Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 25 January 2017

Indication(s)

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

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Advisory information

contraindications

CONTRAINDICATIONS TRANDATE 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 WARNINGS).

Beta-blockers, even those with apparent cardioselectivity, should not be used in patients with a history of obstructive airway disease, including asthma.

Special warnings and precautions

PRECAUTIONS General Impaired Hepatic Function: TRANDATE Tablets should be used with caution in patients with impaired hepatic function since metabolism of the drug may be diminished.

Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients treated with alpha-1 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-1 blocker therapy prior to cataract surgery.

Jaundice or

Hepatic

Dysfunction: (see WARNINGS).

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 TRANDATE Tablets should not be interrupted or discontinued without a physician 's advice.

Patients being treated with TRANDATE Tablets should consult a physician at any signs or symptoms of impending cardiac failure or hepatic dysfunction (see WARNINGS).

Also, transient scalp tingling may occur, usually when treatment with TRANDATE Tablets is initiated (see ADVERSE REACTIONS).

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 can not 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.

Risk of Anaphylactic Reaction: While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic.

Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.

Drug/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., J Chromatogr 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: Teratogenic Effects: Pregnancy Category C: Teratogenic studies were performed with labetalol in rats and rabbits at oral doses up to approximately six and four times the maximum recommended human dose (MRHD), respectively.

No reproducible evidence of fetal malformations was observed.

Increased fetal resorptions were seen in both species at doses approximating the MRHD.

A teratology study performed with labetalol in rabbits at IV doses up to 1.7 times the MRHD revealed no evidence of drug-related harm to the fetus.

There are no adequate and well-controlled studies in pregnant women.

Labetalol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects: Hypotension, bradycardia, hypoglycemia, and respiratory depression have been reported in infants of mothers who were treated with labetalol HCl for hypertension during pregnancy.

Oral administration of labetalol to rats during late gestation through weaning at doses of two to four times the MRHD caused a decrease in neonatal survival.

Labor and 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 TRANDATE Tablets are administered to a nursing woman.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Elderly Patients: 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.

Adverse reactions

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 TRANDATE 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.

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 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 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 US 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 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 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 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.

Usage information

Dosing and administration

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. every 2 or 3 days.

The usual maintenance dosage of labetalol HCl is between 200 and 400 mg twice 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 TRANDATE Tablets are usually lower in patients also receiving a diuretic.

When transferring patients from other antihypertensive drugs, TRANDATE 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. 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 and 200 mg b.i.d.

Pregnancy and lactation
Nursing Mothers: Small amounts of labetalol (approximately 0.004% of the maternal dose) are excreted in human milk. Caution should be exercised when TRANDATE Tablets are administered to a nursing woman.

Interactions

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 can not 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.

Risk of Anaphylactic Reaction: While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic.

Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.

More information

Category Value
Authorisation number NDA018716
Agency product number R5H8897N95
Orphan designation No
Product NDC 65483-391,65483-392,65483-393
Date Last Revised 14-12-2009
Type HUMAN PRESCRIPTION DRUG
RXCUI 896783
Marketing authorisation holder Prometheus Laboratories Inc.