Naviod Co 80 Mg/12,5 Mg/25 Mg Film-Coated Tablets

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

Posology: The recommended dose is 1 tablet per day. When clinically appropriate either NAVIOD CO 80/12, 5 mg, NAVIOD CO 160/12, 5 mg or NAVIOD CO 320/12, 5 mg may be used. When necessary NAVIOD CO 160/25 mg or NAVIOD CO 320/25 mg may be used. The maximum antihypertensive effect is seen within 2 to 4 weeks.

Special Populations

Use in children: The safety and efficacy of NAVIOD CO have not been established in children.

Use in renal impairment: No dosage adjustment is required for patients with mild renal impairment (creatinine clearance > 70 mL/min).

Use in hepatic impairment: No dosage adjustment is required in patients with mild to moderate hepatic insufficiency of non-biliary origin and without cholestasis.

Method of administration: Oral use. NAVIOD CO is given orally with or without food.

• Known hypersensitivity to valsartan, hydrochlorothiazide or to any of the excipients of NAVIOD CO (see section 6.1).
• A history of angioedema related to previous therapy with angiotensin-converting enzyme (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 4.4).
• 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.
• Porphyria.
• Lithium therapy: Concomitant administration with NAVIOD CO may lead to toxic blood concentrations of lithium (see section 4.5).
• Pregnancy and lactation (see section 4.6).
• The concomitant use of NAVIOD CO with aliskiren-containing medicines is contraindicated (see section 4.4).
• Refractory hypokalaemia, hyponatraemia, hypercalcaemia and symptomatic hyperuricaemia.
• Patients with a history of previous and/or current basal cell carcinomas and/or squamous cell carcinomas of the skin and lip.

Pregnancy: Should a woman become pregnant while receiving NAVIOD CO, the treatment should be stopped promptly and switched to a different class of antihypertensive medicine (see sections 4.3 and 4.6).

Serum electrolyte changes: Valsartan

Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other medicines that may increase potassium levels (heparin, etc.) is not recommended. Monitoring of potassium should be undertaken as appropriate.

Hydrochlorothiazide: Hypokalaemia has been reported under treatment with thiazide diuretics, including hydrochlorothiazide. Frequent monitoring of serum potassium is recommended. Treatment with thiazide diuretics, including hydrochlorothiazide, has been associated with hyponatraemia and hypochloraemic alkalosis. Thiazides, including hydrochlorothiazide, increase the urinary excretion of magnesium, which may result in hypomagnesaemia. Calcium excretion is decreased by thiazide diuretics. This may result in hypercalcaemia. As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals.

Sodium and/or volume-depleted patients: Patients receiving thiazide diuretics, including hydrochlorothiazide, should be observed for clinical signs of fluid or electrolyte imbalance. In severely sodium-depleted and/or volume-depleted patients, such as those receiving high doses of diuretics, symptomatic hypotension may occur after initiation of therapy with NAVIOD CO. Sodium and/or volume depletion should be corrected before starting treatment with NAVIOD CO.

Patients with severe chronic heart failure or other conditions with stimulation of the renin-angiotensin-aldosterone system: 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 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. The use of NAVIOD CO in patients with severe chronic heart failure has not been established. Hence, it cannot be excluded that because of the inhibition of the renin-angiotensin-aldosterone system the application of NAVIOD CO as well may be associated with impairment of the renal function. NAVIOD CO should not be used in these patients.

Renal artery stenosis: NAVIOD CO should not be used to treat hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, since blood urea and serum creatinine may increase in such patients.

Primary hyperaldosteronism: Patients with primary hyperaldosteronism should not be treated with NAVIOD CO as their renin-angiotensin system is not activated.

Aortic and mitral valve stenosis, hypertrophic obstructive cardiomyopathy: Special caution is indicated in patients suffering from aortic or mitral stenosis, or hypertrophic obstructive cardiomyopathy (HOCM).

Renal Impairment: No dosage adjustment is required for patients with renal impairment with a creatinine clearance u2265 30 mL/min (see section 4.2). Periodic monitoring of serum potassium, creatinine and uric acid levels is recommended when NAVIOD CO is used in patients with renal impairment.

Kidney transplantation: There is currently no experience on the safe use of NAVIOD CO in patients who have recently undergone kidney transplantation.

Hepatic impairment: In patients with mild to moderate hepatic impairment without cholestasis, NAVIOD CO should be used with caution (see sections 4.2 and 5.2). 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.

History of 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. NAVIOD CO should be immediately discontinued in patients who develop angioedema, and NAVIOD CO should not be re-administered (see section 4.8).

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. In diabetic patients dosage adjustments of insulin or oral hypoglycaemic medicines may be required. Thiazides may reduce 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 underlying hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

Photosensitivity: Cases of photosensitivity reactions have been reported with thiazide 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.

General: Caution should be exercised in patients who have shown prior hypersensitivity to other angiotensin II receptor antagonists. Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergy and asthma.

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 week of a medicine 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 or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore contraindicated (see sections 4.3). NAVIOD CO should not be used concomitantly with aliskiren (see section 4.3).

Concomitant use of fluoroquinolones and ACE inhibitors/Angiotensin receptor blockers: 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.

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 based on the Danish National Cancer Registry. 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 UV rays and, in case of exposure, adequate protection 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 examinations of biopsies. NAVIOD 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 also section 4.8).

Interactions related to both valsartan and hydrochlorothiazide

Concomitant use not recommended: Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors, angiotensin II receptor antagonist or thiazides, including hydrochlorothiazide. Since renal clearance of lithium is reduced by thiazides, the risk of lithium toxicity may presumably be increased further with NAVIOD CO. If the combination proves necessary, a careful monitoring of serum lithium levels is recommended.

Concomitant use requiring caution: Other antihypertensive medicines

NAVIOD CO may increase the effects of other medicines with antihypertensive properties (e.g. guanethidine, methyldopa, vasodilators, ACEI, ARBs, beta-blockers, calcium channel blockers and DRIs).

Pressor amines (e.g. noradrenaline(norepinephrine), adrenaline(epinephrine)): Possible decreased response to pressor amines. The clinical significance of this effect is uncertain and not sufficient to preclude their use.

Non-steroidal anti-inflammatory medicines (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid (>3 g/day), and non-selective NSAIDs: NSAIDS can attenuate the antihypertensive effect of both angiotensin II antagonists and hydrochlorothiazide when administered simultaneously. Furthermore, concomitant use of NAVIOD CO and NSAIDs may lead to worsening of renal function and an increase in serum potassium. Therefore, monitoring of renal function at the beginning of the treatment is recommended, as well as adequate hydration of the patient.

Interactions related to valsartan

Dual blockade of the Renin-Angiotensin-Aldosterone System (RAAS) with ARBs, ACEIs, 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 sections 4.3 and 4.4).

Concomitant use not recommended: Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium and other substances that may increase potassium levels. If a medicine that affects potassium levels is considered necessary in combination with valsartan, monitoring of potassium plasma levels is advised.

Transporters: In vitro data indicates that valsartan is a substrate of the hepatic uptake transporter OATP1B1/OATP1B3 and the hepatic efflux transporter MRP2. The clinical relevance of this finding is unknown. 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. Exercise appropriate care when initiating or ending concomitant treatment with such medicines.

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

No interaction: In interaction studies with valsartan, no interactions of clinical significance have been found with valsartan or any of the following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide. Digoxin and indomethacin could interact with the hydrochlorothiazide component of NAVIOD CO (see interactions related to hydrochlorothiazide).

Interactions related to hydrochlorothiazide

Concomitant use requiring caution: Medicines affecting serum potassium level: The hypokalaemic effect of hydrochlorothiazide may be increased by concomitant administration of kaliuretic diuretics, corticosteroids, laxatives, adrenocorticotropic hormone (ACTH), amphotericin, carbenoxolone, penicillin G, salicylic acid and derivatives. If these medicines are to be prescribed with the hydrochlorothiazide-valartan combination, monitoring of potassium plasma levels is advised (see section 4.4).

Medicines that could induce torsades de pointes: Due to the risk of hypokalaemia, hydrochlorothiazide should be administered with caution when associated with medicines that could induce torsades de pointes, in particular Class Ia and Class III antidysrhythmics and some antipsychotics.

Medicines affecting serum sodium level: The hyponatraemic effect of diuretics may be intensified by concomitant administration of medicines such as antidepressants, antipsychotics, antiepileptics, etc. Caution is advised in long-term administration of these medicines.

Digitalis glycosides: Thiazide-induced hypokalaemia or hypomagnesaemia may occur as undesirable effects favouring the onset of digitalis-induced cardiac dysrhythmias (see section 4.4).

Calcium salts and vitamin D: Administration of thiazide diuretics, including hydrochlorothiazide, with vitamin D or with calcium salts may potentiate the rise in serum calcium. Concomitant use of thiazide type diuretics with calcium salts may cause hypercalcaemia in patients predisposed for hypercalcaemia (e.g. hyperparathyroidism, malignancy or vitamin-D-mediated conditions) by increasing tubular calcium reabsorption.

Antidiabetic medicines (oral age medicines and insulin): Thiazides may alter glucose tolerance. Dose adjustment of the antidiabetic medicinal product may be necessary. Metformin should be used with caution because of the risk of lactic acidosis induced by possible functional renal failure linked to hydrochlorothiazide.

Beta blockers and diazoxide: Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta blockers may increase the risk of hyperglycaemia. Thiazide diuretics, including hydrochlorothiazide, may enhance the hyperglycaemic effect of diazoxide.

Medicines used in the treatment of gout (probenecid, sulfinpyrazone and allopurinol): Dose adjustment of uricosuric medicines may be necessary as hydrochlorothiazide may raise the level of serum uric acid. Increase of dosage of probenecid or sulfinpyrazone may be necessary. Co-administration of thiazide diuretics, including hydrochlorothiazide, may increase the incidence of hypersensitivity reactions to allopurinol.

Anticholinergic medicines and other medicines affecting gastric motility: 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, it is anticipated that prokinetic medicines such as cisapride may decrease the bioavailability of thiazide-type diuretics.

Amantadine: Thiazides, including hydrochlorothiazide, may increase the risk of adverse effects caused by amantadine.

Ion exchange resins: Absorption of thiazide diuretics, including hydrochlorothiazide, is decreased by cholestyramine or colestipol. This could result in sub-therapeutic effects of thiazide diuretics. However, staggering the dosage of hydrochlorothiazide and resin such that hydrochlorothiazide is administered at least 4 hours before or 4-6 hours after the administration of resins would potentially minimize the interaction.

Cytotoxic medicines: Thiazides, including hydrochlorothiazide, may reduce renal excretion of cytotoxic medicines (e.g. cyclophosamide, methotrexate) and potentiate their myelosuppressive effects.

Non-depolarising skeletal muscle relaxants (e.g. tubocurarine): Thiazides, including hydrochlorothiazide, potentiate the action of skeletal muscle relaxants such as curare derivatives.

Ciclosporin: Concomitant treatment with ciclosporin may increase the risk of hyperuricaemia and gout-type complications.

Alcohol, barbiturates or narcotics: Concomitant administration of thiazide diuretics with medicines that also have a blood pressure lowering effect (e.g. by reducing sympathetic central nervous system activity or direct vasodilatation activity) may potentiate orthostatic hypotension.

Methyldopa: There have been isolated reports of haemolytic anaemia in patients receiving concomitant treatment with methyldopa and hydrochlorothiazide.

Iodine contrast media: In case of diuretic-induced dehydration, there is an increased risk of acute renal failure, especially with high doses of the iodine product. Patients should be rehydrated before the administration.

Women of childbearing age: Women of childbearing age should ensure effective contraception.

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

Breast-feeding: No information is available regarding the use of valsartan during breast-feeding. Hydrochlorothiazide is excreted in human milk. Therefore, the use of NAVIOD CO during breast-feeding is contraindicated (see section 4.3). Alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

Fertility: No fertility data is available.

No studies on the effect of NAVIOD CO on the ability to drive and use machines have been performed. When driving vehicles or operating machines it should be taken into account that occasionally dizziness or weariness may occur.

Tabulated summary of adverse reactions

Table 1. Frequency of adverse reactions with valsartan/hydrochlorothiazide:

MedDRA system organ class Frequency Adverse reactions

Metabolism and nutrition disorders Less frequent Dehydration

Nervous system disorders Less frequent Dizziness, paraesthesia Frequency unknown Syncope

Eye disorders Less frequent Vision blurred

Ear and labyrinth disorders Less frequent Tinnitus

Vascular disorders Less frequent Hypotension

Respiratory, thoracic and mediastinal disorders Less frequent Cough Frequency unknown Non cardiogenic pulmonary oedema

Gastrointestinal disorders Less frequent Diarrhoea

Musculoskeletal and connective tissue disorders Less frequent Myalgia, arthralgia

Renal and urinary disorders Frequency unknown Impaired renal function

General disorders and administration site conditions Less frequent Fatigue

Investigations Frequency unknown Serum uric acid increased, serum bilirubin and serum creatinine increased, hypokalaemia, hyponatraemia, elevation of blood urea nitrogen, neutropenia

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

Table 2. Frequency of adverse reactions with valsartan:

MedDRA system organ class Frequency Adverse reactions

Blood and the lymphatic system disorders Frequency unknown Decrease in haemoglobin, decrease in haematocrit, thrombocytopenia

Immune system disorders Frequency unknown Other hypersensitivity/allergic reactions including serum sickness

Metabolism and nutrition disorders Frequency unknown Increase of serum potassium, hyponatraemia

Psychiatric disorders Frequency unknown Decreased libido

Ear and labyrinth disorders Less frequent Vertigo

Vascular disorders Frequency unknown Vasculitis

Gastrointestinal disorders: Less frequent Abdominal pain

Hepatobiliary disorders Frequency unknown Elevation of liver function values

Skin and subcutaneous tissue disorders: Frequency unknown Angioedema, dermatitis bullous, rash, pruritus

Renal and urinary disorders: Frequency unknown Renal failure

Symptoms: Overdose with valsartan may result in marked hypotension, which could lead to depressed level of consciousness, circulatory collapse and/or shock. In addition, the following signs and symptoms may occur due to an overdose of the hydrochlorothiazide component: nausea, somnolence, hypovolaemia, and electrolyte disturbances associated with cardiac dysrhythmias and muscle spasms.

Treatment: The therapeutic measures depend on the time of ingestion and the type and severity of the symptoms, stabilisation of the circulatory condition being of prime importance. If hypotension occurs, the patient should be placed in the supine position and salt and volume supplementation should be given rapidly. Valsartan cannot be eliminated by means of haemodialysis because of its strong plasma binding behaviour whereas clearance of hydrochlorothiazide will be achieved by dialysis.