Ibertan Plus (Tablets) Instructions for Use

Marketing Authorization Holder

Polpharma Pharmaceutical Works, Sa (Poland)

ATC Code

C09DA04 (Irbesartan and diuretics)

Active Substances

Hydrochlorothiazide (Rec.INN registered by WHO)

Irbesartan (Rec.INN registered by WHO)

Dosage Forms

	Ibertan Plus	Film-coated tablets, 12.5 mg+150 mg: 28 or 30 pcs.
		Film-coated tablets, 12.5 mg+150 mg: 28 or 30 pcs.
		Film-coated tablets, 12.5 mg+300 mg: 28 or 30 pcs.
		Film-coated tablets, 12.5 mg+300 mg: 28 or 30 pcs.
		Film-coated tablets, 25 mg+300 mg: 28 or 30 pcs.
		Film-coated tablets, 25 mg+300 mg: 28 or 30 pcs.

Dosage Form, Packaging, and Composition

7 pcs. – blisters (4) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
14 pcs. – blisters (2) – cardboard packs.
15 pcs. – blisters (2) – cardboard packs.

7 pcs. – blisters (4) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
14 pcs. – blisters (2) – cardboard packs.
15 pcs. – blisters (2) – cardboard packs.

7 pcs. – blisters (4) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
14 pcs. – blisters (2) – cardboard packs.
15 pcs. – blisters (2) – cardboard packs.

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Antihypertensive combination agent (angiotensin II receptor blocker + diuretic)

Pharmacological Action

A combined drug with an antihypertensive effect. It contains an angiotensin II receptor antagonist and a thiazide diuretic. The combination of these drugs has an additive antihypertensive effect, reducing blood pressure to a greater extent than each drug separately.

Irbesartan is a selective angiotensin II receptor (type AT₁) antagonist for oral administration. Irbesartan blocks all physiologically significant effects of angiotensin II mediated by AT₁ receptors, regardless of the source or pathway of angiotensin II synthesis. Selective antagonism to angiotensin II (AT₁) receptors leads to an increase in plasma renin and angiotensin II concentrations and a decrease in plasma aldosterone concentration. Serum potassium levels usually do not change significantly when taking irbesartan at recommended doses. Irbesartan does not inhibit kininase II. Irbesartan does not require metabolic activation. It reduces blood pressure with minimal change in heart rate.

Hydrochlorothiazide is a thiazide diuretic. It affects the reabsorption of electrolytes in the renal tubules, directly increasing the excretion of sodium and chloride ions in approximately equal amounts. The diuretic effect of hydrochlorothiazide leads to a decrease in plasma volume, an increase in plasma renin activity, an increase in aldosterone secretion, and an increase in the content of potassium ions and bicarbonates in the urine and hypokalemia. Simultaneous administration with irbesartan leads to a reduction in potassium ion loss, mainly due to the blockade of the renin-angiotensin-aldosterone system.

When hydrochlorothiazide is taken orally, the increase in diuresis occurs after 2 hours and reaches a maximum after 4 hours. The effect of hydrochlorothiazide lasts approximately 6-12 hours.

A decrease in blood pressure when prescribing irbesartan in combination with hydrochlorothiazide appears after the first oral dose and persists for 1-2 weeks, followed by its gradual increase and the development of the maximum effect at 6-8 weeks.

Pharmacokinetics

Simultaneous administration of hydrochlorothiazide and irbesartan does not affect the pharmacokinetics of each drug.

Absorption

After oral administration, the absolute bioavailability of irbesartan is 60-80%, and that of hydrochlorothiazide is 50-80%. Food intake does not affect their bioavailability. C_max of irbesartan in plasma is reached 1.5-2 hours after oral administration, and that of hydrochlorothiazide is reached after 1-2.5 hours.

Distribution

Irbesartan is 96% bound to plasma proteins. The volume of distribution (V_d) of irbesartan is 53-93 liters. The pharmacokinetic parameters of irbesartan are linear and proportional in the dose range from 10 mg to 600 mg. At doses above 600 mg (a dose twice the recommended maximum dose of the drug), the pharmacokinetics of irbesartan becomes nonlinear (decreased absorption).

Hydrochlorothiazide is 68% bound to plasma proteins, V_d is 0.83-1.14 l/kg.

Metabolism

Irbesartan is metabolized in the liver by conjugation with glucuronic acid and oxidation. Its main metabolite circulating in the blood is irbesartan glucuronide (about 6%). In vitro studies have shown that Irbesartan undergoes oxidation mainly via the cytochrome P450 isoenzyme CYP2C9. The influence of the CYP3A4 isoenzyme is insignificant.

Hydrochlorothiazide is not metabolized. It penetrates the placental barrier and is excreted in breast milk. It does not penetrate the blood-brain barrier.

Excretion

The total clearance and renal clearance are 157-176 and 3.0-3.5 ml/min, respectively. T_1/2 of irbesartan is 11-15 hours. Irbesartan and its metabolites are excreted through the intestines (80%) and by the kidneys (20%), with less than 2% of the administered irbesartan dose excreted unchanged by the kidneys.

T_1/2 of hydrochlorothiazide is 5-15 hours. It is excreted by the kidneys. At least 61% of the orally administered dose is excreted unchanged within 24 hours.

Pharmacokinetics in special clinical cases

Somewhat higher plasma concentrations of irbesartan are noted in female patients. However, no differences in the T_1/2 or accumulation of irbesartan were identified. Dose adjustment of irbesartan in female patients is not required.

The values of the area under the concentration-time curve (AUC) and C_max of irbesartan in plasma were somewhat higher in elderly patients (over 65 years) than in younger patients (under 65 years). The T_1/2 of irbesartan did not differ significantly. Dose adjustment of irbesartan in elderly patients is not required.

Renal impairment in patients with impaired renal function or on hemodialysis, the pharmacokinetic parameters of irbesartan are slightly changed.

Hepatic impairment in patients with mild or moderate hepatic impairment, the pharmacokinetic parameters of irbesartan are slightly changed. Studies have not been conducted in patients with severe hepatic impairment.

Indications

• Arterial hypertension (treatment of patients for whom combination therapy is indicated).

ICD codes

Dosage Regimen

Orally, once a day, regardless of meals.

The drug Ibertan Plus 12.5/150 mg (tablets containing Hydrochlorothiazide/Irbesartan 12.5/150 mg, respectively) can be prescribed to patients whose blood pressure is not adequately controlled by hydrochlorothiazide (12.5 mg/day) or irbesartan (150 mg/day) monotherapy alone.

The drug Ibertan Plus 12.5/300 mg (tablets containing Hydrochlorothiazide/Irbesartan 12.5/300 mg, respectively) can be prescribed to patients if blood pressure is not adequately controlled by irbesartan (300 mg/day) or the drug Ibertan Plus (12.5/150 mg).

The drug Ibertan Plus 25-300 mg (tablets containing Hydrochlorothiazide/Irbesartan 25/300 mg, respectively) can be prescribed to patients if blood pressure is not adequately controlled by the drug Ibertan Plus (12.5/300 mg). Doses higher than 25 mg hydrochlorothiazide/300 mg irbesartan once a day are not recommended.

If necessary, Ibertan Plus can be prescribed in combination with other antihypertensive drugs.

Renal impairment due to the fact that Ibertan Plus contains Hydrochlorothiazide, the drug is not recommended for patients with severe renal impairment (creatinine clearance < 30 ml/min). In this patient population, the prescription of “loop” diuretics is preferable. No dose adjustment is required in patients with renal impairment with creatinine clearance >30 ml/min.

Hepatic impairment the use of Ibertan Plus is not recommended in patients with severe hepatic insufficiency. In patients with mild to moderate hepatic insufficiency, no dose adjustment of Ibertan Plus is required.

Elderly patients no dose adjustment of Ibertan Plus is required in elderly patients.

Reduction of circulating blood volume: before prescribing Ibertan Plus, circulating blood volume and/or sodium content should be corrected.

Adverse Reactions

The side effects listed below are given in accordance with the following frequency gradations: very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1 000, < 1/100); rare (> 1/10 000, < 1/1 000); very rare (< 1/10 000). Within each frequency, adverse reactions are listed in order of decreasing severity.

Hydrochlorothiazide/Irbesartan combination

From the central nervous system common – dizziness; uncommon orthostatic dizziness.

From the cardiovascular system uncommon syncope, marked decrease in blood pressure, tachycardia, peripheral edema, flushing.

From the digestive system common – nausea, vomiting; uncommon diarrhea.

From the urinary system common – urination disorder.

From the genitourinary system uncommon – sexual dysfunction, libido disorder.

Other common – increased fatigue.

Laboratory parameters common – increased concentration of blood urea nitrogen, creatinine and creatine phosphokinase; uncommon – decreased serum potassium and sodium levels. These changes in laboratory parameters were rarely clinically significant.

Adverse reactions identified with the use of the Hydrochlorothiazide/Irbesartan combination, reported in the post-marketing period

Allergic reactions rare – skin rash, urticaria, angioedema.

From metabolism very rare – hyperkalemia.

From the central nervous system very rare – headache.

From the sense organs very rare – tinnitus.

From the respiratory system very rare – cough.

From the digestive system very rare – dyspepsia, dysgeusia, dry oral mucosa, hepatitis, liver function disorders.

From the musculoskeletal system very rare arthralgia, myalgia.

From the urinary system very rare – renal function impairment, incl. isolated cases of renal failure in high-risk patients.

Additional information on individual components

In addition to the already mentioned adverse reactions, other side effects previously reported for each of the components are listed below, which may be possible side effects also in the case of using Ibertan Plus.

Irbesartan

Other uncommon – chest pain.

Hydrochlorothiazide (without frequency specification)

From the hematopoietic organs aplastic anemia, bone marrow depression, hemolytic anemia, leukopenia, neutropenia/agranulocytosis, thrombocytopenia.

From the central nervous system depression, sleep disorders, dizziness, paresthesia, restlessness.

From the sense organs transient blurred vision, xanthopsia.

From the cardiovascular system arrhythmias, postural hypotension.

From the respiratory system respiratory distress syndrome (including pneumonitis and pulmonary edema).

From the digestive system jaundice (intrahepatic cholestatic jaundice).

Allergic reactions anaphylactic reactions, toxic epidermal necrolysis, lupus-like syndrome, necrotizing angiitis (vasculitis, cutaneous vasculitis), photosensitivity reactions, skin rash, exacerbation of systemic lupus erythematosus, urticaria.

From the musculoskeletal system muscle spasms, weakness.

From the urinary system interstitial nephritis, renal dysfunction.

Other increased body temperature.

Laboratory parameters water-electrolyte imbalance (incl. hypokalemia and hyponatremia), glycosuria, hyperglycemia, hyperuricemia, increased cholesterol and triglyceride levels.

Contraindications

• Hypersensitivity to any component of the drug or to other sulfonamide derivatives;
• Severe renal failure (creatinine clearance < 30 ml/min), anuria;
• Severe hepatic failure (Child-Pugh class C /more than 9 points/), biliary cirrhosis and cholestasis;
• Refractory hypokalemia, hypomagnesemia, hypercalcemia;
• Primary hyperaldosteronism;
• Hereditary lactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome;
• Pregnancy and lactation;
• Age under 18 years (efficacy and safety not established).

With caution

• In case of aortic or mitral valve stenosis; hypertrophic obstructive cardiomyopathy.
• In case of dehydration, hyponatremia, diarrhea, vomiting, salt-restricted diet, treatment with diuretics.
• In case of bilateral or unilateral renal artery stenosis, chronic heart failure stage III-IV according to NYHA classification (as with the use of other drugs affecting the renin-angiotensin-aldosterone system, the risk of arterial hypotension, oliguria and/or azotemia and progressive acute renal failure cannot be excluded).
• In case of coronary heart disease and/or atherosclerotic cerebrovascular disease.
• In case of mild and moderate renal failure (CC from 60 to 30 ml/min), hemodialysis; in recent kidney transplantation (lack of clinical experience).
• In case of hepatic insufficiency (lack of clinical experience).
• In case of diabetes mellitus; elevated blood cholesterol and triglycerides; gout; latent hyperparathyroidism; sympathectomy.
• In case of hyperkalemia, simultaneous use of potassium-sparing drugs and/or potassium-containing salt substitutes, simultaneous use of other antihypertensive drugs.
• In case of systemic lupus erythematosus.

Use in Pregnancy and Lactation

The use of Ibertan Plus is contraindicated during pregnancy, as exposure of the fetus to drugs affecting the renin-angiotensin-aldosterone system can lead to damage and death of the developing fetus. Thiazide diuretics cross the placental barrier and are found in umbilical cord blood. The use of diuretics in healthy pregnant women is generally not recommended and exposes the mother and fetus to unnecessary risks, including the development of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions observed in adults. The use of hydrochlorothiazide is especially not recommended in the first trimester of pregnancy. The drug is contraindicated in the second and third trimesters of pregnancy. If pregnancy is diagnosed, Ibertan Plus should be discontinued as soon as possible. If the patient took the drug from the second trimester of pregnancy, an ultrasound examination of the skull and renal function should be performed. Ibertan Plus is contraindicated throughout the entire lactation period.

Use in Hepatic Impairment

The use of Ibertan Plus is not recommended in patients with severe hepatic insufficiency. In patients with mild to moderate hepatic insufficiency, no dose adjustment of Ibertan Plus is required.

Use in Renal Impairment

Due to the fact that Ibertan Plus contains Hydrochlorothiazide, the drug is not recommended for patients with severe renal impairment (CC < 30 ml/min). In this patient population, the prescription of “loop” diuretics is preferable. No dose adjustment is required in patients with renal impairment with CC >30 ml/min.

Pediatric Use

Contraindicated in children under 18 years of age.

Geriatric Use

No dose adjustment of Ibertan Plus is required in elderly patients.

Special Precautions

Patients with arterial hypotension and reduced circulating blood volume in patients with hypertension, Ibertan Plus rarely causes symptomatic arterial hypotension. Symptomatic arterial hypotension may be observed in patients with reduced circulating blood volume or low sodium levels during diuretic therapy, a salt-restricted diet, diarrhea, or vomiting. Such conditions should be corrected before starting therapy with Ibertan Plus.

Renovascular hypertension. In patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney, when taking drugs affecting the RAAS, there is an increased risk of developing severe arterial hypotension and renal failure. Although such data were not identified during the use of Ibertan Plus, effects of this kind can be expected during the use of angiotensin II receptor antagonists.

Renal insufficiency and post-kidney transplantation status. When using Ibertan Plus in patients with impaired renal function, periodic monitoring of serum potassium, creatinine, and uric acid levels is indicated. There is no experience with the use of Ibertan Plus in patients after a recent kidney transplantation.

Aortic or mitral valve stenosis, hypertrophic obstructive cardiomyopathy. As with the use of other vasodilators, caution should be exercised when prescribing Ibertan Plus to patients with aortic or mitral stenosis or hypertrophic obstructive cardiomyopathy.

Primary hyperaldosteronism. Antihypertensive drugs acting through inhibition of the renin-angiotensin-aldosterone system are usually ineffective in patients with primary hyperaldosteronism. Therefore, the use of Ibertan Plus in such cases is not advisable.

Metabolic and endocrine effects. Thiazide diuretics may reduce glucose tolerance. In patients with diabetes mellitus, dose adjustment of insulin or oral hypoglycemic drugs may be required. Latent diabetes mellitus may become manifest during thiazide diuretic therapy.

During therapy with thiazide diuretics, hyperuricemia or exacerbation of gout may occur in some patients.

Water-electrolyte balance disturbance. Thiazide diuretics, including Hydrochlorothiazide, can cause water-electrolyte imbalance (hypokalemia, hyponatremia, and hypochloremic alkalosis). Although hypokalemia may develop with the use of thiazide diuretics, concurrent administration with irbesartan may reduce diuretic-induced hypokalemia. The risk of hypokalemia is increased in patients receiving glucocorticosteroids or adrenocorticotropic hormone. Conversely, due to the irbesartan component of Ibertan Plus, hyperkalemia is possible, especially in the presence of renal failure and/or heart failure or diabetes mellitus. Regular monitoring of serum potassium levels is recommended in at-risk patients.

Thiazide diuretics can reduce renal calcium excretion and cause transient hypercalcemia in the absence of known disorders of calcium metabolism. Marked hypercalcemia may indicate latent hyperparathyroidism. Thiazide diuretics should be discontinued before testing parathyroid function.

Thiazide diuretics have been shown to increase renal magnesium excretion, which may lead to hypomagnesemia.

Doping testsHydrochlorothiazide may cause a positive result in doping tests.

Other. As with other antihypertensive drugs affecting the renin-angiotensin-aldosterone system, a significant decrease in blood pressure in patients with coronary artery disease and/or cerebrovascular atherosclerosis may lead to myocardial infarction or stroke. Treatment of such patients should be carried out under strict blood pressure monitoring.

There are reports of exacerbation or activation of systemic lupus erythematosus with the use of thiazide diuretics.

Effect on ability to drive vehicles and operate machinery

The effect of Ibertan Plus on the ability to drive vehicles and perform work requiring increased attention has not been studied. However, caution should be exercised when driving vehicles and operating machinery during drug administration, as dizziness and increased fatigue may occur during treatment.

Overdose

Symptoms (presumed)Irbesartan – marked decrease in blood pressure, tachycardia, bradycardia. Hydrochlorothiazide – hypokalemia, hyponatremia, dehydration due to excessive diuresis. The most frequent manifestations of overdose are nausea and drowsiness. Hypokalemia can lead to seizures and/or development of cardiac arrhythmias associated with the concomitant use of cardiac glycosides and antiarrhythmic agents.

Treatment depends on the time elapsed since ingestion and the severity of symptoms. Suggested measures include induction of vomiting and/or gastric lavage, administration of activated charcoal, careful monitoring of the patient’s condition, and symptomatic and supportive therapy. Plasma electrolyte and creatinine concentrations should be monitored. In case of a marked decrease in blood pressure, the patient should be placed in a supine position with legs elevated and salt and fluid replacement should be initiated as soon as possible. Irbesartan is not removed by hemodialysis.

Drug Interactions

Other antihypertensive drugs the antihypertensive effect of Ibertan Plus may be enhanced by the concomitant administration of other antihypertensive drugs. Hydrochlorothiazide and Irbesartan (in doses up to 25 mg hydrochlorothiazide/300 mg irbesartan) can be safely used in combination with other antihypertensive drugs, including slow calcium channel blockers and beta-blockers. Previous treatment with high doses of diuretics may lead to volume depletion and increase the risk of arterial hypotension.

Lithium there are reports of reversible increases in serum lithium concentrations and toxicity with the concomitant administration of lithium preparations and angiotensin-converting enzyme inhibitors. Similar effects with irbesartan have been extremely rare to date. Furthermore, renal clearance of lithium is reduced during thiazide diuretic administration, so there is an increased risk of lithium toxicity when Ibertan Plus is prescribed. If this combination is necessary, careful monitoring of serum lithium levels is recommended.

Drugs affecting serum potassium levels: the hypokalemic effect of hydrochlorothiazide is attenuated by the potassium-sparing effect of irbesartan. However, this effect of hydrochlorothiazide may be enhanced by other drugs associated with potassium loss and hypokalemia (e.g., other diuretics, laxatives, amphotericin, carbenoxolone, penicillin G sodium, salicylic acid derivatives). Conversely, based on experience with drugs that reduce the activity of the RAAS, concomitant use of potassium-sparing diuretics, dietary supplements, salt substitutes containing potassium, or other drugs that may increase serum potassium levels (e.g., heparin sodium) may cause an increase in serum potassium levels. Appropriate monitoring of serum potassium is recommended in patients at risk for hyperkalemia.

Drugs affected by serum potassium imbalance careful monitoring of serum potassium is recommended when Ibertan Plus is co-administered with drugs affected by serum potassium imbalance (e.g., cardiac glycosides, antiarrhythmic agents).

Non-steroidal anti-inflammatory drugs when angiotensin II receptor antagonists are administered in combination with non-steroidal anti-inflammatory drugs (e.g., selective cyclooxygenase-2 (COX-2) inhibitors, acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs), an attenuation of the antihypertensive effect can be expected. As with the use of both angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists in combination with NSAIDs, there is an increased risk of impaired renal function, up to acute renal failure, and increased serum potassium, especially in patients with pre-existing impaired renal function. This drug combination should be prescribed with caution, especially in elderly patients. Patients should not be dehydrated. Renal function should be monitored after initiation of combination therapy and periodically thereafter.

Additional information on drug interactions of irbesartanHydrochlorothiazide does not affect the pharmacokinetics of irbesartan. No significant pharmacokinetic or pharmacodynamic interactions were identified when irbesartan was administered in combination with warfarin or drugs metabolized by the CYP2C9 isoenzyme. The effect of inducers of the CYP2C9 isoenzyme, such as rifampicin, on the pharmacokinetics of irbesartan has not been evaluated. When irbesartan was administered in combination with digoxin, the pharmacokinetics of the latter were not altered.

Additional information on drug interactions of hydrochlorothiazide:

The following drugs may interact with thiazide diuretics when co-administered

Ethanol, barbiturates, or narcotic drugs increased orthostatic hypotension may be observed.

Hypoglycemic drugs (oral agents and insulin) dose adjustment of hypoglycemic agents may be required.

Cholestyramine and colestipol the absorption of hydrochlorothiazide is impaired in the presence of anion exchange resins. The interval between taking these drugs should be at least 4 hours.

Glucocorticosteroids, adrenocorticotropic hormone marked disturbance of water-electrolyte balance, in particular, increased hypokalemia.

Catecholamines (e.g., norepinephrine) the effectiveness of these drugs may be reduced.

Non-depolarizing muscle relaxants (e.g., tubocurarine)Hydrochlorothiazide may potentiate the effects of non-depolarizing muscle relaxants.

Antigout drugs adjustment of the dose of drugs used to treat gout may be required, as Hydrochlorothiazide may increase plasma uric acid levels. An increase in the dose of probenecid or sulfinpyrazone may be required. Concomitant administration with thiazide diuretics may increase the incidence of hypersensitivity reactions to allopurinol.

Calcium salts thiazide diuretics may increase plasma calcium levels due to reduced excretion. If calcium supplements or drugs affecting calcium levels (e.g., vitamin D) need to be prescribed, the dose of these drugs should be adjusted accordingly and plasma calcium levels should be monitored.

Other types of drug interactions thiazide diuretics may enhance the hyperglycemic effect of beta-blockers and diazoxide. Anticholinergic drugs (e.g., atropine) may increase the bioavailability of thiazide diuretics by reducing gastrointestinal motility and gastric emptying rate. Thiazide diuretics may increase the risk of adverse reactions caused by amantadine. Thiazide diuretics may reduce the renal excretion of cytotoxic drugs (e.g., cyclophosphamide, methotrexate) and potentiate their myelosuppressive effect.

Storage Conditions

At a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

The shelf life is 2 years.

Dispensing Status

By prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.