Labetalol

INDICATIONS AND USAGE Labetalol hydrochloride tablets, USP are indicated in the management of hypertension. Labetalol hydrochloride tablets, USP may be used alone or in combination with other antihypertensive agents, especially thiazide and loop diuretics.

DOSAGE AND ADMINISTRATION DOSAGE MUST BE INDIVIDUALIZED. The recommended initial dosage is 100 mg twice daily whether used alone or added to a diuretic regimen. After 2 or 3 days, using standing blood pressure as an indicator, dosage may be titrated in increments of 100 mg b.i.d. (twice daily) every 2 or 3 days. The usual maintenance dosage of labetalol hydrochloride tablets is between 200 mg and 400 mg twice daily. Since the full antihypertensive effect of labetalol hydrochloride tablets is usually seen within the first 1 to 3 hours of the initial dose or dose increment, the assurance of a lack of an exaggerated hypotensive response can be clinically established in the office setting. The antihypertensive effects of continued dosing can be measured at subsequent visits, approximately 12 hours after a dose, to determine whether further titration is necessary. Patients with severe hypertension may require from 1200 mg to 2400 mg per day, with or without thiazide diuretics. Should side effects (principally nausea or dizziness) occur with these doses administered b.i.d. (twice daily), the same total daily dose administered t.i.d. (three times daily) may improve tolerability and facilitate further titration. Titration increments should not exceed 200 mg b.i.d. (twice daily). When a diuretic is added, an additive antihypertensive effect can be expected. In some cases this may necessitate a labetalol hydrochloride tablet dosage adjustment. As with most antihypertensive drugs, optimal dosages of labetalol hydrochloride tablets are usually lower in patients also receiving a diuretic. When transferring patients from other antihypertensive drugs, labetalol hydrochloride tablets should be introduced as recommended and the dosage of the existing therapy progressively decreased. Elderly Patients As in the general patient population, labetalol therapy may be initiated at 100 mg twice daily and titrated upwards in increments of 100 mg b.i.d. (twice daily) as required for control of blood pressure. Since some elderly patients eliminate labetalol more slowly, however, adequate control of blood pressure may be achieved at a lower maintenance dosage compared to the general population. The majority of elderly patients will require between 100 mg and 200 mg b.i.d. (twice daily).

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. 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 [see Contraindications ] . 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 hydrochloride. Clinical Laboratory Tests There have been reversible increases of serum transaminases in 4% of patients treated with labetalol hydrochloride and tested and, more rarely, reversible increases in blood urea.

Pharmacokinetics and Metabolism Labetalol hydrochloride is completely absorbed from the gastrointestinal tract with peak plasma levels occurring 1 to 2 hours after oral administration. The relative bioavailability of labetalol hydrochloride compared to an oral solution is 100%. The absolute bioavailability (fraction of drug reaching systemic circulation) of labetalol when compared to an intravenous infusion is 25%; this is due to extensive “first-pass” metabolism. Despite “first-pass” metabolism, there is a linear relationship between oral doses of 100 mg to 3000 mg and peak plasma levels. The absolute bioavailability of labetalol is increased when administered with food. The plasma half-life of labetalol following oral administration is about 6 to 8 hours. Steady-state plasma levels of labetalol during repetitive dosing are reached by about the third day of dosing. In patients with decreased hepatic or renal function, the elimination half-life of labetalol is not altered; however, the relative bioavailability in hepatically impaired patients is increased due to decreased “first-pass” metabolism. The metabolism of labetalol is mainly through conjugation to glucuronide metabolites. These metabolites are present in plasma and are excreted in the urine and, via the bile, into the feces. Approximately 55% to 60% of a dose appears in the urine as conjugates or unchanged labetalol within the first 24 hours of dosing. Labetalol has been shown to cross the placental barrier in humans. Only negligible amounts of the drug crossed the blood-brain barrier in animal studies. Labetalol is approximately 50% protein bound. Neither hemodialysis nor peritoneal dialysis removes a significant amount of labetalol hydrochloride from the general circulation (less than 1%). Elderly Patients Some pharmacokinetic studies indicate that the elimination of labetalol is reduced in elderly patients. Therefore, although elderly patients may initiate therapy at the currently recommended dosage of 100 mg b.i.d. (twice daily), elderly patients will generally require lower maintenance dosages than nonelderly patients.