Labetalol Hydrochloride (Page 3 of 4)

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 (VMA) 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-LabA® (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 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 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 acentrally 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 <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 table below which depicts the entire U.S. therapeutic trials data base for adverse reactions that are clearly or possibly dose related.

Labetalol Hydrochloride DailyDose(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 <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
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:

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 (ANF).

Eyes: Dry eyes.

Immunological System: Anti mitochondrial 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; 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.

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