ADVERSE REACTIONS

Most adverse effects are mild, 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 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
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	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 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	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, 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 6800 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 (seeCONTRAINDICATIONS).

**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.