Arbin Co Tablets

ARBIN CO is indicated for the treatment of essential hypertension in patients stabilised on the individual components at the same dosages. ARBIN CO may also be used as initial therapy in previously untreated patients with sitting diastolic blood pressure of 110 mm Hg or higher, or in patients previously treated with one of the components of ARBIN CO whose diastolic blood pressure is 100 mm Hg or higher. The choice of ARBIN CO as initial therapy for hypertension should be based on an assessment of potential benefits and risks.

Posology
ARBIN CO can be taken once daily, with or without food. ARBIN CO is indicated for use in patients who are adequately controlled on the individual components at the same dosages. If blood pressure is not adequately controlled with ARBIN CO alone, another antihypertensive medicine (e.g. beta-adrenergic blocking agent, long-acting calcium channel blocking agent) may be added.

Initial therapy: The usual starting dose is ARBIN CO 150/12,5 mg once daily. The dosage can be increased after 1 to 2 weeks of therapy to a maximum of 300/12,5 mg once daily as needed to control blood pressure. ARBIN CO 300 mg/25 mg may be administered in patients insufficiently controlled by ARBIN CO 300 mg/12,5 mg. Doses higher than 300 mg irbesartan/25 mg hydrochlorothiazide once daily are not recommended.

Special populations
Elderly Patients and Patients with Renal or Hepatic Impairment: No dosage reduction is generally necessary in the elderly or in patients with mild to moderate renal impairment (creatinine clearance > 30 mL/min). However, due to the hydrochlorothiazide component, ARBIN CO is not recommended for patients with severe renal dysfunction (creatinine clearance < 30 mL/min) (see section 4.4). No dosage reduction is generally necessary in patients with mild to moderate hepatic impairment. Due to the hydrochlorothiazide component, ARBIN CO should be used with caution in patients with severe hepatic impairment (see section 4.4).

Patients with Intravascular Volume Depletion: Volume and/or sodium depletion should be corrected prior to administration of ARBIN CO. See section 4.4 u2013 Hypotension u2013 Volume depleted patients.

Paediatric population
Safety and efficacy in paediatric patients has not been established.

Method of administration
For oral use.

• Hypersensitivity to irbesartan, sulphonamide-derived medicines (e.g. thiazides) or to any of the ingredients of ARBIN CO.
• A history of angioedema related to previous therapy with ACE inhibitors or angiotensin receptor blockers (ARBs): These patients must never again be given these medicines.
• Hereditary or idiopathic angioedema.
• Hypertrophic obstructive cardiomyopathy (HOCM).
• Severe renal function impairment (creatinine clearance less than 30 mL/min).
• Bilateral renal artery stenosis.
• Renal artery stenosis in patients with a single kidney.
• Aortic stenosis.
• Concomitant therapy with potassium sparing diuretics such as spironolactone, triamterene, amiloride (see section 4.5).
• Porphyria - hydrochlorothiazide has been associated with acute attacks of porphyria.
• Thiazide diuretics in (fixed dose) combination with irbesartan (i.e. ARBIN CO) should not be given to patients with Addisonu2019s disease. This therapy is also contraindicated in patients with severe renal impairment or anuria.
• Lithium therapy: Concomitant administration with ARBIN CO may lead to toxic blood concentrations of lithium (see section 4.5).
• Pregnancy and lactation (see section 4.6).
• The concomitant use of ARBIN CO with aliskiren-containing products is contraindicated (see section 4.4 and 4.5).
• Concomitantly using fluoroquinolones in moderate to severe renal impairment (creatinine clearance u2264 30 mL/min), and in the elderly.
• Patients with a history of previous and/or current basal cell carcinomas and/or squamous cell carcinomas of the skin and lip.

Thiazides cross the placental barrier and appear in cord blood. The routine use of diuretics in otherwise healthy pregnant women is not recommended and exposes mother and foetus to unnecessary hazard, including foetal or neonatal jaundice thrombocytopenia and possibly other adverse reactions, which have occurred in the adult.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers (ARBs) or aliskiren may increase the risk of hypotension, hyperkalaemia and decreases renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ARBIN CO and aliskiren is therefore contraindicated (see section 4.3). ARBIN CO should not be used concomitantly with aliskiren (see section 4.3).

Should a woman become pregnant while receiving ARBIN CO, the treatment should be stopped promptly and switched to a different class of antihypertensive medicine (See section 4.3 and 4.6).

Fluoroquinolones and ARBs
Concomitant use of fluoroquinolones and ARBs may precipitate acute kidney injury in patients, especially those with moderate to severe renal impairment and elderly patients (see section 4.3). Renal function should be assessed before initiating treatment and monitored during treatment with fluoroquinolones or ARBs whether used separately and/or concomitantly.

Intravascular Volume Depletion
ARBIN CO has been associated 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 ARBIN CO.

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 ARBIN CO, a similar effect should be anticipated. The use of ARBIN CO in patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney contraindicated (see section 4.3).

Renal impairment and kidney transplantation
When ARBIN CO 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 ARBIN CO in patients with a recent kidney transplantation. ARBIN CO should not be used in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see section 4.3). Thiazide diuretic-associated azotaemia may occur in patients with impaired renal function. No dosage adjustment is necessary in patients with renal impairment whose creatinine clearance is u2265 30 mL/min. However, in patients with mild to moderate renal impairment (creatinine clearance u2265 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 ARBIN CO 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 (See section 4.3).

Primary aldosteronism
Patients with primary aldosteronism generally will not respond to antihypertensive medicine acting through inhibition of the renin-angiotensin system. Therefore, the use of ARBIN CO is not recommended.

Metabolic and endocrine effects
Thiazide therapy may impair glucose tolerance. In diabetic patients dosage adjustments of insulin or oral hypoglycaemic 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 dose contained in ARBIN CO, 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 hypochloraemic 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 ARBIN CO 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 supplements or potassium-containing salts substitutes should be co-administered cautiously with ARBIN CO (see section 4.5). There is no evidence that irbesartan would reduce or prevent diuretic-induced hyponatraemia. Chloride deficit is generally mild and usually does not require treatment. Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesaemia.

Lithium
The combination of lithium and ARBIN CO is not recommended (see sections 4.3 and 4.5).

Anti-doping test
Hydrochlorothiazide contained in this medicine could produce a positive analytic result in an anti-doping test.

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 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 (see section 4.5). As with any antihypertensive agent, excessive blood pressure decrease in patients with ischemic cardiopathy or ischemic cardiovascular disease could result in a myocardial infarction or stroke. Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history. Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics. Cases of photosensitivity reactions have been reported with thiazides diuretics (see section 4.8). If photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a re-administration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the sun or to artificial UVA.

Acute Myopia and Secondary Acute Angle - Closure Glaucoma
Sulfonamide medicine or sulfonamide derivative medicine can cause an idiosyncratic reaction, resulting in transient myopia and acute angle-closure glaucoma. While hydrochlorothiazide is a sulfonamide, only isolated cases of acute angle-closure glaucoma have been reported so far with hydrochlorothiazide. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of medicine initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue medicine intake as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy (see section 4.8).

Non-melanoma skin cancer
An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide (HCTZ) exposure has been observed in two epidemiological studies. Photosensitizing actions of HCTZ could act as a possible mechanism for NMSC. Patients taking ARBIN CO should be informed of the risk of NMSC and advised to regularly check their skin for any new lesions and promptly report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and UV rays and, in the case of exposure, adequate protection should be advised to the patients to minimize the risk of skin cancer. Suspicious skin lesions should be promptly examined potentially including histological examinations of biopsies. ARBIN CO should not be used by patients who have had previous and/or current basal cell carcinomas and/or squamous cell carcinomas of the skin and/or lip (see section 4.3).

Lactose
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Dual blockade of the RAAS with ARBs, ACE inhibitors, or aliskiren
Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (see section 4.3 and 4.4).

Other antihypertensive medicines
The antihypertensive effect of ARBIN CO may be increased with the concomitant use of other antihypertensive medicines. Irbesartan and hydrochlorothiazide (at doses up to 300 mg irbesartan/25 mg hydrochlorothiazide) have been safely administered with other antihypertensive medicines 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 (see section 4.4).

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 ARBIN CO. Therefore, the combination of lithium and ARBIN CO is not recommended (see sections 4.3 and 4.4).

Fluoroquinolones
Concomitant use of ARBs and fluoroquinolones may precipitate acute kidney injury. The mechanism of the possible interaction between the different classes of medicines, over and above different mechanisms of kidney damage, is unknown (see section 4.3).

Medicine affecting potassium
The potassium-depleting effect of hydrochlorothiazide is attenuated by the potassium-sparing effect of irbesartan. However, this effect of hydrochlorothiazide on serum potassium would be expected to be potentiated by other medicine associated with potassium loss and hypokalaemia (e.g. other kaliuretic diuretics, laxatives, amphotericin, carbenoxolone, penicillin G sodium). Conversely, based on the experience with the use of other medicine that blunt the renin-angiotensin system, concomitant use of potassium-sparing diuretics (see section 4.3), potassium supplements, salt substitutes containing potassium or other medicine that may increase serum potassium levels (e.g. heparin sodium) may lead to increases in serum potassium. Adequate monitoring of serum potassium in patients at risk is recommended (see section 4.4).

Medicine affected by serum potassium disturbances
Periodic monitoring of serum potassium is recommended when ARBIN CO is administered with medicine affected by serum potassium disturbances (e.g. digitalis glycosides, antiarrhythmics).

Non-steroidal anti-inflammatory drugs
When angiotensin II antagonists are administered simultaneously with nonsteroidal 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.

Additional information on irbesartan interactions
In clinical studies, the pharmacokinetic of irbesartan is not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were observed when irbesartan was co-administered with warfarin, a medicine metabolised by CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic of irbesartan have not been evaluated. The pharmacokinetic of digoxin or simvastatin was not altered by co-administration of irbesartan.

Additional information on hydrochlorothiazide interactions
When administered concurrently, the following medicine may interact with thiazide diuretics: Alcohol, barbiturate or narcotics: potentiation of orthostatic hypotension may occur; Antidiabetic medicine (oral agents and insulins): dosage adjustment of the antidiabetic medicinal product may be required (see section 4.4); Colestyramine and Colestipol resins: absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. ARBIN CO should be taken at least one hour before or four hours after these medications; Corticosteroids, ACTH: electrolyte depletion, particularly hypokalaemia, may be increased; Digitalis glycosides: thiazide induced hypokalaemia or hypomagnesaemia favour the onset of digitalis-induced cardiac arrhythmias (see section 4.4); Non-steroidal anti-inflammatory drugs: the administration of a non-steroidal anti-inflammatory drug may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics in some patients; Pressor amines (e.g. noradrenaline): the effect of pressor amines may be decreased, but not sufficiently to preclude their use; Nondepolarizing skeletal muscle relaxants (e.g. tubocurarine): the effect of nondepolarizing skeletal muscle relaxants may be potentiated by hydrochlorothiazide; Antigout medicine: dosage adjustments of antigout medicine may be necessary as hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or sulfinpyrazone may be necessary. Co-administration of thiazide diuretics may increase the incidence of hypersensitivity reactions to allopurinol; Calcium salts: thiazide diuretics may increase serum calcium levels due to decreased excretion. If calcium supplements or calcium sparing medicine (e.g. vitamin D therapy) must be prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly; Carbamazepine: concomitant use of carbamazepine and hydrochlorothiazide has been associated with the risk of symptomatic hyponatraemia. Electrolytes should be monitored during concomitant use. If possible, another class of diuretics should be used; Other interactions: the hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by thiazides. Anticholinergic medicines (e.g. atropine, beperiden) may increase the bioavailability of thiazide-type diuretics by decreasing gastrointestinal motility and stomach emptying rate. Thiazides may increase the risk of adverse effects caused by amantadine. Thiazides may reduce the renal excretion of cytotoxic medicine (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects.

Pregnancy & Breastfeeding
ARBIN CO is contraindicated in pregnancy and lactation (see sections 4.3 and 4.4). Irbesartan Safety in pregnancy and lactation has not been established (see section 4.3). When pregnancy is planned or confirmed ARBIN CO should be discontinued. Medicines affecting the renin-angiotensin system, such as ARBIN CO, can cause embryonal toxicity, foetal and neonatal morbidity and mortality when administered to pregnant women.

Women of childbearing age should ensure effective contraception.

Hydrochlorothiazide
There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia. Since ARBIN CO contains hydrochlorothiazide, it is not recommended during pregnancy (see section 4.3). A switch to a suitable alternative treatment should be carried out in advance of a planned pregnancy.

Breastfeeding
Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production. The use of ARBIN CO during breastfeeding is contraindicated (see section 4.3).

Fertility
Irbesartan had no effect upon fertility of treated rats and their offspring up to the dose levels inducing the first signs of parental toxicity (see section 5.3).

Based on its pharmacodynamic properties, ARBIN CO may affect the ability to drive and use machines. When driving vehicles or operating machines, it should be taken into account that occasionally dizziness or weariness may occur during treatment of hypertension.

Irbesartan / Hydrochlorothiazide combination
Among 898 hypertensive patients who received various doses of irbesartan/hydrochlorothiazide, 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.

The tables below show all adverse drug reactions (ADRs) observed during clinical trials and postmarket spontaneous reports with irbesartan:

Frequency estimate: Frequent, Less frequent, Not known (cannot be estimated from the available data)

Table 1: Adverse Reactions in Placebo-Controlled Trials and Spontaneous Reports

System Organ Class Frequency Frequent Less Frequent Not known

Immune system disorders Cases of hypersensitivity reactions such as angioedema, rash, urticaria

Metabolism and nutrition disorders Hyperkalaemia

Nervous system disorders Dizziness, Orthostatic dizziness, Headache

Ear and labyrinth disorders Tinnitus

Cardiac disorders Syncope, hypotension, tachycardia, oedema

Vascular disorders Flushing

Respiratory, thoracic and mediastinal disorders Cough

Gastrointestinal disorders Nausea / vomiting, Diarrhoea, Dyspepsia, dysgeusia

Hepatobiliary disorders Jaundice, Hepatitis, abnormal liver function

Musculoskeletal and connective tissue disorders Swelling extremity, Arthralgia, myalgia

Renal and urinary disorders Abnormal urination, Impaired renal function including isolated cases of renal failure in patients at risk (see section 4.4)

Reproductive system and breast disorders Sexual dysfunction, libido changes

General disorders and administration site conditions Fatigue

Investigations increases in blood urea nitrogen (BUN), creatinine and creatine kinase, decreases in serum potassium and sodium

Additional information on individual components:

In addition to the adverse reactions listed above for the combination product, other adverse reactions previously reported with one of the individual components may be potential adverse reactions with ARBIN CO.

No specific information is available on the treatment of overdose with ARBIN CO. However, daily doses of irbesartan up to 900 mg/day for 8 weeks have been well tolerated. 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. 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. The most likely manifestations of irbesartan overdose are expected to be hypotension and tachycardia; bradycardia might also occur. Overdose with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia, hypochloraemia, hyponatraemia) and dehydration resulting from excessive diuresis. The most common signs and symptoms of overdose are nausea and somnolence. Hypokalaemia may result in muscle spasms and/or accentuate cardiac arrhythmias associated with the concomitant use of digitalis glycosides or certain anti-arrhythmic medicine. Irbesartan is not removed by haemodialysis. The degree to which hydrochlorothiazide is removed by haemodialysis has not been established.