.e., methyldopa). Evidence from clinical studies in patients receiving oral labetalol hydrochloride dosages of 200 mg to 2.4 g daily suggests that some adverse effects, including dizziness, fatigue, nausea, vomiting, dyspepsia, paresthesia, nasal congestion, failure to ejaculate, impotence, and edema, are dose related. The incidence and/or severity of some labetalol-induced adverse reactions may occasionally be obviated by slow, upward titration of dosage over 4-12 weeks.

Cardiovascular Effects

The most frequent adverse cardiovascular effect of labetalol is symptomatic orthostatic hypotension, which occurs in about 1-5% or 60% of patients following oral or IV administration of the drug, respectively. Orthostatic hypotension has been associated with loss of consciousness occasionally following IV administration and rarely following oral administration. Symptomatic orthostatic hypotension is likely to occur if supine patients are tilted upward or allowed to assume the upright position within 3 hours following IV administration of labetalol.(See Cautions: Precautions and Contraindications.) Moderate hypotension occurs in about 1% of patients in the supine position who are receiving the drug IV. Following oral administration, orthostatic hypotension appears to occur more frequently during initiation of therapy, in patients receiving concomitant administration of a diuretic, and in those receiving higher dosages of the drug.

Development or exacerbation of heart failure has occurred in some patients receiving labetalol, although the drug appears to be less likely to precipitate heart failure than pure β-adrenergic blocking agents. At the first sign or symptom of impending cardiac failure during labetalol therapy, patients should receive adequate treatment (e.g., cardiac glycoside, diuretic) and should be observed closely; if cardiac failure continues, labetalol should be discontinued, gradually if possible.

Ventricular arrhythmia (including ventricular premature contractions), edema or fluid retention, bradycardia, hypotension, syncope, chest pain, atrioventricular (AV) conduction delay, and AV block have occurred during therapy with labetalol.

Nervous System Effects

Adverse nervous system effects occur with variable frequency with labetalol and most of these effects appear to be dose related. At the usual labetalol hydrochloride dosage of 200-400 mg twice daily, most adverse nervous system effects occur in 5% or less of patients. Adverse nervous system effects of the drug include drowsiness or tiredness, dizziness or lightheadedness (often posture related), headache, fatigue, lethargy, and nightmares or vivid dreams. Paresthesia, usually mild, transient tingling of the scalp or skin, may also occur following oral or IV administration of the drug, usually at the beginning of therapy. Hypoesthesia or numbness and circumoral paresthesia have also occurred. Mental depression, paroniria, vertigo, somnolence, yawning, tremor, asthenia, and insomnia have also been reported. Some adverse nervous system effects such as fatigue, mental depression, and sleep disorders may occur less frequently with labetalol than with pure β-adrenergic blocking agents. Adverse nervous system effects of labetalol may be obviated by a reduction in dosage or alteration of dosage schedule.

GI Effects

The most frequent adverse GI effects associated with labetalol therapy are nausea, dyspepsia, and vomiting. Alteration or distortion in taste, abdominal pain, constipation, diarrhea, and flatulence have also been reported.

Hepatic Effects

Elevated liver function test results, including reversible increases in serum aminotransferase concentrations; jaundice (including cholestatic jaundice); and hepatitis have been reported in patients receiving labetalol. Severe hepatocellular injury, which has recurred during rechallenge, has occurred rarely during labetalol therapy; hepatocellular injury may be accompanied by clinical symptoms of hepatotoxicity, including pruritus, dark urine, persistent anorexia, jaundice, flu-like syndrome, and/or right upper quadrant tenderness. Hepatocellular injury is usually reversible; however, hepatic necrosis and death have been reported. Hepatic injury may occur after short- or long-term labetalol therapy. Similar severe adverse hepatic effects, including at least 2 fatalities, have been reported with dilevalol hydrochloride; dilevalol is one of the 4 stereoisomers that make up the racemic mixture labetalol.(See Chemistry and Stability: Chemistry.)

Respiratory Effects

Adverse respiratory effects of labetalol, including dyspnea, wheezing, bronchospasm, and nasal congestion, occur occasionally. Rhinorrhea and rhinitis also have been reported.

Genitourinary Effects

Ejaculatory failure, impotence, difficult or painful micturition, and acute urinary retention have occurred occasionally in patients receiving labetalol alone or in fixed combination with hydrochlorothiazide. Peyronie's disease and priapism have been reported rarely. Urinary frequency, nocturia, and polyuria have been reported when the drug was used in fixed combination with hydrochlorothiazide.

Dermatologic and Sensitivity Reactions

Rashes, including maculopapular, lichenoid, urticarial, and psoriasiform lesions, have developed in some patients during labetalol therapy (alone or in fixed combination with hydrochlorothiazide). Pruritus, bullous lichen planus, facial erythema, and reversible alopecia have also occurred. Hypersensitivity (e.g., rash, urticaria, pruritus, angioedema, dyspnea) and anaphylactoid reactions have been reported rarely in patients receiving labetalol.

Endocrine Effects

Results of a large prospective cohort study of nondiabetic adults 45-64 years of age indicate that use of β-adrenergic blocking agents in hypertensive patients is associated with increased risk (about 28%) of developing type 2 diabetes mellitus compared with hypertensive patients who were not receiving hypotensive therapy. In this study, the number of new cases of diabetes per 1000 person-years was 33.6 or 26.3 in patients receiving a β-adrenergic blocking agents or no drug therapy, respectively. The association between the risk of developing type 2 diabetes mellitus and use of β-adrenergic blocking agents reportedly was not confounded by weight gain, hyperinsulinemia, or differences in heart rate. It is not known if the risk of developing diabetes is affected by β-receptor selectivity. Further studies are needed to determine whether concomitant use of ACE inhibitors (which may improve insulin sensitivity) would abrogate β-blocker-induced adverse effects related to glucose intolerance. Therefore, until results of such studies are available, the proven benefits of β-adrenergic blocking agents in reducing cardiovascular events in hypertensive patients must be weighed carefully against the possible risks of developing type 2 diabetes mellitus.

Hypoglycemia, which may result in loss of consciousness, also may occur in nondiabetic patients receiving β-adrenergic blocking agents. Patients most at risk for the development of β-blocker-induced hypoglycemia are those undergoing dialysis, prolonged fasting, or severe exercise regimens.

β-Adrenergic blocking agents may mask signs and symptoms of hypoglycemia (e.g., palpitation, tachycardia, tremor) and potentiate insulin-induced hypoglycemia. Although it has been suggested that nonselective β-adrenergic blocking agents are more likely to induce hypoglycemia than selective β-blockers agents, such an adverse effect also has been reported with selective β-blocking agents (e.g., atenolol). In addition, selective β-adrenergic blocking agents are less likely to mask symptoms of hypoglycemia or delay recovery from insulin-induced hypoglycemia than nonselective β-adrenergic blocking agents because of their vascular sparing effects; however, selective β-blockers can decrease insulin sensitivity by approximately 15-30%, which may result in increased insulin requirements.

Other Adverse Effects

Lupus erythematosus-like illness, positive antinuclear antibody (ANA) titer, mild hyperglycemia, leukopenia, and development of positive antimitochondrial antibodies have occurred in patients receiving labetalol. Transient increases in BUN and serum creatinine concentrations associated with decreases in blood pressure have also occurred, usually in patients with renal insufficiency. Flushing or a feeling of warmth, fever, rigors, increased sweating, dry mouth or eyes, blurred vision, visual disturbances, pallor, shivering, decreased libido, muscle cramps, toxic myopathy, claudication, Raynaud's phenomenon, burning sensation of the groin, and pain at the injection site have been reported. In addition, leg cramps, pain, gout, increased appetite, hypokalemia, and increased serum creatine kinase (CK, creatine phosphokinase, CPK) concentrations have been reported when the drug was used in fixed combination with hydrochlorothiazide.

The possibility that other adverse effects associated with other β-adrenergic blocking agents may occur during labetalol therapy should be considered. These include, but may not be limited to, hematologic reactions (e.g., agranulocytosis, nonthrombocytopenic or thrombocytopenic purpura); allergic reactions characterized by fever, sore throat, laryngospasm, and respiratory distress; GI reactions including mesenteric thrombosis or ischemic colitis; and CNS reactions including reversible mental depression progressing to catatonia, short-term memory loss, decreased performance on neuropsychometric tests, and oculomucocutaneous syndrome.

Precautions and Contraindications

Labetalol shares the toxic potentials of β-adrenergic and postsynaptic α₁-adrenergic blocking agents, and the usual precautions of these agents should be observed.

In patients with heart failure, sympathetic stimulation is vital for the support of circulatory function. Labetalol should be used with caution in patients with inadequate cardiac function, since heart failure may be precipitated by blockade of β-adrenergic stimulation when labetalol therapy is administered. In addition, in patients with latent cardiac insufficiency, prolonged β-adrenergic blockade may lead to cardiac failure. Although β-adrenergic blocking agents should be avoided in patients with overt heart failure, labetalol may be administered cautiously, if necessary, to patients with well-compensated heart failure (e.g., those controlled with cardiac glycosides and/or diuretics). Patients receiving labetalol therapy should be instructed to consult their clinician at the first sign or symptom of impending cardiac failure and should be adequately treated (e.g., with a cardiac glycoside and/or diuretic) and observed closely; if cardiac failure continues, labetalol should be discontinued, gradually if possible.

Further experience is necessary, but labetalol may be less likely than pure β-adrenergic blocking agents to produce adverse cardiovascular withdrawal reactions (e.g., angina, rebound hypertension) following abrupt withdrawal. Although angina pectoris has not been reported to date following discontinuance of labetalol therapy, exacerbation of angina pectoris and precipitation of myocardial infarction have occurred following abrupt cessation of therapy with some β-adrenergic blocking agents in patients with coronary artery disease. Therefore, patients receiving labetalol (especially those with ischemic heart disease) should be warned not to interrupt or discontinue therapy without consulting their clinician. When discontinuance of long-term labetalol therapy is planned, particularly in patients with ischemic heart disease, dosage of the drug should be gradually reduced over a period of 1-2 weeks. When labetalol therapy is discontinued, patients should be carefully monitored and advised to temporarily limit their physical activity. If exacerbation of angina occurs or acute coronary insufficiency develops after labetalol therapy is interrupted or discontinued, treatment with the drug should be reinstituted promptly, at least temporarily, and appropriate measures for the management of unstable angina pectoris should be initiated. Because coronary artery disease is common and may be unrecognized, the manufacturers caution that it may be prudent not to discontinue labetalol therapy abruptly, even in patients being treated only for hypertension.

Since β-adrenergic blocking agents may inhibit bronchodilation produced by endogenous catecholamines, the drugs generally should not be used in patients with bronchospastic disease; however, oral labetalol may be used with caution in patients with nonallergic bronchospasm (e.g., chronic bronchitis, emphysema) who do not respond to or cannot tolerate other hypotensive agents.(See Pharmacology: Respiratory Effects.) If oral labetalol is administered to such patients, the smallest effective dose should be used so that inhibition of endogenous or exogenous β-adrenergic agonist activity is minimized. Because IV labetalol at the usual therapeutic doses has not been studied in patients with nonallergic bronchospasm, the manufacturers state that it should not be used in these patients.

Although labetalol has been used effectively in the management of hypertension and relief of symptoms associated with pheochromocytoma, the drug should be used with caution in patients with this tumor since paradoxical hypertensive responses have been reported in a few patients.(See Hypertension Associated with Pheochromocytoma under Uses: Hypertension.)

It is recommended that labetalol be used with caution in patients with diabetes mellitus receiving hypoglycemic agents, especially those with labile disease or those prone to hypoglycemia since the drug may mask the signs and symptoms associated with acute hypoglycemia (e.g., tachycardia and blood pressure changes but not sweating). β-Adrenergic blocking agents also may impair glucose tolerance; delay the rate of recovery of blood glucose concentration following drug-induced hypoglycemia; alter the hemodynamic response to hypoglycemia, possibly resulting in an exaggerated hypertensive response; and possibly impair peripheral circulation.(See Cautions: Endocrine Effects.) However, many clinicians state that patients with diabetes mellitus may be particularly likely to experience a reduction in morbidity and mortality with the use of β-adrenergic blocking agents. If labetalol is used in diabetic patients receiving hypoglycemic agents, it may be necessary to adjust the dosage of the hypoglycemic agent.

The necessity of withdrawing β-adrenergic blocking therapy prior to major surgery is controversial. Severe, protracted hypotension and difficulty in restarting or maintaining a heart beat have occurred during surgery in some patients who have received β-adrenergic blocking agents. The effect of labetalol's α-adrenergic activity in patients undergoing major surgery has not been evaluated. However, several deaths have been reported in patients in whom labetalol hydrochloride injection was used during surgery, including those receiving the drug to control bleeding. In addition, a synergistic hypotensive response occurs in patients receiving IV labetalol and halothane anesthesia concomitantly.(See Drug Interactions: Halothane.) If labetalol therapy is continued in a patient undergoing major surgery, the anesthesiologist should be informed that the patient is receiving the drug.

Caution must be employed when reducing severely elevated blood pressure. The manufacturers state that IV labetalol is intended for use in hospitalized patients. When IV labetalol is used in patients with severely elevated blood pressure, the desired blood pressure reduction should be achieved over as long a period of time as is compatible with the patient's clinical status. Serious adverse effects, including cerebral infarction, optic nerve infarction, angina, and ischemic changes in the ECG, have been reported with other hypotensive agents when severely elevated blood pressure was reduced over periods ranging from several hours to as long as 1 or 2 days. Rapid or excessive reductions in systolic or diastolic blood pressure should be avoided; while these effects are unlikely with the recommended dosage schedules of IV labetalol, they can occasionally occur. Transient hypotension occurring with IV labetalol is usually readily managed by placing the patient in Trendelenburg's position, administering IV fluids, and/or temporarily discontinuing administration of the drug. Patients should remain supine during and for up to 3 hours after IV administration of the drug, since symptomatic orthostatic hypotension is likely to occur if they are tilted upward or allowed to assume an upright position during this period. The patient's ability to tolerate an upright position should be established before any ambulation (e.g., use of toilet facilities) is permitted; the patient should be advised on how to proceed gradually to become ambulatory and should be observed at the time of initial ambulation.

Labetalol should be used with caution in patients with impaired hepatic function, since metabolism of the drug may be decreased in such patients. Since labetalol has been rarely associated with the development of jaundice, hepatitis, severe hepatocellular injury, and elevated liver function test results, the manufacturers recommend that the drug be discontinued immediately if jaundice or laboratory evidence of hepatic injury occurs. Jaundice and hepatic dysfunction usually are reversible following discontinuance of the drug. Liver function tests should be performed at the first signs or symptoms of liver dysfunction (e.g., pruritus, dark urine, persistent anorexia, jaundice, right upper quadrant tenderness, flu-like syndrome).

Routine laboratory tests are usually not required before or after IV administration of labetalol, but the manufacturers recommend that laboratory parameters be monitored at regular intervals in patients receiving long-term oral therapy with the drug. In patients with concomitant illnesses (e.g., impaired renal function), appropriate tests should be performed to monitor these conditions.

Patients should be advised that transient scalp tingling may occur, usually during initiation of labetalol therapy.

Patients with a history of atopy or severe anaphylactic reactions to a variety of allergens may be more reactive to repeated, accidental, diagnostic, or therapeutic challenge with such allergens while receiving a β-adrenergic blocking agent. These patients may be less responsive than other patients to usual dosages of epinephrine or may develop a paradoxical response to epinephrine when that drug is used to treat anaphylactic reactions.

Labetalol is contraindicated in patients with a history of obstructive airway disease (e.g., bronchial asthma), overt cardiac failure, heart block of severity greater than first degree, cardiogenic shock, severe bradycardia, and/or other conditions associated with severe and prolonged hypotension. The drug also is contraindicated in patients with a history of hypersensitivity to any component of the formulation.

Because of similarity in spelling between labetalol hydrochloride and Lamictal (the trade name for lamotrigine, an anticonvulsant agent), several dispensing errors have been reported to the manufacturer of Lamictal (GlaxoSmithKline). These medication errors may be associated with serious adverse events either due to lack of appropriate therapy for seizures (e.g., in patients not receiving the prescribed anticonvulsant, lamotrigine, which may lead to status epilepticus) or, alternatively, to the risk of developing adverse effects (e.g., serious rash) associated with the use of lamotrigine in patients for whom the drug was not prescribed and consequently was not properly titrated. Therefore, the manufacturer of Lamictal cautions that extra care should be exercised in ensuring the accuracy of both oral and written prescriptions for Lamictal and labetalol. The manufacturer also recommends that when appropriate, clinicians might consider including the intended use of the particular drug on the prescription in addition to alerting patients to carefully check the drug they receive and promptly bring any question or concern to the attention of the dispensing pharmacist. The manufacturer also recommends that pharmacists assess the measures of avoiding dispensing errors and implement them as appropriate (e.g., placing drugs with similar names apart from one another in product storage areas, patient counseling).

Pediatric Precautions

Although safety and efficacy remain to be fully established in children, some experts have recommended pediatric dosages for hypertension based on currently limited clinical experience.

Geriatric Precautions

Orthostatic hypotension, dizziness, or lightheadedness, similar to that reported in younger adults, have been reported in geriatric patients (i.e., those 60 years of age or older) receiving labetalol. Geriatric individuals are generally more likely than younger adults to experience orthostatic symptoms and these individuals should be cautioned about the possibility of these adverse effects during therapy with the drug. Because elimination of labetalol may be decreased in some geriatric patients, usual maintenance dosage of the drug is slightly lower in geriatric individuals than in younger adults.(See Dosage and Administration: Dosage.)

Mutagenicity and Carcinogenicity

It is not known if labetalol is mutagenic or carcinogenic in humans. No evidence of labetalol-induced mutagenesis was seen with the modified Ames test or in studies in mice and rats using dominant lethal assays.

No evidence of carcinogenesis was seen in mice receiving oral labetalol hydrochloride dosages up to 200 mg/kg daily for 18 months or in rats receiving oral dosages up to 225 mg/kg daily for up to 113 weeks in females and up to 116 weeks in males.

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rats and rabbits using oral labetalol hydrochloride dosages up to about 6 and 4 times the maximum recommended human dosage, respectively, have not revealed reproducible evidence of fetal malformation; however, oral dosages approximating the maximum recommended human dosage were associated with an increased incidence of fetal resorption in both species. There was no evidence of drug-related fetotoxicity in rabbits receiving IV dosages of the drug up to 1.7 times the maximum recommended human dosage.In rats, oral administration of labetalol hydrochloride at dosages 2-4 times the maximum recommended human dosage during the period of late gestation through weaning was associated with decreased neonatal survival. Reproduction studies in rats or rabbits using combined oral labetalol hydrochloride and hydrochlorothiazide dosages up to about 15 and 80 times the maximum recommended human dosage, respectively, have not revealed evidence of teratogenicity, although combined oral dosages 3.5 and 20 times the maximum recommended human dosage, respectively, were maternotoxic with resultant fetotoxicity in rabbits. The combination appeared to be more toxic than either drug alone in rabbits.

Labetalol has been used orally for the management of hypertension in pregnant women and IV to control blood pressure in severely hypertensive pregnant women requiring urgent blood pressure reduction.(See Hypertension during Pregnancy under Uses: Hypertension.) Labetalol has been effective for the management of hypertension associated with pregnancy, and is one of several preferred agents for such use. Infants of mothers who received labetalol for the management of hypertension during pregnancy have not appeared to be adversely affected by the drug; however, transient hypotension (including slight decreases in systolic blood pressure during the first 24 hours after delivery), bradycardia, respiratory depression, and hypoglycemia have been reported rarely in neonates. Maternal labetalol therapy reportedly has been associated with a beneficial effect on development of fetal pulmonary maturity. Use of labetalol in pregnant women with hypertension does not appear to affect the usual course of labor and delivery, and the drug has been used IV to treat severe hypertension during labor. Following a single IV dose of the drug in pregnant women with preeclampsia, maternal blood pressure was reduced but placental and fetal blood flow were not affected. The manufacturers state that there are no adequate and controlled studies to date using labetalol in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.

Fertility

The effects of labetalol on fertility in humans have not been fully determined. Ejaculatory failure and impotence in males and decreased libido have been reported in patients receiving labetalol.

Lactation

Since small amounts (about 0.004% of the maternal dose) of labetalol are distributed into milk, the drug should be used with caution in nursing women.

Drug Interactions

Since IV labetalol hydrochloride may be administered to patients receiving other drugs, including other hypotensive agents, careful monitoring of these patients is necessary to detect and promptly treat any adverse effect resulting from concomitant administration.

Diuretics and Cardiovascular Drugs

When labetalol is administered with diuretics or other hypotensive drugs, the hypotensive effect may be increased. This effect is usually used to therapeutic advantage, but careful adjustment of dosage is necessary to avoid excessive hypotension when these drugs are used concomitantly. When β-adrenergic blocking agents are administered with calcium-channel blocking agents, therapeutic as well as adverse effects may be additive. Slowing or complete suppression of SA node activity with development of slow ventricular rates (e.g., 30-40 bpm), often misdiagnosed as complete AV block, has been reported in patients receiving the nondihydropyridine calcium-channel blocking agent mibefradil (no longer commercially available in the US), principally in geriatric patients and in association with concomitant β-adrenergic blocker therapy. The manufacturers of labetalol and some clinicians state that labetalol and a calcium-channel blocking agent (e.g., verapamil, diltiazem) should be used concomitantly with caution.

Halothane

Concomitant administration of IV labetalol and halothane anesthesia results in a synergistic hypotensive effect, the degree and duration of which may be controlled by adjusting the halothane concentration; however, excessive hypotension can result in a large reduction in cardiac output and an increase in central venous pressure. To minimize the risk of excessive hypotension during controlled hypotensive anesthesia with IV labetalol and halothane, inspired halothane concentrations of 3% or higher should not be used. If labetalol therapy is continued in a patient undergoing major surgery, the anesthesiologist should be informed that the patient is receiving the drug.

Cimetidine

Concomitant administration of oral cimetidine has been shown to substantially increase the absolute bioavailability of oral labetalol, possibly via enhanced absorption or decreased first-pass hepatic metabolism of labetalol. If labetalol and cimetidine are administered concomitantly, dosage of labetalol required for optimal control of blood pressure should be carefully adjusted.

Glutethimide

Concomitant administration of oral glutethimide (no longer commercially available in the US) has been shown to substantially decrease the absolute bioavailability of oral labetalol, possibly by increasing first-pass hepatic metabolism (glucuronidation) of labetalol. If labetalol and glutethimide are administered concomitantly, dosage of labetalol required for optimal control of blood pressure should be carefully adjusted.

Other Drugs

Labetalol, like other drugs with β-adrenergic blocking activity, can antagonize the bronchodilation produced by β-adrenergic agonists in patients with bronchospasm, and greater than usual dosages of β-adrenergic agonist bronchodilators may be required in patients receiving labetalol.

Labetalol antagonizes the reflex tachycardia produced by nitroglycerin without preventing the hypotensive effect of the nitrate. If labetalol is used concurrently with nitroglycerin, an additive hypotensive effect may occur.

An increased incidence of tremor has been reported in patients receiving labetalol and tricyclic antidepressants concomitantly compared with those receiving labetalol alone. Although the contribution of each drug to this adverse reaction is not known, the possibility of a drug interaction cannot be excluded.

Pharmacokinetics

Absorption

Labetalol hydrochloride is rapidly and approximately 90-100% absorbed from the GI tract following oral administration, but the drug undergoes extensive first-pass metabolism in the liver and/or GI mucosa. Only about 25% of an oral dose reaches systemic circulation unchanged in fasted adults. Although absolute bioavailability in one study reportedly ranged from 11-86% (mean: 33%) following oral administration of a single 100-mg dose in fasted adults, the considerable interindividual variability in this study may have resulted from use of a relatively insensitive spectrofluorometric assay. Food delays GI absorption of labetalol hydrochloride but increases absolute bioavailability of the drug, possibly by decreasing first-pass metabolism and/or hepatic blood flow. Following oral administration of a single 200-mg dose in healthy adults in one study, absolute bioavailability of the drug averaged 26 and 36% in the fasted and nonfasted state, respectively. First-pass metabolism may also be reduced and bioavailability substantially increased in geriatric patients and in patients with hepatic dysfunction. However, in one study in patients with hepatosplenic schistosomiasis, mean absolute bioavailability of the drug was reportedly decreased when compared with healthy individuals. Oral cimetidine increases, and glutethimide decreases, the bioavailability of labetalol.(See Drug Interactions.) Concomitant oral administration of labetalol hydrochloride and hydrochlorothiazide does not affect the bioavailability of either drug.

Following multiple-dose oral administration of labetalol hydrochloride, peak plasma concentrations are generally achieved within 40 minutes to 2 hours. Peak plasma concentrations reportedly increase proportionately with oral dosage at dosages ranging from 100 mg to 3 g daily. In one study in hypertensive patients, peak plasma labetalol concentration following oral administration of 200 mg 3 times daily or 300 mg twice daily averaged 323 or 430 ng/mL, respectively, and the steady-state plasma drug concentration averaged 149 or 145 ng/mL, respectively; based on pharmacokinetic and pharmacodynamic (i.e., blood pressure response) evaluation, these dosage regimens were considered equivalent. Following IV injection over 1 minute of a 1.5-mg/kg dose of labetalol hydrochloride in one study, a mean peak plasma concentration of about 5.7 mcg/mL occurred 2 minutes after injection and plasma concentration had declined to an average of 575 ng/mL at 10.5 minutes after injection.

The relationship between plasma labetalol concentration and pharmacologic effects of the drug has not been clearly established. Relationships between pharmacologic effects (e.g., blood pressure response, response of exercise-induced tachycardia) and dose, logarithm of plasma labetalol concentration, and/or area under the plasma concentration-time curve (AUC) have been reported in some studies, but such relationships were not found in other studies. In general, there appears to be a correlation between plasma labetalol concentration and blood pressure reduction, particularly in the upright position, but there is wide interindividual variation.

Following oral administration of labetalol hydrochloride, the hypotensive effect of the drug is generally apparent within 20 minutes to 2 hours, maximal within 1-4 hours, and persists in a dose-dependent manner for about 8-12 or 12-24 hours after a single 200- or 300-mg dose, respectively. The maximum, steady-state blood pressure response with twice-daily dosing occurs within 1-3 days. Following slow, direct IV injection of the drug, the hypotensive effect is apparent within 2-5 minutes, is usually maximal within 5-15 minutes, and generally persists for about 2-4 hours, although a longer duration of effect (i.e., up to 24 hours) has been reported in some patients.

Distribution

Following IV administration, labetalol is rapidly and widely distributed into the extravascular space. The drug has an apparent volume of distribution of 3.2-15.7 L/kg. In one study in healthy adults, the volume of distribution in the central compartment (V_c) and at steady state (V_ss) averaged 1.1 and 9.4 L/kg, respectively. The apparent volume of distribution is reportedly decreased in patients with impaired hepatic function but is similar to that of healthy individuals in patients with impaired renal function or in pregnant women. In animals, the drug distributes in highest concentrations into the lungs, liver, and kidneys; only minimal amounts cross the blood-brain barrier.

In vitro, labetalol is approximately 50% bound to plasma proteins at plasma labetalol concentrations of 0.1-50 mcg/mL.

Labetalol crosses the placenta. In one study in several pregnant women receiving the drug orally (200 mg 3 times daily) for about 7 days, the median ratio of fetal cord to maternal plasma concentration at parturition was 0.5. Small amounts of unchanged labetalol have been shown to distribute into the fetal uveal tract following administration of radiolabeled drug in pregnant animals; the drug bound reversibly to melanin in the uveal tract but was not oculotoxic. Small amounts of labetalol and its metabolites are distributed into milk, principally as unbound labetalol.

Elimination

Plasma concentrations of labetalol appear to decline in a biphasic or possibly triphasic manner. In healthy adults and adults with hypertension, the half-life in the distribution phase (t_½α) has been reported to average 6-44 minutes and the half-life in the terminal elimination phase (t_½β) has been reported to average 2.5-8 hours. The variability in reported mean half-lives for the drug may have resulted in part from use of a relatively insensitive spectrofluorometric assay in some studies. The manufacturers state that the drug has a plasma elimination half-life of 5.5 or 6-8 hours following IV or oral administration, respectively. The elimination half-life of the drug appears to be unchanged in individuals with renal or hepatic impairment, but may be increased in patients with severe renal impairment (i.e., creatinine clearance less than 10 mL/minute) undergoing dialysis. Results of some studies indicate that elimination of labetalol may be reduced in geriatric individuals; elimination half-life of the drug reportedly may be slightly increased (but within the reported range) in some geriatric individuals. Total body clearance of labetalol from plasma has been reported to average 19-33 mL/minute per kg in individuals with normal renal and hepatic function. Plasma clearance appears to be unaffected by renal impairment but may be decreased in patients with hepatic impairment.

Labetalol is extensively metabolized in the liver and possibly in the GI mucosa following oral administration, principally by conjugation with glucuronic acid. The major metabolite is the O-alkylglucuronide, with smaller amounts of the O-phenylglucuronide and N-glucuronide being formed. Following oral administration, labetalol undergoes extensive first-pass metabolism in the liver and/or GI mucosa.(See Pharmacokinetics: Absorption.)

Labetalol and its metabolites are excreted in feces via biliary elimination and in urine. About 55-60% of a dose is excreted in urine, mainly as glucuronide conjugates, within 24 hours, and about 30% is excreted in feces within 4 days. Less than 5% of a dose is excreted unchanged in urine. Labetalol is not appreciably removed (less than 1% of a dose) by hemodialysis or peritoneal dialysis.