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CARTROL (carteolol hydrochloride) is a synthetic, nonselective, beta-adrenergic receptor blocking agent with intrinsic sympathomimetic activity. It is chemically described as 5-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-3,4-dihydro-2(1H)-quinolinone monohydrochloride. The structural formula is:
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Carteolol hydrochloride is a stable, white crystalline powder which is soluble in water and slightly soluble in ethanol. The molecular weight is 328.84 and C 16 H 24 N 2 O 3 ·HCl is the empirical formula.
CARTROL (carteolol hydrochloride) is available as tablets containing either 2.5 mg or 5 mg of carteolol hydrochloride for oral administration.
2.5 mg Tablet: polymers, corn starch, iron oxide, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, propylene glycol, and titanium dioxide.
5 mg Tablet: polymers, corn starch, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, propylene glycol, and titanium dioxide.
CARTROL (carteolol hydrochloride) is a long-acting, nonselective, beta-adrenergic receptor blocking agent with intrinsic sympathomimetic activity (ISA) and without significant membrane stabilizing (local anesthetic) activity.
Pharmacodynamics:
Carteolol specifically competes with beta-adrenergic receptor agonists for both beta 1 -receptors located principally in cardiac muscle and beta 2 -receptors located in the bronchial and vascular musculature, blocking the chronotropic, inotropic, and vasodilator responses to beta-adrenergic stimulation proportionately. Because of its partial agonist activity, however, carteolol does not reduce resting beta-agonist activity as much as beta-adrenergic blockers lacking this activity. Thus, in clinical trials in man, the decreases in resting pulse rate produced by carteolol (2-5 beats per minute in various studies) were less than those produced by beta-blockers (nadolol and propranolol) without ISA (10-12 beats per minute). There are also equivocal effects on renin secretion, in contrast to beta-blockers without ISA, which inhibit renin secretion.
In controlled clinical trials carteolol, at doses up to 20 mg as monotherapy or in combination with thiazide type diuretics, produced significantly greater reductions in blood pressure than did placebo, with the full effect seen between two and four weeks. The observed differences from placebo ranged from 3.1 to 6.7 mmHg for supine diastolic blood pressure. The antihypertensive effects of carteolol are smaller in black populations but do not seem to be affected by age or sex. Doses of carteolol greater than 10 mg once a day did not produce greater reductions in blood pressure. In fact, doses of 20 mg and above appeared to produce blood pressure reductions less than those produced by 10 mg and below. When carteolol was compared to nadolol and propranolol, although the differences were not statistically significant in relatively small studies, carteolol at doses up to 20 mg produced supine diastolic blood pressure changes consistently 2 mmHg less than that produced by either nadolol or propranolol.
Although the mechanism of the antihypertensive effect of beta-adrenergic blocking agents has not been established, multiple factors are thought to contribute to the lowering of blood pressure, including diminished response to sympathetic nerve outflow from vasomotor centers in the brain, diminished release of renin from the kidneys, and decreased cardiac output. Carteolol does not have a consistent effect on renin and other agents with ISA have been shown to have less effect than other beta-blockers on resting cardiac output (although they cause the usual decrease in exercise cardiac output so that the difference is of uncertain clinical importance), so that the mechanism of its action is particularly uncertain.
Beta-blockade interferes with endogenous adrenergic bronchodilator activity and diminishes the response to exogenous bronchodilators. This is especially important in patients subject to bronchospasm.
Single intravenous doses of carteolol (0.5 mg, 1 mg, 2.5 mg and 5 mg) produced statistically, but not clinically, significant increases from baseline in AV node conduction time and RR and PR intervals.
CARTROL (carteolol hydrochloride) induced no significant alteration in total serum cholesterol and triglycerides.
Following discontinuation of carteolol treatment in man, pharmacologic activity (evaluated by blockade of the tachycardia induced by isoproterenol or postural changes) is present for 2 to 21 days (median 14 days) after the last dose of carteolol. Following administration of recommended doses of CARTROL (carteolol hydrochloride), both beta-blocking and antihypertensive effects persist for at least 24 hours.
and Metabolism:
Following oral administration in man, peak plasma concentrations of carteolol usually occur within one to three hours. Carteolol is well absorbed when administered orally as CARTROL (carteolol hydrochloride) tablets. The presence of food in the gastrointestinal tract somewhat slows the rate of absorption, but the extent of absorption is not appreciably affected. Compared to intravenous administration, the absolute bioavailability of carteolol from CARTROL (carteolol hydrochloride) tablets is approximately 85%.
The plasma half-life of carteolol averages approximately six hours. Steady-state serum levels are achieved within one to two days after initiating therapeutic doses of carteolol in persons with normal renal function. Since approximately 50 to 70% of a carteolol dose is eliminated unchanged by the kidneys, the half-life is increased in patients with impaired renal function. Significant reductions in the rate of carteolol elimination (and prolongations of the half-life) occur in patients as creatinine clearance decreases. Therefore, a reduction in maintenance dose and/or prolongation in dosing interval is appropriate (see DOSAGE and ADMINISTRATION ).
Carteolol is 23-30% bound to plasma proteins in humans. The major metabolites of carteolol are 8-hydroxycarteolol and the glucuronic acid conjugates of both carteolol and 8-hydroxycarteolol. In man, 8-hydroxycarteolol is an active metabolite with a half-life of approximately 8 to 12 hours and represents approximately 5% of the administered dose excreted in the urine.
CARTROL (carteolol hydrochloride) is indicated in the management of hypertension. It may be used alone or in combination with other antihypertensive agents, especially thiazide diuretics. Preliminary data indicate that carteolol does not have a favorable effect on arrhythmias.
CARTROL (carteolol hydrochloride) is contraindicated in patients with: 1) bronchial asthma, 2) severe bradycardia, 3) greater than first degree heart block, 4) cardiogenic shock, and 5) clinically evident congestive heart failure (see ).
Sympathetic stimulation may be a vital component supporting circulatory function in patients with congestive heart failure, and impairing that support by beta-blockade may precipitate more severe decompensation. Although CARTROL (carteolol hydrochloride) should be avoided in clinically evident congestive heart failure, it can be used with caution, if necessary, in patients with a history of failure who are well-compensated and are receiving digitalis and diuretics. Beta-adrenergic blocking agents do not abolish the inotropic action of digitalis on heart muscle.
IN PATIENTS WITHOUT A HISTORY OF CONGESTIVE HEART FAILURE, the use of beta-blockers can, in some instances, lead to congestive heart failure. Therefore, at the first sign or symptom of cardiac decompensation, discontinuation of beta-blocker therapy should be considered. The patient should be closely observed and treatment should include a diuretic and/or digitalization as necessary.
Exacerbation of Angina Pectoris Upon Withdrawal:
In patients with angina pectoris, exacerbation of angina and, in some cases, myocardial infarction have been reported following abrupt discontinuation of therapy with some beta-blockers. Therefore such patients should be cautioned against interruption of therapy without a physician' advice. The long persistence of beta-adrenergic blockade following abrupt discontinuation of CARTROL (carteolol hydrochloride), however, might be expected to minimize the possibility of this complication. When discontinuation of CARTROL (carteolol hydrochloride) is planned, dosage should be tapered gradually, as it is with other beta-blockers. If exacerbation of angina occurs when CARTROL (carteolol hydrochloride) therapy is interrupted, it is advisable to reinstitute CARTROL (carteolol hydrochloride) or other beta-blocker therapy, at least temporarily, and to take other measures appropriate for the management of unstable angina pectoris.
PATIENTS WITHOUT CLINICALLY RECOGNIZED ANGINA PECTORIS should be carefully monitored after withdrawal of CARTROL (carteolol hydrochloride) therapy, since coronary artery disease may be unrecognized.
Nonallergic Bronchospasm (e.g., chronic bronchitis, emphysema):
Patients with bronchospastic disease generally should not receive beta-blocker therapy and carteolol is contraindicated in patients with bronchial asthma. If use of CARTROL (carteolol hydrochloride) is essential, it should be administered with caution since it may block bronchodilation produced by endogenous catecholamine stimulation of beta 2 -receptors or diminish response to therapy with a beta-receptor agonist.
The necessity, or desirability, of withdrawal of beta-blocking therapy prior to major surgery is controversial. Because beta-blockade impairs the ability of the heart to respond to reflex stimuli and may increase risks of general anesthesia and surgical procedures resulting in protracted hypotension or low cardiac output, and difficulty in restarting or maintaining a heartbeat, it has been suggested that beta-blocker therapy should be withdrawn several days prior to surgery. It is also recognized, however, that increased sensitivity to catecholamines of patients recently withdrawn from beta-blocker therapy could increase certain risks. Given the persistence of the beta-blocking activity of CARTROL (carteolol hydrochloride), effective withdrawal would take several weeks and would ordinarily be impractical. When beta-blocker therapy is not discontinued, anesthetic agents that depress the myocardium should be avoided. In one study using intravenous carteolol during surgery, recovery from anesthesia was somewhat delayed in three patients who received carteolol near the end of anesthesia, and respiratory arrest occurred in one of these patients immediately following administration of intravenous carteolol.
In the event that CARTROL (carteolol hydrochloride) treatment is not discontinued before surgery, the anesthesiologist should be informed that the patient is receiving CARTROL (carteolol hydrochloride). The effects on the heart of beta-adrenergic blocking agents, such as CARTROL (carteolol hydrochloride), may be reversed by cautious administration of isoproterenol or dobutamine.
Diabetes Mellitus and Hypoglycemia:
Beta-adrenergic blockade may prevent the appearance of premonitory signs and symptoms (e.g., tachycardia and blood pressure changes) of acute hypoglycemia, and it inhibits glycogenolysis, a normal compensatory mechanism for hypoglycemia. This is especially important for patients with labile diabetes mellitus. Beta-blockade also reduces the release of insulin in response to hyperglycemia; therefore, it may be necessary to adjust the dose of antidiabetic agents used to treat hyperglycemia.
Thyrotoxicosis:
Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism such as tachycardia. Patients suspected of having thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-adrenergic blockade which might precipitate a thyroid storm.
CARTROL (carteolol hydrochloride) should be used with caution in patients with impaired renal function. Patients with impaired renal function clear carteolol at a reduced rate, and dosage should be reduced accordingly (see Dosage and Administration ).
Beta-adrenoreceptor blockade can cause reduction in intraocular pressure. Therefore, CARTROL (carteolol hydrochloride) may interfere with glaucoma testing. Withdrawal may lead to a return of increased intraocular pressure.
Patients, especially those with evidence of coronary artery insufficiency, should be warned against interruption or discontinuation of CARTROL (carteolol hydrochloride) therapy without the physician' advice. Although cardiac failure rarely occurs in properly selected patients, patients being treated with beta-adrenergic blocking agents should be advised to consult the physician at the first sign or symptom of impending failure (i.e., fatigue with exertion, difficulty breathing, cough or unusually fast heartbeat).
Catecholamine-depleting drugs (e.g., reserpine) may have an additive effect when given with beta-blocking agents. Therefore, patients treated with CARTROL (carteolol hydrochloride) plus a catecholamine-depleting agent must be observed carefully for evidence of hypotension and/or excessive bradycardia, which may produce syncope or postural hypotension.
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.
Concurrent administration of general anesthetics and beta-blocking agents may result in exaggeration of the hypotension induced by general anesthetics (see , Major Surgery ).
Blunting of the antihypertensive effect of beta-adrenoreceptor blocking agents by non-steroidal anti-inflammatory drugs has been reported. When using these agents concomitantly, patients should be observed carefully to confirm that the desired therapeutic effect has been obtained.
Literature reports suggest that oral calcium antagonists may be used in combination with beta-adrenergic blocking agents when heart function is normal, but should be avoided in patients with impaired cardiac function. Hypotension, AV conduction disturbances, and left ventricular failure have been reported in some patients receiving beta-adrenergic blocking agents when an oral calcium antagonist was added to the treatment regimen. Hypotension was more likely to occur if the calcium antagonist were a dihydropyridine derivative, e.g., nifedipine, while left ventricular failure and AV conduction disturbances were more likely to occur with either verapamil or diltiazem.
Intravenous calcium antagonists should be used with caution in patients receiving beta-adrenergic blocking agents. The concomitant use of beta-adrenergic blocking agents with digitalis and either diltiazem or verapamil may have additive effects in prolonging AV conduction time.
Concomitant use of oral antidiabetic agents or insulin with beta-blocking agents may be associated with hypoglycemia or possibly hyperglycemia. Dosage of the antidiabetic agent should be adjusted accordingly (see , Diabetes Mellitus and Hypoglycemia ).
CARTROL (carteolol hydrochloride) did not produce carcinogenic effects at doses 280 times the maximum recommended human dose (10 mg/70 kg/day) in two-year oral rat and mouse studies.
Tests of mutagenicity, including the Ames Test, recombinant (rec)-assay, in vivo cytogenetics and dominant lethal assay demonstrated no evidence for mutagenic potential.
Fertility of male and female rats and male and female mice was unaffected by administration of CARTROL (carteolol hydrochloride) at dosages up to 150 mg/kg/day. This dosage is approximately 1052 times the maximum recommended human dose.
Teratogenic Effects: Pregnancy Category C. CARTROL (carteolol hydrochloride) increased resorptions and decreased fetal weights in rabbits and rats at maternally toxic doses approximately 1052 and 5264 times the maximum recommended human dose (10 mg/70 kg/day), respectively. A dose-related increase in wavy ribs was noted in the developing rat fetus when pregnant females received daily doses of approximately 212 times the maximum recommended human dose. No such effects were noted in pregnant mice subjected to up to 1052 times the maximum recommended human dose. There are no adequate and well-controlled studies in pregnant women. CARTROL (carteolol hydrochloride) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Studies have not been conducted in lactating humans and, therefore, it is not known whether carteolol is excreted in human milk. Studies in lactating rats indicate that CARTROL (carteolol hydrochloride) is excreted in milk. Because many drugs are excreted in human milk, caution should be exercised when CARTROL (carteolol hydrochloride) is administered to a nursing woman.
Safety and effectiveness in children have not been established.
The prevalence of adverse reactions has been ascertained from clinical studies conducted primarily in the United States. All adverse experiences (events) reported during these studies were recorded as adverse reactions. The prevalence rates presented below are based on combined data from nineteen placebo-controlled studies of patients with hypertension, angina or dysrhythmias, using once-daily carteolol at doses up to 60 mg. Table 1 summarizes those adverse experiences reported for patients in these studies where the prevalence in the carteolol group is 1% or greater and exceeds the prevalence in the placebo group. Asthenia and muscle cramps were the only symptoms that were significantly more common in patients receiving carteolol than in patients receiving placebo. Patients in clinical trials were carefully selected to exclude those, such as patients with asthma or known bronchospasm, or congestive heart failure, who would be at high risk of experiencing beta-adrenergic blocker adverse effect (See and CONTRAINDICATIONS ):
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The adverse experiences were usually mild or moderate in intensity and transient, but sometimes were serious enough to interrupt treatment. The adverse reactions that were most bothersome, as judged by their being reported as reasons for discontinuation of therapy by at least 0.4% of the carteolol group are shown in Table 2.
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Additional adverse reactions have been reported, but these are, in general, not distinguishable from symptoms that might have occurred in the absence of exposure to carteolol. The following additional adverse reactions were reported by at least 1% of 1568 patients who received carteolol in controlled or open, short- or long-term clinical studies, or represent less common, but potentially important, reactions reported in clinical studies or marketing experience (these rarer reactions are shown in italics): Body as a Whole: fever, infection, injury, malaise, pain, neck pain, shoulder pain; Cardiovascular System: angina pectoris, arrhythmia, heart failure, palpitations, second degree heart block, vasodilation; Digestive System: acute hepatitis with jaundice, constipation, dyspepsia, flatulence, gastrointestinal disorder; Metabolic/Nutritional Disorder: gout; Musculoskeletal System: pain in extremity, joint disorder, arthritis; Nervous System: abnormal dreams, anxiety, depression, dizziness, nervousness, somnolence; Respiratory System: bronchitis, bronchospasm cold symptoms, cough, dyspnea, flu symptoms, lung disorder, rhinitis, sinusitis, wheezing; Skin and Appendages: sweating Special Senses: blurred vision, conjunctivitis, eye disorder, tinnitus; Urogenital: impotence, urinary frequency, urinary tract infection.
In studies of patients with hypertension or angina pectoris where carteolol and positive reference beta-adrenergic blocking agents [nadolol (n=82) and propranolol (n=50)] have been compared, the differences in prevalence rates between the carteolol group and the reference agent group were statistically significant (p</=0.05) for the adverse reactions listed in Table 3.
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In addition, other adverse reactions not listed above have been reported with other beta-adrenergic blocking agents and should be considered potential adverse reactions of CARTROL (carteolol hydrochloride).
Body as a Whole:
Fever combined with aching and sore throat.
Intensification of AV block. (See CONTRAINDICATIONS ).
Mesenteric arterial thrombosis, ischemic colitis.
Agranulocytosis, thrombocytopenic and nonthrombocytopenic purpura.
Reversible mental depression progressing to catatonia; an acute reversible syndrome characterized by disorientation to time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometric testing.
Respiratory System: Laryngospasm, respiratory distress.
Skin and Appendages: Erythematous rash, reversible alopecia.
Urogenital System: Peyronie's disease.
The oculomucocutaneous syndrome associated with the beta-adrenergic blocking agent practolol has not been reported with carteolol.
No specific information on emergency treatment of overdosage in humans is available. The most common effects expected with overdosage of a beta-adrenergic blocking agent are bradycardia, bronchospasm, congestive heart failure and hypotension.
In case of overdosage, treatment with CARTROL (carteolol hydrochloride) should be discontinued and gastric lavage considered. The patient should be closely observed and vital signs carefully monitored. The prolonged effects of carteolol must be considered when determining the duration of corrective therapy. On the basis of the pharmacologic profile, the following additional measures should be considered as appropriate.
Administer atropine. If there is no response to vagal blockade, administer isoproterenol cautiously.
Administer a beta 2 -stimulating agent such as isoproterenol and/or a theophylline derivative.
Administer diuretics and digitalis glycosides as necessary.
Administer vasopressors such as intravenous dopamine, epinephrine or norepinephrine bitartrate.
Dosage must be individualized. The initial dose of CARTROL (carteolol hydrochloride) is 2.5 mg given as a single daily oral dose either alone or added to diuretic therapy. If an adequate response is not achieved, the dose can be gradually increased to 5 mg and 10 mg as single daily doses. Increasing the dose above 10 mg per day is unlikely to produce further substantial benefits and, in fact, may decrease the response. The usual maintenance dose of carteolol is 2.5 or 5 mg once daily.
Dosage Adjustment in Renal Impairment:
Carteolol is excreted principally by the kidneys. When administering CARTROL (carteolol hydrochloride) to patients with renal impairment, the dosage regimen should be adjusted individually by the physician. Guidelines for dose interval adjustment are shown below:
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CARTROL (carteolol hydrochloride) is supplied as:
2.5 mg gray tablets:
Bottles of 100 ............................. ( NDC 0074-1664-13).
5 mg white tablets:
Bottles of 100 ............................. ( NDC 0074-1665-13).
Recommended storage: under controlled room temperature, 59°-86°F (15°-30°C).
Revised: February, 1992
Ref. 01-2531-R3