Labetalol HCl (Page 3 of 5)

Laboratory Tests

As with any new drug given over prolonged periods, laboratory parameters should be observed over regular intervals. In patients with concomitant illnesses, such as impaired renal function, appropriate tests should be done to monitor these conditions.

Drug Interactions

In one survey, 2.3% of patients taking labetalol hydrochloride in combination with tricyclic antidepressants experienced tremor, as compared to 0.7% reported to occur with labetalol hydrochloride 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 anti-asthmatic dose of beta-agonist bronchodilator drugs may be required.

Cimetidine has been shown to increase the bioavailability of labetalol hydrochloride. Since this could be explained either by enhanced absorption or by an alteration of hepatic metabolism of labetalol hydrochloride, 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 hydrochloride. During controlled hypotensive anesthesia using labetalol hydrochloride 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 hydrochloride.

Labetalol hydrochloride blunts the reflex tachycardia produced by nitroglycerin without preventing its hypotensive effect. If labetalol hydrochloride 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 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:

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.

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