Co-Copalia Film-coated tablets

Treatment of essential hypertension in patients stabilised on individual components given at the same doses. CO-COPALIA is not indicated for the initial therapy of hypertension (see section 4.2).

The recommended dose is one tablet per day (the 5 strengths are listed under section 2). If a tablet shows signs of cracking the tablet should not be taken. Patients stabilised with valsartan, amlodipine and hydrochlorothiazide from separate tablets may be switched to CO-COPALIA containing the same component doses. The maximum antihypertensive effect of CO-COPALIA is reached within two weeks after a change in dose. The maximum recommended dose of CO-COPALIA is 10/320/25 mg. CO-COPALIA can be taken with or without food. It is recommended to take CO-COPALIA with water.

In elderly > 65 years Starting with the lowest available dose of amlodipine should be considered. The lowest strength of CO-COPALIA contains 5 mg of amlodipine (see section 2).

Paediatric population (below 18 years) Children and adolescents (below 18 years): CO-COPALIA is not recommended for use in patients aged below 18 years due to a lack of data on safety and efficacy.

Renal impairment: u2022 No dosage adjustment is required for patients with mild to moderate renal impairment (see section 4.8 and section 4.4). u2022 Due to the hydrochlorothiazide component, CO-COPALIA is not recommended in patients with anuria and severe renal impairment (creatinine clearance < 30 ml/min) (see section 4.3 and section 5.2).

Hepatic impairment: Due to the valsartan, hydrochlorothiazide and amlodipine components, particular caution should be exercised when administering CO-COPALIA in patients with hepatic impairment or biliary obstructive disorders. Starting with the lowest available dose of amlodipine should be considered. The lowest strength of CO-COPALIA contains 5 mg of amlodipine. CO-COPALIA is contraindicated in patients with severe hepatic impairment (Child Pugh C) (see section 4.3).

• Hypersensitivity to amlodipine, valsartan, hydrochlorothiazide and other sulfonamides or to any of the excipients of CO-COPALIA.
• The use of CO-COPALIA during pregnancy and lactation is contra-indicated (see section 4.6). CO-COPALIA should be discontinued as soon as possible when pregnancy is suspected.
• A history of angioedema related to previous therapy with angiotensin receptor blockers (ARBs): These patients must never again be given these medicines.
• Hereditary or idiopathic angioedema.
• Severe hepatic impairment (Child Pugh C).
• CO-COPALIA should not be given to patients with Addisonu2019s disease.
• Anuria, severe renal impairment (creatinine clearance less than 30 mL/min).
• Lithium therapy: Concomitant administration with CO-COPALIA may lead to toxic blood concentrations of lithium (see section 4.5).
• Refractory hypokalaemia, hyponatraemia, hypercalcaemia and symptomatic hyperuricaemia.
• Safety and efficacy have not been established in children less than 18 years of age.
• Safety has not been established in porphyria.
• Hypertrophic obstructive cardiomyopathy (HOCM).
• Bilateral renal artery stenosis.
• Renal artery stenosis in patients with a single kidney.
• Aortic stenosis and mitral valve stenosis.
• Concomitant therapy with potassium sparing diuretics such as spironolactone, triamterene, amiloride.
• Concomitant use of fluoroquinolones with ACE inhibitors/Angiotensin blockers is contraindicated in patients with moderate (creatinine clearance <60 mL/min) to severe renal impairment (creatinine clearance <30 mL/min) and in elderly patients.
• The concomitant use of CO-COPALIA with aliskiren-containing products is contraindicated.
• Patients with a history of previous and/or current basal cell carcinomas and/or squamous cell carcinomas of the skin and lip.

Sodium- and/or volume depleted patients: Excessive hypotension, including orthostatic hypotension was seen in 1,7 % of patients treated with the maximum dose of CO-COPALIA (10/320/25 mg) compared to 1,8 % of valsartan/hydrochlorothiazide (320/25 mg) patients, 0,4 % of amlodipine/valsartan (10/320 mg) patients, and 0,2 % of hydrochlorothiazide/amlodipine (25/10 mg) patients in a controlled trial in patients with moderate to severe uncomplicated hypertension. In patients with an activated renin-angiotensin system, such as volume-and/or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur in patients receiving angiotensin receptor blockers. This condition should be corrected prior to administration of CO-COPALIA, or the treatment should start under close medical supervision. If excessive hypotension occurs with CO-COPALIA, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of 0,9 % sodium chloride solution. Treatment can be continued once blood pressure has been stabilised.

Renal impairment: No dosage adjustment of CO-COPALIA is required for patients with mild to moderate renal impairment. Due to the hydrochlorothiazide component, CO-COPALIA is not recommended for use in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see section 4.3). Thiazide diuretics may precipitate azotaemia in patients with chronic kidney disease. When CO-COPALIA is used in patients with renal impairment periodic monitoring of serum electrolytes (including potassium), creatinine and uric acid serum levels is recommended.

Concomitant use with fluoroquinolones: The concomitant use of fluoroquinolones with ACE inhibitors/Angiotensin receptor blockers is contraindicated in patients with moderate (creatinine clearance< 60 mL/min) to severe renal impairment (creatinine clearance< 30 mL/min) and in elderly patients. 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. Patients currently treated with concomitant use of ACE inhibitors/Angiotensin receptor blockers and fluoroquinolones should contact their doctor to re-evaluate their treatment.

Hepatic impairment: Valsartan is mostly eliminated unchanged via the bile whereas amlodipine is extensively metabolised by the liver. Particular caution should be exercised when administering CO-COPALIA to patients with hepatic impairment or biliary obstructive disorders. Because of hydrochlorothiazide, CO-COPALIA is not recommended in patients with severe hepatic impairment (see section 4.3).

Serum electrolyte changes: Hydrochlorothiazide: Concomitant use with potassium supplements, potassium sparing diuretics, salt substitutes containing potassium, or other medicines that may increase potassium levels (heparin, etc.) could lead to hyperkalaemia and should be used with caution. Hypokalaemia has been reported under treatment with thiazide diuretics including hydrochlorothiazide. Frequent monitoring of potassium is recommended (see section 4 . 3). Treatment with thiazide diuretics, including hydrochlorothiazide, has been associated with hyponatraemia and hypochloroaemic alkalosis. Thiazides, including hydrochlorothiazide increase the urinary excretion of magnesium, which may result in hypomagnesaemia. As for any patient receiving diuretic therapy, periodic determination of serum electrolytes and potassium in particular should be performed at appropriate intervals.

Amlodipine -Valsartan - Hydrochlorothiazide: In the controlled trial of CO-COPALIA in moderate to severe hypertensive patients, the incidence of hypokalaemia (serum potassium 5,7 mmol/L) was 0,4 % with CO-COPALIA compared to 0,2 - 0,7 % with the dual therapies. In the controlled trial of CO-COPALIA, the opposite effects of valsartan 320 mg and hydrochlorothiazide 25 mg on serum potassium approximately balanced each other in many patients. In other patients, one or the other effect may be dominant. Periodic determinations of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.

Systemic lupus erythematosus: Thiazide diuretics, including hydrochlorothiazide, have been reported to exacerbate or activate systemic lupus erythematosus.

Other metabolic disturbances: Thiazide diuretics, including hydrochlorothiazide, may alter glucose tolerance and raise serum levels of cholesterol, triglycerides and uric acid. Hydrochlorothiazide may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricemia as well as precipitate gout in susceptible patients. Thiazides decrease urinary calcium excretion and may cause mild elevation of serum calcium in the absence of known disorders of calcium metabolism. Since hydrochlorothiazide can increase serum calcium concentrations, CO-COPALIA is contraindicated in patients with hypercalcaemia (see section 4.3). Marked hypercalcaemia unresponsive to thiazide withdrawal or u2265 12 mg/dL may be evidence of an underlying thiazide independent hypercalcaemic process. Pathological changes in the parathyroid gland of patients with hypercalcaemia and hypophosphatemia have been observed in a few patients on prolonged thiazide therapy.

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 has been observed in two epidemiological studies. 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 minimize the risk of skin cancer. Suspicious skin lesions should be promptly examined, potentially including histological examination of biopsies. CO-COPALIA should not be used by patients who have had previous and/or current basal cell carcinomas of the skin and/or lip (see section 4.3 and 4.8).

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

Patients with heart failure/post-myocardial infarction: In general, calcium channel blockers including amlodipine should be used with caution in patients with serious congestive heart failure (New York Heart Association (NYHA) functional class III-IV). 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 azotaemia, 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.

Patients with acute myocardial infarction: Worsening angina pectoris and acute myocardial infarction can develop after starting or increasing the dose of amlodipine, particularly in patients with severe obstructive coronary artery disease.

Aortic and mitral valve stenosis: As with all other vasodilators, special caution is indicated in patients with mitral stenosis or significant aortic stenosis that is not high grade.

Primary hyperaldosteronism: Patients with primary hyperaldosteronism should not be treated with the angiotensin II antagonist valsartan as their renin-angiotensin system is not activated. Therefore, CO-COPALIA is not recommended in this population.

Choroidal effusion, acute myopia and secondary acute angle-closure glaucoma: Hydrochlorothiazide, a sulfonamide, 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 treatment 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 sulfonamide or penicillin allergy.

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

Photosensitivity: Cases of photosensitivity reactions have been reported with thiazide diuretics (see section 4.8). If photosensitivity reaction occurs during treatment with CO-COPALIA, it is recommended to stop the treatment. If a readministration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the sun or to artificial UVA.

Amlodipine: The following potential medicine interactions may occur due to the amlodipine component of CO-COPALIA: Simvastatin: Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77 % increase in exposure to simvastatin compared to simvastatin alone. It is recommended to limit the dose of simvastatin to 20 mg daily in patients on amlodipine. CYP3A4 Inhibitors: Co-administration of a 180 mg daily dose of diltiazem with 5 mg amlodipine in elderly hypertensive patients resulted in a 1.6-fold increase in amlodipine systemic exposure. However, strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent than diltiazem. Caution should therefore be exercised when co-administering amlodipine with CYP3A4 inhibitors. Grapefruit Juice: The exposure of amlodipine may be increased when co-administered with grapefruit juice due to CYP3A4 inhibition. Administration of amlodipine with grapefruit or grapefruit juice is not recommended.

CYP3A4 Inducers: No information is available on the quantitative effects of CYP3A4 inducers on amlodipine. Patients should be monitored for adequate clinical effect when amlodipine is co-administered with CYP3A4 inducers (e.g. rifampicin, hypericum perforatum). In monotherapy, amlodipine has been safely administered with thiazide diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, atorvastatin, sildenafil, aluminium hydroxide gel, magnesium hydroxide and simeticone, cimetidine, non-steroidal anti-inflammatory drugs, antibiotics, and oral hypoglycaemic medicines.

Valsartan: The following potential medicine interactions may occur due to the amlodipine component of CO-COPALIA: Non-Steroidal Anti-Inflammatory Drugs (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 of renal function. Therefore, monitoring of renal function is recommended when initiating or modifying the treatment in patients on valsartan who are taking NSAIDs concomitantly.

Inhibitors of the uptake or efflux transporters (rifampicin, ciclosporin) or efflux transporter (ritonavir) 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. In monotherapy with valsartan, no medicine interactions of clinical significance have been found with the following medicines: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide. Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other medicines that may increase potassium levels (heparin, etc.) requires caution and frequent monitoring of potassium levels. Concomitant use of fluoroquinolones and ACE inhibitors/Angiotensin receptor blockers may precipitate acute kidney injury (see section 4.3). The mechanism of the possible interaction between the different classes of medicines, over and above different mechanism of kidney damage, is unknown (see section 4.3). Valsartan and hydrochlorothiazide: Reversible increases in serum lithium concentrations and toxicity have been reported during concurrent administration of lithium with ACE inhibitors, angiotensin II receptor antagonists or thiazides. Since renal clearance of lithium is reduced by thiazides, the risk of lithium toxicity may presumably be increased further with CO-COPALIA. Therefore, concurrent use of CO-COPALIA and lithium is contraindicated (see section 4.3).

Hydrochlorothiazide: The following potential medicine interactions may occur due to the hydrochlorothiazide component of CO-COPALIA: Skeletal muscle relaxants: Thiazides, including hydrochlorothiazide, potentiate the action of non-depolarising muscle relaxants. Non-steroidal anti-inflammatory drugs including Cox-2 inhibitors: Concomitant administration of NSAIDs (e.g. salicylic acid derivative, indomethacin) may weaken the diuretic and antihypertensive activity of the thiazide component of CO-COPALIA. Concurrent hypovolaemia may induce acute renal failure. Medicinal products affecting serum potassium level: The hypokalaemic effect of diuretics may be increased by kaliuretic diuretics, corticosteroids, ACTH, amphotericin, carbenoxolone, penicillin G, salicylic acid derivatives. Digoxin: Thiazide (hydrochlorothiazide)-induced hypokalaemia or hypomagnesaemia may occur as unwanted effects, favouring the onset of digoxin-induced cardiac dysrhythmias. Antidiabetic medicinal products: It may prove necessary to readjust the dosage of insulin and of oral antidiabetic medicines. Anticholinergic medicines: The bioavailability of thiazide-type diuretics may be increased by anticholinergic medicines (e.g. atropine, biperiden), apparently due to a decrease in gastrointestinal motility and the stomach emptying rate. Conversely prokinetic medicines 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. Cholestyramine: Absorption of thiazide diuretics, including hydrochlorothiazide, is decreased by cholestyramine. Vitamin D and calcium salts: Administration of thiazide diuretics, including hydrochlorothiazide, with vitamin D or with calcium salts may potentiate the rise in serum calcium. Ciclosporin: Concomitant treatment with ciclosporin may increase the risk of hyperuricaemia and gout-type complications. Carbamazepine: Patients receiving hydrochlorothiazide concomitantly with carbamazepine may develop hyponatraemia. Such patients should therefore be advised about the possibility of hyponatraemic reactions, and should be monitored accordingly. Other interactions: Co-administration of thiazide diuretics, including hydrochlorothiazide, may increase the incidence of hypersensitivity reactions to allopurinol, may increase the risk of adverse effects caused by amantadine, may enhance the hyperglycaemic effect of diazoxide, and may reduce the renal excretion of cytotoxic medicines (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects. Alcohol, barbiturates or narcotics: Concomitant administration of thiazide diuretics with alcohol, barbiturates, or narcotics may potentiate orthostatic hypotension. 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. Medicinal products affecting serum sodium level: The hyponatraemic effect of diuretics, including hydrochlorothiazide, may be intensified by concomitant administration of medicines such as antidepressants, antipsychotics, etc. Caution is indicated in long-term administration of these medicines (see section 4.4).

Women of childbearing potential should use effective contraception. Pregnancy: CO-COPALIA is contraindicated in pregnancy as teratogenicity has been shown in experimental animals (see section 4.3). Medicines affecting the renin-angiotensin system, such as CO-COPALIA, can cause foetal and neonatal morbidity and mortality when administered to pregnant women. When pregnancy is detected, CO-COPALIA should be discontinued as soon as possible.

Lactation: It is not known whether valsartan and/or amlodipine are transferred into human milk. Valsartan was transferred into the milk of lactating rats. Hydrochlorothiazide is transferred into human milk. CO-COPALIA is contra-indicated in women who are breast-feeding.

No studies on the effects on the ability to drive and use machines have been performed. CO-COPALIA may cause dizziness or weariness and may affect mental and/or physical abilities to perform or execute tasks or activities requiring mental alertness, judgment and/or sound coordination and vision. Amlodipine can have mild or moderate influence on the ability to drive and use machines. If patients taking CO-COPALIA suffer from dizziness, headache, fatigue or nausea the ability to react may be impaired.

The presentation of the safety profile of CO-COPALIA is based on the experience with CO-COPALIA, and the individual components. Information on CO-COPALIA: The safety of CO-COPALIA has been evaluated at its maximum dose of 10/320/25 mg for safety in one controlled clinical study with 2 271 patients, 582 of whom received valsartan in combination with amlodipine and hydrochlorothiazide. There were no known adverse reactions which occurred specifically with CO-COPALIA in addition to those known to be associated with the individual components. Information on individual components: Adverse reactions previously reported with one of the individual components may occur with CO-COPALIA even if not observed in the pivotal clinical trial. Adverse drug reactions observed are ranked under heading of frequency, the most frequent first, using the following convention: very common (u2265 1/10); common (u2265 1/100, < 1/10); uncommon (u2265 1/1,000, < 1/100); rare (u2265 1/10,000, < 1/1,000) very rare (< 1/10,000), including isolated reports. Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.

There is no experience of overdose with CO-COPALIA. The major symptom of overdose with valsartan is possibly pronounced hypotension with dizziness. Overdose with amlodipine may result in excessive peripheral vasodilatation and possibly reflex tachycardia. Marked and potentially prolonged systemic hypotension up to and including shock with fatal outcome have been reported. Non-cardiogenic pulmonary oedema has rarely been reported as a consequence of amlodipine overdose that may manifest with a delayed onset (24-48 hours post-ingestion) and require ventilatory support. Early resuscitative measures (including fluid overload) to maintain perfusion and cardiac output may be precipitating factors.

Treatment Amlodipine: If the ingestion is recent, gastric lavage may be considered. Administration of activated charcoal to healthy volunteers immediately or up to two hours after ingestion of amlodipine has been shown to significantly decrease amlodipine absorption.

Valsartan/Amlodipine/Hydrochlorothiazide: Clinically significant hypotension due to CO-COPALIA overdose calls for active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevation of extremities, and attention to circulating fluid volume and urine output. A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade.

Valsartan/Amlodipine: Both valsartan and amlodipine are unlikely to be removed by haemodialysis whereas clearance of hydrochlorothiazide will be achieved by dialysis.

Hydrochlorothiazide: Overdose with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia, hypochloraemia) and hypovolaemia 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 arrhythmia associated with the concomitant use of digitalis glycosides or certain anti-arrhythmic medicinal products. The degree to which hydrochlorothiazide is removed by haemodialysis has not been established.