Labetalol (Page 3 of 4)

Ris k 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.

Carcinogenesis, Mutagenes is, Impairment of Fertility:

Long-term oral dosing studies with labetalol HCl for 18 months in mice and for 2 years in rats showed no evidence of carcinogenesis. Studies with labetalol HCl using dominant lethal assays in rats and mice and exposing microorganisms according to modified Ames tests showed no evidence of mutagenesis.

Pregnancy:

Teratogenic Effects: 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 IV 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.

Nonteratogenic Effects :

Hypotension, bradycardia, hypoglycemia, and respiratory depression have been reported in infants of mothers who were treated with labetalol HCl 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.

Labor and Delivery:

Labetalol HCl given to pregnant women with hypertension did not appear to affect the usual course of labor and delivery.

Nursing Mothers :

Small amounts of labetalol (approximately 0.004% of the maternal dose) are excreted in human milk. Caution should be exercised when labetalol hydrochloride tablets are administered to a nursing woman.

Pediatric Us e:

Safety and effectiveness in pediatric patients have not been established.

Elderly Patients :

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.

ADVERSE 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 labetalol hydrochloride 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.

Labetalol HCl Placebo Propranolol Metoprolol
(n = 227) (n = 98) (n = 84) (n = 49)
% % % %
Body as a whole
Fatigue 5 0 12 12
Asthenia 1 1 1 0
Headache 2 1 1 2
Gastrointestinal
Nausea 6 1 1 2
Vomiting <1 0 0 0
Dyspepsia 3 1 1 0
Abdominal pain 0 0 1 2
Diarrhea <1 0 2 0
Taste distortion 1 0 0 0
Central and peripheral nervous systems
Dizziness 11 3 4 4
Paresthesia <1 0 0 0
Drowsiness <1 2 2 2
Autonomic nervous system
Nasal Stuffiness 3 0 0 0
Ejaculation failure 2 0 0 0
Impotence 1 0 1 3
Increased sweating <1 0 0 0
Cardiovascular
Edema 1 0 0 0
Postural Hypotension 1 0 0 0
Bradycardia 0 0 5 12
Respiratory
Dyspnea 22 0 1 2
Skin
Rash 1 0 0 0
Special sense
Vision abnormality 1 0 0 0
Vertigo 2 1 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 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.

Labetalol HCl Daily Dose (mg) 200 300 400 600 800 900 1200 1600 2400
Number of Patients 522 181 606 608 503 117 411 242 175
Dizziness (%) 2 3 3 3 5 1 9 13 16
Fatigue 2 1 4 4 5 3 7 6 16
Nausea <1 0 1 2 4 0 7 11 19
Vomiting 0 0 <1 <1 <1 0 1 2 3
Dyspepsia 1 0 2 1 1 0 2 2 4
Paresthesia 2 0 2 2 1 1 2 5 5
Nasal stuffiness 1 1 2 2 2 2 4 5 6
Ejaculation failure 0 2 1 2 3 0 4 3 5
Impotence 1 1 1 1 2 4 3 4 3
Edema 1 0 1 1 1 0 1 2 2

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, psoriasiform, 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.

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