Ciplar LA

Ciplar LA Propranolol Hydrochloride Long Acting Tablets
COMPOSITION CIPLAR LA 40 Tablets Each Long Acting tablet contains Propranolol Hydrochloride IP……40 mg
CIPLAR LA 80 Tablets Each Long Acting tablet contains Propranolol Hydrochloride IP……80 mg DOSAGE FORM Tablets PHARMACOLOGY Pharmacodynamics Propranolol is a nonselective, beta-adrenergic receptor-blocking agent possessing no other autonomic nervous system activity. It specifically competes with beta-adrenergic receptor-stimulating agents for available receptor sites. When access to beta-receptor sites is blocked by propranolol , the chronotropic, inotropic, and vasodilator responses to beta-adrenergic stimulation are decreased proportionately.
The mechanism of the antihypertensive effect of propranolol has not been established. Among the factors that may be involved in contributing to the antihypertensive action are: (1) decreased cardiac output, (2) inhibition of renin release by the kidneys, and (3) diminution of tonic sympathetic nerve outflow from vasomotor centers in the brain. Although total peripheral resistance may increase initially, it readjusts to or below the pretreatment level with chronic use. Effects on plasma volume appear to be minor and somewhat variable.
In angina pectoris, propranolol generally reduces the oxygen requirement of the heart at any given level of effort by blocking the catecholamine-induced increases in the heart rate, systolic blood pressure, and the velocity and extent of myocardial contraction. Propranolol may increase oxygen requirements by increasing left ventricular fiber length, end diastolic pressure, and systolic ejection period. The net physiologic effect of beta-adrenergic blockade is usually advantageous and is manifested during exercise by delayed onset of pain and increased work capacity.
In dosages greater than required for beta blockade, propranolol also exerts a quinidine-like or anesthetic-like membrane action which affects the cardiac action potential. The significance of the membrane action in the treatment of arrhythmias is uncertain.
The mechanism of the antimigraine effect of propranolol has not been established. Beta-adrenergic receptors have been demonstrated in the pial vessels of the brain.
Pharmacokinetics Absorption Propranolol is highly lipophilic and is almost completely absorbed after oral administration. However, it undergoes high first-pass metabolism by the liver and on average, only about 25% of propranolol reaches the systemic circulation. CIPLAR LA tablets release propranolol at a controlled and predictable rate.
Distribution Approximately 90% of circulating propranolol is bound to plasma proteins (albumin and alpha 1 acid glycoprotein). The binding is enantiomer-selective. The S-isomer is preferentially bound to alpha 1 glycoprotein and the R-isomer preferentially bound to albumin. The volume of distribution of propranolol is approximately 4 liters/kg. Propranolol crosses the blood-brain barrier and the placenta, and is distributed into breast milk.
Metabolism and Elimination Propranolol is extensively metabolized with most metabolites appearing in the urine. Propranolol is metabolized through three primary routes: aromatic hydroxylation (mainly 4-hydroxylation), N-dealkylation followed by further side-chain oxidation, and direct glucuronidation. It has been estimated that the percentage contributions of these routes to total metabolism are 42%, 41%, and 17%, respectively, but with considerable variability between individuals. The four major metabolites are propranolol glucuronide, naphthyloxylactic acid, and glucuronic acid and sulfate conjugates of 4-hydroxy propranolol.
In vitro studies have indicated that the aromatic hydroxylation of propranolol is catalyzed mainly by polymorphic CYP2D6. Side-chain oxidation is mediated mainly by CYP1A2 and to some extent by CYP2D6. 4-hydroxy propranolol is a weak inhibitor of CYP2D6.
Propranolol is also a substrate for CYP2C19 and a substrate for the intestinal efflux transporter, p-glycoprotein (p-gp). Studies suggest however that p-gp is not dose-limiting for intestinal absorption of propranolol in the usual therapeutic dose range.
In healthy subjects no difference was observed between CYP2D6 extensive metabolizers ( EMs ) and poor metabolizers (PMs) with respect to oral clearance or elimination half-life. Partial clearance to 4-hydroxy propranolol was significantly higher and to naphthyloxylactic acid was significantly lower in EMs than PMs.
Following oral dosing with the sustained release preparation of propranolol, the blood profile is flatter than after conventional propranolol, but the half-life is increased to between 10 and 20 hours. The liver removes up to 90% of an oral dose with an elimination half-life of 3 to 6 hours. INDICATIONS Hypertension Angina pectoris due to coronary atherosclerosis Migraine Hypertrophic subaortic stenosis DOSAGE AND ADMINISTRATION CIPLAR LA provides propranolol hydrochloride in a sustained-release tablet for once daily administration. If patients are switched from CIPLAR tablets to CIPLAR LA tablets, care should be taken to assure that the desired therapeutic effect is maintained. CIPLAR LA should not be considered a simple mg-for-mg substitute for CIPLAR . CIPLAR LA has different kinetics and produces lower blood levels. Retitration may be necessary especially to maintain effectiveness at the end of the 24-hour dosing interval.
Hypertension Dosage must be individualized. The usual initial dosage is 80 mg CIPLAR LA once daily, whether used alone or added to a diuretic. The dosage may be increased to 120 mg once daily or higher until adequate blood pressure control is achieved. The usual maintenance dosage is 120 to 160 mg once daily.
Angina Pectoris Dosage must be individualized. Starting with 80 mg CIPLAR LA once daily, dosage should be gradually increased at three-to seven-day intervals until optimal response is obtained. Although individual patients may respond at any dosage level, the average optimal dosage appears to be 160 mg once daily. If treatment is to be discontinued, reduce dosage gradually over a period of few weeks.
Migraine Dosage must be individualized. The initial oral dose is 80 mg CIPLAR LA once daily. The usual effective dose range is 160 to 240 mg once daily. The dosage may be increased gradually to achieve optimal migraine prophylaxis. If a satisfactory response is not obtained within four to six weeks after reaching the maximal dose; CIPLAR LA therapy should be discontinued. The drug should be withdrawn gradually over a period of several weeks.
Hypertrophic Subaortic Stenosis 80 to 160 mg CIPLAR LA once daily CONTRAINDICATIONS Cardiogenic shock Sinus bradycardia and greater than first-degree block Bronchial asthma Patients with known hypersensitivity to propranolol hydrochloride WARNINGS AND PRECAUTIONS Drug interactions Catecholamine-depleting drugs (reserpine): provide added catecholamine-blocking action when coadministered with propranolol and may produce an excessive reduction of resting sympathetic nervous activity, which may result in hypotension, marked bradycardia, vertigo, syncopal attacks, or orthostatic hypotension.
Nonsteroidal Anti-inflammatory Drugs (NSAIDs): blunt the antihypertensive effect of beta-adrenoceptor blocking agents
Haloperidol: Hypotension and cardiac arrest have been reported with the concomitant use of propranolol and haloperidol.
Aluminium hydroxide gel: greatly reduces intestinal absorption of propranolol. Ethanol: slows the rate of absorption of propranolol.
Phenytoin, phenobarbitone, and rifampin: accelerate propranolol clearance. Chlorpromazine: when used concomitantly with propranolol results in increased plasma levels of both drugs.
Antipyrine and lidocaine: have reduced clearance when used concomitantly with propranolol.
Thyroxine: may result in a lower than expected T 3 concentration when used concomitantly with propranolol.
Cimetidine: decreases the hepatic metabolism of propranolol, delaying elimination and increasing blood levels.
Theophylline: Theophylline clearance is reduced when used concomitantly with propranolol.
Angina pectoris There have been reports of exacerbation of angina and, in some cases, myocardial infarction, following abrupt discontinuance of long-acting propranolol therapy. Therefore, when discontinuance of CIPLAR LA is planned, the dosage should be gradually reduced over at least a few weeks, and the patient should be cautioned against interruption or cessation of therapy without the physician`s advice. If CIPLAR LA therapy is interrupted and exacerbation of angina occurs, it usually is advisable to reinstitute CIPLAR LA therapy and take other measures appropriate for the management of unstable angina pectoris. Since coronary artery disease may be unrecognized, it may be prudent to follow the above advice in patients considered at risk of having occult atherosclerotic heart disease who are given propranolol for other indications.
Cardiac Failure Sympathetic stimulation may be a vital component supporting circulatory function in patients with congestive heart failure, and its inhibition by beta blockade may precipitate more severe failure. Although beta blockers should be avoided in overt congestive heart failure, some have been shown to be highly beneficial when used with close follow-up in patients with a history of failure who are well compensated and are receiving diuretics as needed. Beta-adrenergic blocking agents do not abolish the inotropic action of digitalis on heart muscle. In patients without a history of heart failure, continued use of beta blockers can, in some cases, lead to cardiac failure.
Nonallergic Bronchospasm (e.g., Chronic Bronchitis, Emphysema)
In general, patients with bronchospastic lung disease should not receive beta-blockers.
Propranolol should be administered with caution in this setting since it may provoke a bronchial asthmatic attack by blocking bronchodilation produced by endogenous and exogenous catecholamine stimulation of beta-receptors.
Major Surgery The necessity or desirability of withdrawal of beta-blocking therapy prior to major surgery is controversial. It should be noted, however, that the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anaesthesia and surgical procedures.
Diabetes and Hypoglycaemia Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia, especially in labile insulin-dependent diabetics. In these patients, it may be more difficult to adjust the dosage of insulin. Propranolol therapy, particularly when given to infants and children, diabetic or not, has been associated with hypoglycemia especially during fasting as in preparation for surgery. Hypoglycemia has been reported in patients taking propranolol after prolonged physical exertion and in patients with renal insufficiency.
Thyrotoxicosis Beta blockade may mask certain clinical signs of hyperthyroidism. Therefore, abrupt withdrawal of propranolol may be followed by an exacerbation of symptoms of hyperthyroidism, including thyroid storm. Propranolol may change thyroid-function tests, increasing T4 and reverse T3, and decreasing T3.
Wolff-Parkinson-White Syndrome Beta-adrenergic blockade in patients with Wolff-Parkinson-White syndrome and tachycardia has been associated with severe bradycardia requiring treatment with a pacemaker. In one case, this result was reported after an initial dose of 5 mg propranolol.
Glaucoma Screening Test Beta-adrenoreceptor blockade can cause reduction of intraocular pressure. Patients should be told that CIPLAR LA may interfere with the glaucoma screening test. Withdrawal may lead to a return of increased intraocular pressure.
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.
Renal Impairment CIPLAR LA should be used with caution in patients with renal impairment.
Hepatic Impairment CIPLAR LA should be used with caution in patients with hepatic impairment.
Pregnancy Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. Intrauterine growth retardation, small placentas, and congenital abnormalities have been reported in neonates whose mothers received propranolol during pregnancy. Neonates whose mothers are receiving propranolol at parturition have exhibited bradycardia, hypoglycemia and/or respiratory depression. Ciplar LA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Lactation Propranolol is excreted in human milk. Caution should be exercised when CIPLAR LA is administered to a nursing woman.
Pediatric Use Safety and effectiveness in pediatric patients have not been established.
Geriatric Use In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of the decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. UNDESIRABLE EFFECTS The drug is usually well tolerated. Most adverse effects have been mild and transient and have rarely required the withdrawal of therapy. The commonly observed side effects are bradycardia, hypotension, lethargy, depression, nausea, vomiting and diarrhoea. OVERDOSAGE Propranolol is not significantly dialyzable. In the event of overdosage or exaggerated response, the following measures should be employed: If ingestion is or may have been recent, evacuate gastric contents, taking care to prevent pulmonary aspiration. Hypotension and bradycardia have been reported following propranolol overdose and should be treated appropriately. Glucagon can exert potent inotropic and chronotropic effects and may be particularly useful for the treatment of hypotension or depressed myocardial function after a propranolol overdose. Glucagon should be administered as 50-150 mcg/kg intravenously followed by continuous drip of 1-5 mg/hour for positive chronotropic effect. Isoproterenol, dopamine or phosphodiesterase inhibitors may also be useful. Epinephrine, however, may provoke uncontrolled hypertension. Bradycardia can be treated with atropine or isoproterenol. Serious bradycardia may require temporary cardiac pacing. The electrocardiogram, pulse, blood pressure, neurobehavioral status and intake and output balance must be monitored. Isoproterenol and aminophylline may be used for bronchospasm. PACKAGING INFORMATION CIPLAR LA 40 Blister strip of 10 tablets CIPLAR LA 80 Blister strip of 10 tablets

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