Co-diovan

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CO-DIOVANâ

Composition:

Active substances: valsartan, micronized hydrochlorothiazide;

One tablet contains 80 mg of valsartan and 12.5 mg of micronized hydrochlorothiazide, or 160 mg of valsartan and 12.5 mg of micronized hydrochlorothiazide, or 160 mg of valsartan and 25 mg of micronized hydrochlorothiazide, or 320 mg of valsartan and 12.5 mg of micronized hydrochlorothiazide, or 320 mg of valsartan and 25 mg of micronized hydrochlorothiazide;

Excipients:

anhydrous colloidal silicon dioxide; crospovidone; hypromellose/hydroxypropylmethylcellulose; magnesium stearate; microcrystalline cellulose; macrogol 8000/polyethylene glycol; talc; titanium dioxide (E 171); iron oxide red (E 172) – only in tablets of 80/12.5 mg, 160/12.5 mg, 160/25 mg, 320/12.5 mg; iron oxide yellow (E 172) – only in tablets of 80/12.5 mg, 160/25 mg, 320/25 mg; iron oxide black (E 172) – only in tablets of 160/25 mg, 320/12.5 mg.

Pharmaceutical form. Film-coated tablets.

Main physical and chemical properties:

Co-Diovanâ 80/12.5 mg: light orange-colored, oval, slightly convex tablets with inscriptions (imprints) «HGH» on one side and «CG» on the other;

Co-Diovanâ 160/12.5 mg: dark red-colored, oval, slightly convex tablets with inscriptions (imprints) «HНH» on one side and «CG» on the other;

Co-Diovanâ 160/25 mg: brown-orange-colored, oval, slightly convex tablets with inscriptions (imprints) «HXH» on one side and «NVR» on the other.

Co-Diovanâ 320/12.5 mg: pink-colored, oval tablets with beveled edges, with inscriptions (imprints) «NVR» on one side and «HIL» on the other;

Co-Diovanâ 320/25 mg: yellow-colored, oval tablets with beveled edges, with inscriptions (imprints) «NVR» on one side and «CTI» on the other.

Pharmacotherapeutic group. Angiotensin II antagonists and diuretics. Valsartan and diuretics. ATC code: C09DA03.

Pharmacological Properties

Pharmacodynamics

The active hormone of the renin-angiotensin-aldosterone system (RAAS) is angiotensin II, formed from angiotensin I with the participation of angiotensin-converting enzyme (ACE). Angiotensin II binds to specific receptors located on cell membranes in various tissues. It has a broad spectrum of physiological effects, including both direct and indirect involvement in the regulation of arterial pressure. As a potent vasoconstrictor substance, angiotensin II exerts a direct pressor effect. In addition, it promotes sodium retention and stimulates aldosterone secretion.

Valsartan is an active and specific oral antagonist of angiotensin II receptors. It selectively acts on AT1 subtype receptors, which are responsible for the effects of angiotensin II. Increased levels of angiotensin II resulting from blockade of AT1 receptors by valsartan may stimulate unoccupied AT2 receptors, thereby counterbalancing the effects of AT1 receptor activation. Valsartan has no partial agonist activity at AT1 receptors and has much greater (approximately 20,000 times) affinity for AT1 receptors than for AT2 receptors.

Valsartan does not inhibit ACE, also known as kininase II, which converts angiotensin I to angiotensin II and degrades bradykinin. No bradykinin-related adverse effects are observed. In clinical studies comparing valsartan with an ACE inhibitor, the incidence of dry cough was significantly lower (P < 0.05) in patients treated with valsartan than in those receiving an ACE inhibitor (2.6% vs. 7.9%, respectively). In patients who previously experienced dry cough during ACE inhibitor therapy, this adverse effect occurred in 19.5% of cases during treatment with valsartan and in 19% of cases during treatment with a thiazide diuretic, whereas cough was observed in 68.5% of cases in the group receiving an ACE inhibitor (P < 0.05).

In controlled clinical trials, the incidence of cough in patients receiving the combination of valsartan and hydrochlorothiazide was 2.9%.

Valsartan does not interact with or block receptors of other hormones or ion channels that play an important role in regulating cardiovascular function.

The site of action of thiazide diuretics is the cortical segment of the distal convoluted renal tubules, where receptors highly sensitive to diuretic action are located and where inhibition of Na+ and Cl\− ion transport occurs. The mechanism of action of thiazides involves inhibition of the Na+Cl\− cotransporter, likely through competitive binding at the chloride transport site. As a result, excretion of sodium and chloride ions increases to approximately the same extent. Due to the diuretic effect, plasma volume decreases, leading to increased renin activity, aldosterone secretion, urinary potassium excretion, and consequently, reduced serum potassium concentration. The relationship between renin and aldosterone is mediated by angiotensin II; therefore, administration of an angiotensin II receptor antagonist reduces potassium loss associated with thiazide diuretic use.

Administration of the drug to patients with hypertension leads to a reduction in arterial pressure without affecting pulse rate.

In most patients, after a single oral dose, onset of antihypertensive activity occurs within 2 hours, and maximum reduction in arterial pressure is achieved within 4–6 hours. The antihypertensive effect persists for more than 24 hours after a single dose. With regular administration, the maximum therapeutic effect is usually achieved within 2–4 weeks and is maintained at this level during long-term therapy. Combination with hydrochlorothiazide provides more effective blood pressure reduction.

Discontinuation of valsartan does not lead to a sudden increase in arterial pressure (rebound syndrome) or other adverse effects.

Valsartan does not affect total cholesterol, triglycerides, serum glucose, or serum uric acid levels in patients with arterial hypertension.

Pharmacokinetics

Valsartan. After oral administration, peak plasma concentration (Cmax) of valsartan is reached within 2–4 hours. The mean absolute bioavailability of valsartan is 23% (range 23 ± 7). Within the studied dose range, the pharmacokinetics of valsartan are linear. No changes in kinetic parameters were observed upon repeated administration. With once-daily dosing, accumulation is minimal. Plasma concentrations of the drug are similar in women and men.

When valsartan is administered with food, the area under the concentration-time curve (AUC) decreases by 48% and Cmax by 59%, although approximately 8 hours after administration, plasma concentrations are similar whether the drug is taken fasting or with food. The reduction in AUC and Cmax is not clinically significant; therefore, valsartan can be taken independently of food intake.

Valsartan is highly bound to plasma proteins (94–97%), primarily to albumin. Steady-state conditions are achieved within 1 week. The volume of distribution at steady state after intravenous administration is approximately 17 L, indicating that valsartan is not extensively distributed into tissues. Compared to hepatic blood flow (approximately 30 L/h), the plasma clearance of valsartan is relatively slow (approximately 2 L/h). Valsartan undergoes limited biotransformation, with only about 20% of the dose excreted as metabolites. A hydroxymetabolite is detected in plasma at low concentrations (less than 10% of valsartan AUC). This metabolite is pharmacologically inactive.

Valsartan exhibits multiphasic elimination kinetics (initial half-life < 1 hour, terminal (beta) half-life approximately 9 hours). Valsartan is eliminated primarily via feces (approximately 83% of the dose) and urine (approximately 13% of the dose), mostly in unchanged form. After intravenous administration, plasma clearance of valsartan is approximately 2 L/h, and renal clearance is 0.62 L/h (about 30% of total clearance). The elimination half-life of valsartan is 6 hours.

Hydrochlorothiazide. Absorption of hydrochlorothiazide after oral administration is rapid (tmax approximately 2 hours). The increase in mean AUC is linear and proportional to dose within the therapeutic range. When hydrochlorothiazide is administered with food, both increases and decreases in systemic bioavailability have been observed compared to fasting administration. However, the range of these changes is minor and not clinically significant. Absolute bioavailability of hydrochlorothiazide is approximately 70% after oral administration. Pharmacokinetics during distribution and elimination phases are generally described as biphasic. The apparent volume of distribution is 4–8 L/kg. In circulation, hydrochlorothiazide is bound to plasma proteins (40–70%), primarily to serum albumin. Accumulation in erythrocytes is approximately three times higher than plasma concentration.

Hydrochlorothiazide is excreted predominantly unchanged. It is eliminated from plasma with a mean terminal half-life of 6–15 hours. No changes in hydrochlorothiazide kinetics occur with repeated dosing; accumulation is minimal with once-daily administration. Over 95% of absorbed hydrochlorothiazide is excreted unchanged in urine.

Valsartan/hydrochlorothiazide. When administered concomitantly with valsartan, the systemic bioavailability of hydrochlorothiazide is reduced by approximately 30%. Conversely, co-administration of hydrochlorothiazide does not significantly affect the pharmacokinetics of valsartan. However, this interaction does not impair the efficacy of the combined use of valsartan and hydrochlorothiazide. In controlled clinical trials, a clear antihypertensive effect of this combination was demonstrated, exceeding the effect of either component alone.

Pharmacokinetics in Specific Patient Populations

Hepatic Impairment

In pharmacokinetic studies involving patients with mild to moderate hepatic impairment, valsartan concentrations were approximately twice as high as in healthy volunteers. Data in patients with severe hepatic impairment are lacking. Overall, liver disease with mild to moderate hepatic insufficiency does not significantly affect the pharmacokinetics of hydrochlorothiazide.

Patients with Renal Impairment

As expected for a substance with renal clearance accounting for only 30% of total plasma clearance, no correlation was found between renal function and systemic availability of valsartan. Therefore, dose adjustment is not required in patients with renal impairment (see section "Contraindications" for severe renal insufficiency). Studies in dialysis patients have not been conducted. However, due to the high plasma protein binding of valsartan, removal by dialysis is not expected.

Hydrochlorothiazide is eliminated by the kidneys via passive filtration and active secretion into the renal tubular lumen. Renal function plays a major role in hydrochlorothiazide pharmacokinetics, as this drug is eliminated solely by the kidneys. In renal insufficiency, mean peak plasma levels and AUC values of hydrochlorothiazide increase, while urinary excretion decreases. In patients with mild to moderate renal impairment, the mean elimination half-life nearly doubles due to a significant reduction in renal clearance. Hydrochlorothiazide is dialyzable.

Elderly Patients

In some elderly patients (>65 years), systemic exposure to valsartan was slightly higher than in younger patients, although not clinically significant.

Steady-state concentrations of hydrochlorothiazide are higher and systemic clearance significantly slower in elderly patients compared to younger patients. Therefore, patients of advanced age receiving hydrochlorothiazide require careful monitoring.

Non-melanoma Skin Cancer (NMSC)

Available epidemiological data suggest a cumulative dose-dependent association between hydrochlorothiazide exposure and the development of NMSC. In one study, 71,533 cases of basal cell carcinoma were diagnosed among 1,430,833 individuals in the control group, and 8,629 cases of squamous cell carcinoma among 172,462 individuals in the control group. High-dose hydrochlorothiazide (≥50,000 mg cumulative) was associated with an adjusted odds ratio (OR) of 1.29 (95% CI: 1.23–1.35) for basal cell carcinoma and 3.98 (95% CI: 3.68–4.31) for squamous cell carcinoma. A cumulative dose-response relationship was observed for both basal cell and squamous cell carcinoma. Another study indicated a possible association between lip cancer and hydrochlorothiazide use: 633 cases of lip cancer were matched with 63,067 control subjects using a risk-set sampling strategy. A cumulative dose-response relationship was demonstrated with an adjusted OR of 2.1 (95% CI: 1.7–2.6), increasing to OR 3.9 (3.0–4.9) with high-dose use (~25,000 mg) and OR 7.7 (5.7–10.5) with the highest dose (~100,000 mg). For example, a cumulative dose of 100,000 mg corresponds to daily administration of the defined daily dose of 25 mg over a period exceeding 10 years.

Clinical characteristics.

Indications.

Co-Diovan® is indicated for the treatment of mild to moderate essential arterial hypertension in patients whose blood pressure is not adequately controlled with monotherapy.

Contraindications.

• Hypersensitivity to any component of Co-Diovan® or to other sulfonamide derivatives.
• Severe impairment of liver function, hepatic cirrhosis, and cholestasis.
• Anuria.
• Refractory hypokalemia, hyponatremia, hypercalcemia, symptomatic hyperuricemia.
• Concomitant use of angiotensin receptor antagonists (ARBs), including valsartan, or angiotensin-converting enzyme (ACE) inhibitors with aliskiren in patients with diabetes mellitus (type I or II) or renal impairment (eGFR < 60 mL/min/1.73 m²).
• Pregnancy, planned pregnancy, and lactation (see "Use in pregnancy or breastfeeding").
• Hereditary angioedema or angioedema during previous treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor antagonists (ARBs).

Interaction with other medicinal products and other forms of interaction.

Interactions related to both valsartan and hydrochlorothiazide

Concomitant use not recommended

Lithium. Reversible increases in plasma lithium concentrations and lithium toxicity have been reported with concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or thiazides, including hydrochlorothiazide. Due to lack of experience with co-administration of valsartan and lithium, this combination is not recommended. Since thiazides reduce renal clearance of lithium, lithium toxicity may be enhanced after administration of Co-Diovan®. If such combination use is necessary, careful monitoring of plasma lithium levels is recommended.

Concomitant use requires caution

Other antihypertensive agents

Co-Diovan® may enhance the effect of other antihypertensive agents (such as guanethidine, methyldopa, vasodilators, ACE inhibitors, angiotensin receptor antagonists, beta-blockers, calcium channel blockers, direct renin inhibitors, and dopamine reuptake inhibitors).

Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors

NSAIDs or COX-2 inhibitors may reduce the antihypertensive effect of angiotensin II receptor antagonists (ARBs).

In elderly patients, patients with reduced blood volume (including those on diuretic therapy), or patients with impaired renal function, concomitant use of NSAIDs (or COX-2 inhibitors) with ARBs increases the risk of worsening renal function, including acute renal failure. Combined use of these agents requires caution and monitoring of renal function.

Interactions related to valsartan

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with ARBs, ACE inhibitors, or aliskiren

Caution is required when ARBs, including valsartan, are used concomitantly with other agents that block the RAAS, such as ACE inhibitors or aliskiren.

This is due to an increased incidence of hypotension, loss of consciousness, hyperkalemia, and renal dysfunction (including acute renal failure) compared to monotherapy. Therefore, dual blockade of the RAAS by combined use of ACE inhibitors, angiotensin receptor blockers, or aliskiren is not recommended. If dual RAAS blockade is considered absolutely necessary, treatment should be carried out only under specialist supervision and accompanied by monitoring of renal function, electrolyte levels, and blood pressure.

Concomitant use of angiotensin receptor antagonists (ARBs), including valsartan, or angiotensin-converting enzyme (ACE) inhibitors with aliskiren in patients with diabetes mellitus (type I or II), diabetic nephropathy, or renal impairment (eGFR < 60 mL/min/1.73 m²) is contraindicated.

Concomitant use not recommended

Potassium-sparing diuretics, potassium-containing dietary supplements, potassium-containing salt substitutes, and other substances that may increase potassium levels

If a medicinal product affecting potassium levels must be used concomitantly with valsartan, monitoring of plasma potassium levels is recommended.

Concomitant use of angiotensin II receptor antagonists with other medicinal products capable of increasing serum potassium levels (such as potassium-sparing diuretics, potassium-containing medicinal products, heparin) increases the risk of hyperkalemia. In such cases, Co-Diovan®, which contains valsartan, should be used with caution and potassium levels should be monitored.

Transporters

In vitro data indicate that valsartan is a substrate of the hepatic uptake transporters OATP1B1/OATP1B3 and the hepatic efflux transporter MRP2. The clinical significance of these data has not been fully established. Concomitant use of inhibitors of uptake transporters (e.g., rifampicin, cyclosporine) or efflux transporters (e.g., ritonavir) may lead to increased systemic exposure to valsartan. Appropriate caution is recommended when initiating or discontinuing concomitant treatment with such medicinal products.

Absence of interaction

In drug interaction studies, no clinically significant interactions were observed between valsartan and the following drugs: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glyburide. Digoxin and indomethacin may interact with the hydrochlorothiazide component of Co-Diovan® (see interactions related to hydrochlorothiazide).

Interactions related to hydrochlorothiazide

Concomitant use requires caution

Medicinal products associated with potassium loss and hypokalemia The hypokalemic effect of hydrochlorothiazide may be enhanced when used concomitantly with potassium-wasting diuretics, corticosteroids, laxatives, adrenocorticotropic hormones (ACTH), amphotericin, carbenoxolone, penicillin G, salicylic acid and its derivatives, antiarrhythmic agents.

If these medicinal products must be prescribed together with the hydrochlorothiazide-valsartan combination, monitoring of plasma potassium levels is recommended.

Medicinal products capable of inducing torsades de pointes ventricular tachycardia

Due to the risk of hypokalemia, hydrochlorothiazide should be used cautiously concomitantly with medicinal products that may induce torsades de pointes ventricular tachycardia, particularly class Ia and III antiarrhythmics, as well as certain antipsychotics.

Medicinal products affecting serum sodium levels

The hyponatremic effect of diuretics may be enhanced when used concomitantly with antidepressants, antipsychotics, antiepileptics, etc. Caution is recommended during prolonged use of these medicinal products.

Medicinal products that may cause torsades de pointes

• Class Ia antiarrhythmics (e.g., quinidine, hydroquinidine, disopyramide)
• Class III antiarrhythmics (e.g., amiodarone, sotalol, dofetilide, ibutilide)
• Certain neuroleptics (e.g., thioridazine, chlorpromazine, levomepromazine, trifluoperazine, zuclopenthixol, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol)
• Others (e.g., bepridil, cisapride, diphenylhydantoin, intravenous erythromycin, halofantrine, ketanserin, mizolastine, pentamidine, sparfloxacin, terfenadine, intravenous vincamine)

Due to the risk of hypokalemia, hydrochlorothiazide should be used cautiously concomitantly with medicinal products that may cause torsades de pointes.

Digitalis glycosides

Thiazide-induced hypokalemia or hypomagnesemia may occur as an adverse effect predisposing to digitalis-induced cardiac arrhythmia.

Calcium salts and vitamin D

Concomitant use of thiazide diuretics, including hydrochlorothiazide, with vitamin D or calcium salts may promote an increase in plasma calcium levels. Concomitant use of thiazide diuretics with calcium salts may cause hypercalcemia in patients predisposed to hypercalcemia (e.g., patients with hyperparathyroidism, malignancies, or vitamin D-mediated conditions) due to enhanced tubular reabsorption of calcium.

Antidiabetic agents (oral agents and insulin)

Thiazide treatment may affect glucose tolerance. Dose adjustment of insulin or antidiabetic medicinal agents may be necessary.

Metformin should be used cautiously due to the risk of lactic acidosis induced by possible functional renal impairment associated with hydrochlorothiazide.

Beta-blockers and diazoxide

Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta-blockers increases the risk of hyperglycemia. Thiazide diuretics, including hydrochlorothiazide, may potentiate the hyperglycemic effect of diazoxide.

Medicinal products used in the treatment of gout (probenecid, sulfinpyrazone, and allopurinol)

Dose adjustment of uricosuric agents may be necessary because hydrochlorothiazide may increase plasma uric acid levels. Increased doses of probenecid or sulfinpyrazone may be required. Concomitant use of thiazide diuretics, including hydrochlorothiazide, may increase the frequency of hypersensitivity reactions to allopurinol.

Anticholinergic agents (e.g., atropine, biperiden)

The bioavailability of thiazide diuretics may be increased by anticholinergic agents, likely due to reduced gastrointestinal motility and delayed gastric emptying. Conversely, prokinetic agents such as cisapride may be expected to reduce the bioavailability of thiazide diuretics.

Amantadine

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

Ion-exchange resins

The absorption of thiazide diuretics, including hydrochlorothiazide, is reduced by cholestyramine or colestipol. This may result in subtherapeutic effects of thiazide diuretics. However, staggering the administration of hydrochlorothiazide and ion-exchange resins such that hydrochlorothiazide is taken at least 4 hours before or 4–6 hours after these resins minimizes the risk of interaction.

Cytoxic agents (e.g., cyclophosphamide, methotrexate)

Thiazides, including hydrochlorothiazide, may reduce renal excretion of cytotoxic agents and enhance their myelosuppressive effects.

Non-depolarizing skeletal muscle relaxants (e.g., tubocurarine)

Thiazides, including hydrochlorothiazide, enhance the effect of skeletal muscle relaxants such as curare derivatives.

Cyclosporine

Concomitant administration with cyclosporine increases the risk of hyperuricemia and gout-like complications.

Alcohol, anesthetics, and sedatives

Concomitant use of thiazide diuretics with agents that may also lower blood pressure (e.g., due to reduced activity of the central sympathetic nervous system or direct vasodilatory effects) may potentiate orthostatic hypotension.

Metildopa

Isolated reports of hemolytic anemia have been reported in patients receiving concomitant treatment with methyldopa and hydrochlorothiazide.

Carbamazepine

Hyponatremia may develop in patients receiving hydrochlorothiazide concomitantly with carbamazepine. Such patients should be informed about the possibility of hyponatremic reactions and appropriately monitored.

Contrast agents containing iodine

In cases of diuretic-induced dehydration, there is an increased risk of acute renal failure, particularly with high doses of iodine-containing agents. Adequate fluid repletion should be performed prior to administration.

Pressor amines

Hydrochlorothiazide may reduce the response to pressor amines such as noradrenaline. However, the clinical significance of this effect is not sufficiently established to preclude their use.

Special precautions for use.

Electrolyte changes

Potassium

Thiazide diuretics may cause hypokalemia or exacerbate pre-existing hypokalemia.

Correction of hypokalemia is recommended before initiating thiazide therapy. Concomitant hypomagnesemia may lead to hypokalemia that is difficult to correct.

Since Co-Diovan® contains an angiotensin II receptor antagonist, caution should be exercised when used concomitantly with potassium salts, potassium-sparing diuretics, potassium-containing salt substitutes, or other medicinal products that may increase potassium levels (such as heparin). Cases of hypokalemia have been reported during treatment with thiazide diuretics. Regular monitoring of serum potassium and magnesium levels is recommended in patients with conditions involving increased potassium loss. Electrolyte balance should be monitored in all patients receiving thiazide diuretics.

Patients with sodium and/or circulating blood volume (CBV) deficiency

Treatment with thiazide diuretics is often associated with the development of hyponatremia or worsening of pre-existing hyponatremia and hypochloremic alkalosis. This may be accompanied by neurological symptoms (e.g., vomiting, confusion, apathy). Thiazide diuretics should be administered only after correction of hyponatremia. Serum sodium concentration should be monitored regularly.

Thiazides enhance urinary magnesium excretion, which may lead to hypomagnesemia.

In patients with severe sodium and/or circulating blood volume deficiency, such as those receiving high-dose diuretics, symptomatic hypotension may occasionally occur after initiation of Co-Diovan® therapy. Therefore, correction of sodium and/or circulating blood volume levels should be performed before starting treatment with this medicinal product.

If hypotension occurs, the patient should be placed in a supine position and, if necessary, receive intravenous saline infusion. Treatment may be continued immediately after stabilization of blood pressure.

Calcium

Thiazide diuretics reduce calcium excretion in urine and may cause elevated serum calcium levels. Thiazide diuretics should be administered only after correction of hypercalcemia or treatment of conditions causing hypercalcemia. Serum calcium concentration should be monitored regularly.

Renal artery stenosis

Co-Diovan® should be used with particular caution in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery of a single kidney, as such patients may experience increased blood urea and plasma creatinine levels.

Renal impairment

For patients with mild to moderate renal impairment (creatinine clearance > 30 mL/min), dose adjustment is not required.

Co-Diovan® should be used with caution in patients with severe renal impairment (creatinine clearance < 30 mL/min). Thiazide diuretics may provoke azotemia in patients with chronic renal dysfunction. They are ineffective as monotherapy in severe renal impairment (creatinine clearance < 30 mL/min), but may be used with appropriate caution in combination with loop diuretics, even in patients with creatinine clearance < 30 mL/min.

Concomitant use of angiotensin receptor blockers, including Co-Diovan® or angiotensin-converting enzyme (ACE) inhibitors, with aliskiren is contraindicated in patients with renal impairment (creatinine clearance < 60 mL/min).

There is no experience with the use of valsartan in patients with end-stage renal disease (creatinine clearance < 10 mL/min) or in patients undergoing dialysis.

Renal transplantation

Currently, there are no data on the safety of using this medicinal product in patients who have recently undergone kidney transplantation.

Hepatic impairment

Caution is required when treating patients with hepatic impairment. For patients with mild to moderate hepatic impairment without cholestasis, dose adjustment is not required. However, Co-Diovan® should be used with caution. Liver disease does not significantly alter the pharmacokinetic parameters of hydrochlorothiazide.

Thiazides may cause electrolyte imbalances, hepatic encephalopathy, and hepatorenal syndrome. Therefore, Co-Diovan® should be prescribed to such patients only after careful assessment of risk versus benefit and with monitoring of clinical and laboratory parameters. Co-Diovan® is contraindicated in patients with biliary cirrhosis or cholestasis.

Angioedema

Angioedema (including laryngeal and glottis edema leading to airway obstruction, and/or facial, lip, pharyngeal, and/or tongue swelling) has been observed in patients receiving valsartan. Some of these patients had a history of angioedema with other drugs, including other angiotensin II receptor antagonists and ACE inhibitors. If angioedema occurs, treatment with angiotensin II receptor antagonists should be discontinued immediately. Re-administration of the drug is contraindicated.

Systemic lupus erythematosus

It has been reported that thiazide diuretics may exacerbate or activate manifestations of systemic lupus erythematosus.

Other metabolic disturbances

Thiazide diuretics may alter glucose tolerance and increase serum cholesterol, triglycerides, and uric acid levels, potentially exacerbating hyperuricemia and leading to gout. Therefore, Co-Diovan® is not recommended for patients with hyperuricemia and/or gout. Diabetic patients may require adjustment of insulin or oral hypoglycemic agent dosages. Thiazides may reduce urinary calcium excretion and cause a transient, slight increase in serum calcium in the absence of calcium metabolism disorders. Marked hypercalcemia may indicate underlying hyperparathyroidism. Thiazide use should be discontinued before performing tests to assess parathyroid function.

General warnings

Caution should be exercised when administering the medicinal product to patients with a history of hypersensitivity to other angiotensin II receptor antagonists. Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergies and asthma.

Choroidal effusion, acute myopia, and secondary angle-closure glaucoma

Sulfonamides and their derivatives may cause idiosyncratic reactions leading to choroidal effusion with visual disturbances, transient myopia, and acute angle-closure glaucoma. Symptoms include acute vision loss or eye pain and usually occur within hours to weeks after starting treatment. Untreated angle-closure glaucoma may lead to permanent vision loss. Initial treatment involves immediate discontinuation of the drug. If intraocular pressure remains elevated, immediate medical treatment or surgical intervention should be considered. Risk factors for angle-closure glaucoma include a history of sulfonamide or penicillin allergy.

Patients with heart failure or prior myocardial infarction

In patients whose renal function depends on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe heart failure), treatment with ACE inhibitors or angiotensin receptor antagonists may be associated with oliguria and/or progressive azotemia, and in some cases, acute renal failure and death. Evaluation of patients with heart failure or after myocardial infarction should always include assessment of renal function.

Fertility

There is no information on the effect of valsartan on human fertility. Animal studies in rats showed no effect of valsartan on fertility.

Dose adjustment is not required for elderly patients.

Hydrochlorothiazide may reduce the level of protein-bound iodine in plasma. Hydrochlorothiazide may increase the concentration of free bilirubin in serum.

Non-melanoma skin cancer (NMSC)

An increased risk of NMSC (basal cell carcinoma and squamous cell carcinoma) with increasing cumulative dose of hydrochlorothiazide was observed in two epidemiological studies based on the Danish National Cancer Registry. The photosensitizing effect of hydrochlorothiazide may be a potential mechanism for NMSC development.

Patients taking hydrochlorothiazide should be informed about the risk of NMSC. Regular skin examinations for new lesions are recommended, and any suspicious skin changes should be reported immediately. Preventive measures to minimize skin cancer risk, such as limiting exposure to sunlight and ultraviolet radiation and using adequate sun protection when exposed to sunlight, are advised. Suspicious skin lesions should be promptly evaluated, including histological examination and biopsies. The use of hydrochlorothiazide should also be reconsidered in patients who have experienced NMSC.

Hydrochlorothiazide

Acute respiratory toxicity

Very rare cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported after hydrochlorothiazide administration. Pulmonary edema usually develops within minutes or hours after taking hydrochlorothiazide. Initial symptoms include dyspnea, fever, worsening pulmonary function, and arterial hypotension. If ARDS is suspected, Co-Diovan® should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be prescribed to patients who previously experienced ARDS after taking hydrochlorothiazide.

Patients with severe chronic heart failure or other conditions with increased renin-angiotensin-aldosterone system activity

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 ACE inhibitors has been associated with oliguria and/or progressive azotemia and rarely, acute renal failure. The use of Co-Diovan® in patients with severe chronic heart failure is not justified.

Since it cannot be excluded that suppression of the renin-angiotensin-aldosterone system by Co-Diovan® may also be associated with impaired renal function, Co-Diovan® should not be used in such patients.

Primary hyperaldosteronism

Co-Diovan® should not be used in patients with primary hyperaldosteronism, as their renin-angiotensin system is not activated.

Aortic and mitral valve stenosis, hypertrophic obstructive cardiomyopathy

As with other vasodilators, administration of Co-Diovan® to patients with aortic or mitral valve stenosis or hypertrophic obstructive cardiomyopathy requires particular caution.

Photosensitivity

Cases of photosensitivity reactions have been reported with thiazide diuretics. If a photosensitivity reaction occurs during treatment, discontinuation of therapy is recommended. If re-administration of the diuretic is considered necessary, protection of exposed skin areas from sunlight or artificial ultraviolet radiation is advised.

Pregnancy

Angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continuation of angiotensin II receptor antagonist therapy is considered essential, pregnant patients or those planning pregnancy should be switched to alternative antihypertensive therapies with established safety profiles during pregnancy. If pregnancy is detected, treatment with angiotensin II receptor antagonists should be discontinued immediately and alternative therapy initiated if necessary.

Use during pregnancy or breastfeeding

Pregnancy

Val­sartan

The medicinal product should not be used during pregnancy or by women planning to become pregnant. If pregnancy is confirmed during treatment with this product, its use should be discontinued immediately and replaced with another medicinal product approved for use during pregnancy.

It is known that use of angiotensin II receptor antagonists during the second and third trimesters causes fetotoxicity in humans (reduced renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia).

If angiotensin II receptor antagonists are used from the second trimester of pregnancy, ultrasound monitoring of fetal kidneys and skull is recommended.

Infants whose mothers received angiotensin II receptor antagonists require careful monitoring for hypotension.

Hydrochlorothiazide

Experience with hydrochlorothiazide use during pregnancy is limited, 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 trimesters of pregnancy may impair fetoplacental circulation and cause effects in the fetus and newborn such as jaundice, electrolyte imbalance, and thrombocytopenia.

The physician prescribing a drug acting on the RAAS should inform the woman about the potential risks during pregnancy.

Due to the mechanism of action of angiotensin II receptor antagonists, the risk of embryopathy and fetal disease cannot be excluded. According to retrospective data, use of ACE inhibitors in the first trimester is associated with a potential risk of congenital defects. Moreover, fetal injury and death have been reported with use during the second and third trimesters of drugs directly affecting the renin-angiotensin-aldosterone system (RAAS). Fetal renal perfusion, dependent on RAAS development, begins during the second trimester. Thus, the risk associated with valsartan treatment is higher during the second and third trimesters. Reports of spontaneous abortions, oligohydramnios, and renal dysfunction in newborns whose mothers inadvertently took valsartan during pregnancy have been documented.

Newborns exposed to the drug in utero require careful monitoring of diuresis, hyperkalemia, and blood pressure. If necessary, appropriate medical measures (e.g., rehydration) should be taken to remove the drug from circulation.

Intrauterine exposure to thiazide diuretics, including hydrochlorothiazide, may cause jaundice or thrombocytopenia in the fetus and newborn or other adverse reactions observed in adults.

Lactation

In animal studies (rats), valsartan was excreted in breast milk. Hydrochlorothiazide crosses the placenta and is excreted in human breast milk in small amounts. There are no studies in breastfeeding women; therefore, treatment with Co-Diovan® should not be used during breastfeeding.

If use of the drug is essential, breastfeeding should be discontinued. There is no information on the use of valsartan during breastfeeding. Hydrochlorothiazide crosses the placenta and is excreted in human breast milk in small amounts. Thiazides in high doses cause diuresis, which may suppress milk production. During lactation, alternative treatment options with better-established safety profiles are preferred, especially when breastfeeding a newborn or preterm infant.

Ability to affect reaction speed when driving or operating machinery

During the initial phase of treatment (duration individually determined by the physician), driving and performing work that may lead to accidents are prohibited due to the occasional occurrence of dizziness or fatigue. The extent of restriction thereafter is determined by the physician.

Dosage and Administration

The recommended dose of Co-Diovan® is 1 tablet of 80 mg/12.5 mg once daily. If blood pressure is not adequately controlled after 3–4 weeks of treatment, consideration should be given to continuing therapy with a dose of 1 tablet of 160 mg/12.5 mg once daily. Tablets of 160 mg/25 mg are indicated for patients in whom adequate blood pressure reduction is not achieved with tablets of 160 mg/12.5 mg. If blood pressure remains insufficiently controlled with tablets of 160 mg/25 mg, consideration should be given to continuing therapy with a dose of 320 mg/12.5 mg. Tablets of 320 mg/25 mg are indicated for patients in whom adequate blood pressure reduction is not achieved with tablets of 320 mg/12.5 mg.

The maximum daily dose is 320 mg/25 mg.

If there is no response after 8 weeks of treatment with Co-Diovan®, consideration should be given to using an additional or alternative antihypertensive agent.

Maximum antihypertensive effect is achieved within 2–4 weeks. Some patients may require 4–8 weeks of treatment.

Co-Diovan® may be taken regardless of food intake. Tablets should be swallowed with a small amount of water.

Use in elderly patients (over 65 years of age)

Co-Diovan® can be used in patients of any age.

Use in patients with renal impairment

Dose reduction may be necessary in patients with renal impairment. Since Co-Diovan® contains hydrochlorothiazide, it is contraindicated in patients with anuria, and special caution is required when used in patients with severe renal impairment (creatinine clearance < 30 mL/min).

There are no data on the use of valsartan in patients with end-stage renal disease (creatinine clearance < 10 mL/min) or in patients undergoing dialysis.

Hepatic impairment

Dose reduction may be necessary in patients with hepatic impairment. Since Co-Diovan® contains hydrochlorothiazide, it should be used with caution in patients with hepatic impairment. Since Co-Diovan® contains valsartan, it is contraindicated in patients with biliary cirrhosis or cholestasis.

The dose of valsartan in patients with mild to moderate non-biliary hepatic impairment and without cholestasis should not exceed 80 mg.

Children

Co-Diovan® is not recommended for use in children due to lack of data on safety and efficacy.

Overdose

Overdose with valsartan may lead to pronounced hypotension, which in turn may result in decreased level of consciousness, circulatory failure, and/or shock.

Overdose with hydrochlorothiazide may cause symptoms such as nausea, drowsiness, hypovolemia, electrolyte imbalance, and consequently arrhythmias and muscle spasms. The most characteristic signs of overdose also include tachycardia, arterial hypotension, shock, weakness, confusion, dizziness, muscle cramps, paresthesia, exhaustion, disturbances of consciousness, vomiting, thirst, polyuria, oliguria, anuria, alkalosis, and elevated blood urea nitrogen (mainly due to renal failure).

In all cases of overdose, general supportive measures should be implemented, including continuous monitoring of the patient and measures to stabilize cardiovascular function.

Therapeutic interventions depend on the time elapsed since ingestion and the severity of symptoms; the primary goal is to restore hemodynamic stability.

If the drug was recently ingested, vomiting should be induced. If a significant time has passed since ingestion, the patient should be given an adequate amount of activated charcoal.

In case of hypotension, the patient should be placed in a supine position and immediate restoration of fluid and electrolyte balance should be achieved by intravenous administration of isotonic saline solution.

Valsartan cannot be effectively removed by hemodialysis due to its high plasma protein binding; however, hemodialysis is effective in removing hydrochlorothiazide from the body.

Adverse Reactions

The adverse reactions listed below were observed during 5 controlled clinical studies involving 7616 patients, of whom 4372 received valsartan in combination with hydrochlorothiazide.

The frequency of adverse reactions is defined as follows: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000); very rare (< 1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are listed in order of decreasing severity.

Adverse reactions occurring during administration of valsartan/hydrochlorothiazide

Infections
Uncommon:	viral infections, fever.
Metabolism and nutrition disorders
Uncommon:	dehydration.
Not known:	hypokalemia, hyponatremia.
Nervous system disorders
Common:	headache, fatigue, somnolence.
Uncommon:	asthenia, dizziness, insomnia, anxiety, paresthesia.
Rare:	depression.
Not known:	syncope.
Eye disorders
Uncommon:	vision disorders.
	conjunctivitis.
Ear and labyrinth disorders
Uncommon:	otitis media, tinnitus.
Cardiac disorders
Uncommon:	palpitations, tachycardia.
Vascular disorders
Uncommon:	edema, arterial hypotension, hyperhidrosis.
Respiratory, thoracic and mediastinal disorders
Common:	cough, rhinitis, pharyngitis, upper respiratory tract infections.
Uncommon:	bronchitis, dyspnea, sinusitis, pharyngolaryngeal pain, dry mouth.
Very rare:	epistaxis, acute respiratory distress syndrome (ARDS).
Not known:	non-cardiogenic pulmonary edema.
Gastrointestinal disorders
Common:	diarrhea.
Uncommon:	abdominal pain, dyspepsia, nausea, gastroenteritis.
Musculoskeletal and connective tissue disorders
Common:	back pain, arthralgia.
Uncommon:	limb pain, chest pain, neck pain, arthritis, sprains and deformities, muscle spasms, myalgia.
Renal and urinary disorders
Uncommon:	frequency of urination, urinary tract infections.
Very rare:	renal function impairment.
Reproductive system disorders
Common:	erectile dysfunction.
General disorders
Uncommon:	increased fatigue.
Investigations
Not known:	elevated plasma uric acid levels, elevated plasma bilirubin and creatinine levels, hypokalemia, hyponatremia, increased blood urea nitrogen, neutropenia.

A more than 20% decrease in serum potassium levels was observed in 3.7% of patients receiving Co-Diovan® and in 3.1% of patients receiving placebo.

An increase in creatinine and blood urea nitrogen was observed in 1.9% and 14.7% of patients receiving Co-Diovan®, respectively, and in 0.4% and 6.3% of patients receiving placebo, respectively, in controlled clinical trials.

During clinical trials in hypertensive patients, the following events were observed regardless of causal relationship to the investigational drug: hypesthesia, influenza, insomnia, ligament sprain, muscle strain, nasal congestion, nasopharyngitis, neck pain, peripheral edema, and sinus congestion.

The following reactions were associated with monotherapy with valsartan but were not observed with use of Co-Diovan®.

Rarely, therapy with valsartan may be associated with a reduction in hemoglobin and hematocrit levels. In controlled clinical trials, significant (> 20%) reductions in hematocrit and hemoglobin levels were observed in 0.8% and 0.4% of patients, respectively. Hematocrit or hemoglobin reduction was observed in 0.1% of patients receiving placebo.

Neutropenia was observed in 1.9% of patients receiving valsartan and in 1.6% of patients receiving ACE inhibitors.

In controlled clinical trials, significant increases in serum creatinine, potassium, and total bilirubin levels were observed in 0.8%, 4.4%, and 6% of patients receiving valsartan, respectively, and in 1.6%, 6.4%, and 12.9% of patients receiving ACE inhibitors, respectively.

Elevated liver enzymes were infrequently observed in patients receiving valsartan.

There is no need for special laboratory monitoring in patients with essential hypertension receiving valsartan therapy.

The following reactions were observed during clinical trials in patients with hypertensive disease: upper abdominal pain, anxiety, arthritis, back pain, bronchitis, acute bronchitis, chest pain, dizziness, dyspepsia, dyspnea, dry mouth, epistaxis, impotence, gastroenteritis, headache, increased sweating, hypesthesia, influenza, insomnia, ligament sprain, muscle cramps, muscle strain, nausea, nasal congestion, nasal sinus congestion, neck pain, edema, peripheral edema, otitis media, limb pain, palpitations, pharyngolaryngeal pain, polyuria, increased temperature, nasopharyngitis, sinusitis, somnolence, tachycardia, upper respiratory tract infections, urinary tract infections, vertigo, viral infections, and visual disturbances. It is unknown whether these effects are causally related to therapy.

In the post-marketing period, there have been reports of syncope and very rare cases of angioedema, rash, loss of consciousness, and other hypersensitivity reactions such as serum sickness and vasculitis, as well as cases of renal dysfunction.

Bullous dermatitis has been reported, with unknown frequency.

Additional information regarding individual components

Adverse reactions observed with the use of valsartan and hydrochlorothiazide separately may also be potential adverse effects with Co-Diovan®, even if they were not observed in clinical trials or during the post-marketing period.

Adverse reactions observed with the use of valsartan

From the blood and lymphatic system
Unknown:	decreased hemoglobin levels, decreased hematocrit.
From the immune system
Unknown:	other hypersensitivity reactions/allergic reactions, including serum sickness.
Metabolism and nutrition disorders
Unknown:	increased plasma potassium levels, hyponatremia.
From the ear and labyrinthine disorders
Uncommon:	vestibular vertigo (vertigo).
Vascular disorders
Unknown:	vasculitis.
Gastrointestinal disorders
Uncommon:	abdominal pain.
Hepatobiliary disorders
Unknown:	elevated liver function tests.
From the skin and subcutaneous tissue
Unknown:	pruritus, bullous dermatitis.
From the urinary system
Unknown:	renal failure.
Musculoskeletal and connective tissue disorders
Common:	arthralgia.
Nervous system disorders
Uncommon:	edema, asthenia, insomnia, rash, dizziness.
Rare:	gastroenteritis, neuralgia,
Reproductive system disorders
Uncommon:	decreased libido.
Very rare:	cardiac arrhythmia, thrombocytopenia, acute renal failure. One case of angioneurotic edema has been reported.

Reactions observed during clinical trials in patients with hypertension, regardless of their causal relationship with the investigational drug: arthralgia, asthenia, back pain, diarrhea, dizziness, headache, insomnia, decreased libido, nausea, edema, pharyngitis, rhinitis, sinusitis, upper respiratory tract infections, viral infections.

Adverse reactions occurring with hydrochlorothiazide use

Hydrochlorothiazide has been widely used for many years, often at higher doses than those contained in Co-Diovan®. The adverse reactions listed below have been reported in patients receiving thiazide diuretics, including hydrochlorothiazide, as monotherapy.

Metabolism and nutrition disorders
Very common:	hypokalaemia, increased blood lipid levels.
Common:	hyponatraemia, hypomagnesaemia, hyperuricaemia, decreased appetite.
Rare:	hypercalcaemia, hyperglycaemia, glucosuria, and worsening of metabolism in patients with diabetes mellitus.
Very rare:	hypochloraemic alkalosis.
Blood and lymphatic system disorders
Rare:	thrombocytopenia, sometimes with purpura.
Very rare:	leukopenia, agranulocytosis, bone marrow suppression, haemolytic anaemia.
Not known:	aplastic anaemia.
Immune system disorders
Very rare:	necrotising vasculitis, hypersensitivity reactions.
Psychiatric disorders
Rare:	sleep disturbances.
Nervous system disorders
Rare:	headache, dizziness, depression, paraesthesia.
Eye disorders
Rare:	blurred vision during the first few weeks after starting treatment.
Not known:	choroidal effusion, acute myopia, and acute angle-closure glaucoma.
Cardiac disorders
Rare:	arrhythmia.
Vascular disorders
Common:	orthostatic hypotension, which may be aggravated by alcohol, anaesthetics, and sedative drugs.
Respiratory, thoracic and mediastinal disorders
Very rare:	respiratory failure, including pneumonia and pulmonary oedema.
Gastrointestinal disorders
Common:	mild nausea and vomiting.
Rare:	constipation, gastrointestinal discomfort, diarrhoea.
Very rare:	pancreatitis.
Hepatobiliary disorders
Rare:	intrahepatic cholestasis or jaundice.
Skin and subcutaneous tissue disorders
Common:	urticaria and other types of rash.
Rare:	photosensitisation.
Very rare:	toxic epidermal necrolysis, lupus-like skin reactions, reactivation of cutaneous lupus erythematosus.
Not known:	multiform erythema.
Reproductive system disorders
Common:	impotence.
Renal and urinary disorders
Not known:	acute renal failure, renal dysfunction.
General disorders
Not known:	fever, fatigue.
Musculoskeletal and connective tissue disorders
Not known:	muscle spasms.
Benign and malignant neoplasms (including cysts and polyps)
Not known:	non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma).

Description of individual side effects and additional information

Non-melanoma skin cancer (NMSC) (basal cell carcinoma and squamous cell carcinoma). Based on available epidemiological data, a cumulative dose-dependent association has been observed between exposure to hydrochlorothiazide and the development of NMSC.

Reporting of adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging to protect from moisture. Keep out of reach and sight of children.

Packaging.

14 tablets per blister, 1 or 2 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Novartis Farma S.p.A./Novartis Farma S.p.A.

Manufacturer's address and location of operations.

Via Provinciale Schito 131, 80058 Torre Annunziata (NA), Italy /
Via Provinciale Schito 131, 80058 Torre Annunziata (NA), Italy.