Angina pectoris has not been reported upon labetalol hydrochloride discontinuation. However, hypersensitivity to catecholamines has been observed in patients withdrawn from beta-blocker therapy; exacerbation of angina and, in some cases, myocardial infarction have occurred after abrupt discontinuation of such therapy. When discontinuing chronically administered labetalol hydrochloride, particularly in patients with ischemic heart disease, the dosage should be gradually reduced over a period of 1 to 2 weeks and the patient should be carefully monitored. If angina markedly worsens or acute coronary insufficiency develops, therapy with labetalol hydrochloride should be reinstituted promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken. Patients should be warned against interruption or discontinuation of therapy without the physician’s advice. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue therapy with labetalol hydrochloride abruptly in patients being treated for hypertension.
Nonallergic Bronchospasm (e.g., Chronic Bronchitis and Emphysema) Patients with bronchospastic disease should, in general, not receive beta-blockers. Labetalol hydrochloride may be used with caution, however, in patients who do not respond to, or cannot tolerate, other antihypertensive agents. It is prudent, if labetalol hydrochloride is used, to use the smallest effective dose, so that inhibition of endogenous or exogenous beta-agonists is minimized.
Labetalol hydrochloride has been shown to be effective in lowering blood pressure and relieving symptoms in patients with pheochromocytoma. However, paradoxical hypertensive responses have been reported in a few patients with this tumor; therefore, use caution when administering labetalol hydrochloride to patients with pheochromocytoma.
Diabetes Mellitus and Hypoglycemia
Beta-adrenergic blockade may prevent the appearance of premonitory signs and symptoms (e.g., tachycardia) of acute hypoglycemia. This is especially important with labile diabetics. Beta-blockade also reduces the release of insulin in response to hyperglycemia; it may therefore be necessary to adjust the dose of antidiabetic drugs.
Do not routinely withdraw chronic beta-blocker therapy prior to surgery. The effect of labetalol hydrochloride’s alpha-adrenergic activity has not been evaluated in this setting.
A synergism between labetalol hydrochloride and halothane anesthesia has been shown [see Precautions, Drug Interactions].
Impaired Hepatic Function
Labetalol hydrochloride should be used with caution in patients with impaired hepatic function since metabolism of the drug may be diminished.
Intraoperative Floppy Iris Syndrome (IFIS)
Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients treated with alpha-1 blockers (labetalol is an alpha/beta blocker). This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient’s ophthalmologist should be prepared for possible modifications to the surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit of stopping alpha-1 blocker therapy prior to cataract surgery.
Jaundice or Hepatic Dysfunction
As with all drugs with beta-blocking activity, certain advice to patients being treated with labetalol hydrochloride is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects. While no incident of the abrupt withdrawal phenomenon (exacerbation of angina pectoris) has been reported with labetalol hydrochloride, dosing with labetalol hydrochloride should not be interrupted or discontinued without a physician’s advice. Patients being treated with labetalol hydrochloride should consult a physician at any signs or symptoms of impending cardiac failure or hepatic dysfunction [see Warnings]. Also, transient scalp tingling may occur, usually when treatment with labetalol hydrochloride is initiated [see Adverse Reactions].
As with any new drug given over prolonged periods, laboratory parameters should be observed over regular intervals. In patients with concomitant illnesses, such as impaired renal function, appropriate tests should be done to monitor these conditions.
In one survey, 2.3% of patients taking labetalol hydrochloride in combination with tricyclic antidepressants experienced tremor, as compared to 0.7% reported to occur with labetalol hydrochloride alone. The contribution of each of the treatments to this adverse reaction is unknown, but the possibility of a drug interaction cannot be excluded.
Drugs possessing beta-blocking properties can blunt the bronchodilator effect of beta-receptor agonist drugs in patients with bronchospasm; therefore, doses greater than the normal anti-asthmatic dose of beta-agonist bronchodilator drugs may be required.
Cimetidine has been shown to increase the bioavailability of labetalol hydrochloride. Since this could be explained either by enhanced absorption or by an alteration of hepatic metabolism of labetalol hydrochloride, special care should be used in establishing the dose required for blood pressure control in such patients.
Synergism has been shown between halothane anesthesia and intravenously administered labetalol hydrochloride. During controlled hypotensive anesthesia using labetalol hydrochloride in association with halothane, high concentrations (3% or above) of halothane should not be used because the degree of hypotension will be increased and because of the possibility of a large reduction in cardiac output and an increase in central venous pressure. The anesthesiologist should be informed when a patient is receiving labetalol hydrochloride.
Labetalol hydrochloride blunts the reflex tachycardia produced by nitroglycerin without preventing its hypotensive effect. If labetalol hydrochloride is used with nitroglycerin in patients with angina pectoris, additional antihypertensive effects may occur.
Care should be taken if labetalol is used concomitantly with calcium antagonists of the verapamil type.
Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.
Risk of Anaphylactic Reaction
While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.
The presence of labetalol metabolites in the urine may result in falsely elevated levels of urinary catecholamines, metanephrine, normetanephrine, and vanillylmandelic acid when measured by fluorimetric or photometric methods. In screening patients suspected of having a pheochromocytoma and being treated with labetalol hydrochloride, a specific method, such as a high performance liquid chromatographic assay with solid phase extraction (e.g., J. Chromatogr 385:241,1987) should be employed in determining levels of catecholamines.
Labetalol hydrochloride has also been reported to produce a false-positive test for amphetamine when screening urine for the presence of drugs using the commercially available assay methods TOXI-LAB® A (thin-layer chromatographic assay) and EMIT-d.a.u.® (radioenzymatic assay). When patients being treated with labetalol have a positive urine test for amphetamine using these techniques, confirmation should be made by using more specific methods, such as a gas chromatographic-mass spectrometer technique.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term oral dosing studies with labetalol hydrochloride for 18 months in mice and for 2 years in rats showed no evidence of carcinogenesis. Studies with labetalol hydrochloride using dominant lethal assays in rats and mice and exposing microorganisms according to modified Ames tests showed no evidence of mutagenesis.
Pregnancy Category C
Teratogenic studies were performed with labetalol in rats and rabbits at oral doses up to approximately six and four times the maximum recommended human dose (MRHD), respectively. No reproducible evidence of fetal malformations was observed. Increased fetal resorptions were seen in both species at doses approximating the MRHD. A teratology study performed with labetalol in rabbits at intravenous doses up to 1.7 times the MRHD revealed no evidence of drug-related harm to the fetus. There are no adequate and well-controlled studies in pregnant women. Labetalol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Hypotension, bradycardia, hypoglycemia, and respiratory depression have been reported in infants of mothers who were treated with labetalol hydrochloride for hypertension during pregnancy. Oral administration of labetalol to rats during late gestation through weaning at doses of two to four times the MRHD caused a decrease in neonatal survival.
Labetalol hydrochloride given to pregnant women with hypertension did not appear to affect the usual course of labor and delivery.
Small amounts of labetalol (approximately 0.004% of the maternal dose) are excreted in human milk. Caution should be exercised when labetalol hydrochloride is administered to a nursing woman.
Safety and effectiveness in pediatric patients have not been established.
As in the general population, some elderly patients (60 years of age and older) have experienced orthostatic hypotension, dizziness, or lightheadedness during treatment with labetalol. Because elderly patients are generally more likely than younger patients to experience orthostatic symptoms, they should be cautioned about the possibility of such side effects during treatment with labetalol.
Most adverse effects are mild and transient and occur early in the course of treatment. In controlled clinical trials of 3 to 4 months’ duration, discontinuation of labetalol hydrochloride due to one or more adverse effects was required in 7% of all patients. In these same trials, other agents with solely beta-blocking activity used in the control groups led to discontinuation in 8% to 10% of patients, and a centrally acting alpha-agonist led to discontinuation in 30% of patients.
The incidence rates of adverse reactions listed in the following table were derived from multicenter, controlled clinical trials comparing labetalol hydrochloride, placebo, metoprolol, and propranolol over treatment periods of 3 and 4 months. Where the frequency of adverse effects for labetalol hydrochloride and placebo is similar, causal relationship is uncertain. The rates are based on adverse reactions considered probably drug related by the investigator. If all reports are considered, the rates are somewhat higher (e.g., dizziness, 20%; nausea, 14%; fatigue, 11%), but the overall conclusions are unchanged.
|Labetalol Hydrochloride (N=227) %||Placebo (N=98) %||Propranolol (N=84) %||Metoprolol (N=49) %|
|Body as a whole|
|Vomiting||less than 1||0||0||0|
|Diarrhea||less than 1||0||2||0|
|Central and Peripheral Nervous Systems|
|Paresthesia||less than 1||0||0||0|
|Drowsiness||less than 1||2||2||2|
|Autonomic Nervous System|
|Increased sweating||less than 1||0||0||0|
The adverse effects were reported spontaneously and are representative of the incidence of adverse effects that may be observed in a properly selected hypertensive patient population, i.e., a group excluding patients with bronchospastic disease, overt congestive heart failure, or other contraindications to beta-blocker therapy.
Clinical trials also included studies utilizing daily doses up to 2400 mg in more severely hypertensive patients. Certain of the side effects increased with increasing dose, as shown in the following table that depicts the entire U.S. therapeutic trials data base for adverse reactions that are clearly or possibly dose related.
|Labetalol Hydrochloride Daily Dose (mg)||200||300||400||600||800||900||1200||1600||2400|
|Number of Patients||522||181||606||608||503||117||411||242||175|
|Nausea||less than 1||0||1||2||4||0||7||11||19|
|Vomiting||0||0||less than 1||less than 1||less than 1||0||1||2||3|
In addition, a number of other less common adverse events have been reported:
Body as a Whole
Hypotension, and rarely, syncope, bradycardia, heart block.
Central and Peripheral Nervous Systems
Paresthesia, most frequently described as scalp tingling.
In most cases, it was mild and transient and usually occurred at the beginning of treatment.
Systemic lupus erythematosus, positive antinuclear factor.
Liver and Biliary System
Hepatic necrosis, hepatitis, cholestatic jaundice, elevated liver function tests.
Muscle cramps, toxic myopathy.
Skin and Appendages
Rashes of various types, such as generalized maculopapular, lichenoid, urticarial, bullous lichen planus, psoriaform, and facial erythema; Peyronie’s disease, reversible alopecia.
Difficulty in micturition, including acute urinary bladder retention.
Rare reports of hypersensitivity (e.g., rash, urticaria, pruritus, angioedema, dyspnea) and anaphylactoid reactions.
Following approval for marketing in the United Kingdom, a monitored release survey involving approximately 6,800 patients was conducted for further safety and efficacy evaluation of this product. Results of this survey indicate that the type, severity, and incidence of adverse effects were comparable to those cited above.
Potential Adverse Effects
In addition, other adverse effects not listed above have been reported with other beta-adrenergic blocking agents.
Central Nervous System
Reversible mental depression progressing to catatonia, an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on psychometrics.
Intensification of A-V block [see Contraindications].
Fever combined with aching and sore throat, laryngospasm, respiratory distress.
Agranulocytosis, thrombocytopenic or nonthrombocytopenic purpura.
Mesenteric artery thrombosis, ischemic colitis.
The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with labetalol hydrochloride.
Clinical Laboratory Tests
There have been reversible increases of serum transaminases in 4% of patients treated with labetalol hydrochloride and tested and, more rarely, reversible increases in blood urea.
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