Rotazar Plus (Tablets)

(Irbesartan + hydrochlorothiazide)

COMPOSITION:

Film-coated tablets. A film-coated tablet contains irbesartan 150 mg and hydrochlorothiazide 12.5 mg. A film-coated tablet contains irbesartan 300 mg and hydrochlorothiazide 12.5 mg. A film-coated tablet contains irbesartan 300 mg and hydrochlorothiazide 25 mg. 

 

PHARMACOLOGICAL PROPERTIES:

PHARMACODYNAMICS. 

Rotazar Plus is a combination of an angiotensin-II receptor antagonist, irbesartan, and a thiazide diuretic, hydrochlorothiazide. The combination of these ingredients has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone.

Irbesartan is a potent, orally active, selective angiotensin-II receptor (AT1 subtype) antagonist. It is expected to block all actions of angiotensin-II mediated by the AT1 receptor, regardless of the source or route of synthesis of angiotensin-II. The selective antagonism of the angiotensin-II (AT1) receptors results in increases in plasma renin levels and angiotensin-II levels, and a decrease in plasma aldosterone concentration. Serum potassium levels are not significantly affected by irbesartan alone at the recommended doses in patients without risk of electrolyte imbalance (see sections 4.4 and 4.5). Irbesartan does not inhibit ACE (kininase-II), an enzyme which generates angiotensin-II and also degrades bradykinin into inactive metabolites. Irbesartan does not affect the serum uric acid concentration and its renal excretion. 

Hydrochlorothiazide is a thiazide diuretic. The mechanism of antihypertensive effect of thiazide diuretics is not fully known. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. The diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma renin activity, increases aldosterone secretion, with consequent increases in urinary potassium and bicarbonate loss, and decreases in serum potassium. Presumably through blockade of the renin-angiotensin-aldosterone system, co-administration of irbesartan tends to reverse the potassium loss associated with these diuretics. With hydrochlorothiazide, onset of diuresis occurs in 2 hours, and peak effect occurs at about 4 hours, while the action persists for approximately 6-12 hours.

The combination of hydrochlorothiazide and irbesartan produces dose-related additive reductions in blood pressure across their therapeutic dose ranges. The blood pressure lowering effect of irbesartan in combination with hydrochlorothiazide is apparent after the first dose and substantially present within 1-2 weeks, with the maximal effect occurring by 6-8 weeks. There is no difference in response to Rotazar Plus, regardless of age or gender.

PHARMACOKINETICS.

Absorption. the absolute oral bioavailability is 60-80% and 50-80% for irbesartan and hydrochlorothiazide, respectively. Peak plasma concentration occurs at 1.5-2 hours after oral administration for irbesartan and 1-2.5 hours for hydrochlorothiazide.

Distribution. Plasma protein binding of irbesartan is approximately 96%, with negligible binding to cellular blood components. The volume of distribution for irbesartan is 53-93 litres. Hydrochlorothiazide is 68% protein-bound in the plasma, and its apparent volume of distribution is

0.83-1.14 l/kg.

Steady-state plasma concentrations are attained within 3 days after initiation of a once-daily dosing regimen. Limited accumulation of irbesartan (< 20%) is observed in plasma upon repeated once-daily dosing. Irbesartan exhibits linear and dose proportional pharmacokinetics over the dose range of 10 to 600 mg. Hydrochlorothiazide crosses the placental but not the blood-brain barrier, and is excreted in breast milk.

Metabolism. Irbesartan is mainly metabolised by CYP2C9 and to a lesser extent by glucuronidation. In vitro studies indicate that irbesartan is primarily oxidised by the cytochrome P450 enzyme CYP2C9.

Hydrochlorothiazide is not metabolized. 

Elimination.

The total body and renal clearance are 157-176 and 3.0-3.5 ml/min, respectively. The terminal elimination halflife of irbesartan is 11-15 hours. After either oral or intravenous administration of 14C irbesartan, about 20% of the radioactivity is recovered in the urine, and the remainder in the faeces. Less than 2% of the dose is excreted in the urine as unchanged irbesartan. The mean plasma half-life of hydrochlorothiazide reportedly ranges from 5-15 hours. Hydrochlorothiazide is quickly excreted by kidneys. At least 61 % of oral dose is excreted unchanged during 24 hours.

Pharmacokinetics in special populations.

In a study, somewhat higher plasma concentrations of irbesartan were observed in female hypertensive patients. However, there was no difference in the half-life and accumulation of irbesartan. No dosage adjustment is necessary in female patients.

Irbesartan AUC and C_max values were also somewhat greater in older subjects (≥ 65 years) than those of young subjects (18-40 years). However the terminal half-life was not significantly altered. No dosage adjustment is necessary in older people.

In patients with renal impairment or those undergoing haemodialysis, the pharmacokinetic parameters of irbesartan are not significantly altered. Irbesartan is not removed by haemodialysis. In patients with creatinine clearance < 20 ml/min, the elimination half-life of hydrochlorothiazide was reported to increase to 21 hours.

Hepatic impairment: in patients with mild to moderate cirrhosis, the pharmacokinetic parameters of irbesartan are not significantly altered. Studies have not been performed in patients with severe hepatic impairment.

THERAPEUTIC INDICATIONS

 

•          Moderate or severe arterial hypertension (treatment of patients indicated for combination therapy)

 

 

CONTRAINDICATIONS.

•          Severe renal impairment (creatinine clearance < 30 ml/min); anuria (due to the presence of hydrochlorothiazide)
•          Refractory            hypokalaemia,     hypomagnesaemia,           hypercalcaemia   (due       to                the         presence               of hydrochlorothiazide);
•          Severe hepatic impairment (C-class/over 9 scores according to the  Child – Pugh scores, biliary cirrhosis and cholestasis (due to the presence of hydrochlorothiazide as the minimal disturbances of waterelectrolytic balance may cause hepatic coma in such patients).
•          Hereditary lactose intolerance, lactose insufficiency or glucose or lactose absorption disturbances. - Pregnancy;
•          Lactation;
•          Age below 18 (efficacy and safety have not been determined);
•          Hypersensitivity to the ingredients;
•          Hypersensitivity to the sulfonamide derivatives (hydrochlorothiazide is a sulfonamide derivative).

Rotazar Plus is administered with caution in:

•          aortic or mitral valve stenosis; obstructive hypertrophic cardiomyopathy;
•          dehydration, hyponatremia, diarrhea, vomiting, diet including the limitation of salt consumption, treatment of diuretics (the risk of evident arterial hypotension);
•          Renal artery stenosis - Renovascular hypertension: there is an increased risk of severe hypotension, oliguresis and/or azotemia and developing renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with angiotensin converting enzyme inhibitors or angiotensin-II receptor antagonists’
•          In CAD and/or atherosclerotic vascular disease (excessive blood pressure decrease in patients with ischemic cardiopathy or ischemic cardiovascular disease could result in a myocardial infarction or stroke);
•          Mild to moderate renal insufficiency (creatinine clearance is 30-60 ml/min), hemodialysis (the risk of azotemia due to hydrochlorothiazide and the developmemt of Hyperkalaemia due to irbesartan);
•          kidney transplantation (the absence of clinical experience);
•          hepatic insufficiency (A and B-class/6-scores 5-6 and 7-9 according to the Child-Pugh score;
•          diabetes mellitus (due to the presence of hydrochlorothiazide the decrease of glucose tolerability may occur);
•          increased blood cholesterol and triglyceride level (due to the presence of hydrochlorothiazide as thiazide diuretics, especially in high doses, may increase blood cholesterol and triglyceride levels);
•          gout (due to the presence of hydrochlorothiazide the blood urate level may be increased);
•          hyperkalemia, concomitant administration of potassium-sparing agents and/or salt substitutes containing potassium (the risk of hyperkalemia);
•          systemic erythema centrifugum (due to the presence of hydrochlorothiazide the aggravation may occur);
•          concurrent administration of other hypotensive agents (the risk of potentiationof their hypotensive effect);
•          latent hyperparathyroidism (due to the presence of hydrochlorothiazide, as thiazide diuretics, especially in high doses, may increase the risk of the development of aggravation of hypercalcemia);
•          sympathectomy (the risk of intensification of hypotensive effect of hydrochlorothiazide);
•          concurrent administration of lithium salts (hydrochlorothiazide increases the risk of toxic effect of lithium).

 

ADVERSE REACTIONS.

Irbesartan/hydrochlorothiazide groups and placebo have not shown  any difference in total incidence of adverse reactions. Therapy withdrawal due to any clinical or laboratory adverse reaction has occurred more rarely in Irbesartan/hydrochlorothiazide groups of patients rather than placebo group. The incidence of adverse reactions has not been determined by sex, age, race or dose (in the recommended dose range).

CNS reactions: common – headache; uncommon - orthostatic dizziness.

Cardiovascular reactions: common – excessive arterial pressure decrease, peripheral edema (for  example, lower limbs), syncope, tachycardia, fluxion to face.

Gastrointestinal disorders:common – nausea, vomiting; uncommon – diarrhea.

 

Renal and urinary disorders: abnormal urination.

Reproductive system reactions: libido changes, sexual dysfunction.

Other reactions: common – tiredness.

Investigations: increases in blood urea nitrogen (BUN), creatinine and UFC plasma; uncommon – serum potassium and sodium decrease.

The data regarding the changes of laboratory parameters has rarely reached the clinical threshold.

 

DOSAGE AND ADMINISTRATION

Rotazar Plus is administered once daily with no regard to food intake.

Rotazar Plus is administered to patients whose arterial pressure is not sufficiently controlled by irbesartan and hydrochlorothiazide during monotherapy.  

Rotazar Plus 150/12.5 mg (tablets containing irbesartan and hydrochlorothiazide 150/12.5 mg, respectively) may be administered to patients whose arterial pressure is not sufficiently controlled by irbesartan (150 mg) or hydrochlorothiazide (12.5 mg) in monotherapy.

Rotazar Plus 300/12.5 mg (tablets containing irbesartan and hydrochlorothiazide 300/12.5 mg, respectively) may be administered to patients whose arterial pressure is not sufficiently controlled by irbesartan (300 mg) or Rotazar Plus (300/12.5 mg).

If needed, patients whose arterial pressure is not sufficiently controlled by Rotazar Plus (300/12.5 mg), the doses of combination medication may be increased up to 300 mg irbesartan and 25 mg hydrochlorothiazide daily: 2 tablets of Rotazar Plus 150/12.5 mg or one tablet of Rotazar Plus 300/25 mg.

Maximum daily dose is 2 tablets of Rotazar Plus 150/12.5 mg or one tablet of Rotazar Plus 300/25 mg. in case of failure to reach the targeted arterial pressure using Rotazar Plus 300/25 mg, other hypotensive drugs (betablockers, calcium channel blockers of prolonged release) may be added.

Administration of Rotazar Plus is not recommended to patients with compromised kidney function (creatinine clearance is <30 ml/min). Loop diuretics are preferable.

In patients with compromised kidney function (creatinine clearance is >30 ml/min the dose adjustment is not required.

In patients with mild to moderate hepatic insufficiency (scores 5-6 and 7-9 according to the Child – Pugh scores) the dose decrease is not required. 

The dose adjustment is not required in elderly patients.

 

PACKAGING

Film-coated tablets.

14 tablets in a  blister. 2 blisters with a leaflet in a carton box. 15 tablets in a blister. 6 blisters with a leaflet in a carton box.