Pr TRANDATE(r) (labetalol hydrochloride)
Squire Pharmaceuticals Inc. Date of Preparation: 6111 Royalmount Avenue, Suite 108 July 10, 2007 Montreal, Quebec H4P 2T4
Control # 115194
Pr TRANDATE(r) (labetalol hydrochloride)
TRANDATE(r) (labetalol hydrochloride) is an adrenergic receptor blocking agent possessing both alpha1-(post-synaptic) and beta-receptor blocking activity. Its action on beta-receptors is four times stronger than that on alpha-receptors. It antagonizes beta1- and beta2-receptors equally. The mechanism of the antihypertensive action of labetalol has not been fully established. It is considered that labetalol lowers blood pressure by partially blocking the alpha-adrenoreceptors in the peripheral arterioles, thus causing vasodilation and a resulting reduction of peripheral resistance. At the same time, blockade of the beta-adrenoreceptors in the myocardium prevents reflex tachycardia and subsequent elevation of cardiac output. Peripheral vasodilation is achieved with incomplete blockade of alpha-adrenoreceptors in the arterioles and the barostatic reflexes remain sufficiently active to reduce the incidence of postural hypotension. At rest labetalol slightly reduces the heart rate, increases the stroke volume but does not significantly affect cardiac output. It reduces exercise-induced increases in systolic pressure and heart rate, again without significantly influencing cardiac output. Following oral administration to hypertensive patients, labetalol decreases plasma renin activity and aldosterone levels, both at rest and during exercise, particularly when these were elevated prior to treatment. Labetalol is significantly more efficacious in hypertensive patients with high baseline plasma noradrenaline levels. Labetalol is well absorbed from the gastrointestinal tract with peak blood levels occurring 1 to 2 hours after oral dosing. A single oral dose of 200 mg produced average peak plasma levels of 360 :g per 100 mL. The drug undergoes extensive "first pass" metabolism following oral administration. The bioavailability of oral compared to intravenous (i.v.) labetalol is approximately 25%. When taken with food, the bioavailability of unchanged drug is increased although peak plasma levels remain the same. The drug is metabolized mostly by conjugation with glucuronic acid; the resulting metabolite is inactive. Rapid and extensive distribution within tissue compartments occurs after i.v. administration. The drug is approximately 50% bound to plasma proteins. Labetalol and its metabolites are rapidly excreted in urine, and via bile into the feces. The plasma half-life of labetalol is approximately 6 to 8 hours following oral administration. Labetalol produces a significant fall in blood pressure in 1 to 4 hours after the first oral dose. The maximum blood pressure lowering effect at any particular dose level is usually achieved within 24 to 72 hours. In a clinical pharmacologic study in severe hypertensives, an initial 0.25 mg/kg injection of labetalol administered to patients in the supine position decreased blood pressure by an average of 11/7mm Hg. Additional injections of 0.5 mg/kg at 15 minute intervals up to a total cumulative dose of 1.75 mg/kg of labetalol caused further dose-related decreases in blood pressure. Some patients required cumulative doses of up to 3.25 mg/kg. The maximal effect of each dose level occurred within 5 minutes. Following discontinuation of i.v. treatment with labetalol, the blood pressure rose gradually and progressively, approaching pretreatment baseline values within an average of 16 to 18 hours in the majority of patients. Similar results were obtained in the treatment of patients with severe hypertension requiring urgent blood pressure reduction with an initial dose of 20 mg (which corresponds to 0.25 mg/kg for an 80 kg patient) followed by additional doses of either 40 mg or 80 mg at 10-minute intervals to achieve the desired effect or up to a cumulative dose of 300 mg.
For treatment of hypertension. TRANDATE(r) (labetalol hydrochloride) is usually used in combination with other drugs, particularly a thiazide diuretic. However, TRANDATE(r) may be tried alone as an initial agent in those patients in whom, in the judgement of the physician, treatment should be started with an alpha- beta-blocker rather than with a diuretic. TRANDATE(r) may be used in combination with diuretics and/or other antihypertensive agents to treat severe hypertension. The combination of TRANDATE(r) with a diuretic has been found to be compatible. Limited experience with other antihypertensive agents has not shown evidence of incompatibility with TRANDATE(r).
Uncontrolled congestive heart failure (see Warnings); asthma or a history of obstructive lung disease; greater than first degree AV block; cardiogenic shock and states of hypoperfusion; sinus bradycardia; known sensitivity to labetalol.
Cardiac failure should be controlled with digitalis and diuretics before TRANDATE(r) (labetalol hydrochloride) treatment is initiated. TRANDATE(r) should not be given to patients with digitalis- resistant heart failure. Sympathetic stimulation is a vital component supporting circulatory function in congestive heart failure and inhibition with beta-blockade always carries the potential hazard of further depressing myocardial contractibility and precipitating cardiac failure. A few patients developed heart failure while on TRANDATE(r). Therefore, administration of TRANDATE(r) to patients with controlled failure or those likely to develop such failure, must be carried out under careful supervision. The drug does not abolish the inotropic action of digitalis on heart muscle. Patients with angina should be warned against abrupt discontinuation of beta-adrenergic blocking agents. There have been reports of severe exacerbation of angina, and of myocardial infarction or ventricular arrhythmias occurring in patients with angina pectoris, following abrupt discontinuation of therapy. The last two complications may occur with or without preceeding exacerbation of angina pectoris. Therefore, when discontinuation of TRANDATE(r) is planned in patients with angina pectoris, the dosage should be gradually reduced over a period of about two weeks and the patient should be carefully observed. The same frequency of administration should be maintained. In situations of greater urgency, TRANDATE(r) therapy should be discontinued stepwise and under conditions of closer observation. If angina markedly worsens or acute coronary insufficiency develops, it is recommended that treatment with labetalol be re- instituted promptly, at least temporarily. Various skin rashes and conjunctival xerosis have been reported with beta-blockers. A severe syndrome (oculomucocutaneous syndrome) whose signs include conjunctivitis sicca and psoriasiform rashes, otitis, and sclerosing serositis has occurred with the chronic use of one beta-adrenergic blocking agent (practolol). This syndrome has not been observed in association with TRANDATE(r) or any other such agent. However, physicians should be alert to the possibility of such reactions and should discontinue treatment in the event that they occur. Animal studies have shown that labetalol binds to the melanin of the uveal tract. The significance of this in humans is not known but periodic ophthalmic examinations are advisable while the patient is taking TRANDATE(r). There have been rare reports of severe hepatocellular injury with TRANDATE(r) therapy. Injury has occurred after both short term and long term treatment and may be slowly progressive despite minimal symptomatology. The hepatic injury is usually reversible but rare cases of hepatic necrosis and death have been reported. Appropriate laboratory testing should be performed at regular intervals during TRANDATE(r) therapy. Tests should also be done at the first sign or symptom of liver dysfunction (eg., pruritus, dark urine, persistent anorexia, jaundice, right upper quadrant tenderness or unexplained flu-like symptoms). If there is laboratory evidence of liver injury or the patient is jaundiced, TRANDATE(r) should be stopped and not restarted. Severe sinus bradycardia may occur with the use of labetalol from unopposed vagal activity remaining after blockade of beta1-adrenergic receptors; in such cases, dosage should be reduced. In patients with thyrotoxicosis, possible deleterious effects from long-term use of TRANDATE(r) have not been adequately appraised. Beta-blockade may mask the clinical signs of continuing hyperthyroidism or complications, and give a false impression of improvement. Therefore, abrupt withdrawal of TRANDATE(r) may be followed by an exacerbation of the symptoms of hyperthyroidism, including thyroid storm. While TRANDATE(r) has been shown to be effective in lowering the blood pressure and relieving symptoms in patients with pheochromocytoma, paradoxical hypertensive responses have been reported in a few patients with this tumour. Use caution when administering TRANDATE(r) to patients with pheochromocytoma.
Postural hypotension and syncope may occur in patients treated with TRANDATE(r) (labetalol hydrochloride), particularly if the initial dose is too high or if dose titration is too rapid (see Dosage). Treatment should start with small doses without additional alpha-or beta-adrenergic blocking drugs. Beta-receptor blocking drugs may enhance hypoglycemia in patients prone to this condition. Also, diabetics on insulin or oral hypoglycemic medication may have an increased tendency towards hypoglycemia when treated with these drugs. Care should be taken if TRANDATE(r) is used concomitantly with either Class I antiarrhythmic agents or calcium antagonists of the verapamil class since these drugs may potentiate the cardiac depressant activities of TRANDATE(r). In patients with chronic liver disease the oral bioavailability of labetalol is enhanced due to reduced first pass metabolism. Lower doses of TRANDATE(r) are likely to be required in these patients. There may be increased difficulty in treating an allergic-type reaction in patients on beta- blockers. In these patients, the reaction may be more severe due to pharmacological effects of beta-blockers and problems with fluid changes. Epinephrine should be administered with caution since it may not have its usual effects in the treatment of anaphylaxis. On the one hand, larger doses of epinephrine may be needed to overcome the bronchospasm, while on the other, these doses can be associated with excessive alpha adrenergic stimulation with consequent hypertension, reflex bradycardia and heart block and possible potentiation of bronchospasm. Alternatives to the use of large doses of epinephrine include vigorous supportive care such as fluids and the use of beta agonists including parenteral salbutamol or isoproterenol to overcome bronchospasm and norepinephrine to overcome hypotension.
The bioavailability and half-life of TRANDATE(r) are increased in the elderly. In addition, the hypotensive response is greater in this age group following administration. Therefore, lower doses of TRANDATE(r) are likely to be required in elderly patients.
Although no teratogenic effects were seen in animal testing, the safety of the use of TRANDATE(r) during pregnancy has not been established. Labetalol crosses the placental barrier in women and has been found to bind to the eyes of fetal animals. TRANDATE(r) should be used in pregnant women only if the expected benefit to the mother justifies the potential risk to the fetus.
Labetalol has been found in the breast milk of lactating women. If the use of TRANDATE(r) is considered essential, then mothers should stop nursing.
Safety and effectiveness in children have not been established.
When used with diuretics and/or other antihypertensive agents the dose of TRANDATE(r) must be appropriately adjusted (see Dosage). TRANDATE(r) and halothane have additive hypotensive effects. High doses of halothane (3%) with TRANDATE(r) predispose the patient to the myocardial depressant effects of halothane and an undesirable reduction in myocardial performance. The anaesthesiologist should be informed when a patient is receiving TRANDATE(r). TRANDATE(r) blunts the reflex tachycardia produced by nitroglycerin without preventing its hypotensive effect. When TRANDATE(r) is used with nitroglycerin in patients with angina pectoris, additional antihypertensive effects may occur. Cimetidine has been shown to increase the oral bioavailability of TRANDATE(r) As cimetidine might be given to patients with hypertension also receiving TRANDATE(r), special care should be used in establishing the dose required for blood pressure control in such patients. In one survey, 2.3% of patients taking TRANDATE(r) in combination with tricyclic antidepressants experienced tremor as compared to 0.7% reported to occur with TRANDATE(r) alone. The contribution of each of the treatments to this adverse reaction is unknown, but the possibility of a drug interaction cannot be excluded.
The presence of a metabolite of TRANDATE(r) in the urine may result in falsely elevated levels of urinary catecholamines when measured by a nonspecific trihydroxyindole (THI) reaction. In screening patients suspected of having a pheochromocytoma and being treated with TRANDATE(r), specific radioenzymatic or high performance liquid chromatographic assay techniques should be used to determine levels of catecholamines or their metabolites.
The most serious reported adverse effects of TRANDATE(r) (labetalol hydrochloride) are severe postural hypotension, jaundice and bronchospasm. In well controlled clinical trials, the most common transient adverse reactions reported at routinely administered therapeutic doses, were postural hypotension and/or dizziness (16.9%), fatigue/malaise (13.1%), and headache (8.0%). Other transient effects include acute retention of urine and difficulty in micturition. The following summarizes the adverse effects reported.
Cardiovascular:
Postural hypotension/dizziness (16.9%), angina pectoris (3.2%), Raynaud's phenomenon (3.2%), pedal edema (1.9%), palpitations (1.3%), bradycardia (<1.0%).
Gastrointestinal
: Nausea/vomiting (6.1%), dyspepsia (1.9%), constipation (1.6%), dry
mouth/sore throat (1.6%).
Respiratory
: Dyspnea (3.8%), nasal congestion (1.3%).
Dermatological
: Drug rash (3.2%), paresthesia (especially "scalp tingling") (3.8%), pruritus (0.6%) and angioedema.
Urogenital
: Impotence (2.2%), failure of ejaculation (0.6%), dysuria (0.6%).
Musculoskeletal:
Aches/pains (3.5%), muscle cramps (1.3%).
Central Nervous System
: Fatigue/malaise (13.1%), headache (8.0%), depression (2.6%), loss of libido (1.3%), dreaming (1.3%).
Miscellaneous
: Visual blurring (4.2%), epistaxis (1.6%).
In addition, in the more extensive trials, bronchospasm and severe bradycardia were reported with an incidence of less than 1%. There are rare reports of raised liver function tests, jaundice (both hepatic and cholestatic), and hepatic necrosis (see Warnings). Other published or unpublished reports describe other rare, isolated adverse events in patients who were taking TRANDATE(r) (oral or injectable), as follows: bronchospasm and reduction in PEFR, difficulty in micturition including acute urinary retention, ejaculatory failure, Peyronie's disease, toxic myopathy, tremor, taste distortion, hypersensitivity, hypoesthesia, rashes of various types such as generalized maculopapular, lichenoid, urticarial, bullous lichen planus, psoriasiform, facial erythema, reversible alopecia and very rarely drug fever. A skin lesion resembling disseminated lupus erythematosus occurred rarely in one patient receiving a high dose of TRANDATE(r). There are rare reports of patients who developed lupus-like syndromes while on TRANDATE(r) which cleared upon discontinuation of treatment. Positive antinuclear factor and antimitochondrial antibodies have been reported in patients receiving the drug, but the significance of these findings is not clear.
Clinical laboratory tests
: Occasional elevations of serum transaminases and blood urea have been reported following oral administration.
Excessive hypotension which is posture-sensitive, and sometimes, excessive bradycardia. Patients should be laid supine and their legs raised, if necessary. Gastric lavage or pharmacologically-induced emesis (using syrup of ipecac) is useful for removal of the drug shortly after ingestion. Hemodialysis removes less than 1% of circulating labetalol, and is therefore not recommended. The following additional measures should be employed if necessary.
Administer atropine to induce vagal blockage. If bradycardia persists, isoproterenol may be administered cautiously. In refractory cases, the use of a cardiac pacemaker may be considered.
Conventional therapy with cardiac glycosides and diuretics.
Administer vasopressors, e.g. norepinephrine.
Bronchospasm: Administer a beta2-stimulating agent and/or a theophylline preparation. Oliguric renal failure has been reported after massive overdosage of TRANDATE(r) (labetalol hydrochloride) orally. In one case, the use of dopamine to increase blood pressure may have aggravated the renal failure.
TRANDATE(r) (labetalol hydrochloride) should be taken preferably after food. The dosage of TRANDATE(r) must always be adjusted in accordance with the individual requirements of the patient. The recommended initial dose is 100 mg twice daily whether used alone or with a diuretic. Thereafter, the dose should be adjusted semi-weekly or weekly according to the response. The usual maintenance dose is 200 to 400 mg twice daily. Patients may require up to 1200 mg per day, in two divided doses. Optimal doses are usually lower in patients also receiving a diuretic since an additive antihypertensive effect can be expected. Geriatrics: Lower doses of TRANDATE(r) are likely to be required in elderly patients (see PRECAUTIONS). Children: Safe and effective use of TRANDATE(r) in children have not presently been elucidated. Patients with liver function impairment will likely require lower doses since metabolism of the drug will be diminished.
labetalol hydrochloride
2-hydroxy-5-[1-hyd ro xy-2 - [ ( 1 - me t h yl -3-phenyl-
propyl)amino]ethyl] benzamidehydrochloride.
H2NOC HO
CHCH2NHCHCH2CH2 OH CH3
.HCl
Molecular Formula: C19H24N2O3.HCI
364.9
Labetalol hydrochloride is a white to off-white powder with a
melting point around 185degC
In water = 1:60 In ethanol = 1:60
In ether = almost insoluble In chloroform = almost insoluble
The pH of a 1% w/v solution of labetalol hydrochloride is between 4.0 - 5.0
TRANDATE(r) (labetalol hydrochloride) contains either 100 mg or 200 mg of labetalol hydrochloride. TRANDATE(r) tablets also contain the following excipients: cornstarch, hydroxy propyl methylcellulose, lactose monohydrate, magnesium stearate, pregelatinized starch, sodium benzoate, titanium dioxide (100 mg tablets only) or AD & C yellow no. 6 (200 mg tablets only).
Store below 30degC.
100 mg Tablets: Each capsule-shaped, orange, film-coated tablet, engraved ?TRANDATE 100" on one side, scored and engraved ?RP" on the other side, contains: labetalol hydrochloride USP 100 mg. Bottles of 100. 200 mg Tablets: Each capsule-shaped, white, film-coated tablet, engraved ?TRANDATE 200" on one side, scored and engraved ?RP" on the other side, contains: labetalol hydrochloride USP 200 mg. Bottles of 100.
Adam WR, Meagher EJ, Barter CE. Labetalol, beta-blockers, and acute deterioration of chronic airway obstruction. Clin Exp Hyperten 1982; A4(8):1419-1428. Bellamy GR, Hunyor SN, et al. Magnitude and mechanisms of the antihypertensive action of labetalol, including ambulatory assessment. Br J Clin Pharmacol 1983; 16:916. Brogden RN, Heel RC, et al. Labetalol: a review of its pharmacology and therapeutic use in hypertension. Drugs 1978; 15(4):251-270. Cummings AMM, Brown JJ, et al. Blood pressure reduction by incremental infusion of labetalol in patients with severe hypertension. Br J Clin Pharmacol 1979; 8:359-364. Eisalo A, Virta P. Treatment of hypertension in the elderly with labetalol. Acta Med Scan 1982; Suppl 665:129-133. Farmer JB, Kennedy I, et al. Pharmacology of AH 5158: a drug which blocks both - and - adrenoceptors. Br J Pharmacol 1972; 45:660-675. George RB, Burford JG, et al. Effects of a new alpha and beta adrenergic antagonist in hypertensive patients with reversible chronic airways obstruction. Chest 1981; 80(3):356. Homeida M, Jackson L, Roberts CJC. Decreased first-pass metabolism of labetalol in chronic liver disease. Br Med J 1978; 2:1048-1050. Jackson SHD, Beevers DG. Comparison of the effects of single doses of atenolol and labetalol on airways obstruction in patient with hypertension and asthma. Br J Clin Pharmacol 1983; 15:553-556. Kanto JH. Current status of labetalol, the first alpha- and beta-blocking agent. Int J Clin Pharmacol Ther Toxicol 1985; 23(11):617-628. Kelly JG, McGarry K et al. Bioavailability of labetalol increases with age. Br J Clin Pharmacol 1982; 14:304-305. Lund-Johansen P. Short- and long-term (six-year) hemodynamic effects of labetalol in essential hypertension. Am J Med 1983; 75 (Suppl 4A):24-31. MacCarthy EP, Bloomfield SS. Labetalol: a review of its pharmacology, pharmacokinetics, clinical uses and adverse effects. Pharmacother 1983; 3(4):193-219. Maconochie JG, Woodings EP, Richards DA. Effects of labetalol and propranolol on histamine- induced bronchoconstriction in normal subjects. Br J Clin Pharmacol 1977; 4:157-162. Mazzola C. Guffanti E, et al. Respiratory effects of labetalol in anginous or hypertensive patients. Curr Ther Res 1982; 31(2):219-231. Morgan T, Gilles A, et al. The effect of labetalol in the treatment of severe drug-resistant hypertension. Med J Austr 1978; 1:393-396. Papademetriou V, Notargiacomo AV, et al. Treatment of severe hypertension with intravenous labetalol. Clin Pharmacol Ther 1982; 32(4):431-435. Prichard BNC. Combined alpha- and beta-receptor inhibition in the treatment of hypertension. Drugs 1984; 28(Suppl 2):51-68. Richards DA, Woodings EP, et al. The effects of oral AH5158, a combined - and - adrenoceptor antagonist, in healthy volunteers. Br J Clin Pharmacol 1974; 1:505-510. Richards DA, Turner P (eds). Proceedings of a symposium on labetalol - April 1976. Br J Clin Pharmacol 1976; 3(Suppl 3); 677-678. Richards DA, Woodings EP, Maconochie JG. Comparison of the effects of labetalol and propranolol in healthy men at rest and during exercise. Br J Clin Pharmacol 1977; 4:15-21. Richards DA, Prichard BNC. Proceedings of the second symposium on labetalol - March 1979. Br J Clin Pharmacol 1979; 8(Suppl 2):85S-244S. Richards DA, Robertson JIS, Prichard BNC. Proceedings of the third symposium on labetalol - June 1981. Br J Clin Pharmacol 1982; 13(Suppl 1):1S-141S. Weber MA, Drayer JIM, Kaufman CA. The combined alpha- and beta-adrenergic blocker labetalol and propranolol in the treatment of high blood pressure: similarities and differences. J Clin Pharmacol 1984; 24:103-112.