Probertan

Uses

Treatment of essential hypertension. Treatment of renal disease in patients with hypertension and type 2 diabetes mellitus as part of an antihypertensive drug regimen.

Probertan is also used to associated treatment for these conditions: Diabetic Nephropathy, High Blood Pressure (Hypertension)

How Probertan works

Probertan prevents angiotensin II binding to the AT₁ receptor in tissues like vascular smooth muscle and the adrenal gland. Probertan and its active metabolite bind the AT₁ receptor with 8500 times more affinity than they bind to the AT₂ receptor. Probertan's prevention of angiotensin II binding causes vascular smooth muscle relaxation and prevents the secretion of aldosterone, lowering blood pressure.

Angiotensin II would otherwise bind to the AT₁ receptor, inducing vasoconstriction and aldosterone secretion, raising blood pressure.

Dosage

Probertan dosage

Adult: The usual recommended initial and maintenance dose is Probertan 150 mg once daily, withor without food. Probertan at a dose of 150 mg once daily generally provides a better 24 hourblood pressure control than 75 mg. However, initiation of therapy with Probertan 75 mg couldbe considered, particularly in haemodialysed patients and in the elderly over 75 years.In patients insufficiently controlled with Probertan 150 mg once daily, the dose of Probertancan be increased to Probertan 300 mg, or other anti-hypertensive agents can be added. In particular, the addition of a diuretic such as hydrochlorothiazide has been shown to have anadditive effect with Probertan.In hypertensive type 2 diabetic patients, therapy should be initiated at Probertan 150 mgonce daily and titrated up to Probertan 300 mg once daily as the preferred maintenance dosefor treatment of renal disease.The demonstration of renal benefit of Probertan in hypertensive type 2 diabetic patients is basedon studies where Probertan was used in addition to other antihypertensive agents, as needed, toreach target blood pressure.

Elderly: although consideration should be given to initiating therapy with Probertan 75 mg in patients over 75 years of age, dosage adjustment is not usually necessary for the elderly

Paediatric: Probertan is not recommended for use in children and adolescents due toinsufficient data on safety and efficacy.

Side Effects

Diarrhoea, fatigue, dyspepsia or heartburn, dizziness, orthostatic hypotension, nausea, vomiting, musculoskeletal pain, thrombocytopaenia, hyperkalaemia, elevated serum creatinine.

Toxicity

The oral TDLO in humans is 30mg/kg/6W.

Symptoms of overdose include hypotension and tachycardia or bradycardia. Terlipressin may be given to treat hypotension and tachycardia if conventional vasopressors fail to control blood pressure.

Precaution

Patients with unilateral or bilateral renal artery stenosis, depletion of intravascular volume, aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy. Renal impairment. Lactation.

Interaction

Diuretics and other antihypertensive agents: prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with Probertan.

Potassium supplements and potassium-sparing diuretics: based on experience with the use of other drugs that affect the renin-angiotensin system, concomitant use of potassiumsparing diuretics, potassium supplements, salt substitutes containing potassium or other drugs that may increase serum potassium levels (e.g. heparin) may lead to increases in serum potassium and is, therefore, not recommended.

Lithium: reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar effects have been very rarely reported with irbesartan so far. Therefore, this combination is not recommended. If the combination proves necessary, careful monitoring of serum lithium levels is recommended.

Non-steroidal anti-inflammatory drugs: When angiotensin II antagonists are administered simultaneously with non-steroidal anti- inflammatory drugs (i.e. selective COX-2 inhibitors, acetylsalicylic acid > 3 g/day and non-selective NSAIDs), attenuation of the antihypertensive effect may occur. Additional information on irbesartan interactions: In clinical studies, the pharmacokinetic of irbesartan is not affected by hydrochlorothiazide. Probertan is mainly metabolised by CYP2C9 and to a lesser extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were observed when irbesartan was coadministered with warfarin, a drug metabolised by CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic of irbesartan have not been evaluated. The pharmacokinetic of digoxin was not altered by coadministration of irbesartan.

Food Interaction

• Take with or without food. The absorption is unaffected by food.

[Moderate] GENERALLY AVOID: Moderate-to-high dietary intake of potassium, especially salt substitutes, may increase the risk of hyperkalemia in some patients who are using angiotensin II receptor blockers (ARBs).

ARBs can promote hyperkalemia through inhibition of angiotensin II-induced aldosterone secretion.

Patients with diabetes, heart failure, dehydration, or renal insufficiency have a greater risk of developing hyperkalemia.

MANAGEMENT: Patients should receive dietary counseling and be advised to not use potassium-containing salt substitutes or over-the-counter potassium supplements without consulting their physician.

If salt substitutes are used concurrently, regular monitoring of serum potassium levels is recommended.

Patients should also be advised to seek medical attention if they experience symptoms of hyperkalemia such as weakness, irregular heartbeat, confusion, tingling of the extremities, or feelings of heaviness in the legs.

Probertan Drug Interaction

Moderate: aspirin, aspirinUnknown: ubiquinone, ubiquinone, rosuvastatin, rosuvastatin, apixaban, apixaban, omega-3 polyunsaturated fatty acids, omega-3 polyunsaturated fatty acids, atorvastatin, atorvastatin, metoprolol, metoprolol, cyanocobalamin, cyanocobalamin, ascorbic acid, ascorbic acid, cholecalciferol, cholecalciferol

Probertan Disease Interaction

Major: diabetes, angioedema, hypotensionModerate: CHF, hyperkalemia, renal artery stenosis, renal impairment, renal/liver disease

Volume of Distribution

The volume of distribution of irbesartan is 53-93L.

Elimination Route

Probertan is 60-80% bioavailable with a T_max of 1.5-2hours. Taking irbesartan with food does not affect the bioavailability.

In one study, healthy subjects were given single or multiple oral doses of 150mg, 300mg, 600mg, and 900mg of irbesartan. A single 150mg dose resulted in an AUC of 9.7±3.0µg\•hr/mL, a T_max of 1.5 hours, a half life of 16±7 hours, and a C_max of 1.9±0.4µg/mL. A single 300mg dose resulted in an AUC of 20.0±5.2µg\•hr/mL, a T_max of 1.5 hours, a half life of 14±7 hours, and a C_max of 2.9±0.9µg/mL. A single 600mg dose resulted in an AUC of 32.6±11.9µg\•hr/mL, a T_max of 1.5 hours, a half life of 14±8 hours, and a C_max of 4.9±1.2µg/mL. A single 900mg dose resulted in an AUC of 44.8±20.0µg\•hr/mL, a T_max of 1.5 hours, a half life of 17±7 hours, and a C_max of 5.3±1.9µg/mL.

Multiple 150mg doses resulted in an AUC of 9.3±3.0µg\•hr/mL, a T_max of 1.5 hours, a half life of 11±4 hours, and a C_max of 2.04±0.4µg/mL. Multiple 300mg doses resulted in an AUC of 19.8±5.8µg\•hr/mL, a T_max of 2.0 hours, a half life of 11±5 hours, and a C_max of 3.3±0.8µg/mL. Multiple 600mg doses resulted in an AUC of 31.9±9.7µg\•hr/mL, a T_max of 1.5 hours, a half life of 15±7 hours, and a C_max of 4.4±0.7µg/mL. Multiple 900mg doses resulted in an AUC of 34.2±9.3µg\•hr/mL, a T_max of 1.8 hours, a half life of 14±6 hours, and a C_max of 5.6±2.1µg/mL.

Half Life

The terminal elimination half life of irbesartan is 11-15 hours.

Clearance

Total plasma clearance of irbesartan is 157-176mL/min while renal clearance is 3.0-3.5mL/min.

Elimination Route

20% of a radiolabelled oral dose of irbesartan is recovered in urine, and the rest is recovered in the feces. 10

Pregnancy & Breastfeeding use

Pregnancy: Probertan is contraindicated in the second and third trimesters of pregnancy. In the second and third trimesters, substances that act directly on the renin-angiotensin-system can cause foetal or neonatal renal failure, foetal skull hypoplasia and even foetal death. As precautionary measure, irbesartan should preferably not be used during first trimester of pregnancy. A switch to a suitable alternative treatment should be carried out in advance of a planned pregnancy. If pregnancy is diagnosed, irbesartan should be discontinued as soon as possible, skull and renal function should be checked with echography if, inadvertently, the treatment was taken for a long period.

Lactation: Probertan is contraindicated during lactation. It is not known whether irbesartan is excreted in human milk. Probertan is excreted in the milk of lactating rats. Precautions: Intravascular volume depletion: symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of Probertan.

Contraindication

Concomitant use with aliskiren in patients with diabetes and renal impairment (GFR <60 ml/min). Pregnancy.

Special Warning

Renal impairment: no dosage adjustment is necessary in patients with impaired renal function. A lower starting dose of Probertan 75 mg should be considered for patients undergoing haemodialysis. Intravascular volume depletion: volume and/or sodium depletion should be corrected prior to administration of Probertan.

Hepatic impairment: no dosage adjustment is necessary in patients with mild to moderate hepatic impairment. There is no clinical experience in patients with severe hepatic impairment.

Hypertensive patients with type 2 diabetes and renal disease: the effects of irbesartan both on renal and cardiovascular events were not uniform across all subgroups, in an analysis carried out in the study with patients with advanced renal disease. In particular, they appeared less favourable in women and non-white subjects.

Hyperkalaemia: as with other drugs that affect the renin-angiotensin-aldosterone system, hyperkalaemia may occur during the treatment with Probertan, especially in the presence of renal impairment, overt proteinuria due to diabetic renal disease, and/or heart failure. Close monitoring of serum potassium in patients at risk is recommended.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: as with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

Primary aldosteronism: patients with primary aldosteronism generally will not respond to anti-hypertensive drugs acting through inhibition of the renin-angiotensin system. Therefore, the use of Probertan is not recommended.

General: in patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensinaldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with angiotensin converting enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated with acute hypotension, azotaemia, oliguria, or rarely acute renal failure. As with any anti-hypertensive agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaemic cardiovascular disease could result in a myocardial infarction or stroke.

Acute Overdose

Experience in adults exposed to doses of up to 900 mg/day for 8 weeks revealed no toxicity. The most likely manifestations of overdosage are expected to be hypotension and tachycardia; bradycardia might also occur from overdose. No specific information is available on the treatment of overdosage with Probertan. The patient should be closely monitored, and the treatment should be symptomatic and supportive. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal may be useful in the treatment of overdosage. Probertan is not removed by haemodialysis.

Storage Condition

Store in a cool and dry place, protected from light.

Innovators Monograph

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