Cilamet XL

Indications

Cilamet XL is indicated for the treatment of hypertension

Adverse Effects

Cilnidipine General: Gastrointestinal disturbances, lethargy, increased frequency or urination, muscle aches, impotence, abnormal liver function, allergic reaction Eye: Transient blindness, eye pain Metoprolol Most common adverse reactions: tiredness, dizziness, depression, shortness of breath, bradycardia, hypotension, diarrhea, pruritus, rash.

Drug Interactions

Cilnidipine: Drugs with antihypertensive effect:It is considered to enhance the action additively or synergistically:Blood pressure may drop excessively; It is believed that rifampicin-induced hepatic drug-metabolizing enzyme (cytochrome P-450) promotes the metabolism of calcium channel blockers and increases clearance; It is considered that the azole antifungal agent inhibits the drug-metabolizing enzyme CYP3A4 of this drug Metoprolol: Catecholamine-depleting drugs may have an additive effect when given with beta-blocking agents. CYP2D6 Inhibitors are likely to increase metoprolol concentration Concomitant use of glycosides, clonidine, and diltiazem and verapamil with beta-blockers can increase the risk of bradycardia. Beta-blockers including metoprolol, may exacerbate the rebound hypertension that can follow the withdrawal of clonidine

Mechanism of Action

Metoprolol Hypertension: The mechanism of the antihypertensive effects of beta-blocking agents has not been elucidated However, several possible mechanisms have been proposed: (1) competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuron sites, leading to decreased cardiac output (2) a central effect leading to reduced sympathetic outflow to the periphery (3) suppression of renin activity Heart Failure: The precise mechanism for the beneficial effects of beta-blockers in heart failure has not been elucidated Cilnidipine Cilnidipine is a dihydropyridine calcium-channel blocker. Cilnidipine is the novel calcium antagonist having L-type and N-type calcium channel blocking function. It inhibits cellular influx of calcium, thus causing vasodilatation. It has greater selectivity for vascular smooth muscle. Due to its N-type calcium-channel blocking properties, it has more advantages compared to conventional calcium-channel blockers. It has lower incidence of Pedal edema, one of the major adverse effects of other calcium channel blockers. It has little or no action at the SA or AV nodes and negative inotropic activity is rarely seen at therapeutic doses.

Pharmacokinetics

Cilnidipine Cilnidipine is absorbed from the small intestine. The time to maximum plasma concentration is 1.8 to 2.2 hours. It has a half life of 7.5 hours. Cilnidipine is metabolized by the liver. 20% of the drug is eliminated in the urine and 80% in the faeces Metoprolol Absorption of metoprolol is rapid and complete. Plasma levels following oral administration of conventional metoprolol tablets, however, approximate 50% of levels following intravenous administration, indicating about 50% first-pass metabolism Metoprolol crosses the blood-brain barrier and has been reported in the CSF in a concentration 78% of the simultaneous plasma concentration Plasma levels achieved are highly variable after oral administration Only a small fraction of the drug (about 12%) is bound to human serum albumin Metoprolol is a racemic mixture of R- and S- enantiomers, and is primarily metabolized by CYP2D6. Elimination is mainly by biotransformation in the liver, and the plasma half-life ranges from approximately 3 to 7 hours Less than 5% of an oral dose of metoprolol is recovered unchanged in the urine; the rest is excreted by the kidneys as metabolites that appear to have no beta-blocking activity In comparison to conventional metoprolol, the plasma metoprolol levels following administration of Metoprolol-XL are characterized by lower peaks, longer time to peak and significantly lower peak to trough variation. The peak plasma levels following once-daily administration of Metoprolol-XL average one-fourth to one-half the peak plasma levels obtained following a corresponding dose of conventional metoprolol, administered once daily or in divided doses.

Drug Use in Pregnancy

Cilnidipine: Pregnancy: Category C Animal reproduction studies have shown adverse effects on the fetus and there are no adequate and well controlled studies in humans. Cilnidipine may be used in pregnancy only if the potential benefits justify the risk Lactation: It is not known if Cilnidipine is secreted in breast milk. A decision should be made to discontinue lactation, if the nursing mother needs to be prescribed Cilnidipine Metoprolol: Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, use this drug 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. Consider possible infant exposure when Metoprolol-XL is administered to a nursing woman

Drug Use in Renal Impairment

Metoprolol: Renal Impairement:Renal Impairment: The systemic availability and half-life of metoprolol in patients with renal failure do not differ to a clinically significant degree from those in normal subjects. No reduction in dosage is needed in patients with chronic renal failure Cilnidipine: Renal impairment Cilnidipine has been used in patients with renal disease however data on pharmacokinetics in renal disease are not available. Hence caution should be observed when cilnidipine is prescribed to such patients

Drug Use in Hepatic Impairment

Metoprolol: Hepatic Impairment: Consider initiating Metoprolol therapy at low doses and gradually increase dosage to optimize therapy, while monitoring closely for adverse events Cilnidipine: Hepatic impairment Cilnidipine must be used with caution in patients with abnormal liver function. Abnormal liver function is an adverse effect of cilnidipine, hence careful monitoring is required in patients with liver disease

Drug Use in Pediatric Population

Metoprolol: Pediatric Use: Safety and effectiveness have not been established in patients < 6 years of age. Cilnidipine: Safety has not been established for low birth weight infants, newborns, infants, toddlers or children

Drug Use in Geriatric Population

Cilnidipine: Administration to the elderly In general, excessive hypotension is not preferable for the elderly, so when using it for the elderly, start administration from a low dose (for example, 5 mg) and carefully observe the course. Metoprolol: Geriatrics: No notable difference in efficacy or safety vs. younger patients. Clinical studies of Metoprolol-XL in hypertension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience in hypertensive patients has not identified differences in responses between elderly and younger patients. Of the 1,990 patients with heart failure randomized to Metoprolol-XL in the MERIT-HF trial, 50% (990) were 65 years of age and older and 12% (238) were 75 years of age and older. There were no notable differences in efficacy or the rate of adverse reactions between older and younger patients. In general, use a low initial starting dose in elderly patients given their greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.