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Labetalol Hydrochloride
Overview
What is Labetalol HCL?
Labetalol hydrochloride tablets, USP are adrenergic receptor blocking agents that have both selective alpha-adrenergic and nonselective beta-adrenergic receptor blocking actions in a single substance.
Labetalol hydrochloride (HCl) is a racemate chemically designated as 2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl) amino] ethyl] benzamide monohydrochloride, and it has the following structure:
Labetalol HCl has the molecular formula CHNO•HCl and a molecular weight of 364.9. It has two asymmetric centers and therefore exists as a molecular complex of two diastereoisomeric pairs. Dilevalol, the R, R´stereoisomer, makes up 25% of racemic labetalol.
Labetalol HCl is a white or off-white crystalline powder, soluble in water.
Labetalol hydrochloride tablets contain 100, 200, or 300 mg of labetalol HCl and are taken orally. The tablets also contain the inactive ingredients lactose monohydrate, corn starch, crospovidone, colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, polyethylene glycol, titanium dioxide and talc.
What does Labetalol HCL look like?
What are the available doses of Labetalol HCL?
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What should I talk to my health care provider before I take Labetalol HCL?
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How should I use Labetalol HCL?
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 MUST BE INDIVIDUALIZED. The recommended dosage is 100 mg 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. every 2 or 3 days. The usual dosage of labetalol HCl is between 200 and 400 mg daily.
Since the full antihypertensive effect of labetalol HCl 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 1,200 to 2,400 mg per day, with or without thiazide diuretics. Should side effects (principally nausea or dizziness) occur with these doses administered twice daily, the same total daily dose administered three times daily may improve tolerability and facilitate further titration. Titration increments should not exceed 200 mg twice daily.
When a diuretic is added, an additive antihypertensive effect can be expected. In some cases this may necessitate a labetalol HCl 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:
What interacts with Labetalol HCL?
Labetalol hydrochloride tablets are contraindicated in bronchial asthma, overt cardiac failure, greater-than-first-degree heart block, cardiogenic shock, severe bradycardia, other conditions associated with severe and prolonged hypotension, and in patients with a history of hypersensitivity to any component of the product (see ).
Beta-blockers, even those with apparent cardioselectivity, should not be used in patients with a history of obstructive airway disease, including asthma.
What are the warnings of Labetalol HCL?
Advise patients with Cockayne syndrome to stop taking metronidazole immediately if they experience any symptoms of potential liver injury, such as abdominal pain, nausea, change in stool color or jaundice, and to contact their healthcare provider.
should be withdrawn (gradually, if possible).
Angina pectoris has not been reported upon labetalol HCl discontinuation. However, hypersensitivity to catecholamines has been observed in patients withdrawn from beta-blocker therapy; exacerbation of angina and, in some cases, myocardial infarction have occurred after discontinuation of such therapy. When discontinuing chronically administered labetalol hydrochloride tablets, particularly in patients with ischemic heart disease, the dosage should be gradually reduced over a period of 1 to 2 weeks and the patient should be carefully monitored. If angina markedly worsens or acute coronary insufficiency develops, therapy with labetalol hydrochloride tablets
should be reinstituted promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken. Patients should be warned against interruption or discontinuation of therapy without the physician's advice. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue therapy with labetalol hydrochloride tablets
abruptly in patients being treated for hypertension.
Labetalol hydrochloride tablets
may be used with caution, however, in patients who do not respond to, or
cannot tolerate, other antihypertensive agents. It is prudent, if labetalol hydrochloride tablets
are used, to use the smallest effective dose, so that
inhibition of endogenous or exogenous beta-agonists is minimized.
Labetalol HCl has been shown to be effective in lowering blood pressure and relieving symptoms in patients with pheochromocytoma. However, paradoxical hypertensive responses have been reported in a few patients with this tumor; therefore, use caution when administering labetalol HCl to patients with pheochromocytoma.Beta-adrenergic blockade may prevent the appearance of premonitory signs and symptoms (e.g., tachycardia) of acute hypoglycemia. This is especially important with labile diabetics. Beta-blockade also reduces the release of insulin in response to hyperglycemia; it may therefore be necessary to adjust the dose of antidiabetic drugs.
Do not routinely withdraw chronic beta blocker therapy prior to surgery. The effect of labetalol 's alpha adrenergic activity has not been evaluated in this setting.
A synergism between labetalol HCl and halothane anesthesia has been shown (see ).
What are the precautions of Labetalol HCL?
General Precautions
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should be used with caution in patients with impaired hepatic function since metabolism of the drug may be diminished.
has been observed during cataract surgery in some patients treated with alpha-l blockers (labetalol is an alpha/beta blocker). This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient's ophthalmologist should be prepared for possible modifications to the surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit of stopping alpha-l blocker therapy prior to cataract surgery.
(see ).
Information for Patients
As with all drugs with beta-blocking activity, certain advice to patients being treated with labetalol HCl is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects. While no incident of the abrupt withdrawal phenomenon (exacerbation of angina pectoris) has been reported with labetalol HCl, dosing with labetalol hydrochloride tablets should not be interrupted or discontinued without a physician's advice. Patients being treated with labetalol hydrochloride tabletsshould consult a physician at any signs or symptoms of impending cardiac failure or hepatic dysfunction (see ). Also, transient scalp tingling may occur, usually when treatment with labetalol hydrochloride tabletsis initiated (see ).
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 HCl in combination with tricyclic antidepressants experienced tremor, as compared to 0.7% reported to occur with labetalol HCl 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 antiasthmatic dose of beta-agonist bronchodilator drugs may be required. Cimetidine has been shown to increase the bioavailability of labetalol HCl. Since this could be explained either by enhanced absorption or by an alteration of hepatic metabolism of labetalol HCl, 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 HCl. During controlled hypotensive anesthesia using labetalol HCl 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 HCl.
Labetalol HCl blunts the reflex tachycardia produced by nitroglycerin without preventing its hypotensive effect. If labetalol HCl 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.
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Drug & OR 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 HCl, a specific method, such as a high performance liquid chromatographic assay with solid phase extraction (e.g., 385:241,1987) should be employed in determining levels of catecholamines.
Labetalol HCl 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 HCl for 18 months in mice and for 2 years in rats showed no evidence of carcinogenesis. Studies with labetalol HCl using dominant lethal assays in rats and mice and exposing microorganisms according to modified Ames tests showed no evidence of mutagenesis.
Pregnancy
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Labor & Delivery
Labetalol HCl 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 tablets are administered to a nursing woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
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.
What are the side effects of Labetalol HCL?
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 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 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 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.
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 2,400 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.
In addition, a number of other less common adverse events have been reported:
Potential Adverse Effects:
Clinical Laboratory Tests:
| Labetalol HCI | Placebo | Propranolol | Metoprolol | ||||||
| (n = 227) | (n = 98) | (n = 84) | (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 | |||||||||
| Visionabnormality | 1 | 0 | 0 | 0 | |||||
| Vertigo | 2 | 1 | 0 | 0 | |||||
| Labetalol HClDaily Dose (mg) | 200 | 300 | 400 | 600 | 800 | 900 | 1,200 | 1,600 | 2,400 |
| 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 |
| Paresthesia | 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 |
What should I look out for while using Labetalol HCL?
Labetalol hydrochloride tablets are contraindicated in bronchial asthma, overt cardiac failure, greater-than-first-degree heart block, cardiogenic shock, severe bradycardia, other conditions associated with severe and prolonged hypotension, and in patients with a history of hypersensitivity to any component of the product (see ).
Beta-blockers, even those with apparent cardioselectivity, should not be used in patients with a history of obstructive airway disease, including asthma.
Hepatic Injury:
should be withdrawn (gradually, if possible).
Angina pectoris has not been reported upon labetalol HCl discontinuation. However, hypersensitivity to catecholamines has been observed in patients withdrawn from beta-blocker therapy; exacerbation of angina and, in some cases, myocardial infarction have occurred after discontinuation of such therapy. When discontinuing chronically administered labetalol hydrochloride tablets, particularly in patients with ischemic heart disease, the dosage should be gradually reduced over a period of 1 to 2 weeks and the patient should be carefully monitored. If angina markedly worsens or acute coronary insufficiency develops, therapy with labetalol hydrochloride tablets
should be reinstituted promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken. Patients should be warned against interruption or discontinuation of therapy without the physician's advice. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue therapy with labetalol hydrochloride tablets
abruptly in patients being treated for hypertension.
Labetalol hydrochloride tablets
may be used with caution, however, in patients who do not respond to, or
cannot tolerate, other antihypertensive agents. It is prudent, if labetalol hydrochloride tablets
are used, to use the smallest effective dose, so that
inhibition of endogenous or exogenous beta-agonists is minimized.
Labetalol HCl has been shown to be effective in lowering blood pressure and relieving symptoms in patients with pheochromocytoma. However, paradoxical hypertensive responses have been reported in a few patients with this tumor; therefore, use caution when administering labetalol HCl to patients with pheochromocytoma.Beta-adrenergic blockade may prevent the appearance of premonitory signs and symptoms (e.g., tachycardia) of acute hypoglycemia. This is especially important with labile diabetics. Beta-blockade also reduces the release of insulin in response to hyperglycemia; it may therefore be necessary to adjust the dose of antidiabetic drugs.
Do not routinely withdraw chronic beta blocker therapy prior to surgery. The effect of labetalol 's alpha adrenergic activity has not been evaluated in this setting.
A synergism between labetalol HCl and halothane anesthesia has been shown (see ).
What might happen if I take too much Labetalol HCL?
Overdosage with labetalol HCl causes excessive hypotension that is posture sensitive and, sometimes, excessive bradycardia. Patients should be placed supine and their legs raised if necessary to improve the blood supply to the brain. If overdosage with labetalol HCl follows oral ingestion, gastric lavage or pharmacologically induced emesis (using syrup of ipecac) may be useful for removal of the drug shortly after ingestion. The following additional measures should be employed if necessary: —administer atropine or epinephrine. —administer a digitalis glycoside and a diuretic. Dopamine or dobutamine may also be useful. —administer vasopressors, e.g., norepinephrine. There is pharmacologic evidence that norepinephrine may be the drug of choice. —administer epinephrine and/or an aerosolized beta-agonist. —administer diazepam.
In severe beta-blocker overdose resulting in hypotension and/or bradycardia, glucagon has been shown to be effective when administered in large doses (5 to 10 mg rapidly over 30 seconds, followed by continuous infusion of 5 mg per hour that can be reduced as the patient improves).
Neither hemodialysis nor peritoneal dialysis removes a significant amount of labetalol HCl from the general circulation (<1%).
The oral LDvalue of labetalol HCl in the mouse is approximately 600 mg/kg and in the rat is >2 g/kg. The IV LDin these species is 50 to 60 mg/kg.
How should I store and handle Labetalol HCL?
Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Manufactured and Distributed by: Carlsbad, CA 92008 Revised: 06/12CTI-12 Rev. C Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Manufactured and Distributed by: Carlsbad, CA 92008 Revised: 06/12CTI-12 Rev. C Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Manufactured and Distributed by: Carlsbad, CA 92008 Revised: 06/12CTI-12 Rev. C Labetalol hydrochloride tablets, USP 100 mg, white, round, film-coated tablets with bisect, debossed “N” on top and “T” on bottom of the bisect on one side and "041" on the other side of the tablet. Labetalol hydrochloride tablets, USP 200 mg, white, round, film-coated tablets with bisect, debossed “N” on top and “T” on bottom of the bisect on one side and "042" on the other side of the tablet, blistercards of 30 (NDC 0615-8131-39). Labetalol hydrochloride tablets, USP 300 mg, white, round, film-coated tablets with bisect, debossed “N” on top and “T” on bottom of the bisect on one side and "043" on the other side of the tablet.Labetalol hydrochloride tablets, USP should be stored at 20° to 25°C (68° to 77°F)[ See USP Controlled Room Temperature]. Dist. by:Par PharmaceuticalChestnut Ridge, NY 10977 U.S.A.Mfg. Lic. No.: TN00002121OS122-01-74-01Revised: 03/2017Labetalol hydrochloride tablets, USP 100 mg, white, round, film-coated tablets with bisect, debossed “N” on top and “T” on bottom of the bisect on one side and "041" on the other side of the tablet. Labetalol hydrochloride tablets, USP 200 mg, white, round, film-coated tablets with bisect, debossed “N” on top and “T” on bottom of the bisect on one side and "042" on the other side of the tablet, blistercards of 30 (NDC 0615-8131-39). Labetalol hydrochloride tablets, USP 300 mg, white, round, film-coated tablets with bisect, debossed “N” on top and “T” on bottom of the bisect on one side and "043" on the other side of the tablet.Labetalol hydrochloride tablets, USP should be stored at 20° to 25°C (68° to 77°F)[ See USP Controlled Room Temperature]. Dist. by:Par PharmaceuticalChestnut Ridge, NY 10977 U.S.A.Mfg. Lic. No.: TN00002121OS122-01-74-01Revised: 03/2017Labetalol hydrochloride tablets, USP 100 mg, white, round, film-coated tablets with bisect, debossed “N” on top and “T” on bottom of the bisect on one side and "041" on the other side of the tablet. Labetalol hydrochloride tablets, USP 200 mg, white, round, film-coated tablets with bisect, debossed “N” on top and “T” on bottom of the bisect on one side and "042" on the other side of the tablet, blistercards of 30 (NDC 0615-8131-39). Labetalol hydrochloride tablets, USP 300 mg, white, round, film-coated tablets with bisect, debossed “N” on top and “T” on bottom of the bisect on one side and "043" on the other side of the tablet.Labetalol hydrochloride tablets, USP should be stored at 20° to 25°C (68° to 77°F)[ See USP Controlled Room Temperature]. Dist. by:Par PharmaceuticalChestnut Ridge, NY 10977 U.S.A.Mfg. Lic. No.: TN00002121OS122-01-74-01Revised: 03/2017Labetalol hydrochloride tablets, USP 100 mg, white, round, film-coated tablets with bisect, debossed “N” on top and “T” on bottom of the bisect on one side and "041" on the other side of the tablet. Labetalol hydrochloride tablets, USP 200 mg, white, round, film-coated tablets with bisect, debossed “N” on top and “T” on bottom of the bisect on one side and "042" on the other side of the tablet, blistercards of 30 (NDC 0615-8131-39). Labetalol hydrochloride tablets, USP 300 mg, white, round, film-coated tablets with bisect, debossed “N” on top and “T” on bottom of the bisect on one side and "043" on the other side of the tablet.Labetalol hydrochloride tablets, USP should be stored at 20° to 25°C (68° to 77°F)[ See USP Controlled Room Temperature]. Dist. by:Par PharmaceuticalChestnut Ridge, NY 10977 U.S.A.Mfg. Lic. No.: TN00002121OS122-01-74-01Revised: 03/2017Labetalol hydrochloride tablets, USP 100 mg, white, round, film-coated tablets with bisect, debossed “N” on top and “T” on bottom of the bisect on one side and "041" on the other side of the tablet. Labetalol hydrochloride tablets, USP 200 mg, white, round, film-coated tablets with bisect, debossed “N” on top and “T” on bottom of the bisect on one side and "042" on the other side of the tablet, blistercards of 30 (NDC 0615-8131-39). Labetalol hydrochloride tablets, USP 300 mg, white, round, film-coated tablets with bisect, debossed “N” on top and “T” on bottom of the bisect on one side and "043" on the other side of the tablet.Labetalol hydrochloride tablets, USP should be stored at 20° to 25°C (68° to 77°F)[ See USP Controlled Room Temperature]. Dist. by:Par PharmaceuticalChestnut Ridge, NY 10977 U.S.A.Mfg. Lic. No.: TN00002121OS122-01-74-01Revised: 03/2017Labetalol hydrochloride tablets, USP 100 mg, white, round, film-coated tablets with bisect, debossed “N” on top and “T” on bottom of the bisect on one side and "041" on the other side of the tablet. Labetalol hydrochloride tablets, USP 200 mg, white, round, film-coated tablets with bisect, debossed “N” on top and “T” on bottom of the bisect on one side and "042" on the other side of the tablet, blistercards of 30 (NDC 0615-8131-39). Labetalol hydrochloride tablets, USP 300 mg, white, round, film-coated tablets with bisect, debossed “N” on top and “T” on bottom of the bisect on one side and "043" on the other side of the tablet.Labetalol hydrochloride tablets, USP should be stored at 20° to 25°C (68° to 77°F)[ See USP Controlled Room Temperature]. Dist. by:Par PharmaceuticalChestnut Ridge, NY 10977 U.S.A.Mfg. Lic. No.: TN00002121OS122-01-74-01Revised: 03/2017Labetalol hydrochloride tablets, USP 100 mg, white, round, film-coated tablets with bisect, debossed “N” on top and “T” on bottom of the bisect on one side and "041" on the other side of the tablet. Labetalol hydrochloride tablets, USP 200 mg, white, round, film-coated tablets with bisect, debossed “N” on top and “T” on bottom of the bisect on one side and "042" on the other side of the tablet, blistercards of 30 (NDC 0615-8131-39). Labetalol hydrochloride tablets, USP 300 mg, white, round, film-coated tablets with bisect, debossed “N” on top and “T” on bottom of the bisect on one side and "043" on the other side of the tablet.Labetalol hydrochloride tablets, USP should be stored at 20° to 25°C (68° to 77°F)[ See USP Controlled Room Temperature]. Dist. by:Par PharmaceuticalChestnut Ridge, NY 10977 U.S.A.Mfg. Lic. No.: TN00002121OS122-01-74-01Revised: 03/2017
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
Labetalol HCl combines both selective, competitive, alpha-adrenergic blocking and nonselective, competitive, beta-adrenergic blocking activity in a single substance. In man, the ratios of alpha- to beta-blockade have been estimated to be approximately 1:3 and 1:7 following oral and intravenous (IV) administration, respectively. Beta-agonist activity has been demonstrated in animals with minimal beta-agonist (ISA) activity detected. In animals, at doses greater than those required for alpha- or beta-adrenergic blockade, a membrane stabilizing effect has been demonstrated.
The capacity of labetalol HCl to block alpha receptors in man has been demonstrated by attenuation of the pressor effect of phenylephrine and by a significant reduction of the pressor response caused by immersing the hand in ice-cold water ("cold-pressor test"). Labetalol HCl's beta-receptor blockade in man was demonstrated by a small decrease in the resting heart rate, attenuation of tachycardia produced by isoproterenol or exercise, and by attenuation of the reflex tachycardia to the hypotension produced by amyl nitrite. Beta-receptor blockade was demonstrated by inhibition of the isoproterenol-induced fall in diastolic blood pressure. Both the alpha- and beta-blocking actions of orally administered labetalol HCl contribute to a decrease in blood pressure in hypertensive patients. Labetalol HCl consistently, in dose-related fashion, blunted increases in exercise-induced blood pressure and heart rate, and in their double product. The pulmonary circulation during exercise was not affected by labetalol HCl dosing.
Single oral doses of labetalol HCl administered to patients with coronary artery disease had no significant effect on sinus rate, intraventricular conduction, or QRS duration. The atrioventricular (A-V) conduction time was modestly prolonged in two of seven patients. In another study, IV labetalol HCl slightly prolonged A-V nodal conduction time and atrial effective refractory period with only small changes in heart rate. The effects on A-V nodal refractoriness were inconsistent.
Labetalol HCl produces dose-related falls in blood pressure without reflex tachycardia and without significant reduction in heart rate, presumably through a mixture of its alpha- and beta-blocking effects. Hemodynamic effects are variable, with small, nonsignificant changes in cardiac output seen in some studies but not others, and small decreases in total peripheral resistance. Elevated plasma renins are reduced.
Doses of labetalol HCl that controlled hypertension did not affect renal function in mildly to severely hypertensive patients with normal renal function.
Due to the alpha-receptor blocking activity of labetalol HCl, blood pressure is lowered more in the standing than in the supine position, and symptoms of postural hypotension (2%), including rare instances of syncope, can occur. Following oral administration, when postural hypotension has occurred, it has been transient and is uncommon when the recommended starting dose and titration increments are closely followed (see ). Symptomatic postural hypotension is most likely to occur 2 to 4 hours after a dose, especially following the use of large initial doses or upon large changes in dose.
The peak effects of single oral doses of labetalol HCl occur within 2 to 4 hours. The duration of effect depends upon dose, lasting at least 8 hours following single oral doses of 100 mg and more than 12 hours following single oral doses of 300 mg. The maximum, steady-state blood pressure response upon oral, twice-a-day dosing occurs within 24 to 72 hours.
The antihypertensive effect of labetalol has a linear correlation with the logarithm of labetalol plasma concentration, and there is also a linear correlation between the reduction in exercise-induced tachycardia occurring at 2 hours after oral administration of labetalol HCl and the logarithm of the plasma concentration.
About 70% of the maximum beta-blocking effect is present for 5 hours after the administration of a single oral dose of 400 mg with suggestion that about 40% remains at 8 hours.
The antianginal efficacy of labetalol HCl has not been studied. In 37 patients with hypertension and coronary artery disease, labetalol HCl did not increase the incidence or severity of angina attacks.
Exacerbation of angina and, in some cases, myocardial infarction and ventricular dysrhythmias have been reported after abrupt discontinuation of therapy with beta-adrenergic blocking agents in patients with coronary artery disease. Abrupt withdrawal of these agents in patients without coronary artery disease has resulted in transient symptoms, including tremulousness, sweating, palpitation, headache, and malaise. Several mechanisms have been proposed to explain these phenomena, among them increased sensitivity to catecholamines because of increased numbers of beta receptors.
Although beta-adrenergic receptor blockade is useful in the treatment of angina and hypertension, there are also situations in which sympathetic stimulation is vital. For example, in patients with severely damaged hearts, adequate ventricular function may depend on sympathetic drive. Beta-adrenergic blockade may worsen A-V block by preventing the necessary facilitating effects of sympathetic activity on conduction. Beta-adrenergic blockade results in passive bronchial constriction by interfering with endogenous adrenergic bronchodilator activity in patients subject to bronchospasm, and it may also interfere with exogenous bronchodilators in such patients.
Labetalol HCl is completely absorbed from the gastrointestinal tract with peak plasma levels occurring 1 to 2 hours after oral administration. The relative bioavailability of labetalol HCl tablets compared to an oral solution is 100%. The absolute bioavailability (fraction of drug reaching systemic circulation) of labetalol when compared to an IV 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 to 3,000 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 HCl from the general circulation (<1%).
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., elderly patients will generally require lower maintenance dosages than nonelderly patients.
Non-Clinical Toxicology
Labetalol hydrochloride tablets are contraindicated in bronchial asthma, overt cardiac failure, greater-than-first-degree heart block, cardiogenic shock, severe bradycardia, other conditions associated with severe and prolonged hypotension, and in patients with a history of hypersensitivity to any component of the product (see ).Beta-blockers, even those with apparent cardioselectivity, should not be used in patients with a history of obstructive airway disease, including asthma.
Hepatic Injury:
should be withdrawn (gradually, if possible). Angina pectoris has not been reported upon labetalol HCl discontinuation. However, hypersensitivity to catecholamines has been observed in patients withdrawn from beta-blocker therapy; exacerbation of angina and, in some cases, myocardial infarction have occurred after discontinuation of such therapy. When discontinuing chronically administered labetalol hydrochloride tablets, particularly in patients with ischemic heart disease, the dosage should be gradually reduced over a period of 1 to 2 weeks and the patient should be carefully monitored. If angina markedly worsens or acute coronary insufficiency develops, therapy with labetalol hydrochloride tablets
should be reinstituted promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken. Patients should be warned against interruption or discontinuation of therapy without the physician's advice. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue therapy with labetalol hydrochloride tablets
abruptly in patients being treated for hypertension. Labetalol hydrochloride tablets
may be used with caution, however, in patients who do not respond to, or
cannot tolerate, other antihypertensive agents. It is prudent, if labetalol hydrochloride tablets
are used, to use the smallest effective dose, so that
inhibition of endogenous or exogenous beta-agonists is minimized. Labetalol HCl has been shown to be effective in lowering blood pressure and relieving symptoms in patients with pheochromocytoma. However, paradoxical hypertensive responses have been reported in a few patients with this tumor; therefore, use caution when administering labetalol HCl to patients with pheochromocytoma.Beta-adrenergic blockade may prevent the appearance of premonitory signs and symptoms (e.g., tachycardia) of acute hypoglycemia. This is especially important with labile diabetics. Beta-blockade also reduces the release of insulin in response to hyperglycemia; it may therefore be necessary to adjust the dose of antidiabetic drugs. Do not routinely withdraw chronic beta blocker therapy prior to surgery. The effect of labetalol 's alpha adrenergic activity has not been evaluated in this setting. A synergism between labetalol HCl and halothane anesthesia has been shown (see ).
In one survey, 2.3% of patients taking labetalol HCl in combination with tricyclic antidepressants experienced tremor, as compared to 0.7% reported to occur with labetalol HCl 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 antiasthmatic dose of beta-agonist bronchodilator drugs may be required. Cimetidine has been shown to increase the bioavailability of labetalol HCl. Since this could be explained either by enhanced absorption or by an alteration of hepatic metabolism of labetalol HCl, 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 HCl. During controlled hypotensive anesthesia using labetalol HCl 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 HCl.
Labetalol HCl blunts the reflex tachycardia produced by nitroglycerin without preventing its hypotensive effect. If labetalol HCl 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.
Impaired Hepatic Function:
should be used with caution in patients with impaired hepatic function since metabolism of the drug may be diminished. has been observed during cataract surgery in some patients treated with alpha-l blockers (labetalol is an alpha/beta blocker). This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient's ophthalmologist should be prepared for possible modifications to the surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit of stopping alpha-l blocker therapy prior to cataract surgery. (see ).
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 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 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 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.
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 2,400 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.
In addition, a number of other less common adverse events have been reported:
Potential Adverse Effects:
Clinical Laboratory Tests:
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
While we update our database periodically, we cannot guarantee it is always updated to the latest version.
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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
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A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).