Side Effects of Trandate (labetalol)

Trandate (labetalol) is a beta-blocker used to treat high blood pressure (hypertension). 

Nerves from the adrenergic nervous system travel from the spinal cord to the arteries where they release norepinephrine. Norepinephrine attaches to adrenergic receptors on arteries and causes the arteries to contract, narrowing the arteries, and increasing blood pressure. 

Trandate blocks receptors of the adrenergic nervous system. When Trandate attaches to and blocks the receptors, arteries expand, resulting in a fall in blood pressure. 

The brand name Trandate is discontinued; generic forms of labetalol are available. 

Common side effects of Trandate include

• fatigue,
• dizziness,
• nausea,
• headache,
• diarrhea,
• fluid retention (edema),
• shortness of breath, and rarely,
• postural hypotension (a rapid decrease in blood pressure when going from the lying or seated position to the standing position that may cause light-headedness or fainting).

Serious side effects of Trandate include

• sexual dysfunction,
• abnormal heart rhythm,
• slow heart rate,
• liver failure, and
• allergic reactions.

Drug interactions of Trandate include medications that lower blood sugar such as insulin or oral antidiabetic medications, because Trandate can mask early warning symptoms of hypoglycemia (low blood sugar) such as tremors and increased heart rate, which are the result of activation of the adrenergic nervous system. 

Combining Trandate with tricyclic antidepressants such as amitriptyline, imipramine, or nortriptyline may lead to an increase in tremor which is a side effect of tricyclic antidepressants. 

If combined with adrenergic stimulating drugs used for treating asthma, for example, albuterol or pirbuterol, the adrenergic blocking effects of Trandate may counteract the effects of the stimulating drugs and reduce their effectiveness for treating asthmatic attacks. More of the adrenergic drug may be needed. 

Glutethimide may decrease the effectiveness of Trandate by increasing its elimination. When both drugs are used together, more Trandate or less glutethimide may be needed. 

Cimetidine may increase the effectiveness of Trandate by blocking its elimination and increasing its levels in the blood. Therefore, less Trandate may be needed when cimetidine and Trandate are used together. 

Halothane anesthesia may contribute to the blood pressure lowering effects of Trandate. 

There are no adequate studies of Trandate during pregnancy. Trandate is excreted in breast milk. It should be used cautiously in breastfeeding mothers because of the risk that the infant may develop a slow heart rate.

The most common side effects of labetalol are:

• fatigue,
• dizziness,
• nausea,
• headache,
• diarrhea,
• edema (fluid accumulation), and
• shortness of breath.

Postural hypotension (a rapid decrease in blood pressure when going from the lying or seated position to the standing position that may cause light-headedness or fainting) occurs rarely. Patients should be observed for this possible side effect within two to four hours of the first labetalol dose and after any changes in dose.

Other important side effects include:

• sexual dysfunction,
• abnormal heart rhythm,
• slow heart rate,
• liver failure, and
• allergic reactions.

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 Trandate (labetalol) Tablets 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 HCl, placebo, metoprolol, and propranolol over treatment periods of 3 and 4 months. Where the frequency of adverse effects for labetalol HCl 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.

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 2,400 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 US therapeutic trials data base for adverse reactions that are clearly or possibly dose related.

In addition, a number of other less common adverse events have been reported:

Body as a Whole: Fever.

Cardiovascular: 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.

Collagen Disorders: Systemic lupus erythematosus, positive antinuclear factor.

Eyes: Dry eyes.

Immunological System: Antimitochondrial antibodies.

Liver and Biliary System: Hepatic necrosis, hepatitis, cholestatic jaundice, elevated liver function tests.

Musculoskeletal System: Muscle cramps, toxic myopathy.

Respiratory System: Bronchospasm.

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.

Urinary System: Difficulty in micturition, including acute urinary bladder retention.

Hypersensitivity: 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.

Cardiovascular

Intensification of A-V block (see CONTRAINDICATIONS).

Allergic

Fever combined with aching and sore throat, laryngospasm, respiratory distress.

Hematologic

Agranulocytosis, thrombocytopenic or nonthrombocytopenic purpura.

Gastrointestinal

Mesenteric artery thrombosis, ischemic colitis.

The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with labetalol HCl.

Clinical Laboratory Tests

There have been reversible increases of serum transaminases in 4% of patients treated with labetalol HCl and tested and, more rarely, reversible increases in blood urea.

• In one survey, 2.3% of patients taking labetalol HCl in combination with tricyclic antidepressants experienced tremor, as compared to 0.7% reported to occur with labetalol HCl 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 antiasthmatic dose of beta-agonist bronchodilator drugs may be required.
• Cimetidine has been shown to increase the bioavailability of labetalol HCl. Since this could be explained either by enhanced absorption or by an alteration of hepatic metabolism of labetalol HCl, 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 HCl. During controlled hypotensive anesthesia using labetalol HCl 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 HCl.
• Labetalol HCl blunts the reflex tachycardia produced by nitroglycerin without preventing its hypotensive effect. If labetalol HCl 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.

Drug/Laboratory Test Interactions

• 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 HCl, 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 HCl 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.