Carvidon Mt

Uses

ln the management of hypertension and angina pectoris. Cardiac arrhythmias, especially supraventricular tachyarrhythmias. Adjunct to the treatment of hyperthyroidism. Early intervention with Metoprolol in acute myocardial infarction reduces infarct size and the incidence of ventricular fibrillation. Pain relief may also decrease the need for opiate analgesics. Metoprolol has been shown to reduce mortality when administered to patients with acute myocardial infarction.

Long-term treatment of Ischaemic heart disease (angina pectoris, sequelae of infarction).

Carvidon Mt is also used to associated treatment for these conditions: Angina Pectoris, Atrial Fibrillation, High Blood Pressure (Hypertension), Migraine, Myocardial Infarction, Tachycardia, Supraventricular, Thyroid Crisis, Acute hemodynamically stable Myocardial infarction, Chronic heart failure with reduced ejection fraction (NYHA Class II), Chronic heart failure with reduced ejection fraction (NYHA Class III)Angina Pectoris, Chronic Stable Angina Pectoris, Dizziness, Tinnitus, Decreased visual acuity caused by Vascular Disorders

How Carvidon Mt works

Metoprolol is a beta-1-adrenergic receptor inhibitor specific to cardiac cells with negligible effect on beta-2 receptors. This inhibition decreases cardiac output by producing negative chronotropic and inotropic effects without presenting activity towards membrane stabilization nor intrinsic sympathomimetics.

During myocardial ischemia, anaerobic metabolism takes over, increasing levels of lactic acid. The decreased intracellular pH and increased concentration of protons activates sodium-hydrogen and sodium-calcium antiport systems, raising intracellular calcium concentrations, finally leading to decreased contractility.

This injury to the myocardium raises concentrations of catecholamines, which activate hormone sensitive lipase, and increasing fatty acid concentrations in plasma. When the myocardium is repurfused, fatty acid oxidation becomes the dominant form of ATP production, maintaining an acidic pH, and further exacerbating the injury.

The mechanism of action of trimetazidine is not fully understood. Trimetazidine may inhibit mitochondrial 3-ketoacyl coenzyme A thiolase, decreasing long chain fatty acid β-oxidation but not glycolysis in the myocardium. The decreased long chain fatty acid β-oxidation is compensated for by increased use of glucose, preventing a lowered myocardial pH, and further decreases in contractility. However, another study suggests that 3-ketoacyl coenzyme A thiolase may not be trimetazidine's target, and that this mechanism may be incorrect.

Dosage

Carvidon Mt dosage

Oral-

Hypertension: Total daily dosage Metoprolol 100-400 mg to be given as a single or twice daily dose. The starting dose is 100 mg (two Metoprolol-50 tablets) per day. This may be increased by 100 mg per day at weekly intervals. lf full control is not achieved using a single daily dose, a b.i.d. regimen should be initiated. Combination therapy with a diuretic or other anti-hypertensive agent may also be considered.

Angina: Usually Metoprolol 50 mg (one Metoprolol-50 tablet) to 100 mg (two Metoprolol-50 tablets)twice or three times daily.

Cardiac arrhythmias: Metoprolol 50 mg (one Metoprolol-50 tablet) b.i.d or t.i.d should usually control the condition. It necessary the dose can be increased up to 300 mg per day in divided doses. Following the treatment of an acute arrhythmia with Metoprolol injection, continuationtherapy with Metoprolol tablets should be initiated 4-6 hours later. The initial oral dose should not exceed 50 mg t.i.d.

Hyperthyroidism: Metoprolol 50 mg (one Metoprolol-50 tablet) four times a day.The dose should bereduced as the euthyroid state is achieved.

Myocardial infarction: Orally, therapy should commence 15 minutes after the last injection with50 mg every 6 hours for 48 hours. Patients who fail to tolerate the full intravenous dose should begiven half the suggested oral dose. Maintenance – The usual maintenance dose is 200 mg dailygiven in divided doses. Elderly’ There are no special dosage requirements in otherwise healthyelderly patients. Signidcant hepatic dysfunction: A reduction in dosage may be necessary.

Injection-

Arrhythmias: By intravenous injection, up to 5 mg at a rate of 1-2 mg/minute, repeated after 5 minutes if necessary, total dose 10-15 mg.

In surgery: By slow intravenous injection 2-4 mg at induction or to control arrhythmias developing during anaesthesia; 2 mg doses may be repeated to a maximum of 10 mg.

Myocardial Infarction: Early intervention within 12 hours of infarction, by intravenous injection 5 mg every 2 minutes to a maximum of 15 mg, followed after 15 minutes by 50 mg by mouth every 6 hours for 48 hours; maintenance 200 mg daily in divided doses.

Impaired Renal Function: Dose adjustment is not needed in patients with impaired renal function.

Impaired Hepatic Function: Dose adjustment is not normally needed in patients suffering from liver cirrhosis because Metoprolol has low protein binding (5-10%). When there are signs of serious impairment of liver function (e.g. shunt-operated patients), a reduction in dose should be considered.

Elderly: Dose adjustment is not needed.

One 20 mg tablet thrice daily after meals. No dosage adjustments are required in patients with impaired renal and hepatic function.

One 35 mg modified release tablet twice daily at mealtimes in the morning and evening.

Side Effects

Bradycardia, bronchospasm, hypotension, headache, fatigue, sleep & gastro-intestinal disturbances, dizziness, vertigo, visual disturbances etc.

Trimetazidine is safe and well tolerated. The most commonly encountered side effects are gastric discomfort, nausea, headache and vertigo. However, the side effects are mild and non-specific.

Toxicity

Oral administration of metoprolol to rats presents an LD50 in the range of 3090 to 4670 mg/kg. Cases of overdose have reported bradycardia, hypotension, bronchospasm, and cardiac failure. In the case of an overdose, gastric lavage is recommended followed by specific treatment according to symptoms.

Metoprolol is not reported to be carcinogenic nor mutagenic nor to impair fertility. The only event registered is the increase of macrophages in pulmonary alveoli and slight biliary hyperplasia. When metoprolol was given for long periods of time on the highest dose, there was evidence of small benign lung tumors.

Data regarding overdoses of trimetazidine are not readily available. Treat overdoses with symptomatic and supportive therapy.

The oral LD₅₀ in rats is 1700 mg/kg, and in mice is 1550 mg/kg. The subcutaneous LD₅₀ in rats is 1500 mg/kg, and in mice is 410 mg/kg.

Precaution

The second or third dose should not be given if the heart rate is <40 beats/minute, the P-R interval is > 0.26 seconds and the systolic blood pressure is <90 mmHg or if there is any aggravation of dyspnoea or cold sweating. Intravenous administration of calcium antagonists of the Verapamil-type should not be given to patients treated with beta-blockers. When treating patients with suspected or definite myocardial infarction, the haemodynamic status of the patient should be carefully monitored after each of the three 5 mg intravenous doses. Use in Pregnancy: As with most medicines, Metoprolol should not be given during pregnancy and lactation unless its use is considered essential. As with all antihypertensive agents, beta-blockers may cause side effects (e.g. bradycardia) in the foetus and in the newborn and breast-fed infant. Use in Lactation: The amount of Metoprolol ingested via breast-milk seems to be negligible as regards beta-blocking effect in the infant if the mother is treated with Metoprolol doses within the normal therapeutic range.

Interaction

Plasma level of Metoprolol may be raised by co-administration of compounds metabolished by CYP2D6 e.g. Antiarrhythmics, antihistamines, H2 receptor antagonists, antidepressants, antipsychotics and COX-2 inhibitors. The plasma conc. of Metoprolol is lowered by Rifampicin.

No drug interactions have so far been reported. In particular, no interactions of Trimetazidine with beta-blockers, calcium antagonists, nitrates, heparin, hypolipidemic agents or digitalis have been reported.

Volume of Distribution

The reported volume of distribution of metoprolol is 4.2 L/kg. Due to the characteristics of metoprolol, this molecule is able to cross the blood-brain barrier and even 78% of the administered drug can be found in cerebrospinal fluid.

The volume of distribution of trimetazidine is 4.8 L/kg.

Elimination Route

When metoprolol is administered orally, it is almost completely absorbed in the gastrointestinal tract. The maximum serum concentration is achieved 20 min after intravenous administration and 1-2 hours after oral administration. The bioavailability of metoprolol is of 100% when administered intravenously and when administered orally it presents about 50% for the tartrate derivative and 40% for the succinate derivative.

The absorption of metoprolol in the form of the tartrate derivative is increased by the concomitant administration of food.

In elderly patients, a 35 mg oral modified release tablet reaches a mean C_max of 115 µg/L, with a T_max of 2.0-5.0 hours, and a mean AUC_0-12 of 1104 h*µg/L. In young, healthy patients, the same dose reaches a mean C_max of 91.2 µg/L, with a T_max of 2.0-6.0 hours, and an AUC_0-12h 720 h*µg/L.

Half Life

The immediate release formulations of metoprolol present a half-life of about 3-7 hours.

In young, healthy subjects, the half life of trimetazidine is 7.81 hours. In patients over 65, the half life increases to 11.7 hours.

Clearance

The reported clearance rate on patients with normal kidney function is 0.8 L/min. In cirrhotic patients, the clearance rate changes to 0.61 L/min.

Trimetazidine clearance is strongly correlated with creatinine clearance. In eldery patients with a creatinine clearance of 72 ± 8 mL/min, trimetazidine clearance was 15.69 L/h. In young, healthy patients with a creatinine clearance of 134 ± 18 mL/min, trimetazidine clearance was 25.2 L/h.

Elimination Route

Metoprolol is mainly excreted via the kidneys. From the eliminated dose, less than 5% is recovered unchanged.

Trimetazidine is 79-84% eliminated in the urine, with 60% as the unchanged parent compound. In a study of 4 healthy subjects, individual metabolites made up 0.01-1.4% of the dose recovered in urine. In the urine, 2-desmethyltrimetazidine made up 0-1.4% of the recovered dose, 3- and 4-desmethyltrimetazidine made up 0.039-0.071% each, N-methyltrimetazidine made up 0.015-0.11%, trimetazidine ketopiperazine made up 0.011-0.4%, N-formyltrimetazidine made up 0.035-0.42%, N-acetyltrimetazidine made up 0.016-0.19%, desmethyl trimetazidine O-sulphate made up 0.01-0.65%, and an unknown metabolite made up0.026-0.67%.

Pregnancy & Breastfeeding use

Metoprolol should not be used in pregnancy or lactating mothers unless the physician considers that the benefit outweighs the possible hazard to the fetus or infant.

Pregnancy: Studies in animals have not demonstrated a teratogenic effect. However, in the absence of clinical data and for safety reasons, prescription should be avoided during pregnancy.

Nursing Mothers: There is no information on the secretion of Trimetazidine into breast milk. However, breast feeding should be discontinued if the use of Trimetazidine is considered essential.

Contraindication

2nd or 3rd degree AV block, sick sinus syndrome, hypotension, decompensated heart failure, sinus bradycardia, severe peripheral arterial circulatory disorders, cardiogenic shock, severe asthma and bronchospasm, untreated phaeochromocytoma, Prinzmetal's angina, metabolic acidosis.

Hypersensitivity to Trimetazidine Dihydrochloride.

Special Warning

Renal Impairment: No dosage adjustment needed.

Hepatic Impairment: Reduce dose.

Acute Overdose

Poisoning due to an overdose of metoprolol may lead to severe hypotension, sinus bradycardia, atrioventricular block, heart failure, cardiogenic shock, cardiac arrest, bronchospasm, impairment of consciousness, coma, nausea, vomiting, cyanosis, hypoglycaemia and, occasionally, hyperkalaemia. The first manifestations usually appear 20 minutes to 2 hours after drug ingestion. Treatment: Treatment should include close monitoring of cardiovascular, respiratory and renal function, and blood glucose and electrolytes. Further absorption may be prevented by induction of vomiting, gastric lavage or administration of activated-charcoal if ingestion is recent. Cardiovascular complications should be treated symptomatically, which may require the use of sympathomimetic agents (e.g. noradrenaline, metaramionl), atropine or inotropic agents (e.g. dopamine, dobutamine). Temporary pacing may be required for AV block. Glucagon can reverse the effects of excessive B-blockade, given in a dose of 1-10 mg intravenously. Intravenous B2-stimulants e.g. terbutaline may be required to relieve bronchospasm. Metoprolol cannot be effectively removed by haemodialysis.

Storage Condition

Store in a cool, dry place protected from light. Keep out of reach of children.

Store in a cool and dry place, protect from light and moisture. Keep out of the reach of children.

Innovators Monograph

You find simplified version here Carvidon Mt