Celavi O

Uses

Cilnidipine is used for the management of hypertension for end-organ protection. It is reported to be useful in elderly patients and in those with diabetes and albuminuria. Cilnidipine has been increasingly used in patients with chronic kidney disease.

Hypertension is the term used to describe the presence of high blood pressure. The blood pressure is generated by the force of the blood pumped from the heart against the blood vessels. Thus hypertension is caused when there is too much pressure on the blood vessels and this effect can damage the blood vessel

Olmesartan is used for the treatment of mild to moderate essential hypertension. Olmesartan may be used alone or in combination with thiazide diuretic.

Celavi O is also used to associated treatment for these conditions: High Blood Pressure (Hypertension)Diabetic Nephropathy, High Blood Pressure (Hypertension), Severe Hypertension, Moderate Hypertension

How Celavi O works

Cilnidipine acts on the L-type calcium channels of blood vessels by blocking the incoming calcium and suppressing the contraction of blood vessels, thereby reducing blood pressure. Cilnidipine also works on the N-type calcium channel located at the end of the sympathetic nerve, inhibiting the emission of norepinephrine and suppressing the increase in stress blood pressure.

Olmesartan belongs to the angiotensin II receptor blocker (ARB) family of drugs, which also includes telmisartan, candesartan, losartan, valsartan, and irbesartan. ARBs selectively bind to angiotensin receptor 1 (AT1) and prevent the protein angiotensin II from binding and exerting its hypertensive effects. As the principal pressor agent of the renin-angiotensin system, Angiotensin II causes vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium. Olmesartan blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in vascular smooth muscle. Its action is, therefore, independent of the pathways for angiotensin II synthesis. Overall, olmesartan's physiologic effects lead to reduced blood pressure, lower aldosterone levels, reduced cardiac activity, and increased excretion of sodium.

Olmesartan also effects on the renin-angiotensin aldosterone system (RAAS) plays an important role in hemostasis and regulation of kidney, vascular, and cardiac functions. Pharmacological blockade of RAAS via AT1 receptor blockade inhibits negative regulatory feedback within RAAS, which is a contributing factor to the pathogenesis and progression of cardiovascular disease, heart failure, and renal disease. In particular, heart failure is associated with chronic activation of RAAS, leading to inappropriate fluid retention, vasoconstriction, and ultimately a further decline in left ventricular function. ARBs have been shown to have a protective effect on the heart by improving cardiac function, reducing afterload, increasing cardiac output and preventing ventricular hypertrophy and remodelling.

Dosage

Celavi O dosage

5-10 mg once daily, increase to 20 mg once daily if necessary.

Adult:Dosage must be individualized. The usual initial dose is 10 mg once daily. In patients whose blood pressure is not adequately controlled at this dose, the dose may be increased to 20 mg once daily as the optimal dose. For patients requiring further reduction in blood pressure after 2 weeks of therapy, the dose of Olmesartan may be increased to 40 mg. Doses above 40 mg do not appear to have greater effect.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Geriatric Use: Of the total number of hypertensive patients receiving Olmesartan Medoxomil in clinical studies, more than 20% were 65 years of age and over, while more than 5% were 75 years of age and older. No overall differences in effectiveness or safety were observed between elderly patients and younger patients.

Side Effects

Dizziness; flushing; headache; hypotension; peripheral oedema; tachycardia; palpitations; GI disturbances; increased micturition frequency; lethargy; eye pain; depression; ischaemic chest pain; cerebral or myocardial ischaemia; transient blindness; rashes; fever; abnormal liver function; gingival hyperplasia; myalgia; tremor; impotence.

Common or very common: Arthritis, chest pain, cough, fatigue, gastro-intestinal disturbances, haematuria, hypertriglyceridaemia, hyperuricaemia, influenza-like symptoms, musculoskeletal pain, peripheral edema, pharyngitis, rhinitis, urinary-tract infection.

Uncommon: Angina, rash, vertigo.

Very rare: Headache, myalgia, pruritus, thrombocytopenia, urticaria.

Toxicity

The percentage of reports of cilnidipine that express drug toxicity reported as side effects are 5.26%.

The reported LD50 of olmesartan in dogs was reported to be greater of 1500 mg/kg. Overdose is expressed as hypotension, tachycardia, and bradycardia when there is parasympathetic stimulation. In case of overdose, supportive treatment is recommended.

Olmesartan was shown to be safe on carcinogenic and fertility studies. However, in in vitro mutagenic studies showed a potential to induce chromosomal aberrations in cells and it tested positive for thymidine kinase mutations in the mouse lymphoma assay.

Precaution

Hypotension, poor cardiac reserve, heart failure. Sudden withdrawal may exacerbate angina. Discontinue in patients who experience ischemic pain following administration. Pregnancy, lactation.

Fetal/Neonatal Morbidity and Mortality: Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature of patients who were taking angiotensin converting enzyme inhibitors. When pregnancy is detected, Olmesartan Medoxomil should be discontinued as soon as possible.

Hypotension in Volume- or Salt-Depleted Patients: In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of treatment with Olmesartan Medoxomil. Treatment should start under close medical supervision. If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline.

Interaction

Other antihypertensives; aldesleukin; antipsychotics that cause hypotension; may modify insulin and glucose responses; quinidine; carbamazepine; phenytoin; rifampicin; cimetidine; erythromycin.

No significant drug interactions were reported in studies in which Olmesartan Medoxomil was co-administered with digoxin or warfarin in healthy volunteers. The bioavailability of Olmesartan was not significantly altered by the co-administration of antacids [Al(OH)3/Mg(OH)2]. Olmesartan Medoxomil is not metabolized by the cytochrome P450 system and has no effects on P450 enzymes; thus, interactions with drugs that inhibit, induce or are metabolized by those enzymes are not expected.

Volume of Distribution

Drugs on the group of dihydropyridines such as cilnidipine tend to have a large volume of distribution.

17 L[L5566]

Elimination Route

Cilnidipine presents a very rapid absorption with a maximum peaked concentration after 2 hours. Its distribution tends to be higher in the liver as well as in kidneys, plasma and other tissues. Cilnidipine does not present a high accumulation in the tissue after repeated oral administration.

Cilnidipine is reported to present very low bioavailability determined to be approximately 13%. This low bioavailability is suggested to be due to its low aqueous solubility and high permeability. Hence, efforts have been made in order to find an innovative formulation that can significantly improve the bioavailability of this drug. One of these formulations corresponds to the generation of polymeric nanoparticles which enhance the bioavailability by 2.5-3-fold.

When taken orally, the prodrug olmesartan medoxomil is rapidly absorbed in the gastrointestinal tract and metabolized to olmesartan. The esterification with medoxomil was created with the intention of increasing olmesartan bioavailability from 4.5% to 28.6%.

Oral administration of 10-160 mg of olmesartan has been shown to reach peak plasma concentration of 0.22-2.1 mg/L after 1-3 hours with an AUC of 1.6-19.9mgh/L. The pharmacokinetic profile of olmesartan has been observed to be nearly linear and dose-dependent under the therapeutic range. The steady-state level of olmesartan is achieved after once a day dosing during 3 to 5 days.[L5566]

Half Life

The half-life of the hypotensive effect for cilnidipine is of about 20.4 min.

The mean plasma olmesartan half-life is reported to be from 10-15 hours after multiple oral administration.

Clearance

Total plasma clearance is 1.3 L/h and the renal clearance is 0.6 L/h.[L5566]

Elimination Route

Cilnidipine gets eliminated through the urine in a proportion of 20% of the administered dose and 80% is eliminated by the feces.

The main elimination route of olmesartan is in the unchanged form through the feces. From the systemically bioavailable dose, about 10-16% is eliminated in the urine.

Pregnancy & Breastfeeding use

No specific information about USFDA pregnancy category. Caution should be exercised during Cilnidipine use in pregnancy. Nursing mothers should consult a physician before taking Cilnidipine.

Pregnancy Categories C (first trimester) and D (second and third trimesters).

Nursing Mothers: It is not known whether Olmesartan is excreted in human milk, but Olmesartan is secreted at low concentration in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Contraindication

Cardiogenic shock; recent MI or acute unstable angina; severe aortic stenosis.

Olmesartan is contraindicated in patients who are hypersensitive to any component of this product.

Special Warning

Hepatic Impairment: Dose should not exceed 20 mg daily in moderate impairment.

Renal Impairment: Max. 20 mg daily if eGFR 20–60 mL/minute/1.73 m2. Avoid if eGFR less than 20 mL/minute/1.73 m2.

Acute Overdose

Only limited information is available regarding overdosage in humans. The most likely effect of overdosage is hypotension. In the event of overdosage, the patient should be carefully monitored and treatment should be symptomatic and supportive. No information is available regarding the dialysability of olmesartan.

Storage Condition

Keep out of the reach of children. Keep in the original package in a cool & dry place. Protect from light and moisture.

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