Labetalol Hydrochloride (Page 3 of 5)

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 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

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 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.

Nonteratogenic Effects

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.

Labor and Delivery

Labetalol hydrochloride 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 is 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 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 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
Fatigue 5 0 12 12
Asthenia 1 1 1 0
Headache 2 1 1 2
Gastrointestinal
Nausea 6 1 1 2
Vomiting less than 1 0 0 0
Dyspepsia 3 1 1 0
Abdominal pain 0 0 1 2
Diarrhea less than 1 0 2 0
Taste distortion 1 0 0 0
Central and Peripheral Nervous Systems
Dizziness 11 3 4 4
Paresthesia less than 1 0 0 0
Drowsiness less than 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 less than 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 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
Dizziness (%) 2 3 3 3 5 1 9 13 16
Fatigue 2 1 4 4 5 3 7 6 10
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
Dyspepsia 1 0 2 1 1 0 2 2 4
Paresthesias 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:

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