Xiletil

Properties

Xiletil is an antihypertensive based on Candesartan Cilexetil, which works by inhibiting the AT1 receptor of angiotensin II. Xiletil H, Xiletil D and Xiletil Forte contain Candesartan Cilexetil plus Hydrochlorothiazide . Angiotensin II is formed by Angiotensin I in a reaction catalyzed by the Angiotensin converting enzyme (ECA, Kinase II). Angiotensin II is the main vasopressor agent of the renin-angiotensin system, the effects of which include vasoconstriction, stimulation of aldosterone synthesis and release, cardiac stimulation, and renal reabsorption of sodium. Candesartan blocks the vasoconstrictor and secretory effect of aldosterone by Angiotensin II, selectively blocking its binding to the AT1 receptor in vascular smooth muscle and the adrenal gland. Its action, therefore, is independent of the pathways for the synthesis of Angiotensin II. In the tissues, an AT2 receptor can also be found, but this is not associated with cardiovascular homeostasis. Candesartan has a higher affinity (10,000 times) for the AT1 receptor than for AT2.

Candesartan does not inhibit ACE (Kinase II) and therefore does not affect the response to bradykinin, the clinical relevance of which is not yet known. Candesartan does not bind or block other hormone receptors or ion channels important in cardiovascular regulation. Angiotensin II receptor blockade inhibits its negative feedback on renin secretion, but the results of increased plasma renin activity and circular Angiotensin II levels do not outweigh the effect of candesartan on blood pressure.

Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the tubular mechanism in the reabsorption of electrolytes, directly increasing the excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, resulting in increases in plasma renin activity, in aldosterone secretion, in urinary potassium loss, and in decreased serum potassium. The renin-aldosterone bond is mediated by Angiotensin II; therefore, co-administration of an Angiotensin II receptor antagonist tends to invent the potassium loss associated with these diuretics. The mechanism of the antihypertensive effects of thiazides is unknown.

Pharmacokinetics

General

Candesartan Cilexetil

Candesartan Cilexetil is rapidly and completely bioactivated by hydrolysis of the ester during absorption from the gastrointestinal tract to candesartan, a selective antagonist of the AT1 receptor, Angiotensin II subtype. Candesartan is excreted largely unchanged in the urine and feces (bile duct). It is subjected by a minor hepatic metabolism by O-detilation, to an inactive metabolite. The elimination half-life is approximately 9 hours. After single and repeated administration, the pharmacokinetics of candesartan is linear for oral doses up to 32 mg candesartan cilexetil. Candesartan and its inactive metabolites do not accumulate in the serum after repeated single daily doses. Following administration of candesartan cilexetil, the bioavailability of candesartan is approximately 15%. After ingestion of the tablets, the maximum concentration in the serum (Cmax) is reached after 3 to 4 hours. Foods high in fat do not affect the bioavailability of candesartan after administration of candesartan cilexetil.

Hydrochlorothiazide

When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours.

Metabolism and Excretion

Candesartan Cilexetil: The total plasma clearance of candesartan is 0.37 ml / min / kg, with a renal clearance of 0.19 ml / min / kg. Biliary excretion contributes to the elimination of candesartan.

Hydrochlorothiazide: Hydrochlorothiazide is not metabolized, but it is rapidly eliminated by the kidney. At least 61% of the oral dose is eliminated unchanged within 24 hours.

Distribution

Candesartan Cilexetil: The volume of distribution is 0.13 l / kg. Candesartan is highly bound to plasma proteins (> 99%) and does not penetrate red blood cells.

Hydrochlorothiazide: This substance crosses the placenta but not the blood-brain barrier, and is excreted in breast milk.

Special populations

Geriatrics: the pharmacokinetics of candesartan has been studied in people over 65 years of age. The plasma concentration of candesartan was higher in older people (the Cmax) was approximately 50% higher and the AUC was 80% higher compared to younger people who were administered the same dose.

Renal Insufficiency: In hypertensive patients with renal insufficiency, the concentration of candesartan in the serum was elevated. In patients with chronic kidney disease (creatinine clearance <30 ml / min / 1.73 m2) compared to patients with normal kidney function. The pharmacokinetics of candesartan in hypertensive patients undergoing hemodialysis is similar to that of hypertensive patients with chronic kidney disease. Candesartan cannot be removed through hemodialysis. No initial dose adjustment is necessary in patients with renal impairment. Thiazide diuretics are eliminated through the kidney, with a terminal half-life of 5 to 15 hours. In a study among patients with impaired renal function (average creatinine clearance is 19 ml / min), the elimination half-life of hydrochlorothiazide was extended to 12 hours.

Hepatic Impairment: No difference was observed in the pharmacokinetics of candesartan and patients with chronic liver disease. Thiazide diuretics should be used with caution in patients with hepatic impairment.

Pharmacodynamics

Candesartan Cilexetil: Candesartan inhibits the pressuring effects of the Angiotensin II infusion, in a dose-dependent manner. After a week of daily dose of candesartan cilexetil 8 mg, the pressor effect was inhibited approximately 90% to the maximum with approximately 50% inhibition persisting for 24 hours. Plasma concentrations of Angiotensin I and Angiotensin II, and plasma renin activity (PRA), were increased in a dose-dependent manner after simple and repeated administration of candesartan cilexetil to healthy individuals and hypertensive patients. ACE activity was not altered in healthy individuals after repeated administration of candesartan cilexetil. Daily administration of up to 16 mg of candesartan cilexetil to healthy individuals did not influence plasma aldosterone concentration, but a decrease in plasma aldosterone concentration was observed when 32 mg candesartan cilexetil was administered to hypertensive patients. Despite the effect of candesartan cilexetil on aldosterone secretion, little effect was observed on serum potassium.

Hydrochlorothiazide: After oral administration of hydrochlorothiazide, diuresis begins in a period of 2 hours, reaches its maximum level in 4 hours and lasts from 6 to 12 hours.

 

Indications and uses

Xiletil 8, Xiletil 16, and Xiletil 32  are indicated for the treatment of essential and renovascular hypertension.

Xiletil H, Xiletil D and Xiletil Forte are indicated for the treatment of essential hypertension in patients in whom the combined treatment of candesartan cilexetil plus hydrochlorothiazide is appropriate, and should be started only after the patient has failed to achieve the desired effects with monotherapy. . This combination is not indicated as initial therapy.

Contraindications

Xiletil is contraindicated in patients hypersensitive to the components of this product.

Due to the hydrochlorothiazide component, Xiletil H, Xiletil D and Xiletil Forte are contraindicated in patients with anuria or hypersensitivity to other drugs derived from sulfonamide.


Cautions

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. When pregnancy is detected, Xiletil should be discontinued as soon as possible.

Hypotension in patients with depletion of volume and salts

Initiation of antihypertensive therapy may cause hypotension in patients with intravascular volume and sodium depletion, such as in patients vigorously treated with diuretics or patients on dialysis. These conditions must be corrected before administration of Xylethyl H and D or treatment must begin under strict medical supervision. A transient hypotensive response is not a contraindication to subsequent treatments, which can usually be continued without difficulty, once the blood pressure has stabilized.

Hydrochlorothiazide

Impaired liver function: Thiazide diuretics should be used with caution in patients with impaired function or with progressive liver disease, since a minimal alteration in fluid and electrolyte balance can precipitate hepatic coma.

Hypersensitive reaction: Hypersensitive reactions to hydrochlorothiazide may occur with or without a history of allergy or bronchial asthma, but are more frequent in patients with such a history.

Systemic Lupus Erythematosus: Thiazide diuretics have been reported to cause exacerbation or activation.

Interaction with lithium: lithium generally should not be administered with thiazides.

Side effects

Respiratory System Disorder: Upper respiratory tract infection (3.6% vs. 3.0%); Body: Back pain (3.3% vs. 2.4%); Influenza symptoms (2.5% vs. 1.9%); Central / Peripheral Nervous System: Dizziness (2.9% vs. 1.2%).

Body: inflicted injuries, fatigue, chest pain, peripheral edema, asthenia. Central and Peripheral Nervous System: vertigo, paraesthesia, hyperesthesia; Respiratory System Disorders: bronchitis, sinusitis, pharyngitis, cough, rhinitis, dyspnea; Musculoskeletal System Disorders: arthralgia, myalgia, osteoarthritis, arthritis, leg cramps, sciatica; Gastrointestinal System Disorders: nausea, abdominal pain, diarrhea, dyspepsia, gastritis, gastroenteritis, vomiting; Metabolic and Nutritional Disorders: hyperuricemia, hyperglycemia, hypokalemia, increased BUN, increased transaminases; Heart rhythm disorders: tachycardia, palpitation, extrasystoles, bradycardia; Psychiatric Disorders: depression, insomnia, anxiety; Cardiovascular disorders: abnormal ECG; Skin and Companion Disorders: eczema, increased sweating, itching, dermatitis, rash; Coagulation Disorders: epistaxis; Disorders in the resistance mechanism: infection, viral infection; Vision disorders: conjunctivitis; Vestibular hearing disorders: Tinnitus. Some reported events of less than 0.5% seen include angina pectoris, myocardial infarction, and angioedema.

Candesartan Cilexetil

Other adverse reactions that have been reported with candesartan cilexetil are: Body: Fever; Metabolic and Nutritional Disorders: Hypertriglyceridemia; Psychiatric Disorders: Drowsiness; Disorders in the urinary system: Albuminuria.

Warnings

Sale under prescription. Keep out of the reach of children.

Composition

Xiletil – 8

Each coated tablet contains:

Candesartan Cilexetil     8 mg

C.S. excipients

Xiletil – 16

Each coated tablet contains:

Candesartan Cilexetil     16 mg

C.S. excipients

Xiletil – 32

Each coated tablet contains:

Candesartan Cilexetil     32 mg

C.S. excipients

Xiletil – H

Each coated tablet contains:

Candesartan Cilexetil     8 mg

Hydrochlorothiazide     12.5 mg

C.S. excipients

Xiletil – D

Each coated tablet contains:

Candesartan Cilexetil     16 mg

Hydrochlorothiazide     12.5 mg

C.S. excipients

Xiletil – Forte

Each coated tablet contains:

Candesartan Cilexetil     32 mg

Hydrochlorothiazide     25 mg

C.S. excipients


Administration route

Oral


Posology

 

The usual dose of Xiletil 8, 16, 32, H, D and Forte is one tablet given once a day.


Presentation

Xiletil 8: Box containing 30 coated tablets.

Xiletil 16: Box containing 30 coated tablets.

Xiletil 32: Box containing 30 coated tablets.

Xiletil H: Box containing 30 coated tablets.

Xiletil D: Box containing 30 coated tablets.

Xiletil Forte: Box containing 30 coated tablets.


Storage Recommendations

Keep in a cool place (below 30 °C). Protect  from light and moisture.

General precautions

Candesartan Cilexetil – Hydrochlorothiazide: In clinical trials of various doses of candesartan cilexetil and hydrochlorothiazide, the incidence of hypertensive patients who developed hypokalemia (serum potassium 3.5 mE / L) was 2.5% versus 2.1% by placebo.

Hydrochlorothiazide: periodic determinations of electrolytes in the serum, to detect a possible electrolyte imbalance, should be conducted at appropriate intervals. Hypokalemia can develop, especially with strong urine output, when severe cirrhosis is present or after prolonged therapy. Interference with proper oral electrolyte intake will also contribute to hypokalemia. Hypokalemia can cause cardiac arrhythmia and can sensitize or exaggerate the heart’s response to toxic digitalis effects (eg, elevated ventricular irritability).

Dilutional hyponatremia can occur in edematous patients in hot climates; appropriate therapy is water restriction, rather than salt administration, except on rare occasions when hyponatremia is fatal. Hyperuricemia can occur or acute gout precipitate in certain patients receiving thiazide therapy.

In diabetic patients, adjustments in the dose of insulin or oral hypoglycemic agents may be required. Hyperglycemia can occur with thiazide diuretics; Although latent diabetes can manifest during thiazide therapy.

The antihypertensive effects of the drug can be increased in the post-sympathectomy patient.

If progressive kidney damage becomes evident, consideration should be given to withholding or discontinuing diuretic therapy. In patients in whom their renal function depends on the activity of the renin-angiotensin-aldosterone system (for example, patients with severe congestive heart failure), treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists II has been associated with oliguria and / or progressive azoemia and, rarely, with severe renal failure and / or death. Similar results can be anticipated in patients treated with Candesartan Cilexetil. Thiazide diuretics should be used with caution in severe kidney disease; since, they can precipitate the azoemia. Cumulative effects of the drug can develop in patients with damage to kidney function.

Information for patients

Pregnancy: When used during pregnancy, in the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause harm and even death to the developing fetus. When pregnancy is detected, Xiletil should be discontinued as soon as possible.

Patients of childbearing age should be informed about the consequences of exposure to drugs that act on the renin-angiotensin system during the second and third trimesters.

Symptomatic Hypotension: A patient receiving Xiletil H, D and Plus should be informed that dizziness may occur, especially during the first days of therapy and that it should be reported to his doctor. Patients should be informed that if syncope occurs, Xiletil H, D, and Plus should be discontinued until the treating physician is informed. All patients should be informed that inadequate fluid intake, excessive sweating, diarrhea or vomiting can cause an excessive decrease in blood pressure, with the same consequences of dizziness and possible syncope.

Potassium supplements: A patient receiving Xiletil H, D and Plus should be informed that they should not use potassium supplements or salt substitutes without first consulting their doctor.

Drug interactions

Candesartan Cilexetil: No significant drug interactions have been reported in studies of Candersartan Cilexetil when administered to healthy volunteers, with other drugs such as glyburide, nifedipine, digoxin, warfarin, hydrochlorothiazide, and oral contraceptives. Because Candesartan Cilexetil is not significantly metabolized by the cytochrome p450 system and has no effect on p450 enzymes at therapeutic concentrations, interaction with drugs that are metabolized by these enzymes is not expected.

Hydrochlorothiazide: When the following drugs are co-administered, they may interact with thiazide diuretics: alcohol, barbiturates, or narcotics – potentiation of orthostatic hypotension may occur.

Anti-diabetic drugs (oral agents and insulin) – An adjustment in the dose of these drugs may be required.

Other antihypertensive drugs – Potential additive effects.

Cholestyramine and cholestypolic resins – the absorption of hydrochlorothiazide is impaired in the presence of anion exchange resins. Doses of cholestyramine or cholestypolic resins bind hydrochlorothiazide and reduce absorption from the gastrointestinal tract by up to 85% and 43%, respectively.

Corticosteroids, ACHT – Intensified electrolyte depletion, particularly hypokalemia.

Pressor amines (eg, norepinephrine) – Possible decrease in response to pressor amines but not enough to preclude their use.

Non-depolarizing skeletal muscle relaxants (eg, tubocurarine) – possible increase in muscle relaxant response.

Lithium – generally should not be administered with diuretics. Diuretics reduce the renal clearance of lithium and add a high risk of lithium toxicity.