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Trandate Injection

Generic Name: labetalol hydrochloride

Dosage Form: injection

DESCRIPTION:

Trandate Injection is an adrenergic receptor blocking agent that has both selective alpha1-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 empirical formula C19H24N2O3•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. Trandate Injection is a clear, colorless to light yellow, aqueous, sterile, isotonic solution for intravenous (IV) injection. It has a pH range of 3 to 4. Each milliliter contains 5 mg of labetalol HCl, 45 mg of anhydrous dextrose, 0.1 mg of edetate disodium; 0.8 mg of methylparaben and 0.1 mg of propylparaben as preservatives; and citric acid anhydrous and sodium hydroxide, as necessary, to bring the solution into the pH range.

CLINICAL PHARMACOLOGY:

Labetalol HCl combines both selective, competitive, alpha1-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 IV administration, respectively. Beta2-agonist activity has been demonstrated in animals with minimal beta1-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.

Pharmacodynamics: 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 beta1-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. Beta2-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 alpha1-receptor blocking activity of labetalol HCl, blood pressure is lowered more in the standing than in the supine position, and symptoms of postural hypotension can occur. During dosing with IV labetalol HCl, the contribution of the postural component should be considered when positioning the patient for treatment, and the patient should not be allowed to move to an erect position unmonitored until his ability to do so is established.

In a clinical pharmacologic study in severe hypertensives, an initial 0.25-mg/kg injection of labetalol HCl administered to patients in the supine position decreased blood pressure by an average of 11/7 mmHg. Additional injections of 0.5 mg/kg at 15-minute intervals up to a total cumulative dose of 1.75 mg/kg of labetalol HCl 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 IV treatment with labetalol HCl, 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 who required 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 or 80 mg at 10-minute intervals to achieve the desired effect, or up to a cumulative dose of 300 mg.

Labetalol HCl administered as a continuous IV infusion, with a mean dose of 136 mg (27 to 300 mg) over a period of 2 to 3 hours (mean of 2 hours and 39 minutes), lowered the blood pressure by an average of 60/35 mmHg.

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. Beta2-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.

Pharmacokinetics and Metabolism: Following IV infusion of labetalol, the elimination half-life is about 5.5 hours and the total body clearance is approximately 33 mL/min per kilogram. The plasma half-life of labetalol following oral administration is about 6 to 8 hours. 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. The 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%).

INDICATIONS AND USAGE:

Trandate Injection is indicated for control of blood pressure in severe hypertension.

CONTRAINDICATIONS:

Trandate Injection is 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.

WARNINGS:

Hepatic Injury: Severe hepatocellular injury, confirmed by rechallenge in at least one case, occurs rarely with labetalol therapy. The hepatic injury is usually reversible, but hepatic necrosis and death have been reported. Injury has occurred after both short- and long-term treatment and may be slowly progressive despite minimal symptomatology. Similar hepatic events have been reported with a related research compound, dilevalol HCl, including two deaths. Dilevalol HCl is one of the four isomers of labetalol HCl. Thus, for patients taking labetalol, periodic determination of suitable hepatic laboratory tests would be appropriate. Appropriate laboratory testing should be done at the first symptom/sign of liver dysfunction (e.g., pruritus, dark urine, persistent anorexia, jaundice, right upper quadrant tenderness, or unexplained “flulike” symptoms). If the patient has laboratory evidence of liver injury or jaundice, labetalol should be stopped and not restarted.

Cardiac Failure: Sympathetic stimulation is a vital component supporting circulatory function in congestive heart failure. Beta-blockade carries a potential hazard of further depressing myocardial contractility and precipitating more severe failure. Although beta-blockers should be avoided in overt congestive heart failure, if necessary, labetalol HCl can be used with caution in patients with a history of heart failure who are well compensated. Congestive heart failure has been observed in patients receiving labetalol HCl. Labetalol HCl does not abolish the inotropic action of digitalis on heart muscle.

In Patients Without a History of Cardiac Failure: In patients with latent cardiac insufficiency, continued depression of the myocardium with beta-blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of impending cardiac failure, patients should be fully digitalized and/or be given a diuretic, and the response should be observed closely. If cardiac failure continues despite adequate digitalization and diuretic, therapy with Trandate Injection should be withdrawn (gradually, if possible).

Ischemic Heart Disease: Angina pectoris has not been reported upon labetalol HCl discontinuation. However, following abrupt cessation of therapy with some beta-blocking agents in patients with coronary artery disease, exacerbations of angina pectoris and, in some cases, myocardial infarction have been reported. Therefore, such patients should be cautioned against interruption of therapy without the physician's advice. Even in the absence of overt angina pectoris, when discontinuation of Trandate Injection is planned, the patient should be carefully observed and should be advised to limit physical activity. If angina markedly worsens or acute coronary insufficiency develops, administration of Trandate Injection should be reinstituted promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken.

Nonallergic Bronchospasm (e.g., Chronic Bronchitis and Emphysema): Since Trandate Injection at the usual IV therapeutic doses has not been studied in patients with nonallergic bronchospastic disease, it should not be used in such patients.

Pheochromocytoma: Intravenous labetalol HCl has been shown to be effective in lowering blood pressure and relieving symptoms in patients with pheochromocytoma; higher than usual doses may be required. 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.

Diabetes Mellitus and Hypoglycemia: 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.

Major Surgery: The necessity or desirability of withdrawing beta-blocking therapy before major surgery is controversial. Protracted severe hypotension and difficulty in restarting or maintaining a heartbeat have been reported with beta-blockers. The effect of labetalol HCl's alpha-adrenergic activity has not been evaluated in this setting.

Several deaths have occurred when TRANDATE (labetalol HCI) Injection was used during surgery (including when used in cases to control bleeding).

A synergism between labetalol HCl and halothane anesthesia has been shown (see PRECAUTIONS: Drug Interactions).

Rapid Decreases of Blood Pressure: Caution must be observed when reducing severely elevated blood pressure. A number of adverse reactions, including cerebral infarction, optic nerve infarction, angina, and ischemic changes in the electrocardiogram, have been reported with other agents when severely elevated blood pressure was reduced over time courses of several hours to as long as 1 or 2 days. The desired blood pressure lowering should therefore be achieved over as long a period of time as is compatible with the patient's status.

PRECAUTIONS:

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

Hypotension: Symptomatic postural hypotension (incidence, 58%) is likely to occur if patients are tilted or allowed to assume the upright position within 3 hours of receiving Trandate Injection. Therefore, the patient's ability to tolerate an upright position should be established before permitting any ambulation.

Following Coronary Artery Bypass Surgery: In one uncontrolled study, patients with low cardiac indices and elevated systemic vascular resistance following intravenous labetalol HCl experienced significant declines in cardiac output with little change in systemic vascular resistance. One of these patients developed hypotension following labetalol treatment. Therefore, use of labetalol HCl should be avoided in such patients.

High Dose Labetalol: Administration of up to 3 g/d as an infusion for up to 2 to 3 days has been anecdotally reported; several patients have experienced hypotension or bradycardia.

Jaundice or Hepatic Dysfunction: (see WARNINGS).

Information for Patients: The following 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. During and immediately following (for up to 3 hours) Trandate Injection, the patient should remain supine. Subsequently, the patient should be advised on how to proceed gradually to become ambulatory and should be observed at the time of first ambulation.

When the patient is started on TRANDATE® (labetalol HCl) Tablets following adequate control of blood pressure with Trandate Injection, appropriate directions for titration of dosage should be provided (see DOSAGE AND ADMINISTRATION).

As with all drugs with beta-blocking activity, certain advice to patients being treated with labetalol HCl is warranted. 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: Routine laboratory tests are ordinarily not required before or after IV labetalol HCl. In patients with concomitant illnesses, such as impaired renal function, appropriate tests should be done to monitor these conditions.

Drug Interactions: Since Trandate Injection may be administered to patients already being treated with other medications, including other antihypertensive agents, careful monitoring of these patients is necessary to detect and treat promptly any undesired effect from concomitant administration.

In one survey, 2.3% of patients taking labetalol HCl orally 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 administered orally. 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.

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 Injection is administered to a nursing woman.

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

ADVERSE REACTIONS:

Trandate Injection is usually well tolerated. Most adverse effects have been mild and transient and, in controlled trials involving 92 patients, did not require labetalol HCl withdrawal. Symptomatic postural hypotension (incidence, 58%) is likely to occur if patients are tilted or allowed to assume the upright position within 3 hours of receiving Trandate Injection. Moderate hypotension occurred in 1 of 100 patients while supine. Increased sweating was noted in 4 of 100 patients, and flushing occurred in 1 of 100 patients.

The following also were reported with Trandate Injection with the incidence per 100 patients as noted:

Cardiovascular System: Ventricular arrhythmia in 1.

Central and Peripheral Nervous Systems: Dizziness in 9, tingling of the scalp/skin in 7, hypoesthesia (numbness) and vertigo in 1 each.

Gastrointestinal System: Nausea in 13, vomiting in 4, dyspepsia and taste distortion in 1 each.

Metabolic Disorders: Transient increases in blood urea nitrogen and serum creatinine levels occurred in 8 of 100 patients; these were associated with drops in blood pressure, generally in patients with prior renal insufficiency.

Psychiatric Disorders: Somnolence/yawning in 3.

Respiratory System: Wheezing in 1.

Skin: Pruritus in 1.

The incidence of adverse reactions depends upon the dose of labetalol HCl. The largest experience is with oral labetalol HCl (see TRANDATE® [labetalol hydrochloride] Tablets Product Information for details). Certain of the side effects increased with increasing oral 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 HCI
Daily Dose (mg)	200	300	400	600	800	900	1200	1600	2400
Number of      patients	522	181	606	608	503	117	411	242	175
Dizziness (%)	2	3	3	3	5	1	9	13	16
Fatigue	2	1	4	4	5	3	7	6	10
Nausea	<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:

Cardiovascular: Hypotension, and rarely, syncope, bradycardia, heart block.

Liver and Biliary System: Hepatic necrosis, hepatitis, cholestatic jaundice, elevated liver function tests.

Hypersensitivity: Rare reports of hypersensitivity (e.g., rash, urticaria, pruritus, angioedema, dyspnea) and anaphylactoid reactions.

The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with labetalol HCl during investigational use and extensive foreign marketing experience.

Clinical Laboratory Tests: Among patients dosed with TRANDATE Tablets, there have been reversible increases of serum transaminases in 4% of patients tested and, more rarely, reversible increases in blood urea.

OVERDOSAGE:

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: Excessive bradycardia—administer atropine or epinephrine. Cardiac failure—administer a digitalis glycoside and a diuretic. Dopamine or dobutamine may also be useful. Hypotension—administer vasopressors, e.g., norepinephrine. There is pharmacologic evidence that norepinephrine may be the drug of choice. Bronchospasm—administer epinephrine and/or an aerosolized beta2-agonist. Seizures—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/h that can be reduced as the patient improves).

Neither hemodialysis nor peritoneal dialysis removes a significant amount of labetalol from the general circulation (<1%).

The oral LD50 value of labetalol HCl in the mouse is approximately 600 mg/kg and in the rat is greater than 2 g/kg. The IV LD50 in these species is 50 to 60 mg/kg.

DOSAGE AND ADMINISTRATION:

Trandate Injection is intended for IV use in hospitalized patients. DOSAGE MUST BE INDIVIDUALIZED depending upon the severity of hypertension and the response of the patient during dosing.

Patients should always be kept in a supine position during the period of IV drug administration. A substantial fall in blood pressure on standing should be expected in these patients. The patient's ability to tolerate an upright position should be established before permitting any ambulation, such as using toilet facilities.

Either of two methods of administration of Trandate Injection may be used: a) repeated IV injection, or b) slow continuous infusion.

Repeated Intravenous Injection: Initially, Trandate Injection should be given in a 20-mg dose (which corresponds to 0.25 mg/kg for an 80-kg patient) by slow IV injection over a 2-minute period.

Immediately before the injection and at 5 and 10 minutes after injection, supine blood pressure should be measured to evaluate response. Additional injections of 40 or 80 mg can be given at 10-minute intervals until a desired supine blood pressure is achieved or a total of 300 mg of labetalol HCl has been injected. The maximum effect usually occurs within 5 minutes of each injection.

Slow Continuous Infusion: Trandate Injection is prepared for continuous IV infusion by diluting the vial contents with commonly used IV fluids (see below). Examples of two methods of preparing the infusion solution are:

Add 40 mL of Trandate Injection to 160 mL of a commonly used IV fluid such that the resultant 200 mL of solution contains 200 mg of labetalol HCl, 1 mg/mL. The diluted solution should be administered at a rate of 2 mL /min to deliver 2 mg/min.

Alternatively, add 40 mL of Trandate Injection to 250 mL of a commonly used IV fluid. The resultant solution will contain 200 mg of labetalol HCl, approximately 2 mg/3 mL. The diluted solution should be administered at a rate of 3 mL /min to deliver approximately 2 mg/min.

The rate of infusion of the diluted solution may be adjusted according to the blood pressure response, at the discretion of the physician. To facilitate a desired rate of infusion, the diluted solution can be infused using a controlled administration mechanism, e.g., graduated burette or mechanically driven infusion pump.

Since the half-life of labetalol is 5 to 8 hours, steady-state blood levels (in the face of a constant rate of infusion) would not be reached during the usual infusion time period. The infusion should be continued until a satisfactory response is obtained and should then be stopped and oral labetalol HCl started (see below). The effective IV dose is usually in the range of 50 to 200 mg. A total dose of up to 300 mg may be required in some patients.

Blood Pressure Monitoring: The blood pressure should be monitored during and after completion of the infusion or IV injection. Rapid or excessive falls in either systolic or diastolic blood pressure during IV treatment should be avoided. In patients with excessive systolic hypertension, the decrease in systolic pressure should be used as an indicator of effectiveness in addition to the response of the diastolic pressure.

Initiation of Dosing With TRANDATE Tablets: Subsequent oral dosing with TRANDATE Tablets should begin when it has been established that the supine diastolic blood pressure has begun to rise. The recommended initial dose is 200 mg, followed in 6 to 12 hours by an additional dose of 200 or 400 mg, depending on the blood pressure response. Thereafter, inpatient titration with TRANDATE Tablets may proceed as follows:

Inpatient Titration Instructions

*If needed, the total daily dose may be given in three divided doses.
Regimen	Daily Dose*
200 mg b.i.d.	400 mg
400 mg b.i.d.	800 mg
800 mg b.i.d.	1600 mg
1200 mg b.i.d	2400 mg

The dosage of TRANDATE Tablets used in the hospital may be increased at 1-day intervals to achieve the desired blood pressure reduction.

For subsequent outpatient titration or maintenance dosing, see DOSAGE AND ADMINISTRATION in the TRANDATE Tablets Product Information for additional recommendations.

Compatibility With Commonly Used Intravenous Fluids: Parenteral drug products should be inspected visually for particulate matter and discoloration before administration whenever solution and container permit.

Trandate Injection was tested for compatibility with commonly used IV fluids at final concentrations of 1.25 to 3.75 mg of labetalol HCl per milliliter of the mixture. Trandate Injection was found to be compatible with and stable (for 24 hours refrigerated or at room temperature) in mixtures with the following solutions: ringer's injection, USP; lactated ringer's injection, USP; 5% dextrose and ringer's injection; 5% lactated ringer's and 5% dextrose injection; 5% dextrose injection, USP; 0.9% sodium chloride injection, USP; 5% dextrose and 0.2% sodium chloride injection, USP; 2.5% dextrose and 0.45% sodium chloride injection, USP; 5% dextrose and 0.9% sodium chloride injection, USP; and 5% dextrose and 0.33% sodium chloride injection, USP.

Trandate Injection was NOT compatible with 5% sodium bicarbonate injection, USP. Care should be taken when administering alkaline drugs, including furosemide, in combination with labetalol. Compatibility should be assured prior to administering these drugs together.

HOW SUPPLIED:

Trandate Injection, 5 mg/mL, is supplied in 20-mL (100-mg) vials, box of one (NDC 65483-355-02) and 40-mL (200-mg) vials, box of one (NDC 65483-355-04).

Store between 2° and 30°C (36° and 86°F). Do not freeze. Protect from light.

Manufactured by Faulding Puerto Rico, Inc.

Aguadilla, PR 00604-0471

for Prometheus Laboratories Inc.

San Diego, CA 92121

TR020A03 ©Copyright 2003

All rights reserved.

Jan. 2003

PI076/JD

TR020A03

TRANDATE  labetalol hydrochloride  injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 65483-355 Route of Administration INTRAVENOUS DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength labetalol hydrochloride (labetalol) Active 5 MILLIGRAM  In 1 MILLILITER anhydrous dextrose Inactive   edetate disodium Inactive   methylparaben Inactive   propylparaben Inactive   citric acid anhydrous Inactive   sodium hydroxide Inactive

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 65483-355-02 20 mL (MILLILITER) In 1 VIAL, SINGLE-DOSE None 2 65483-355-04 40 mL (MILLILITER) In 1 VIAL, SINGLE-DOSE None

Revised: 04/2009Prometheus Laboratories Inc.

More Trandate Injection resources

• Trandate Injection Side Effects (in more detail)
• Trandate Injection Use in Pregnancy & Breastfeeding
• Drug Images
• Trandate Injection Drug Interactions
• Trandate Injection Support Group
• 2 Reviews for Trandate Injection - Add your own review/rating

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Rectanal

Rectanal may be available in the countries listed below.

Ingredient matches for Rectanal

Sodium Phosphate

Sodium Phosphate Dibasic dodecahydrate (a derivative of Sodium Phosphate) is reported as an ingredient of Rectanal in the following countries:

• Poland

Sodium Phosphate Monobasic dihydrate (a derivative of Sodium Phosphate) is reported as an ingredient of Rectanal in the following countries:

• Poland

International Drug Name Search

Sunitinib Malate

Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: N - [2 - (Diethylamino)ethyl] - 5 - [(Z) - (5 - fluoro - 2 - oxo - 1,2 - dihydro - 3H - indol - 3 - ylidene)methyl] - 2,4 - dimethyl - 1H - pyrrole - 3 - carboxamide
Molecular Formula: C₂₂H₂₇FN₄O₂
CAS Number: 557795-19-4
Brands: Sutent

Special Alerts:

[Posted 07/14/2008] Genentech, Inc. informed healthcare professionals of reports of several cases of microangiopathic hemolytic anemia (MAHA) in patients with solid tumors receiving bevacizumab (Avastin) in combination with sunitinib malate (Sutent). Bevacizumab is not approved for use in combination with sunitinib malate and this combination is not recommended. Twenty-five patients were enrolled in a Phase I dose-escalation study combining bevacizumab and sunitinib malate. The study consisted of 3 cohorts using a fixed dose of bevacizumab at 10mg/kg/IV every 2 weeks and escalating doses of sunitinib that included 25, 37.5, and 50 mg orally daily given in a 4 weeks on/ 2 weeks off schedule. Five of 12 patients at the highest sunitinib dose level exhibited laboratory findings consistent with MAHA. Two of these cases were considered severe with evidence of thrombocytopenia, anemia, reticulocytosis, reductions in serum haptoglobin, schistocytes on peripheral smear, modest increases in serum creatinine levels, and severe hypertension, reversible posterior leukoencephalopathy syndrome, and proteinuria. The findings in these two cases were reversible within three weeks upon discontinuation of both drugs without additional interventions. Healthcare professionals should report cases of MAHA or any serious adverse events suspected to be associated with the use of bevacizumab. For more information visit the FDA website at: and .

REMS:

FDA approved a REMS for sunitinib malate to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Antineoplastic agent; an inhibitor of multiple receptor tyrosine kinases.^{1 2 4 5 6 7 9 10 11 12 14 15}

Uses for Sunitinib Malate

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Gastrointestinal Stromal Tumor (GIST)

Treatment of GIST in adults who are intolerant of or whose disease has progressed during imatinib therapy.^{1 2 9}

Effects on overall survival remain to be established.^{1 9}

Renal Cell Carcinoma

Treatment of advanced renal cell carcinoma.^{1 2 7 14 15}

Sunitinib Malate Dosage and Administration

Administration

Oral Administration

Administer orally without regard to meals.^{1 11}

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as sunitinib malate; dosage expressed in terms of sunitinib.^{1 2}

Adults

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

GIST

Oral

50 mg once daily for 4 consecutive weeks followed by a 2-week period without the drug.¹ May continue therapy (i.e., 6-week cycles) for as long as the patient derives clinical benefit or until unacceptable toxicity occurs; in principal efficacy study, therapy was continued for a median of 5–6 cycles.²

Renal Cell Carcinoma

Oral

50 mg once daily for 4 consecutive weeks followed by a 2-week period without the drug.^{1 6} May continue therapy (i.e., 6-week cycles) for as long as the patient derives clinical benefit or until unacceptable toxicity occurs.²

Dosage Modification for Toxicity

Oral

Adjust dosage in increments or decrements of 12.5 mg daily (i.e., 1 dose level), depending on individual patient safety and tolerability.^{1 2}

In clinical studies, dosages reduced following drug-related adverse effects generally were not re-escalated, even in absence of toxicity; however, re-escalation back to previous dosage was permitted based on clinical judgment.² Initiation of next treatment cycle could be delayed if additional time (i.e., >2 weeks) was required to recover from toxicities that developed during previous treatment cycle.²

Cardiovascular Toxicities

If manifestations of CHF develop, discontinue sunitinib.¹ In patients without clinical evidence of CHF but in whom left ventricular ejection fraction (LVEF) is <50% and is reduced from baseline by >20%, interrupt therapy and/or reduce sunitinib dosage.¹

If severe hypertension occurs, temporarily interrupt therapy until BP is controlled.¹

In clinical studies, sunitinib was temporarily withheld following development of certain grade 2 (i.e., asymptomatic decrease in LVEF from baseline by 20% and to a level below the lower limit of normal [LVEF <50%], nonurgent ventricular paroxysmal dysrhythmia requiring intervention) or grade 3 cardiac toxicities.² When manifestations resolved or decreased in intensity to ≤grade 1, patients who originally experienced grade 2 cardiac toxicity could resume sunitinib therapy at same dosage (if toxicity resolved within 1 week) or at 1 dose level lower than previous dosage; patients who originally experienced grade 3 cardiac toxicity could resume therapy at 1 dose level lower than previous dosage.² Patients who developed grade 4 cardiac toxicity were required to permanently discontinue therapy.²

If thrombotic microangiopathy occurs, temporarily suspend drug.¹ After resolution, may resume treatment as appropriate.¹ (See Cardiovascular and Cerebrovascular Effects under Cautions.)

Other Nonhematologic Toxicities

If manifestations of pancreatitis or hepatic failure develop, discontinue sunitinib.¹ (See Pancreatic and Hepatic Effects under Cautions.)

In clinical studies, sunitinib was temporarily withheld following development of grade 3 or 4 nonhematologic toxicity.² When manifestations resolved or decreased in intensity to ≤grade 1, patients with GIST who originally experienced grade 3 nonhematologic toxicity could resume sunitinib therapy at same dosage, while those with advanced renal cell carcinoma could resume therapy at same dosage or at 1 dose level lower than previous dosage; patients who originally experienced grade 4 nonhematologic toxicity could resume therapy at 1 dose level lower than previous dosage or discontinue therapy based on clinical judgment.²

If manifestations of nephrotic syndrome develop, discontinue sunitinib.¹ (See Renal and Metabolic Effects under Cautions.)

If seizures or manifestations of reversible posterior leukoencephalopathy syndrome (RPLS) occur, discontinue sunitinib.¹ Institute medical management including control of hypertension.¹ Following recovery, may resume treatment as appropriate.¹ (See Reversible Posterior Leukoencephalopathy Syndrome under Cautions.)

Hematologic Toxicity

In clinical studies, sunitinib was temporarily withheld following development of grade 3 or 4 hematologic toxicity (excluding lymphopenia).² When manifestations resolved or decreased in intensity to ≤grade 2, patients who originally experienced grade 3 hematologic toxicity could resume sunitinib therapy at same dosage; patients who originally experienced grade 4 hematologic toxicity could resume therapy at 1 dose level lower than previous dosage.² Patients who experienced grade 3 or 4 lymphopenia could continue therapy without interruption.²

Concomitant Use with Drugs and Foods Affecting Hepatic Microsomal Enzymes

Concomitant use with potent inhibitors or inducers of CYP3A4 may alter the combined plasma concentrations of sunitinib and its primary active metabolite.¹ (See Drugs and Foods Affecting Hepatic Microsomal Enzymes under Interactions.)

If concomitant use with a potent CYP3A4 inhibitor cannot be avoided, consider reducing sunitinib dosage to no less than 37.5 mg daily.¹

If concomitant use with a CYP3A4 inducer cannot be avoided, consider increasing sunitinib dosage, up to maximum of 87.5 mg daily; monitor patient carefully for toxicity.¹

Special Populations

Hepatic Impairment

No dosage adjustment required in patients with Child-Pugh class A or B hepatic impairment; not studied in patients with severe (Child-Pugh class C) hepatic impairment.^{1 2 12} Discontinue drug if manifestations of hepatic failure develop.¹ (See Pancreatic and Hepatic Effects and also Hepatic Impairment under Cautions.)

Renal Impairment

Dosage adjustment based on Cl_cr not required.² However, discontinue drug if nephrotic syndrome develops.¹ (See Renal and Metabolic Effects under Cautions and also see Absorption: Special Populations under Pharmacokinetics.)

Cautions for Sunitinib Malate

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm;¹ teratogenicity and embryolethality demonstrated in animals.¹ Avoid pregnancy during therapy.¹ If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.¹

Major Toxicities

Cardiovascular Effects

Decreases in LVEF to below the lower limit of normal reported; grade 3 reductions in left ventricular systolic function (i.e., LVEF <40%) reported rarely.¹ Fatal heart failure and fatal cardiac arrest reported rarely.¹

Unknown whether patients with recent (i.e., within 12 months) history of cardiovascular disease (e.g., MI, severe or unstable angina, coronary or peripheral artery bypass graft, symptomatic CHF, cerebrovascular accident or TIA, pulmonary embolism) may be at a higher risk of developing drug-related left ventricular dysfunction since such patients were excluded from clinical studies.¹ Weigh this risk against potential benefits of the drug.¹ Carefully monitor such patients for clinical signs and symptoms of CHF during sunitinib therapy and consider baseline and periodic evaluations of LVEF.¹ Also consider baseline evaluation of ejection fraction in patients without cardiac risk factors.¹ (See Cardiovascular Toxicities under Dosage and Administration.)

Venous thromboembolic events (including DVT and pulmonary embolism) reported.¹

Thrombotic microangiopathy reported rarely.¹ (See Cardiovascular Toxicities under Dosage and Administration.)

QT Interval Prolongation and Torsades de Pointes

Dose-dependent prolongation of the QT interval reported; may result in increased risk of ventricular arrhythmias, including torsades de pointes.¹ Torsades de pointes reported rarely.¹

Use with caution in patients with history of QT interval prolongation, patients receiving antiarrhythmic agents or potent CYP3A4 inhibitors, and patients with relevant preexisting cardiac disease, bradycardia, or electrolyte disturbances.¹ (See Specific Drugs under Interactions.)

Consider periodic monitoring of ECG and electrolytes (potassium, magnesium).¹

Hypertension

Hypertension, including severe hypertension (SBP >200 mm Hg or DBP >110 mm Hg) reported.^{1 9 10}

Monitor BP and treat hypertension with standard antihypertensive therapy as needed.¹ If severe hypertension develops, withhold sunitinib until BP is controlled.¹

Hemorrhage

Bleeding events (epistaxis or, less commonly, rectal/gingival/upper GI/genital/wound bleeding) reported.¹ Most events were grade 1–2; grade 3–5 events also reported.¹

Tumor-related hemorrhage (including fatal pulmonary hemorrhage) reported.¹ May occur suddenly and, in the case of pulmonary tumors, may present as severe and life-threatening hemoptysis or pulmonary hemorrhage.¹ Monitor patients carefully with periodic clinical and laboratory evaluations (e.g., serial CBCs, physical examinations) for development of tumor hemorrhage.¹

Serious, sometimes fatal GI complications, including GI perforation, reported rarely in patients with intra-abdominal malignancies.¹

Other Hematologic Effects

Possible hematologic laboratory abnormalities, including anemia, thrombocytopenia, leukopenia, neutropenia, and lymphopenia.¹

Serious infections, with or without neutropenia, may occur; sometimes fatal.^b

Hypothyroidism

Hypothyroidism reported.^{1 13 14}

Obtain baseline thyroid function tests and treat hypothyroidism before initiating sunitinib therapy.¹

During sunitinib therapy, observe all patients closely; if signs and symptoms of hypothyroidism develop, obtain thyroid function tests and provide treatment per standard medical practice.¹

Adrenal Toxicity

Adrenal toxicity (characterized histologically by hemorrhage, necrosis, congestion, hypertrophy, and inflammation) reported in animals; however, no evidence of adrenal hemorrhage or necrosis in humans.¹

Abnormal response to rapid corticotropin (ACTH) stimulation tests (e.g., decreased plasma cortisol concentrations) observed in some patients; however, no clinical evidence of adrenal insufficiency.¹

Monitor for development of adrenal insufficiency in patients who experience stress (e.g., surgery, trauma, severe infection).¹

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

Seizures and radiologic evidence of RPLS reported rarely.¹

If seizures and manifestations of RPLS (e.g., hypertension, headache, decreased alertness, altered mental functioning, visual loss [including cortical blindness]) occur, temporarily withhold sunitinib and treat manifestations (including management of hypertension).¹ (See Other Nonhematologic Toxicities under Dosage and Administration.)

Pancreatic and Hepatic Effects

Pancreatitis and hepatic failure reported.¹ (See Other Nonhematologic Toxicities under Dosage and Administration.)

Possible hepatic laboratory abnormalities including elevated AST, ALT, bilirubin, and alkaline phosphatase.¹

Possible pancreatic laboratory abnormalities including elevated amylase and elevated serum lipase.¹

Renal and Metabolic Effects

Hypophosphatemia, hyperuricemia, elevated S_cr and elevated serum creatine kinase reported.^{1 15}

Proteinuria, and rarely, nephrotic syndrome reported.^b Perform baseline urinalysis and monitor for development or worsening of proteinuria.¹ Safety of continued treatment in moderate-to-severe proteinuria not yet evaluated.^b (See Other Nonhematologic Toxicities under Dosage and Administration.)

General Precautions

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Clinical and Laboratory Monitoring

Obtain CBCs (including platelet count) and serum chemistry tests (including phosphate) at beginning of each treatment cycle.¹

Perform clinical and/or laboratory assessments periodically to detect severe adverse effects (e.g., left ventricular dysfunction, hypertension, tumor hemorrhage, myelosuppression).^{1 2} (See Major Toxicities under Cautions.)

Musculoskeletal Effects

Myopathy and/or rhabdomyolysis, some with acute renal failure, reported rarely; most involved patients with pre-existing risk factors and/or taking concomitant drugs associated with myopathy and/or rhabdomyolysis.^b Manage signs and symptoms of muscle toxicity per standard medical protocol.^b

Specific Populations

Pregnancy

Category D.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Distributed into milk in rats; drug concentration up to 12-fold higher in milk than in plasma.¹ Not known whether sunitinib or its primary active metabolite is distributed into human milk.¹ Discontinue nursing or the drug because of potential risk in nursing infants.¹

Pediatric Use

Safety and efficacy not established.¹

Geriatric Use

No substantial differences in safety and efficacy in patients ≥65 years of age relative to younger adults.¹

Hepatic Impairment

Clinical studies excluded patients with AST or ALT concentrations >2.5 times the ULN or, if due to liver metastases, >5 times the ULN.¹ (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Safety and efficacy not established in patients with renal impairment.^{1 2} Clinical studies excluded patients with S_cr >2 times the ULN.^{1 2}

Common Adverse Effects

Fatigue,¹ asthenia,¹ diarrhea,¹ nausea,¹ mucositis/stomatitis,¹ vomiting,¹ dyspepsia,¹ abdominal pain,¹ constipation,¹ hypertension,¹ rash,¹ hand-foot syndrome,¹ skin discoloration,¹ altered taste,¹ anorexia,¹ bleeding.¹

Interactions for Sunitinib Malate

Sunitinib and its primary active metabolite are metabolized principally by CYP3A4.^{1 5}

Sunitinib does not inhibit or induce major CYP isoenzymes.¹

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Potent inhibitors of CYP3A4: Potential pharmacokinetic interaction (increased combined plasma concentrations of sunitinib and its primary active metabolite).¹ (See Specific Drugs and Foods under Interactions and also see QT Interval Prolongation and Torsades de Pointes under Cautions.)

Inducers of CYP3A4: Potential pharmacokinetic interaction (decreased combined plasma concentrations of sunitinib and its primary active metabolite).¹ (See Specific Drugs and Foods under Interactions.)

Drugs Metabolized by Hepatic Microsomal Enzymes

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Substrates of CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, or 4A9/11: Pharmacokinetic interaction unlikely.¹

Drugs that Prolong QT Interval

Risk of prolonged QT interval and potentially serious or life-threatening arrhythmias.¹ Use with caution in patients taking antiarrhythmics.¹ (See QT Interval Prolongation and Torsades de Pointes under Cautions.)

Specific Drugs and Foods

Drug or Food	Interaction	Comments
Antiarrhythmic agents		Use concomitantly with caution1 (see QT Interval Prolongation and Torsades de Pointes under Cautions)
Anticonvulsants (carbamazepine, phenobarbital, phenytoin)	Possible decreased combined plasma concentrations of sunitinib and its primary active metabolite1	Select an alternative agent with minimal or no enzyme induction potential; if concomitant use cannot be avoided, consider increasing sunitinib dosage to no more than 87.5 mg daily and carefully monitor patient for toxicity1
Antifungals, azoles (itraconazole, ketoconazole, voriconazole)	Ketoconazole: Increased combined plasma concentrations of sunitinib and its primary active metabolite1	Select an alternative agent with minimal or no enzyme inhibition potential; if concomitant use cannot be avoided, consider reducing sunitinib dosage to no less than 37.5 mg daily1
Antimycobacterials (rifabutin, rifampin, rifapentine)	Rifampin: Decreased combined plasma concentrations of sunitinib and its primary active metabolite1	Select an alternative agent with minimal or no enzyme induction potential; if concomitant use cannot be avoided, consider increasing sunitinib dosage to no more than 87.5 mg daily and carefully monitor patient for toxicity1
Dexamethasone	Possible decreased combined plasma concentrations of sunitinib and its primary active metabolite1	Select an alternative agent with minimal or no enzyme induction potential; if concomitant use cannot be avoided, consider increasing sunitinib dosage to no more than 87.5 mg daily and carefully monitor patient for toxicity1
Grapefruit	Possible increased combined plasma concentrations of sunitinib and its primary active metabolite1	Select alternative product with minimal or no enzyme inhibition potential; if concomitant use cannot be avoided, consider decreasing sunitinib dosage to no less than 37.5 mg daily1
HIV protease inhibitors (e.g., atazanavir, indinavir, nelfinavir, ritonavir, saquinavir)	Possible increased combined plasma concentrations of sunitinib and its primary active metabolite1	Select an alternative agent with minimal or no enzyme inhibition potential; if concomitant use cannot be avoided, consider reducing sunitinib dosage to no less than 37.5 mg daily1
Macrolides (e.g., clarithromycin, telithromycin)	Possible increased combined plasma concentrations of sunitinib and its primary active metabolite1	Select an alternative agent with minimal or no enzyme inhibition potential; if concomitant use cannot be avoided, consider reducing sunitinib dosage to no less than 37.5 mg daily1
Nefazodone	Possible increased combined plasma concentrations of sunitinib and its primary active metabolite1	Select an alternative agent with minimal or no enzyme inhibition potential; if concomitant use cannot be avoided, consider reducing sunitinib dosage to no less than 37.5 mg daily1
St. John's wort (Hypericum perforatum)	Possible unpredictable decreases in plasma sunitinib concentrations1	Avoid concomitant use1

Sunitinib Malate Pharmacokinetics

Absorption

Bioavailability

Following oral administration, peak plasma concentrations are attained within 6–12 hours.¹

Food

Food has no effect on bioavailability of sunitinib.^{1 11}

Special Populations

Systemic exposures after a single dose were similar in individuals with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment compared with those with normal hepatic function.¹

Pharmacokinetics of sunitinib and its primary active metabolite are not substantially affected by age, body weight, Cl_cr (i.e., in the range of 42–347 mL/minute), race, gender, or ECOG performance status.¹

Distribution

Extent

Sunitinib and metabolites are distributed into milk in animals; not known whether the drug or its primary active metabolite is distributed into human milk.¹

Plasma Protein Binding

Approximately 95% (for sunitinib) and 90% (for primary active metabolite).¹

Elimination

Metabolism

Metabolized in the liver, principally by CYP3A4 to several metabolites.^{1 5 11 12}

Primary active metabolite appears to be equipotent to sunitinib;^{1 5} this metabolite accounts for approximately 23–37% of total plasma concentrations of the drug and also is metabolized by CYP3A4.¹

Elimination Route

Excreted in feces (61%) and urine (16%), mainly as sunitinib and primary active metabolite.^{1 2} Minor metabolites recovered in feces and urine but generally not found in plasma.^{1 2}

Half-life

Approximately 40–60 hours (for sunitinib) or 80–110 hours (for primary active metabolite).^{1 12}

Special Populations

Results of one pharmacokinetic study indicated a slightly longer sunitinib half-life in individuals with mild (Child-Pugh score of 5–6) or moderate (Child-Pugh score of 7–9) hepatic impairment; however, clearance of sunitinib not significantly different from that in individuals with normal hepatic function.¹²

Stability

Storage

Oral

Capsules

25°C (may be exposed to 15–30°C).¹

Actions

• 
  

  Inhibits multiple receptor tyrosine kinases (RTKs), ^{1 2 4 5 6 7 9 10 11 12} which are involved in the initiation of various cascades of intracellular signaling events that lead to cell proliferation and/or influence processes critical to cell survival and tumor progression (e.g., angiogenesis, metastasis, inhibition of apoptosis), based on the respective kinase.^{1 2 4 6 7 11}

  
  


• 
  

  May inhibit signal transduction pathways involving multiple receptor (i.e., cell surface) tyrosine kinases, including platelet-derived growth factor receptors (i.e., PDGFR-α, PDGFR-β), vascular endothelial growth factor receptors (i.e., VEGFR-1, VEGFR-2, VEGFR-3), stem cell factor receptor (i.e., c-Kit), fms-like tyrosine kinase 3 (Flt-3), colony stimulating factor receptor type 1 (CSF-1R), and the glial cell line-derived neurotrophic factor receptor (RET).^{1 2 4 5 9 10 11 12}

  
  


• 
  

  Shown to inhibit growth of tumor cells expressing dysregulated target RTKs (i.e., PDGFR, RET, c-Kit) in vitro; also shown to inhibit PDGFR-β- and VEGFR-2-dependent tumor angiogenesis in vivo.¹

  
  

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• 
  

  Risk of adverse GI effects (e.g., diarrhea, nausea, vomiting, dyspepsia, mouth pain/irritation/stomatitis, taste disturbance).¹ Supportive care for adverse GI effects requiring treatment may include antiemetic or antidiarrheal therapy.¹

  
  


• 
  

  Risk of adverse dermatologic effects (e.g., skin discoloration due to the drug color [yellow]; hair or skin depigmentation; skin dryness, thickness, or cracking; blisters or rash on the hands and soles of the feet).¹

  
  


• 
  

  Risk of fatigue, hypertension, bleeding, and edema.¹

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹ Advise pregnant women of risk to the fetus and/or of potential risk for loss of pregnancy.¹

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements (e.g., St. John’s wort), as well as any concomitant illnesses.¹

  
  


• 
  

  Importance of informing patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Sunitinib Malate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	12.5 mg (of sunitinib)	Sutent	Pfizer
		25 mg (of sunitinib)	Sutent	Pfizer
		50 mg (of sunitinib)	Sutent	Pfizer

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Sutent 12.5MG Capsules (PFIZER U.S.): 28/$2,596.10 or 84/$7,396.68

Sutent 25MG Capsules (PFIZER U.S.): 28/$5,214.86 or 84/$14,954.77

Sutent 50MG Capsules (PFIZER U.S.): 28/$10,465.92 or 84/$30,651.87

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Pfizer Labs. Sutent (sunitinib malate) capsules prescribing information. New York, NY; 2007 Feb .

2. Pfizer Inc., Parsippany, NJ: Personal communication.

4. Arora A, Scholar EM. Role of tyrosine kinase inhibitors in cancer therapy. J Pharmacol Exp Ther. 2005; 315:971-9. [PubMed 16002463]

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6. Schöffski P, Dumez H, Clement P et al. Emerging role of tyrosine kinase inhibitors in the treatment of advanced renal cell cancer: a review. Ann Oncol. 2006 (Advance access [doi:]).

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b. Pfizer Labs. Sutent (sunitinib malate) capsules prescribing information. New York, NY; 2008 May.

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