Canartan-H® 16/12.5
Canartan-H® 16/12.5
Antihypertensive

Indication

  • Canartan®-H is indicated for essential hypertension, where monotherapy with candesartan cilexetil or hydrochlorothiazide is not sufficient.

Composition

Each tablet of Canartan®-H 16/ 12.5  contains: 

  • Candesartan Cilexetil                       16 mg
  • Hydrochlorothiazide                     12.5 mg 

Each tablet of Canartan®-H 8/ 12.5  contains:  

  • Candesartan Cilexetil                       8 mg 
  • Hydrochlorothiazide                      12.5 mg 

Dosage

  • The recommended dose of Canartan®-H is one tablet once daily. 
  • Most of the antihypertensive effect is usually attained within 4 weeks of initiation of treatment.
  • Canartan®-H should be taken once daily with or without food.
  • Use in the elderly: No initial dosage adjustment is necessary in elderly patients.
  • In patients with mild to moderate renal impairment whose creatinine clearance is ≥ 30 ml/min/1.73 m2BSA : Dose titration of candesartan cilexetil is recommended before treatment with Canartan®-H (the recommended starting dose of candesartan cilexetil is 4 mg ).
  • Patients with mild to moderate hepatic impairment: Dose titration of candesartan cilexetil is recommended  before treatment with Canartan®-H (the recommended starting dose of candesartan cilexetil is 2 mg ).
  • Use in children: The safety and efficacy of Canartan®-H have not been established in children.
  • Candesartan cilexetil: is a prodrug, which is rapidly converted to the active drug, candesartan, by ester hydrolysis during absorption from the gastrointestinal tract.
  • Candesartan is an angiotensin II receptor antagonist, selective for AT1 receptors, with tight binding to and slow dissociation from the receptor. It has no agonist activity.
  • Candesartan does not influence ACE or other enzyme systems usually associated with the use of ACE inhibitors. Since there is no effect on the degradation of kinins, or on the metabolism of other substances, such as substance P,
  • angiotensin II receptor antagonists are unlikely to be associated with cough.
  • Candesartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. The antagonism of the AT1 receptors results in dose related increases in plasma renin levels, angiotensin I and angiotensin II levels, and a decrease in plasma aldosterone concentration.
  • Hydrochlorothiazide: inhibits the active reabsorption of sodium, mainly in the distal kidney tubules, and promotes the excretion of sodium, chloride and water. The renal excretion of potassium and magnesium increases dose-dependently, while calcium is reabsorbed to a greater extent.
  • Hydrochlorothiazide decreases plasma volume and extracellular fluid and reduces cardiac output and blood pressure.
  • During long-term therapy, reduced peripheral resistance contributes to the blood pressure reduction.
  • Candesartan and hydrochlorothiazide: have additive antihypertensive effects. In hypertensive patients, Canartan®-H causes an effective and long-lasting reduction in arterial blood pressure without reflex increase in heart rate.

¤ Absorption And Distribution:

  • Candesartan cilexetil is rapidly and completely bioactivated by ester hydrolysis from the gastrointestinal tract to candesartan.
  • The average absolute bioavailability of candesartan is approximately 40%.
  • The mean peak serum concentration (Cmax) is reached in 3 - 4 hours after oral dministration.
  • Candesartan is highly bound to plasma proteins (more than 99%). The evident volume of distribution of candesartan is 0.1 L/kg.
  • The pharmacokinetics of candesartan is not gender related.
  • The area under the serum concentration versus time curve (AUC) of candesartan is not significantly affected by food.
  • Hydrochlorothiazide: is rapidly absorbed from the gastrointestinal tract with an absolute  bioavailability of approximately 70%.
  • Concomitant intake of food increases the absorption by approximately 15%. The bioavailability may decrease in patients with cardiac failure and pronounced oedema.
  • The plasma protein binding of hydrochlorothiazide is approximately 60%. The apparent volume of distribution is approximately 0.8 L/kg.

¤ Metabolism and Elimination:

  • Candesartan is mainly excreted unchanged in urine and bile. It undergoes minor hepatic metabolism to an inactive metabolite.
  • The terminal half-life of candesartan is approximately 9 hours.
  • Total plasma clearance of candesartan is about 0.37 ml/min/kg, with a renal clearance of about 0.19 ml/min/kg. Following an oral dose of 14C-labelled candesartan cilexetil, approximately 26% of the dose is excreted in the urine as candesartan and 7% as an inactive metabolite while approximately 56% of the dose is recovered in the faeces as candesartan and 10% as the inactive metabolite.
  • Hydrochlorothiazide is not metabolized and is excreted almost entirely as unchanged drug by glomerular filtration and active tubular secretion.
  • The terminal t1/ 2 of hydrochlorothiazide is approximately 8 hours. Approximately 70% of an oral dose is eliminated in the urine within 48 hours.
  • The half-life of hdrochlorothiazide remains unchanged (approximately 8 h) after administration of hydrochlorothiazide in combination with candesartan cilexetil. No additional accumulation of hydrochlorothiazide occurs after repeated doses of the combination compared to monotherapy.
  • The terminal t1/ 2 of hydrochlorothiazide is prolonged in patients with renal impairment.

Each tablet of Canartan®-H 16/ 12.5  contains: 

  • Candesartan Cilexetil                       16 mg
  • Hydrochlorothiazide                     12.5 mg 

Each tablet of Canartan®-H 8/ 12.5  contains:  

  • Candesartan Cilexetil                       8 mg 
  • Hydrochlorothiazide                      12.5 mg 
  • Canartan®-H is indicated for essential hypertension, where monotherapy with candesartan cilexetil or hydrochlorothiazide is not sufficient.
  • Hypersensitivity to Candesartan , Hydrochlorothiazide or to any of the components.
  • Severe renal impairment (creatinine clearance <30 ml/min/1.73 m2 BSA).
  • Severe hepatic impairment and/or cholestasis.
  • Refractory hypokalaemia and hypercalcaemia.
  • Gout.
  • No drug interactions of clinical significance have been identified for candesartan cilexetil. 
  • The antihypertensive effect of Canartan®-H may be enhanced by other antihypertensives. 
  • The potassium depleting effect of hydrochlorothiazide could be expected to be potentiated by other drugs associated with potassium loss and hypokalaemia (e.g. other kaliuretic diuretics, laxatives, amphotericin, carbenoxolone, penicillin G sodium, salicylic acid derivates). 
  • Diuretic-induced hypokalaemia and hypomagnesaemia predisposes to the potential cardiotoxic effects of digitalis glycosides and antiarrhythmics. Periodic monitoring of serum potassium is recommended when Canartan®-H is administered with such drugs.
  • Canartan®-H may increase in serum lithium concentrations and toxicity and careful monitoring of serum lithium concentrations is recommended 
  • NSAIDs may decrease  the diuretic, natriuretic and antihypertensive effect of hydrochlorothiazide 
  • Colestipol or cholestyramine reduce the absorption of hydrochlorothiazide.
  • Nondepolarizing skeletal muscle relaxants effects (e.g. tubocurarine) may be potentiated by hydrochlorothiazide.
  • Hydrochlorothiazide may increase serum calcium levels due to decreased excretion. If calcium supplements or Vitamin D must be prescribed, serum calcium levels should be monitored and dosage adjusted accordingly.
  • The hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by hydrochlorothiazide. 
  • Anticholinergic agents (e.g. atropine, biperiden) may increase the bioavailability of hydrochlorothiazide by decreasing gastrointestinal motility and stomach emptying rate. 
  • Hydrochlorothiazide may increase the risk of adverse effects caused by amantadine. 
  • hydrochlorothiazide may reduce the renal excretion of cytotoxic drugs (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects.
  • The risk for hypokalaemia may be increased during concomitant use of steroids or adrenocorticotropic hormone (ACTH). 
  • Postural hypotension may become aggravated by simultaneous intake of alcohol, barbiturates or anaesthetics.
  • Treatment with a thiazide diuretic may impair glucose tolerance. Dosage adjustment of antidiabetic drugs, including insulin, may be required. 
  • Hydrochlorothiazide may cause the arterial response to pressor amines (e.g. adrenaline) to decrease but not enough to exclude a pressor effect. 
  • Hydrochlorothiazide may increase the risk of acute renal insufficiency especially with high doses of iodinated contrast media.
  • There is no clinically significant interaction between hydrochlorothiazide and food.
  • Canartan®-H should not be used in pregnancy. If pregnancy is detected during treatment, Canartan®-H should be discontinued. 
  • Canartan®-H should not be given during breast-feeding.
  • Nervous system disorders: Dizziness/vertigo.

¤ Candesartan cilexetil:

  • Leukopenia, neutropenia and agranulocytosis, Hyperkalaemia, hyponatraemia, Dizziness, headache, Nausea, Increased liver enzymes, abnormal hepatic function or hepatitis, Angioedema, rash, urticaria, pruritus, Back pain, arthralgia, myalgia, Renal impairment, including renal failure in susceptible patients.

¤ Hydrochlorothiazide:

  • Common: Hyperglycaemia, hyperuricaemia, electrolyte imbalance (including hyponatraemia and hypokalaemia), Light-headedness, vertigo, Glycosuria, Weakness, Increases in cholesterol and triglycerides.
  • uncommon: Postural hypotension, Anorexia, loss of appetite, gastric irritation, diarrhoea, constipation, Rash, urticaria, photosensitivity reactions,
  • Rare: Leucopenia, neutropenia/agranulocytosis, thrombocytopenia, aplastic anaemia, bone marrow depression, haemolytic anaemia, Anaphylactic reactions, Sleep disturbances, depression, restlessness, Paraesthesia, Transient blurred vision, Cardiac arrhythmias, Necrotising angitis (vasculitis, cutaneous vasculitis), Respiratory distress (including pneumonitis and pulmonary oedema), Pancreatitis, Jaundice (intrahepatic cholestatic jaundice), Toxic epidermal necrolysis, cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus, Muscle spasm, Renal dysfunction and interstitial nephritis, Fever, Increases in BUN and serum creatinine.
  • The recommended dose of Canartan®-H is one tablet once daily. 
  • Most of the antihypertensive effect is usually attained within 4 weeks of initiation of treatment.
  • Canartan®-H should be taken once daily with or without food.
  • Use in the elderly: No initial dosage adjustment is necessary in elderly patients.
  • In patients with mild to moderate renal impairment whose creatinine clearance is ≥ 30 ml/min/1.73 m2BSA : Dose titration of candesartan cilexetil is recommended before treatment with Canartan®-H (the recommended starting dose of candesartan cilexetil is 4 mg ).
  • Patients with mild to moderate hepatic impairment: Dose titration of candesartan cilexetil is recommended  before treatment with Canartan®-H (the recommended starting dose of candesartan cilexetil is 2 mg ).
  • Use in children: The safety and efficacy of Canartan®-H have not been established in children.
  • When Canartan®-H is used in patients with impaired renal function, a periodic monitoring of potassium,  creatinine and uric acid levels is recommended. There is no experience regarding the administration of Canartan®-H in patients with a recent kidney transplantation.
  • Canartan®-H should be used with caution in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney becuase candesartan cilexetile  may increase blood urea and serum creatinine .
  • Canartan®-H should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. 
  • Risk of hypotension in patients with intravascular volume and/or sodium depletion . Therefore, the use of Canartan®-H is not recommended until this condition has been corrected.
  • Canartan®-H should be used with particular caution in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy as with all vasodilators.
  • Canartan®-H is not recommended in  Patients with primary hyperaldosteronism , because patients they will not respond to antihypertensive drugs acting through inhibition of the renin-angiotensin-aldosterone system.
  • Periodic determination of serum electrolytes should be performed at appropriate intervals. Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (hypercalcaemia, hypokalaemia, hyponatraemia, hypomagnesaemia and hypochloraemic alkalosis). 
  • Concomitant use of Canartan®-H with potassium-sparing diuretics, potassium supplements or salt substitutes or other drugs that may increase serum potassium levels (e.g. heparin sodium) may lead to increases in serum potassium.
  • Treatment with a thiazide diuretic may impair glucose tolerance. Dosage adjustment of antidiabetic drugs, including insulin, may be required. Latent diabetes mellitus may become manifest during thiazide therapy.
  • Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy. However, at the 12.5 mg dose contained in Canartan®-H minimal or no effects were reported.
  • Thiazide diuretics increase serum uric acid concentration and may precipitate gout in susceptible patients.
  • General: In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with other drugs that affect this system has  been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal failure. The possibility of similar effects cannot be excluded with angiotensin receptor
    antagonists.
  • As with any antihypertensive agent, excessive blood pressure decrease in patients with 

Canartan®-H  16 / 12.5  :

  • Blister of 10 tablets, pack of 2 blisters. 

Canartan®-H  8 / 12.5:

  • Blister of 10 tablets, pack of 2 blisters.
  • In dry place store below 25ºC.