Labetalol Hydrochloride
(British Approved Name Modified, US Adopted Name, rINNM)
Drug Nomenclature
INNs in main languages (French, Latin, Russian, and Spanish):
Pharmacopoeias. In Europe and US.
European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Labetalol Hydrochloride). A white or almost white powder. Sparingly soluble in water and in alcohol; practically insoluble in dichloromethane. A 1 % solution in water has a pH of 4.0 to 5.0.
The United States Pharmacopeia 31, 2008, and Supplements 1 and 2 (Labetalol Hydrochloride). A white to off-white powder. Soluble in water and in alcohol; insoluble in chloroform and in ether. A 1% solution in water has apH of 4.0 to 5.0. Store in airtight containers at a temperature of 25°, excursions permitted between 15° and 30°. Protect from light.
Incompatibility. Labetalol hydrochloride is compatible with standard intravenous solutions such as glucose 5% and sodium chloride 0.9%. However, precipitation has been reported when labetalol hydrochloride is added to sodium bicarbonate injection 5%. The precipitate is probably labetalol base. Immediate formation of a precipitate has also been reported when labetalol (generally 5 mg/mL in glucose 5%) was mixed with other drugs including ceftriaxone, furosemide, heparin, insulin, proton pump inhibitors such as pantoprazole, and thiopental There has also been a report of immediate haze after admixture of labetalol hydrochloride (800 micrograms/mL) with warfarin sodium.
Adverse Effects
The adverse effects associated with beta blockers are described. Labetalol also has alpha-blocking activity, which contributes to its adverse effects and these effects may predominate. Orthostatic hypotension may be a problem with high doses or at the start of treatment. Other effects associated with alpha blockade include dizziness, scalp tingling, and nasal congestion. Male sexual function may be impaired to a greater extent than with beta blockade alone. Muscle weakness, tremor, urinary retention, hepatitis, and jaundice have also been reported.
Effects on the liver. By 1990, the FDA had received 11 reports of hepatocellular damage associated with labetalol therapy. Three patients died. Liver function should be monitored and labetalol stopped in patients who develop liver function abnormalities. The R,R-isomer of labetalol, dilevalol, was withdrawn from the market because of hepatotoxicity.
Hypersensitivity. Hypersensitivity reactions associated with labetalol may manifest as fever. Anaphylactoid reaction to labetalol has also been reported.
Overdosage. Acute oliguric renal failure developed after a short period of moderate hypotension in a patient who ingested labetalol 16 g. Renal function subsequently recovered. Renal failure has also been reported after ingestion of labetalol 6 g. The patient recovered after treatment with glucagon, isoprenaline, and dialysis. Another patient developed circulatory collapse and impaired consciousness after being given labetalol 800 mg orally for hypertensive crisis; glucagon and sympathomimetics were given to restore blood pressure, but amrinone infusion was also needed to improve cardiac output and mental state.
Precautions
As for Beta Blockers.
Because labetalol causes orthostatic hypotension it is recommended that injections are given to patients when they are lying down and that patients should remain lying down for the next 3 hours.
Labetalol should be withdrawn from patients who develop signs of hepatic impairment.
Breast feeding. Labetalol is distributed into breast milk, although it has been suggested that the proportion of a maternal dose likely to be ingested by the infant is very low. In a study in 25 patients, the mean concentration of labetalol in breast milk was less than in maternal plasma in patients given doses between 330 and 800 mg daily, although in 1 patient given 1200 mg daily a higher concentration was found in breast milk. In another study, the concentration of drug in milk exceeded maternal plasma concentration in 2 of 3 mothers, and in 1 infant the plasma-labetalol concentration was similar to that of the mother. However, no adverse effects have been seen in breast-feeding infants whose mothers were given labetalol, and the American Academy of Pediatrics considers that it is therefore usually compatible with breast feeding.
Interactions
The interactions associated with beta blockers are discussed.
Pharmacokinetics
Labetalol is readily absorbed from the gastrointestinal tract, but is subject to considerable first-pass metabolism. Bioavailability varies widely between patients and may be increased in the presence of food. Peak plasma concentrations occur about 1 to 2 hours after an oral dose. Labetalol has low lipid solubility and only very small amounts appear to cross the blood-brain barrier in animals. It is about 50% protein bound. Labetalol crosses the placenta and is distributed into breast milk (see above). Labetalol is metabolised mainly in the liver, the metabolites being excreted in the urine with only small amounts of unchanged labetalol; its major metabolite has not been found to have significant alpha- or beta-blocking effects. Excretion also occurs in the faeces via the bile. The elimination half-life at steady state is reported to be about 6 to 8 hours. On intravenous infusion, the elimination half-life is about 5.5 hours. Labetalol is not removed by dialysis.
The elderly. Analysis of data from 4 single-dose studies and 3 multi dose studies indicated that age did not appear to be a significant factor in oral clearance in elderly patients receiving labetalol for long-term management of hypertension.
Pregnancy. The concentration of labetalol has been found to be lower in amniotic fluid and fetal plasma than in maternal plasma. A ratio of infant to maternal drug concentration of 0.2 to 0.8 has been reported based on concentration in infant cord blood at delivery [time since last maternal dose not stated]. In another study, however, higher concentrations were found in cord plasma than in maternal plasma at delivery when infants were delivered 12 to 24 hours after the last maternal dose. The half-life of labetalol was reported as 24 hours in a neonate of 37 weeks’ gestation whose mother had received labetalol 600 mg daily for 11 weeks prior to delivery
Uses and Administration
Labetalol is a non-cardioselective beta blocker. It is reported to possess some intrinsic sym-pathomimetic and membrane-stabilising activity. In addition, it has selective alpha1-blocking properties which decrease peripheral vascular resistance. The ratio of alpha- to beta-blocking activity has been estimated to be about 1:3 after oral doses and 1:7 after intravenous doses.
Labetalol is used as the hydrochloride in the management of hypertension. It is also used to induce hypotension during surgery. Labetalol decreases blood pressure more rapidly than other beta blockers; the full antihypertensive effect may be seen within 1 to 3 hours of an oral dose.
In hypertension labetalol hydrochloride is usually given in an initial oral dose of 100 mg twice daily with food, gradually increased if necessary according to response and standing blood pressure, to 200 to 400 mg twice daily; total daily doses of 2.4 g, in two to four divided doses, have occasionally been required. Lower doses may be adequate in elderly patients; an initial dose of 50 to 100 mg twice daily has been recommended, and the usual maintenance dose is 100 to 200 mg twice daily.
For the emergency treatment of hypertension labetalol hydrochloride may be given by slow intravenous injection. In the UK a dose of 50 mg is recommended, given over a period of at least 1 minute; if necessary this dose may be repeated at intervals of 5 minutes until a total of 200 mg has been given. In the USA an initial dose of 20 mg is recommended, given over 2 minutes; subsequent doses of 40 to 80 mg may be given every 10 minutes, if necessary, up to a maximum of 300 mg. Blood pressure should be monitored, and the patient should remain supine during the injection and for 3 hours afterwards, to avoid excessive orthostatic hypotension. After bolus intravenous injection a maximum effect is usually obtained within 5 minutes and usually lasts up to 6 hours, although it may extend as long as 18 hours.
Labetalol hydrochloride has also been given by intravenous infusion in usual doses of 2 mg/minute. Suggested concentrations for intravenous infusions are 1 mg/mL or 2 mg/3 niL of suitable diluent. In hypertension in pregnancy, labetalol infusion may be started at the rate of 20 mg/hour, then doubled every 30 minutes until a satisfactory response is obtained or a dose of 160 mg/hour is reached. In hypertension after myo-cardial infarction, labetalol infusion may be started at the rate of 15 mg/hour and gradually increased until a satisfactory response is obtained or a dose of 120 mg/hour is reached.
The initial dose in hypotensive anaesthesia is 10 to 20 mg intravenously, with increments of 5 to 10 mg if satisfactory hypotension is not achieved after 5 minutes. A higher initial dose may be required in patients who do not receive halothane anaesthesia. For the use of labetalol in children, see below.
Action. Labetalol has 2 optical centres; it is used as the racemic mixture of the 4 stereoisomers. The R,R-isomer is responsible for the beta-blocking activity and has limited alpha-blocking activity; it also has beta-adrenergic mediated peripheral vasodilating activity. The S,R-isomer has the most potent alpha-blocking activity. The S,S-isomer has some alpha-blocking activity and the R,S-isomer does not appear to have either alpha- or beta-adrenergic blocking effect. The pure R,R-isomer, dilevalol, was withdrawn from the market because of hepatotoxicity.
Administration in children. Labetalol has been used in the management of hypertension in children, although experience is limited. The BNFC suggests the following doses:
for hypertensive emergencies, labetalol hydrochloride may be given by intravenous infusion as follows:
• neonates: 500 micrograms/kg per hour adjusted at intervals of at least 15 minutes according to response, to a maximum of 4 mg/kg per hour
• 1 month to 12 years: 0.5 to 1 mg/kg per hour adjusted at intervals of at least 15 minutes according to response, to a maximum of 3 mg/kg per hour
• 12 to 18 years: 30 to 120 mg/hour adjusted at intervals of at least 15 minutes according to response
for hypertension, labetalol hydrochloride may be given as follows:
• 1 month to 12 years: 1 to 2 mg/kg three or four times daily by mouth or a single intravenous injection in a dose of 250 to 500 micrograms/kg to a maximum of 20 mg
• 12 to 18 years: similar doses to adults (see above) although a lower initial oral dose of 50 to 100 mg twice daily is recommended
Preparations
British Pharmacopoeia, 2008: Labetalol Injection; Labetalol Tablets;
The United States Pharmacopeia 31, 2008, and Supplements 1 and 2: Labetalol Hydrochloride Injection; Labetalol Hydrochloride Oral Suspension; Labetalol Hydrochloride Tablets.
Single-ingredient Preparations
The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.
Argentina: Biascor; Australia: Presolol; Trandate; Austria: Trandate; Belgium: Trandate; Canada: Trandate; Chile: Trandate; Czech Republic: Coreton; Trandate; Denmark: Trandate; Finland: Albetol; France: Trandate; Germany: Trandate¤; Hong Kong: Trandate; Ireland: Trandate; Israel: Trandate; Italy: Abetol¤; Alfabetal¤; Amipress¤; Betadren¤; Ipolab; Lolum¤; Mitalolo¤; Pressalolo¤; Trandate; Malaysia: Tolbetol¤; Trandate; Netherlands: Trandate; Norway: Trandate; New Zealand: Hybloc; Trandate; Portugal: Trandate; South Africa: Trandate; Singapore: Trandate¤; Spain: Trandate; Sweden: Trandate; Switzerland: Trandate; United Kingdom: Labrocol¤; Trandate; United States: Normodyne; Trandate; Venezuela: Trandate
Multi-ingredient Preparations
Italy: Biotens¤; Diurolab¤; Pressalolo Diuretico¤; Trandiur; United States: Normozide¤; Trandate HCT¤
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