Co-Tareg 25 mg Film-Coated Tablets

Treatment of mild to moderate hypertension. CO-TAREG is indicated for the treatment of hypertension in patients whose blood pressure has been stabilized at the same dosages of the individual components given together.

Posology: The recommended dose is 1 (one) tablet per day. When clinically appropriate either 80 mg valsartan and 12,5 mg hydrochlorothiazide (CO-TAREG 80) or 160 mg valsartan and 12,5 mg hydrochlorothiazide (CO-TAREG 160) may be used. When necessary 160 mg valsartan and 25 mg hydrochlorothiazide (CO-TAREG 160 PLUS) may be used. The maximum antihypertensive effect is seen within 2 to 4 weeks. For initial therapy, the usual starting dose is 160/12,5 mg once daily, the dosage can be increased after 1 u2013 2 weeks of therapy to a maximum of one 320/25 mg tablet once daily as needed to control blood pressure. CO-TAREG is not recommended as initial therapy in patients with intravascular volume depletion. (see section 4.4). The maximum daily dose is 320/25 mg.

Renal impairment: No dosage adjustment is required for patients with mild to moderate renal impairment (Glomerular Filtration Rate (GFR) u2265 30 mL/min). Due to the hydrochlorothiazide component, CO-TAREG is contraindicated in patient with anuria (see section 4.3) and should be used in caution with patients with severe renal impairment (GFR < 30 mL/min) (see section 4.4). Thiazide diuretics are ineffective as monotherapy in severe renal impairment, but may be useful in these patients when used with due caution in combination with a loop diuretic even in patients with GFR < 30 mL/min.

Hepatic Impairment: No dose adjustment is required in patients with mild to moderate hepatic impairment. Due to the hydrochlorothiazide component, CO-TAREG should be used with caution in patients with severe hepatic impairment. Due to the valsartan component, CO-TAREG should be used with particular caution in patients with biliary obstructive disorders. (see section 4.4). The safety and efficacy of CO-TAREG have not been established in children.

• Hypersensitivity to valsartan or hydrochlorothiazide or to any of the excipients of CO-TAREG.
• 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).
• Moderate to 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.
• Lithium therapy: Concomitant administration with CO-TAREG may lead to toxic blood concentrations of lithium (see section 4.5).
• Pregnancy and lactation (see section 4.6).
• Severe hepatic impairment, biliary cirrhosis and cholestasis.
• Anuria.
• Refractory hypokalaemia, hyponatraemia, hypercalcaemia, and symptomatic hyperuricemia / gout.
• Addisonu2019s disease.
• The concomitant use of CO-TAREG with renin inhibitors such as aliskiren-containing products is contraindicated (see section 4.4).
• Concomitant use of fluoroquinolones with ACE inhibitors / angiotensin receptor blockers is contraindicated in patients with moderate to severe renal impairment (creatinine clearance u2264 30 mL / min) and in elderly patients.

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

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 CO-TAREG and aliskiren is therefore contraindicated (see section 4.3). CO-TAREG should not be used concomitantly with aliskiren (see section 4.3).

Sodium and/or volume-depleted patients: In sodium depleted and/or volume depleted patients such as those receiving doses of diuretics, and/or patients with moderate to severe renal impairment, symptomatic hypotension may occur after initiation of therapy with CO-TAREG. Sodium and/or volume depletion should be corrected before starting treatment with CO-TAREG. If hypotension occurs, symptomatic treatment should be given. Treatment can be continued once the blood pressure has been stabilised.

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 exposure. The risk for NMSC appears to increase with long-term use. Photosensitising actions of hydrochlorothiazide could act as a possible mechanism for NMSC. Patients taking hydrochlorothiazide 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 adequate protection when exposed to sunlight should be advised to the patients in order to minimise the risk of skin cancer. Suspicious skin lesions should be promptly examined, potentially including histological examination of biopsies. The use of hydrochlorothiazide may also need to be reconsidered in patients who have previously experienced NMSC.

Serum electrolyte changes: Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other medicines that may increase potassium levels (heparin, etc.) should be used with caution. Thiazide diuretics can precipitate new onset hypokalaemia or exacerbate pre-existing hypokalaemia. Thiazide diuretics should be administered with caution in patients with conditions involving enhanced potassium loss, for example salt u2013 losing nephropathies and prerenal (cardiogenic) impairment of kidney function. If hypokalaemia is accompanied by clinical signs (e.g. muscular weakness, paresis, or ECG alterations), CO-TAREG should be discontinued. Correction of hypokalaemia and any hypomagnesemia is recommended prior to the initiation of Thiazides. Frequent monitoring of serum potassium and magnesium levels is recommended.

Treatment with thiazide diuretics have been associated with hyponatraemia and hypochloroaemic alkalosis or exacerbate pre-existing hyponatraemia. Hyponatraemia, accompanied by neurological symptoms (nausea, progressive disorientation, apathy) has been observed in isolated cases. Regular monitoring of serum sodium concentrations is recommended. Thiazides increase the urinary excretion of magnesium, which may result in hypomagnesaemia.

Renal Artery stenosis: CO-TAREG should not be used in patients with unilateral or bilateral renal artery stenosis or stenosis to a solitary kidney, aortic valve stenosis or hypertrophic obstructive cardiomyopathy (see section 4.3), since blood urea and serum creatinine may increase in such patients.

Renal impairment: No dosage adjustment is required for patients with mild renal impairment. CO-TAREG is contraindicated in patients with severe renal function impairment (creatinine clearance less than 30 mL/min) (see section 4.3). Thiazide diuretics may precipitate azotaemia in patients with chronic kidney disease.

Hepatic impairment: CO-TAREG is mostly eliminated in the bile, patients with mild to moderate hepatic impairment, including patients with biliary obstructive disorders, showed lower valsartan clearance. Care should be exercised in administering CO-TAREG to these patients.

Systemic Lupus erythematosus: CO-TAREG has been reported to exacerbate or activate systemic lupus erythematosus.

Other metabolic disturbances: Thiazide diuretics may alter the glucose tolerance and raise serum levels of cholesterol and triglycerides. Like other diuretics, hydrochlorothiazide may raise the serum uric acid level due to the reduced clearance of uric acid and may cause or exacerbate hyperuricaemia and precipitate gout in susceptible patients. Thiazides may decrease the urinary calcium excretion. Thiazides may cause 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.

General: Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergy and asthma.

Concomitant use of fluoroquinolones and ACE-inhibitors / angiotensin receptor blockers 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 ACE inhibitors / angiotensin receptor blockers whether used separately and/or concomitantly.

Angioedema: Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx and/or tongue have been reported in patients treated with valsartan; some of these patients previously experience angioedema with other drugs including ACE inhibitors. CO-TAREG should immediately be discontinued in patients who develop angioedema, and CO-TAREG should not be re-administered.

Acute angle-closure glaucoma: Hydrochlorothiazide, a sulphonamide, has been associated with an idiosyncratic reaction resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of a drug initiation. Untreated acute-angle closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatment may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulphonamide or penicillin allergy.

Patients with heart failure / post-myocardial infarction: In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure), treatment with angiotensin converting enzyme inhibitors or angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia, and in rare cases with acute renal failure and/or death. Evaluation of patients with heart failure or post-myocardial infarction should always include assessment of renal function.

Valsartan u2013 hydrochlorothiazide: The following interactions may occur due to both components (valsartan and/or hydrochlorothiazide) of CO-TAREG:

Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concurrent use of ACE inhibitors and thiazides. Since renal clearance of lithium is reduced by thiazides, the risk of lithium toxicity may be increased further with CO-TAREG. Therefore, careful monitoring of serum lithium concentrations is recommended during concomitant use (see section 4.3).

Valsartan: The following potential drug interactions may occur due to the valsartan component for CO-TAREG:

Dual blockade of the RAAS with ARBs, ACE inhibitors or aliskiren: Clinical trial data has shown that dual blockade or 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). The antihypertensive effect may be increased with concomitant use of other antihypertensive drugs.

Potassium: Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other drugs that may alter potassium levels (heparin, etc.) should be used with caution and with frequent monitoring of potassium.

Non-Steroidal Anti-Inflammatory Agents (NSAIDs): including selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors): When angiotensin II antagonists are administered simultaneously with NSAIDs, attenuation of the antihypertensive effect may occur. Furthermore, in patients who are elderly, volume-depleted (including those on diuretic therapy), or have compromised renal function, concomitant use of angiotensin II antagonists and NSAIDs may lead to an increased risk of worsening renal function. Therefore, monitoring of renal function is recommended when initiating or modifying the treatment in patients on valsartan who are taking NSAIDs concomitantly.

Transporters: the results from an in vitro study with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2. Co-administration of inhibitors of the uptake transporter (e.g., rifampin, ciclosporin) or efflux transporter (e.g. ritonavir) may increase the systemic exposure to valsartan.

Under monotherapy with DIOVAN, no drug interactions of clinical significance have been found with the following drugs: cimetidine, warfarin, furosemide, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide.

Concomitant use of fluoroquinolones and ACE inhibitors / angiotensin receptor blockers 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).

Hydrochlorothiazide: The following potential drug interactions may occur due to the thiazide component of CO-TAREG: thiazides potentiate the action of curare derivatives. Other anti-hypertensive drugs: Thiazides potentiate the antihypertensive action of other antihypertensive drugs (e.g. guanethidine, methyldopa, beta-blockers, vasodilators, calcium channel blockers, ACE inhibitors, Angiotensin Receptor Blockers (ARBs) and Direct Renin Inhibitors (DRIs)).

Skeletal muscle relaxants: thiazides potentiate the action of skeletal muscle relaxants such as curare derivatives. NSAIDs and COX-2 Selective inhibitors: Concomitant administration of non-steroidal anti-inflammatory agents (e.g. salicylic acid derivative, indomethacin) may weaken the diuretic and antihypertensive activity of the thiazide component of CO-TAREG. Concurrent hypovolemia may induce acute renal failure.

Medicinal products affecting serum potassium levels: The hypokalaemic effect of diuretics may be increased by kaliuretic diuretics, corticosteroids, ACTH, amphotericin, carbenoxolone, penicillin G, salicylic acid derivatives.

Medicinal products affecting serum sodium levels: The hyponatremic effect of diuretics may be intensified by concomitant administration of medicines such as anti-depressants, antipsychotics, antiepileptics, etc. Caution is advised in long term administration of these medicines (see section 4.4).

Digitalis glycosides: Thiazide-induced hypokalaemia or hypomagnesaemia may occur as unwanted effects, favouring the onset of digitalis-induced cardiac dysrhythmia.

Antidiabetic agents: Thiazides may alter glucose tolerance. It may prove necessary to readjust the dose of insulin and of oral antidiabetic agents.

Allopurinol: Co-administration of thiazide diuretics (including hydrochlorothiazide) may increase the incidence of hypersensitivity reactions to allopurinol.

Amantadine: Co-administration of thiazide diuretics (including hydrochlorothiazide) may increase the risk of adverse effects caused by amantadine.

Antineoplastic agents (e.g. cyclophosphamide, methotrexate): Concomitant use of thiazide diuretics may reduce renal excretion of cytotoxic agents and enhance their myelosuppressive effects.

Anticholinergic agents: The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents (e.g. atropine, biperiden), apparently due to a decrease in gastrointestinal motility and the stomach-emptying rate. Conversely prokinetic drugs such as cisapride may decrease the bioavailability of thiazide-type diuretics.

Methyldopa: There have been reports in the literature of haemolytic anaemia occurring with concomitant use of hydrochlorothiazide and methyldopa.

Ion Exchange resins: Absorption of thiazide diuretics, including hydrochlorothiazide, is decreased by cholestyramine or colestipol. However, staggering the dose of hydrochlorothiazide and resin such that hydrochlorothiazide is administered at least 4 hours before or 4-6 hours after administration of resins would potentially minimise the interaction.

Vitamin D: Administration of thiazide diuretics, including hydrochlorothiazide, with vitamin D or with calcium salts may potentiate the rise in serum calcium.

Cyclosporine: Concomitant treatment with cyclosporine may increase the risk of hyperuricemia and gout-type complications.

Diazoxide: thiazide diuretics may enhance the hyperglycaemic effect of diazoxide.

Pressor amines: Hydrochlorothiazide may reduce the response to pressor amines such as noradrenaline. The clinical significance of this effect is uncertain and not sufficient to preclude their use.

Alcohol, barbiturates or narcotics: Alcohol, barbiturates and narcotics may potentiate orthostatic hypotension.

CO-TAREG is contraindicated in pregnancy and lactation. CO-TAREG treatment may cause congenital abnormalities. Should a woman become pregnant while receiving CO-TAREG, the treatment must be stopped promptly and switched to a different medicine. Should a woman contemplate pregnancy, the doctor should consider alternative medication.

Safety in pregnancy and lactation has not been established (see section 4.3). When pregnancy is planned or confirmed CO-TAREG should be discontinued. Medicines affecting the renin-angiotensin system, such as CO-TAREG, can cause embryonal toxicity, foetal and neonatal morbidity and mortality when administered to pregnant women. There have been reports of spontaneous abortion, oligohydramnios and newborn renal dysfunction, when pregnant women have inadvertently taken valsartan. Intrauterine exposure to thiazide diuretics, including hydrochlorothiazide, is associated with fatal or neonatal jaundice or thrombocytopenia, and may be associated with other adverse reaction that have occurred in adults.

Lactation: Hydrochlorothiazide crosses the placenta and is excreted in human milk. Thus, it is not advisable to use CO-TAREG in lactating mothers.

Females and males of reproductive potential: CO-TAREG should not be used in women planning to become pregnant. Healthcare professionals prescribing any agents acting on the RAAS, should counsel women of childbearing potential about the potential risk of these agents during pregnancy.

It is advisable to exercise caution when driving and operating machinery.

Adverse drug reactions reported in clinical trials and laboratory findings occurring more frequently with valsartan plus hydrochlorothiazide versus placebo and individual post-marketing reports are presented below according to system organ class. Adverse reactions known to occur with each component given individually but which have not been seen in clinical trials may occur during the treatment with valsartan/hydrochlorothiazide. Adverse reactions have been ranked under headings of frequency using the following convention: very common (> 1/10); common (> 1/100, 1/1 000, 1/10 000, < 1/1 000); very rare (< 1/10 000), not known (cannot be estimated form the available data). Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.

Table 1: frequency of adverse drug reactions with valsartan/hydrochlorothiazide

Blood and lymphatic system disorders: Not known Neutropenia

Metabolism and nutrition disorders: Uncommon Dehydration; Not known Hypokalaemia, Hyponatraemia

Nervous system disorders: Very rare Dizziness; Uncommon Parasthesia; Not known Syncope

Eye Disorders: Uncommon Blurred vision

Ear and Labyrinth disorders: Uncommon Tinnitus

Vascular disorders: Uncommon Hypotension

Respiratory, thoracic and mediastinal disorders: Uncommon Cough; Not known Non-cardiogenic pulmonary oedema

Gastrointestinal disorders: Very rare Diarrhoea

Musculoskeletal and connective tissue disorders: Uncommon Myalgia; Very rare Arthralgia

Renal and urinary disorders: Not known Renal impairment

General disorders and administration site conditions: Uncommon Fatigue

Investigations: Not known Increased blood uric acid, increased blood bilirubin and blood creatinine, increased blood urea

The following events have also been observed during clinical trials: Abdominal pain, upper abdominal pain, anxiety, arthritis, asthenia, back pain, bronchitis, acute bronchitis, chest pain, postural dizziness, dyspepsia, dyspnoea, dry mouth, epistaxis, erectile dysfunction, gastroenteritis, headache, hyperhydrosis, hypoesthesia, influenza, insomnia, ligament sprain, muscle spasms, muscle strain, nasal congestion, nasopharyngitis, nausea, neck pain, oedema, peripheral oedema, otitis media, pain in extremity, palpitations, pharyngolaryngal pain, pollakiuria, pyrexia, rash, sinusitis, sinus congestion, somnolence tachycardia, upper respiratory tract infections, urinary tract infections, vertigo, viral infections, vision disturbance.

Post-marketing data revealed cases of angioneurotic oedema, rash, pruritus, and other hypersensitivity/ allergic reactions including serum sickness, and vasculitis. Cases of renal impairment and myalgia have also been reported. There have also been reported cases of hydrochlorothiazide-induced pulmonary oedema with granulocytic infiltration and IgG deposition in alveolar membranes. Non-cardiogenic pulmonary oedema may be an immunologically mediated idiosyncratic reaction to hydrochlorothiazide.

Additional Information on the individual components: Adverse reactions previously reported with one of the individual components may be potential undesirable effect with CO-TAREG as well, even if not observed in clinical trials or during post-marketing period.

Valsartan: Table 2 Frequency of adverse drug reactions with Valsartan Infections and infestations: Less frequent Pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, viral infections; Blood and lymphatic system disorders: Not known Decreased haemoglobin, decreased haematocrit, thrombocytopenia; Immune system disorders: Not known Hypersensitivity including serum sickness, Angioedema; Metabolism and nutrition disorders: Not known Increased blood potassium; Psychiatric disorders: Less frequent Insomnia, decreased libido; Nervous system disorders: Less frequent Dizziness, headache; Ear and labyrinth disorders: Less frequent Vertigo; Vascular: Not known Vasculitis; Gastrointestinal disorders: Less frequent Abdominal pain, diarrhoea; Hepatobiliary disorders: Not known Abdominal liver function test; Skin and subcutaneous tissue disorders: Less frequent Rash, dermatitis bullous, pruritus; Musculoskeletal and connective tissue disorders: Less frequent Arthralgia, asthenia, back pain; Renal and urinary disorders: Less frequent Renal failure.

Hydrochlorothiazide: Table 3 Frequency of adverse reactions with Hydrochlorothiazide Neoplasms benign, malignant and unspecified (incl. cysts and polyps): Not known: Non-melanoma skin cancer (Basal cell carcinoma and Squamous cell carcinoma); Blood and lymphatic disorders: Rare: Thrombocytopenia sometimes with purpura; Less frequent: Leucopenia, agranulocytosis, bone marrow failure and haemolytic anaemia; Not known: Aplastic anaemia; Immune system disorders: Less frequent: Necrotizing vasculitis, vascular disorders, hypersensitivity reactions u2013 respiratory distress including pneumonitis and pulmonary oedema, respiratory disorders; Metabolism and nutrition disorders: Frequent: Mainly at higher doses, increased blood lipids, hypomagnesaemia, hyperuricaemia, decreased appetite. Less frequent: Hypercalcaemia, hyperglycaemia, glucosuria and worsening of diabetic metabolic state, hypochloraemia alkalosis, metabolic alkalosis; Psychiatric disorder: Less frequent: Sleep Disorders, depression; Nervous System disorders: Less frequent: Headache, dizziness, and paraesthesia; Eye disorders: Less frequent: Visual impairment; Not known: Angle-closure glaucoma; Cardiac disorder: Less frequent: Dysrhythmias; Vascular disorders: Frequent: Orthostatic hypotension, which may be aggravated by alcohol, anaesthetics or sedatives; Gastrointestinal disorders: Frequent: Nausea, vomiting; Rare: Abdominal discomfort, constipation and diarrhoea; Less frequent: Pancreatitis; Hepatobiliary disorders: Less frequent: Cholestasis or jaundice; Skin or subcutaneous tissue disorders: Frequent: Urticaria and other forms of rash; Rare: Photosensitivity reaction; Less frequent: Toxic epidermal necrolysis, cutaneous lupus- erythematosus-like reactions, reactivation of cutaneous lupus erythematosus; Not known: Erythema multiforme; Musculoskeletal and connective tissue disorders: Not known: Muscle spasms; Renal and urinary disorders: Not known: Acute renal failure, renal disorder; Reproductive system and breast disorders: Common: Erectile dysfunction; General disorders and administration site conditions: Not known: Pyrexia, asthenia.

Overdose with valsartan may result in marked hypotension which could lead to depressed level of consciousness, circulatory collapse and/shock. If the ingestion is recent, vomiting should be induced. Otherwise, the usual treatment would be intravenous infusion of normal saline solution. Valsartan cannot be eliminated by means of haemodialysis because of its strong plasma binding behaviour whereas clearance of hydrochlorothiazide will be achieved by dialysis.