COMPOSITION: Each film-coated tablet contains
Povidone, Croscarmellose sodium, Microcrystalline cellulose, Maltose, Colloidal anhydrous silica, Magnesium stearate, Opadry rosa.
NACARDIO 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.
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 addition of 12.5 mg hydrochlorothiazide to 300 mg irbesartan once daily in patients not adequately controlled on 300 mg irbesartan alone resulted in further placebo-corrected diastolic blood pressure reductions at trough (24 hours post-dosing) of 6.1 mm Hg. The combination of 300 mg irbesartan and 12.5 mg hydrochlorothiazide resulted in an overall placebo-subtracted systolic/diastolic reductions of up to 13.6/11.5 mm Hg.
Concomitant administration of hydrochlorothiazide and irbesartan has no effect on the pharmacokinetics of either medicinal product.
Irbesartan and hydrochlorothiazide are orally active agents and do not require biotransformation for their activity. Following oral administration of NACARDIO PLUS, the absolute oral bioavailability is 60-80% and 50-80% for irbesartan and hydrochlorothiazide, respectively. Food does not affect the bioavailability of NACARDIO PLUS. Peak plasma concentration occurs at 1.5-2 hours after oral administration for irbesartan and 1-2.5 hours for hydrochlorothiazide.
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.
Treatment of essential hypertension.
This fixed dose combination is indicated in adult patients whose blood pressure is not adequately controlled on irbesartan or hydrochlorothiazide alone
POSOLOGY AND METHOD OF ADMINISTRATION
NACARDIO PLUS can be taken once daily, with or without food.
Dose titration with the individual components (i.e. irbesartan and hydrochlorothiazide) may be recommended.
When clinically appropriate direct change from monotherapy to the fixed combinations may be considered:
- NACARDIO PLUS 150 mg/12.5 mg may be administered in patients whose blood pressure is not adequately controlled with hydrochlorothiazide or irbesartan 150 mg alone;
- NACARDIO PLUS 300 mg/12.5 mg may be administered in patients insufficiently controlled by irbesartan 300 mg or by NACARDIO PLUS 150 mg/12.5 mg.
- NACARDIO PLUS 300 mg/25 mg may be administered in patients insufficiently controlled by NACARDIO PLUS 300 mg/12.5 mg.
Doses higher than 300 mg irbesartan/25 mg hydrochlorothiazide once daily are not recommended.
When necessary, NACARDIO PLUS may be administered with another antihypertensive medicinal product
Renal impairment: due to the hydrochlorothiazide component, NACARDIO PLUS is not recommended for patients with severe renal dysfunction (creatinine clearance < 30 ml/min). Loop diuretics are preferred to thiazides in this population. No dosage adjustment is necessary in patients with renal impairment whose renal creatinine clearance is ≥ 30 ml/min
Hepatic impairment: NACARDIO PLUS is not indicated in patients with severe hepatic impairment. Thiazides should be used with caution in patients with impaired hepatic function. No dosage adjustment of NACARDIO PLUS is necessary in patients with mild to moderate hepatic impairment .
Elderly patients: no dosage adjustment of NACARDIO PLUSis necessary in elderly patients.
- Hypersensitivity to the active substances, to any of the excipients, or to other sulfonamide‑derived substances (hydrochlorothiazide is a sulfonamide‑derived substance)
- Second and third trimesters of pregnancy
- Severe renal impairment (creatinine clearance < 30 ml/min)
- Refractory hypokalaemia, hypercalcaemia
- Severe hepatic impairment, biliary cirrhosis and cholestasis
SPECIAL WARNINGS AND PRECAUTIONS FOR USE
Hypotension – Volume-depleted patients: NACARDIO PLUS has been rarely associates with symptomatic hypotension in hypertensive patients without other risk factors for hypotension. Symptomatic hypotension may be expected to 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 initiating therapy with NACARDIO PLUS
Renal artery stenosis – Renovascular hypertension: there is an increased risk of severe hypotension and 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. While this is not documented with NACARDIO PLUS , a similar effect should be anticipated.
Renal impairment and kidney transplantation: when NACARDIO PLUS is used in patients with impaired renal function, a periodic monitoring of potassium, creatinine and uric acid serum levels is recommended. There is no experience regarding the administration of NACARDIO PLUS in patients with a recent kidney transplantation. NACARDIO PLUS should not be used in patients with severe renal impairment (creatinine clearance < 30 ml/min). Thiazide diuretic-associated azotemia may occur in patients with impaired renal function. No dosage adjustment is necessary in patients with renal impairment whose creatinine clearance is ≥ 30 ml/min. However, in patients with mild to moderate renal impairment (creatinine clearance ≥ 30 ml/min but < 60 ml/min) this fixed dose combination should be administered with caution.
Hepatic impairment: thiazides 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. There is no clinical experience with NACARDIO PLUS in patients with hepatic impairment.
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 antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of NACARDIO PLUS is not recommended.
Metabolic and endocrine effects: thiazide therapy may impair glucose tolerance. In diabetic patients dosage adjustments of insulin or oral hypoglycemic agents 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 NACARDIO PLUS, minimal or no effects were reported.
Hyperuricaemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.
Electrolyte imbalance: as for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals.
Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (hypokalaemia, hyponatraemia, and hypochloremic alkalosis). Warning signs of fluid or electrolyte imbalance are dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting.
Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy with irbesartan may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greatest in patients with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or ACTH. Conversely, due to the irbesartan component of NACARDIO PLUS hyperkalaemia might occur, especially in the presence of renal impairment and/or heart failure, and diabetes mellitus. Adequate monitoring of serum potassium in patients at risk is recommended. Potassium-sparing diuretics, potassium supplements or potassium-containing salts substitutes should be co-administered cautiously with NACARDIO PLUS
Lithium: the combination of lithium and NACARDIO PLUS is not recommended
Anti-doping test: hydrochlorothiazide contained in this medicinal product could produce a positive analytic result in an anti-doping test.
PREGNANCY AND LACTATION
Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started
INTERACTION WITH OTHER MEDICINAL PRODUCTS
Other antihypertensive agents: the antihypertensive effect of NACARDIO PLUS may be increased with the concomitant use of other antihypertensive agents. Irbesartan and hydrochlorothiazide (at doses up to 300 mg irbesartan/25 mg hydrochlorothiazide) have been safely administered with other antihypertensive agents including calcium channel blockers and beta-adrenergic blockers. Prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with irbesartan with or without thiazide diuretics unless the volume depletion is corrected first
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. Furthermore, renal clearance of lithium is reduced by thiazides so the risk of lithium toxicity could be increased with NACARDIO PLUS . Therefore, the combination of lithium and NACARDIO PLUS 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.
As with ACE inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES
No studies on the effects on the ability to drive and use machines have been performed. Based on its pharmacodynamic properties, NACARDIO PLUS is unlikely to affect this ability. When driving vehicles or operating machines, it should be taken into account that occasionally dizziness or weariness may occur during treatment of hypertension.
Among 898 hypertensive patients who received various doses of irbesartan/hydrochlorothiazide (range: 37.5 mg/6.25 mg to 300 mg/25 mg) in placebo-controlled trials, 29.5% of the patients experienced adverse reactions. The most commonly reported ADRs were dizziness (5.6%), fatigue (4.9%), nausea/vomiting (1.8%), and abnormal urination (1.4%). In addition increases in blood urea nitrogen (BUN) (2.3%), creatine kinase (1.7%) and creatinine (1.1%) were also commonly observed in the trials.
Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled trials.
The frequency of adverse reactions listed below is defined using the following convention:
very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 1: Adverse Reactions in Placebo-Controlled Trials and Spontaneous Reports*
increases in blood urea nitrogen (BUN), creatinine and creatine kinase
decreases in serum potassium and sodium
syncope, hypotension, tachycardia, oedema
Nervous system disorders:
Ear and labyrinth disorders:
Respiratory, thoracic and mediastinal disorders:
Renal and urinary disorders:
impaired renal function including isolated cases of renal failure in patients at risk (see section 4.4)
Musculoskeletal and connective tissue disorders:
Metabolism and nutrition disorders:
General disorders and administration site conditions:
Immune system disorders:
cases of hypersensitivity reactions such as angioedema, rash, urticaria
hepatitis, abnormal liver function
Reproductive system and breast disorders:
sexual dysfunction, libido changes
* Frequency for adverse reactions detected by spontaneous reports is described as “not known”
No specific information is available on the treatment of overdose with NACARDIO PLUS. The patient should be closely monitored, and the treatment should be symptomatic and supportive. Management depends on the time since ingestion and the severity of the symptoms. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal may be useful in the treatment of overdose. Serum electrolytes and creatinine should be monitored frequently. If hypotension occurs, the patient should be placed in a supine position, with salt and volume replacements given quickly.
STORAGE: Store at temperature below 300C. Protect from sunlight and moisture.
SHELF-LIFE: 36 months from the manufacturing date.
HOW SUPPLIED: 2 blisters x 14 Tablets/Box.
- Keep all medicines out of the reach of children.
- Read carefully the leaflet before use.
- For further information, please contact your doctor.
- This drug is dispensed on prescription only.
Manufactured by: LABORATORIOS LESVI, S.L
Avda. Barcelona, 69 08970 Sant Joan Despí (Barcelona)- Spain
Product-licence holder: QUALIGEN, S.L
Avda. Barcelona, 69 08970 Sant Joan Despí (Barcelona)- Spain