Celiprolol Hydrochloride
Adverse Effects, Treatment, Precautions & interactions as for beta blocker , metoprolol, whose record is given below.
Tremor and palpitations associated with intrinsic sympathomimetic activity at beta-receptors have been reported.
METOPROLOL
CONTRAINDICATIONS
Hypertension and Angina: METOPROLOL is contraindicated in sinus bradycardia, heart block greater than first degree, cardiogenic shock, and overt cardiac failure (see WARNINGS ).
WARNINGS
Hypertension and Angina
Cardiac Failure-- Sympathetic stimulation is a vital component supporting circulatory function in congestive heart failure, and beta-blockade carries the potential hazard of further depressing myocardial contractility and precipitating more severe failure. In hypertensive and angina patients who have congestive heart failure controlled by digitalis and diuretics, METOPROLOL should be administered cautiously. Both digitalis and METOPROLOL slow AV conduction.
In Patients Without a History of Cardiac Failure-- 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 given a diuretic. The response should be observed closely. If cardiac failure continues, despite adequate digitalization and diuretic therapy, METOPROLOL should be withdrawn.
Ischemic Heart Disease: Following abrupt cessation of therapy with certain beta-blocking agents, exacerbations of angina pectoris and, in some cases, myocardial infarction have occurred. When discontinuing chronically administered METOPROLOL, particularly in patients with ischemic heart disease, the dosage should be gradually reduced over a period of 1-2 weeks and the patient should be carefully monitored. If angina markedly worsens or acute coronary insufficiency develops, METOPROLOL administration should be reinstated promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken. Patients should be warned against interruption or discontinuation of therapy without the physician' advice. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue METOPROLOL therapy abruptly even in patients treated only for hypertension.
Bronchospastic Diseases-- PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT RECEIVE BETA-BLOCKERS. Because of its relative beta 1 -selectivity, however, METOPROLOL may be used with caution in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment. Since beta 1 -selectivity is not absolute, a beta 2 -stimulating agent should be administered concomitantly, and the lowest possible dose of METOPROLOL should be used (see DOSAGE AND ADMINISTRATION ).
Major Surgery-- The necessity or desirability of withdrawing beta-blocking therapy prior to major surgery is controversial; the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.
METOPROLOL like other beta-blockers, is a competitive inhibitor of beta-receptor agonists, and its effects can be reversed by administration of such agents, e.g., dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension. Difficulty in restarting and maintaining the heart beat has also been reported with beta-blockers.
Diabetes and Hypoglycemia-- METOPROLOL should be used with caution in diabetic patients if a beta-blocking agent is required. Beta-blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected.
Thyrotoxicosis Beta-adrenergic blockade may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-blockade, which might precipitate a thyroid storm.
PRECAUTIONS
General: METOPROLOL should be used with caution in patients with impaired hepatic function.
Information for Patients: Patients should be advised to take METOPROLOL regularly and continuously, as directed, preferably with or immediately following meals. If a dose should be missed, the patient should take only the next scheduled dose (without doubling it). Patients should not discontinue METOPROLOL without consulting the physician.
Patients should be advised (1) to avoid operating automobiles and machinery or engaging in other tasks requiring alertness until the patient' response to therapy with Toprol- XL has been determined; (2) to contact the physician if any difficulty in breathing occurs; (3) to inform the physician or dentist before any type of surgery that he or she is taking METOPROLOL.
Laboratory Tests: Clinical laboratory findings may include elevated levels of serum transaminase, alkaline phosphatase, and lactate dehydrogenase.
Drug Interactions: Catecholamine-depleting drugs (e.g., reserpine) may have an additive effect when given with beta-blocking agents. Patients treated with METOPROLOL plus a catecholamine depletor should therefore be closely observed for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals have been conducted to evaluate the carcinogenic potential of metoprolol tartrate. In 2-year studies in rats at three oral dosage levels of up to 800 mg/kg/day, there was no increase in the development of spontaneously occurring benign or malignant neoplasms of any type. The only histologic changes that appeared to be drug related were an increased incidence of generally mild focal accumulation of foamy macrophages in pulmonary alveoli and a slight increase in biliary hyperplasia. In a 21-month study in Swiss albino mice at three oral dosage levels of up to 750 mg/kg/day, benign lung tumors (small adenomas) occurred more frequently in female mice receiving the highest dose than in untreated control animals. There was no increase in malignant or total (benign plus malignant) lung tumors, nor in the overall incidence of tumors or malignant tumors. This 21-month study was repeated in CD-1 mice, and no statistically or biologically significant differences were observed between treated and control mice of either sex for any type of tumor.
All mutagenicity tests performed on metoprolol tartrate (a dominant lethal study in mice, chromosome studies in somatic cells, a Salmonella/mammalian-microsome mutagenicity test, and a nucleus anomaly test in somatic interphase nuclei) and metoprolol succinate (a Salmonella/mammalian-microsome mutagenicity test) were negative.
No evidence of impaired fertility due to metoprolol tartrate was observed in a study performed in rats at doses up to 55.5 times the maximum daily human dose of 450 mg.
Pregnancy Category C: Metoprolol tartrate has been shown to increase post-implantation loss and decrease neonatal survival in rats at doses up to 55.5 times the maximum daily human dose of 450 mg. Distribution studies in mice confirm exposure of the fetus when metoprolol tartrate is administered to the pregnant animal. These studies have revealed no evidence of impaired fertility or teratogenicity. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Nursing Mothers: Metoprolol is excreted in breast milk in very small quantities. An infant consuming 1 liter of breast milk daily would receive a dose of less than 1 mg of the drug. Caution should be exercised when METOPROLOL is administered to a nursing woman.
Pediatric Use: Safety and effectiveness in pediatric patients have not been established.
Risk of Anaphylactic Reactions: While taking beta-blockers, patients with a history of severe anaphylactic reactions 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.
ADVERSE REACTIONS
Hypertension and Angina: Most adverse effects have been mild and transient. The following adverse reactions have been reported for metoprolol tartrate.
Central Nervous System-- Tiredness and dizziness have occurred in about 10 of 100 patients. Depression has been reported in about 5 of 100 patients. Mental confusion and short-term memory loss have been reported. Headache, somnolence, nightmares, and insomnia have also been reported.
Cardiovascular Shortness of breath and bradycardia have occurred in approximately 3 of 100 patients. Cold extremities; arterial insufficiency, usually of the Raynaud type; palpitations; congestive heart failure; peripheral edema; syncope; chest pain; and hypotension have been reported in about 1 of 100 patients (see CONTRAINDICATIONS , WARNINGS and PRECAUTIONS ).
Respiratory Wheezing (bronchospasm) and dyspnea have been reported in about 1 of 100 patients (see WARNINGS ).
Gastrointestinal Diarrhea has occurred in about 5 of 100 patients. Nausea, dry mouth, gastric pain, constipation, flatulence, digestive tract disorders and heartburn have been reported in about 1 of 100 patients.
Hypersensitive Reactions-- Pruritus or rash have occurred in about 5 of 100 patients. Worsening of psoriasis has also been reported.
Miscellaneous-- Peyronie' disease has been reported in fewer than 1 of 100,000 patients. Musculoskeletal pain, blurred vision, decreased libido and tinnitus have also been reported.
There have been rare reports of reversible alopecia, agranulocytosis, and dry eyes. Discontinuation of the drug should be considered if any such reaction is not otherwise explicable. The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with metoprolol.
Potential Adverse Reactions: A variety of adverse reactions not listed above have been reported with other beta-adrenergic blocking agents and should be considered potential adverse reactions to METOPROLOL.
Central Nervous System-- Reversible mental depression progressing to catatonia; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometrics.
Cardiovascular Intensification of AV block (see CONTRAINDICATIONS ).
Hematologic-- Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura.
Hypersensitive Reactions-- Fever combined with aching and sore throat, laryngospasm, and respiratory distress.
OVERDOSAGE
Acute Toxicity: There have been a few reports of overdosage with METOPROLOL and no specific overdosage information was obtained with this drug, with the exception of animal toxicology data. However, since METOPROLOL (metoprolol succinate salt) contains the same active moiety, metoprolol, as conventional metoprolol tablets (metoprolol tartrate salt), the recommendations on overdosage for metoprolol conventional tablets are applicable to METOPROLOL.
Signs and Symptoms: Potential signs and symptoms associated with overdosage with metoprolol are bradycardia, hypotension, bronchospasm, and cardiac failure.
Treatment: There is no specific antidote.
In general, patients with acute or recent myocardial infarction may be more hemodynamically unstable than other patients and should be treated accordingly. On the basis of the pharmacologic actions of metoprolol tartrate, the following general measures should be employed.
Elimination of the Drug-- Gastric lavage should be performed.
Bradycardia Atropine should be administered. If there is no response to vagal blockade, isoproterenol should be administered cautiously.
Hypotension A vasopressor should be administered, e.g., levarterenol or dopamine.
Bronchospasm-- A beta 2 -stimulating agent and/or a theophylline derivative should be administered.
Cardiac Failure-- A digitalis glycoside and diuretics should be administered. In shock resulting from inadequate cardiac contractility, administration of dobutamine, isoproterenol or glucagon may be considered.
CELIPROLOL
Pharmacokinetics
Celiprolol is absorbed from the gastro-intestinal
tract in a non-linear fashion: the percentage of the
dose absorbed increases with increasing dose. The
plasma elimination half-life is about 5 to 6 hours.
Celiprolol crosses the placenta. It has low lipid sol-
ubility. Metabolism is minimal and celiprolol is
mainly excreted unchanged in the urine and faeces.
Uses and Administration
Celiprolol is a cardioselective beta blocker .
It is reported to possess intrinsic sympathomimetic
activity and direct vasodilator activity. Celiprolol is
used as the hydrochloride in the management of hy-
pertension and angina pectoris .
The usual dose of celiprolol hydrochloride is 200 to
400 mg once daily by mouth. Reduced doses may be
required in patients with impaired renal function;
suggested guidelines are to reduce the dose by 50%
when creatinine clearance is between 15 and 40 mL
per minute, but not to use at all when it is below
15 mL per minute.
References.