Labetalol Hydrochloride: Package Insert and Label Information (Page 2 of 3)

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.

Carcinogenesis, Mutagenesis, 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 HCl tablets are administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Elderly Patients

As in the general population, some elderly patients (60 years of age or 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 HCl 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

(n = 227)

%

Placebo

(n = 98)

%

Propranolol

(n = 84)

%

Metoprolol

(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
Paresthesias < 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 2 0 1 2
Skin
Rash 1 0 0 0
Special Senses
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 U.S. therapeutic trials data base for adverse reactions that are clearly or possibly dose related.

Labetalol HCl Daily Dose (mg) 200 300 400 600 800
Number of patients 522 181 606 608 503
Dizziness (%) 2 3 3 3 5
Fatigue 2 1 4 4 5
Nausea < 1 0 1 2 4
Vomiting 0 0 < 1 < 1 < 1
Dyspepsia 1 0 2 1 1
Paresthesia 2 0 2 2 1
Nasal stuffiness 1 1 2 2 2
Ejaculation failure 0 2 1 2 3
Impotence 1 1 1 1 2
Edema 1 0 1 1 1
Daily Dose (mg) 900 1,200 1,600 2,400
Number of patients 117 411 242 175
Dizziness (%) 1 9 13 16
Fatigue 3 7 6 10
Nausea 0 7 11 19
Vomiting 0 1 2 3
Dyspepsia 0 2 2 4
Paresthesia 1 2 5 5
Nasal stuffiness 2 4 5 6
Ejaculation failure 0 4 3 5
Impotence 4 3 4 3
Edema 0 1 2 2

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

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