Excorge h

FOR MEDICAL USE OF THE MEDICINAL PRODUCT EXFORGE H

Composition:

Active substances: amlodipine besylate, valsartan, hydrochlorothiazide;

1 tablet of 5 mg/160 mg/12.5 mg contains: amlodipine besylate 6.94 mg, equivalent to 5 mg amlodipine base, valsartan 160 mg, and hydrochlorothiazide 12.5 mg;

1 tablet of 10 mg/160 mg/12.5 mg contains: amlodipine besylate 13.87 mg, equivalent to 10 mg amlodipine base, valsartan 160 mg, and hydrochlorothiazide 12.5 mg;

1 tablet of 5 mg/160 mg/25 mg contains: amlodipine besylate 6.94 mg, equivalent to 5 mg amlodipine base, valsartan 160 mg, and hydrochlorothiazide 25 mg;

1 tablet of 10 mg/160 mg/25 mg contains: amlodipine besylate 13.87 mg, equivalent to 10 mg amlodipine base, valsartan 160 mg, and hydrochlorothiazide 25 mg;

Excipients: microcrystalline cellulose, crospovidone type A, colloidal anhydrous silicon dioxide, magnesium stearate, hypromellose, substitution type 2910 (3 mPa·s), titanium dioxide (E 171), macrogol 4000, talc, iron oxide yellow (E 172) – only for tablets of 5 mg/160 mg/25 mg, 10 mg/160 mg/12.5 mg, 10 mg/160 mg/25 mg; iron oxide red (E 172) – only for tablets of 10 mg/160 mg/12.5 mg.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Tablets 5 mg/160 mg/12.5 mg – white, oval, biconvex, film-coated tablets with bevelled edges, without a break line, marked with "NVR" on one side and "VCL" on the other;

Tablets 10 mg/160 mg/12.5 mg – pale yellow, oval, biconvex, film-coated tablets with bevelled edges, without a break line, marked with "NVR" on one side and "VDL" on the other;

Tablets 5 mg/160 mg/25 mg – yellow, oval, biconvex, film-coated tablets with bevelled edges, without a break line, marked with "NVR" on one side and "VEL" on the other;

Tablets 10 mg/160 mg/25 mg – yellow-brown, oval, biconvex, film-coated tablets with bevelled edges, without a break line, marked with "NVR" on one side and "VHL" on the other.

Pharmacotherapeutic group. Angiotensin II antagonists, other combinations. Valsartan, amlodipine and hydrochlorothiazide. ATC code C09DX01.

Pharmacological properties.

Pharmacodynamics.

Exforge H contains three antihypertensive agents with complementary mechanisms of blood pressure control in patients with essential hypertension: amlodipine belongs to the class of calcium channel blockers, valsartan belongs to the class of angiotensin II antagonists, and hydrochlorothiazide belongs to the class of thiazide diuretics. The combination of these three components demonstrates complementary antihypertensive effects.

Amlodipine

Amlodipine, included in Exforge H, inhibits transmembrane influx of calcium ions into cardiac muscle and vascular smooth muscle. The antihypertensive mechanism of action of amlodipine occurs via direct vasodilatory effects on vascular smooth muscle, resulting in decreased peripheral vascular resistance and blood pressure.

At therapeutic doses in patients with arterial hypertension, amlodipine causes vasodilation, leading to reduced blood pressure in both supine and standing positions. This reduction in blood pressure is not accompanied by significant changes in heart rate or plasma catecholamine levels during long-term treatment.

Plasma concentrations correlate with effect in both young and elderly patients.

In patients with arterial hypertension and normal renal function, amlodipine at therapeutic doses reduces renal vascular resistance and increases glomerular filtration rate and effective renal plasma flow without altering filtration fraction or proteinuria.

Valsartan

Valsartan is an orally active, potent, and specific angiotensin II receptor antagonist. Valsartan selectively acts on the AT1 receptor subtype, which mediates the known effects of angiotensin II.

Administration of valsartan to patients with arterial hypertension leads to reduced blood pressure without affecting pulse rate.

In most patients, after oral administration of a single dose, onset of the hypotensive effect occurs within 2 hours, and maximum reduction in blood pressure is achieved within 4–6 hours. The antihypertensive effect persists for 24 hours after drug administration. With repeated dosing, maximum reduction in blood pressure (at all dosage regimens) is typically achieved within 2–4 weeks.

Hydrochlorothiazide

The site of action of thiazide diuretics is primarily the distal convoluted tubules of the kidneys. It has been confirmed that high-affinity receptors exist in the renal cortex, serving as the main binding site for thiazide diuretics and inhibition of NaCl transport in the distal convoluted tubules. The mechanism of action of thiazides involves inhibition of Na+Cl– transporters, possibly through competition for Cl– binding sites, thereby affecting electrolyte reabsorption mechanisms: directly enhancing excretion of sodium and chloride to approximately equivalent degrees, and indirectly, via diuretic effect, reducing plasma volume, which leads to increased plasma renin activity, aldosterone secretion, and urinary potassium excretion, as well as decreased serum potassium levels.

Non-melanoma skin cancer (NMSC)

Available epidemiological data indicate a cumulative dose-dependent association between hydrochlorothiazide exposure and development of NMSC. One study included 71,533 cases of basal cell carcinoma (with 1,430,833 individuals in the control group) and 8,629 cases of squamous cell carcinoma (with 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 carcinomas. Another study showed a possible association between lip cancer and hydrochlorothiazide use: 633 cases of lip cancer were compared with 63,067 population-based controls 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) for high dose (~25,000 mg) and OR 7.7 (5.7–10.5) for the highest dose (~100,000 mg).

Other: Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

Two large randomized controlled trials, ONTARGET (Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (Veterans Affairs Nephropathy in Diabetes trial), investigated the concomitant use of an ACE inhibitor with an angiotensin II receptor antagonist.

The ONTARGET trial included patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of target organ damage. The VA NEPHRON-D trial included patients with type 2 diabetes and diabetic nephropathy.

These studies did not demonstrate significant beneficial effects on renal and/or cardiovascular function or mortality; however, an increased risk of hyperkalemia, acute kidney injury, and/or hypotension was observed compared to monotherapy. Given the similar pharmacodynamic properties, these findings are also relevant for other ACE inhibitors and angiotensin II receptor antagonists.

Therefore, concomitant use of ACE inhibitors and angiotensin II receptor antagonists is not recommended in patients with diabetic nephropathy (see section "Special precautions").

Additionally, the ALTITUDE trial (Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints) evaluated the benefits of adding aliskiren to standard therapy (an ACE inhibitor or angiotensin II receptor antagonist) in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. The trial was prematurely terminated due to increased risk of adverse outcomes. Fatal cardiovascular events and stroke occurred more frequently in the aliskiren group than in the placebo group; furthermore, adverse events and serious adverse events (hyperkalemia, hypotension, and renal dysfunction) were more frequent in the aliskiren group than in the placebo group.

Pharmacokinetics.

Linearity

Amlodipine, valsartan, and hydrochlorothiazide demonstrate linear pharmacokinetics.

Amlodipine/valsartan/hydrochlorothiazide

After oral administration of Exforge H to healthy adult volunteers, maximum plasma concentrations of amlodipine, valsartan, and hydrochlorothiazide were reached within 6–8 hours, 3 hours, and 2 hours, respectively. The rate and extent of absorption of amlodipine, valsartan, and hydrochlorothiazide following administration of Exforge H are similar to those observed when the components are administered as individual drugs.

Amlodipine

Absorption. After oral administration of amlodipine alone at therapeutic doses, maximum plasma concentration is reached within 6–12 hours. Absolute bioavailability ranges from 64% to 80%. Food intake does not affect the bioavailability of amlodipine.

Distribution. The volume of distribution is approximately 21 L/kg. In vitro studies with amlodipine showed that approximately 97.5% of the drug in circulation is bound to plasma proteins.

Metabolism. Amlodipine is extensively metabolized (approximately 90%) in the liver to inactive metabolites.

Elimination. Amlodipine is eliminated from plasma in a biphasic manner, with a terminal elimination half-life of approximately 30–50 hours. Steady-state plasma levels are achieved after 7–8 days of continuous administration. Approximately 10% of unchanged amlodipine and 60% of its metabolites are excreted in urine.

Valsartan

Absorption. After oral administration of valsartan alone, maximum concentrations are reached within 2–4 hours. Mean absolute bioavailability is 23%. Food intake reduces exposure (as defined by AUC) to valsartan by approximately 40% and maximum plasma concentration (Cmax) by approximately 50%, although approximately 8 hours after administration, plasma concentrations are similar between fasting and postprandial groups. However, this reduction in AUC is not associated with clinically significant reduction in therapeutic effect; therefore, valsartan can be administered independently of food intake.

Distribution. The steady-state volume of distribution of valsartan after intravenous administration is approximately 17 liters, indicating limited tissue distribution. Valsartan is highly bound to serum proteins (94–97%), primarily to serum albumin.

Metabolism. Valsartan undergoes minimal biotransformation, with only about 20% of the dose excreted as metabolites. A hydroxymetabolite has been identified in plasma at low concentrations (less than 10% of valsartan AUC). This metabolite is pharmacologically inactive.

Elimination. Valsartan is primarily eliminated via feces (approximately 83% of dose) and urine (approximately 13% of dose), mainly as unchanged drug. After intravenous administration, plasma clearance of valsartan is about 2 L/hour, and renal clearance is 0.62 L/hour (about 30% of total clearance). The elimination half-life of valsartan is 6 hours.

Hydrochlorothiazide

Absorption. 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 dose range. No changes in hydrochlorothiazide kinetics are observed with repeated administration, and accumulation is minimal with once-daily dosing. When administered with food, both increases and decreases in systemic availability of hydrochlorothiazide have been observed compared to administration under fasting conditions. The magnitude of these effects is minor and of limited clinical significance. Absolute bioavailability of hydrochlorothiazide after oral administration is 60–80%.

Distribution. The apparent volume of distribution is 4–8 L/kg. Hydrochlorothiazide in circulation is bound to plasma proteins (40–70%), primarily to serum albumin. Hydrochlorothiazide also accumulates in erythrocytes at levels 1.8 times higher than in plasma.

Metabolism. Hydrochlorothiazide is excreted unchanged.

Elimination. More than 95% of the absorbed dose is excreted unchanged in urine. Renal clearance involves passive filtration and active secretion in renal tubules. Elimination half-life is 6–15 hours.

Special patient populations

Children (under 18 years of age)

No pharmacokinetic data are available in children.

Elderly patients (aged 65 years and older)

Time to reach Cmax for amlodipine is similar in younger and elderly patients. In elderly patients, amlodipine clearance tends to be reduced, resulting in increased AUC and elimination half-life. Mean systemic AUC of valsartan is 70% higher in elderly patients than in younger patients; therefore, dose escalation in these patients should be done with caution.

Systemic exposure to valsartan is slightly higher in elderly patients compared to younger patients, but this difference is not clinically significant.

Limited data suggest that systemic clearance of hydrochlorothiazide is reduced in both healthy elderly volunteers and elderly patients with arterial hypertension compared to younger healthy volunteers.

Since the three components of the drug are similarly well tolerated by both younger and elderly patients, the recommended dosing regimen is the same for both groups.

Renal impairment

Renal impairment does not significantly affect the pharmacokinetics of amlodipine. As expected for a drug with renal clearance accounting for only 30% of total plasma clearance, no correlation was observed between renal function and systemic exposure to valsartan.

Therefore, patients with mild to moderate renal impairment can be treated with the usual initial dose.

Hepatic impairment

In patients with hepatic impairment, amlodipine clearance is reduced, resulting in an increase in AUC by approximately 40–60%. On average, systemic exposure (as measured by AUC) to valsartan is twice as high in patients with mild to moderate chronic liver disease compared to healthy adult volunteers (matched for age, sex, and body weight). The drug should be used with caution in patients with hepatic disease.

The combination of amlodipine/valsartan/hydrochlorothiazide has not been tested for genotoxicity or carcinogenicity, as no signs of interaction between these long-marketed agents have been observed. However, amlodipine, valsartan, and hydrochlorothiazide have been individually tested for genotoxicity and carcinogenicity, and all results were negative.

Clinical Characteristics

Indications

Treatment of essential hypertension in adult patients whose blood pressure is adequately controlled with the combination of amlodipine, valsartan, and hydrochlorothiazide, administered either as three separate agents or as two agents, one of which is a combination product.

Contraindications

• Hypersensitivity to the active substances, other sulfonamides, dihydropyridine derivatives, or to any excipients.
• Pregnancy or planned pregnancy (see "Use during pregnancy or breastfeeding").
• Hepatic impairment, biliary cirrhosis, or cholestasis.
• Severe renal impairment (glomerular filtration rate (GFR) <30 mL/min/1.73 m²), anuria, or patients on dialysis.
• Concomitant use of Exforge HCT with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR <60 mL/min/1.73 m²).
• Refractory hypokalemia, hyponatremia, hypercalcemia, symptomatic hyperuricemia.
• Severe hypotension.
• Shock (including cardiogenic shock).
• Obstruction of the left ventricular outflow tract (e.g., hypertrophic obstructive cardiomyopathy, severe aortic stenosis).
• Hemodynamically unstable heart failure following acute myocardial infarction.

Interaction with other medicinal products and other forms of interaction

No drug interaction studies have been conducted specifically with Exforge HCT. Table 1 provides information only on interactions known for each individual active component.

However, it is important to note that Exforge HCT may enhance the hypotensive effect of other antihypertensive agents.

Table 1

Dual blockade of the RAAS with angiotensin II receptor antagonists, ACE inhibitors, or aliskiren

Clinical data have shown that dual blockade of the RAAS by concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is associated with an increased risk of adverse reactions, such as hypotension, hyperkalemia, and renal dysfunction (including acute renal failure), compared to monotherapy with an agent acting on the RAAS.

Special precautions for use.

The safety and efficacy of amlodipine in hypertensive crisis have not been studied.

Patients with sodium depletion and dehydration

Excessive hypotension, including orthostatic hypotension, was observed in 1.7% of patients receiving the maximum dose of Exforge HCT (10 mg/320 mg/25 mg), compared to 1.8% of patients receiving valsartan/hydrochlorothiazide (320 mg/25 mg), 0.4% of patients receiving amlodipine/valsartan (10 mg/320 mg), and 0.2% of patients receiving hydrochlorothiazide/amlodipine (25 mg/10 mg) in a controlled study involving patients with moderate to severe uncomplicated hypertension.

Symptomatic arterial hypotension may occur in patients with salt depletion and/or dehydration who are receiving high-dose diuretics upon initiation of Exforge HCT. It is recommended to correct such conditions prior to starting Exforge HCT or to closely monitor the patient at the beginning of treatment.

If marked hypotension occurs during treatment with Exforge HCT, the patient should be placed in a supine position with elevated legs. If necessary, intravenous infusion of physiological saline solution should be administered. Treatment may be continued after stabilization of blood pressure.

Changes in serum electrolyte levels

Amlodipine/valsartan/hydrochlorothiazide

In a controlled study of Exforge HCT, the opposing effects of valsartan 320 mg and hydrochlorothiazide 25 mg on serum potassium levels approximately balance each other in many patients. In others, one or the other effect may predominate.

Serum electrolyte levels should be monitored periodically to detect potential electrolyte imbalances.

Periodic monitoring of serum electrolytes, particularly potassium, should be performed at appropriate intervals to prevent possible electrolyte imbalances, especially in patients with risk factors such as impaired renal function, concomitant use of other medications, or a history of electrolyte imbalance.

Valsartan

Concomitant use with potassium-containing supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other agents that may increase potassium levels (e.g., heparin) is not recommended. If necessary, serum potassium levels should be monitored.

Hydrochlorothiazide

Hypokalemia has been reported during treatment with thiazide diuretics, including hydrochlorothiazide.

Treatment with Exforge HCT should be initiated only after correction of hypokalemia and any coexisting hypomagnesemia. Thiazide diuretics may cause hypokalemia or exacerbate pre-existing hypokalemia. Thiazide diuretics should be used with caution in patients with conditions involving potassium loss, such as salt-wasting nephropathy and prerenal (cardiogenic) renal dysfunction. If hypokalemia develops during hydrochlorothiazide therapy, Exforge HCT should be discontinued until potassium balance is stably corrected.

Treatment with thiazide diuretics, including hydrochlorothiazide, is associated with the development of hyponatremia and hypochloremic alkalosis or worsening of pre-existing hyponatremia. Hyponatremia may occur with neurological symptoms (nausea, progressive disorientation, apathy). Treatment with hydrochlorothiazide should be initiated only after correction of existing hyponatremia. In cases of severe or rapidly developing hyponatremia during Exforge HCT therapy, the drug should be discontinued until serum sodium levels normalize. Thiazides, including hydrochlorothiazide, increase urinary magnesium excretion, which may lead to hypomagnesemia. Thiazide diuretics reduce calcium excretion, potentially leading to hypercalcemia.

All patients receiving thiazide diuretics should undergo periodic monitoring of electrolyte levels, particularly potassium, sodium, and magnesium.

Renal impairment

Thiazide diuretics may accelerate azotemia in patients with chronic kidney disease.

When using Exforge HCT, periodic monitoring of serum potassium, creatinine, and uric acid levels is recommended in patients with impaired renal function.
Exforge HCT is contraindicated in patients with severe renal impairment, anuria, or those on dialysis.

Dose adjustment of Exforge HCT is not required in patients with mild to moderate renal impairment (GFR ≥30 mL/min/1.73 m²).

Renal artery stenosis

Exforge HCT should be used with caution in the treatment of hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis of a solitary kidney, as serum urea and creatinine levels may increase.

Kidney transplantation

There is currently no information on the safety of Exforge HCT in patients who have recently undergone kidney transplantation.

Hepatic impairment

Valsartan is primarily excreted unchanged in bile. The elimination half-life of amlodipine is prolonged and the AUC (plasma concentration–time) is higher in patients with hepatic impairment; dosage recommendations are lacking. For patients with mild to moderate hepatic impairment not associated with cholestasis, the maximum recommended dose of valsartan is 80 mg. Therefore, Exforge HCT is not recommended for this patient group.

Angioedema.

Angioedema, including laryngeal and glottal edema that may lead to airway obstruction, and/or facial, lip, pharyngeal, and/or tongue swelling, has been observed in patients taking valsartan. Some of these patients had a history of angioedema with other drugs, including angiotensin-converting enzyme (ACE) inhibitors. Exforge HCT should be discontinued immediately if angioedema occurs; re-administration is not recommended.

Heart failure and coronary artery disease/post-myocardial infarction

Due to inhibition of the renin-angiotensin-aldosterone system, renal dysfunction may be expected in sensitive patients. In patients with severe heart failure, in whom renal function may depend on renin-angiotensin-aldosterone system activity, treatment with ACE inhibitors and angiotensin receptor antagonists may lead to oliguria and/or progressive azotemia (rarely) with acute renal failure and/or fatal outcomes. Similar outcomes have been reported with valsartan. Evaluation of patients with heart failure or post-myocardial infarction should always include assessment of renal function.

In a long-term placebo-controlled study of amlodipine (PRAISE-2) in patients with NYHA (New York Heart Association) class III–IV non-ischemic heart failure, the incidence of pulmonary edema was higher with amlodipine compared to placebo, despite a negligible difference in the development or worsening of heart failure.

Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of cardiovascular events and mortality.

Exforge HCT should be prescribed with caution in patients with heart failure and coronary artery disease, particularly at the maximum dose of 10 mg/320 mg/25 mg, due to limited data in this patient population.

Aortic and mitral valve stenosis

As with other vasodilators, Exforge HCT should be administered with particular caution in patients with mild aortic or mitral valve stenosis.

Pregnancy

Treatment with angiotensin II receptor antagonists (ARAs-II) should not be initiated during pregnancy. If continued ARA-II therapy is necessary, patients planning pregnancy should be switched to alternative antihypertensive agents with an established safety profile in pregnancy. If pregnancy occurs, ARA-II therapy should be discontinued immediately and, if necessary, alternative therapy initiated.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism should not be treated with the angiotensin II antagonist valsartan, as the renin-angiotensin system is not activated in these patients. Therefore, Exforge HCT is not recommended for this patient group.

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 increase serum cholesterol, triglycerides, and uric acid levels. Dose adjustments of insulin or oral hypoglycemic agents may be necessary in patients with diabetes.

Since Exforge HCT contains hydrochlorothiazide, it is contraindicated in systemic hyperuricemia. Hydrochlorothiazide may increase serum uric acid levels due to reduced uric acid clearance and may precipitate hyperuricemia or acute gout attacks in susceptible patients.

Thiazides may reduce urinary calcium excretion and cause transient, mild increases in serum calcium levels in the absence of known calcium metabolism disorders. Exforge HCT should be discontinued if hypercalcemia develops during treatment. Serum calcium levels should be monitored periodically during thiazide therapy. Marked hypercalcemia may indicate occult hyperparathyroidism. Thiazide use should be discontinued before parathyroid function testing.

Photosensitivity

Cases of photosensitivity reactions have been reported with thiazide diuretics. If photosensitivity reactions occur during treatment with Exforge HCT, therapy should be discontinued. If reinitiation of diuretic therapy is considered necessary, protection of exposed skin from sunlight or artificial UV radiation is recommended.

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

Hydrochlorothiazide, a sulfonamide, has been associated with an allergic reaction leading to choroidal effusion with visual field defects, acute transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and usually occur within hours to the first week after initiation of therapy. Untreated angle-closure glaucoma may lead to irreversible vision loss.

Hydrochlorothiazide should be discontinued as soon as possible. If intraocular pressure remains uncontrolled, immediate medical or surgical intervention should be considered. Risk factors for angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

General

Exforge HCT should be prescribed with caution in patients with a history of hypersensitivity to other angiotensin II receptor antagonists. Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergies or asthma.

Elderly patients (aged 65 years and older)

Exforge HCT should be prescribed with caution, particularly with frequent blood pressure monitoring, in elderly patients, especially at the maximum dose of 10 mg/320 mg/25 mg, due to limited data in this population.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

Evidence indicates that concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of hypotension, hyperkalemia, and renal impairment (including acute renal failure).

Therefore, dual RAAS blockade through concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is not recommended.

If dual blockade is required, it should be performed under close specialist supervision with continuous monitoring of renal function, electrolyte levels, and blood pressure. Concomitant use of ACE inhibitors and angiotensin II receptor antagonists is not recommended in patients with diabetic nephropathy.

Non-melanoma skin cancer (NMSC)

An increased risk of non-melanoma skin cancer (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. They should be advised to regularly check their skin for new lesions and to report any suspicious changes immediately. Preventive measures to minimize skin cancer risk, such as limiting sun and UV exposure and using adequate protection when exposed to sunlight, are recommended. Suspicious skin lesions should be promptly evaluated, including histological examination of biopsies. Hydrochlorothiazide use should also be reconsidered in patients with a history of NMSC.

Acute respiratory toxicity

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

Use during pregnancy or breastfeeding.

Pregnancy

Amlodipine

Safety studies of amlodipine use during pregnancy have not been conducted. Reproductive toxicity was observed in animal studies at high doses. Use during pregnancy is recommended only if no safer alternative is available and if the condition poses greater risk to the mother and fetus.

Valsartan

The drug is contraindicated in pregnant women or women planning pregnancy. If pregnancy is confirmed during treatment, the drug should be discontinued immediately and, if necessary, replaced with a medication approved for use in pregnancy.

Hydrochlorothiazide

Clinical experience with hydrochlorothiazide use during pregnancy, especially in the first trimester, is limited. Animal data are insufficient.

Hydrochlorothiazide crosses the placenta. Its pharmacological mechanism suggests that use during the second and third trimesters of pregnancy may impair fetoplacental perfusion and cause fetal and neonatal adverse reactions such as jaundice, electrolyte imbalances, and thrombocytopenia, as well as other adverse effects observed in adults.

Amlodipine/valsartan/hydrochlorothiazide

There is no experience with Exforge HCT use in pregnant women. Available data on the components suggest that Exforge HCT is contraindicated.

Breastfeeding period

Amlodipine is excreted in breast milk. The infant’s exposure, expressed as a fraction of the maternal dose, has been estimated at an interquartile range of 3–7%, with a maximum of 15%. The effect of amlodipine on the infant is unknown. Information on valsartan use during breastfeeding is lacking. Hydrochlorothiazide is present in breast milk in small amounts. High-dose thiazides causing strong diuresis may interfere with breast milk production.

Exforge HCT is contraindicated during breastfeeding.

Fertility

No clinical studies on the effect of Exforge HCT on fertility have been conducted.

Valsartan

Valsartan had no adverse effect on reproductive function in male or female rats at oral doses up to 200 mg/kg/day. This dose is 6 times the maximum recommended human dose based on mg/m² (calculations assume an oral dose of 320 mg/day for a 60 kg patient).

Amlodipine

Reversible biochemical changes in sperm heads have been reported in some patients receiving calcium channel blockers. Clinical data on the potential effect of amlodipine on fertility are insufficient. Adverse effects on male fertility were observed in one rat study.

Ability to affect reaction speed when driving or operating machinery.

Dizziness or weakness may occur in patients taking Exforge HCT; therefore, patients should take this into account when driving or operating potentially hazardous machinery.

Amlodipine may have a slight or moderate effect on the ability to drive or operate machinery. If patients experience dizziness, headache, fatigue, or nausea while taking amlodipine, their reaction time may be impaired.

Dosage and Administration

Administration

Exforge HCT can be taken independently of food intake. The tablets should be swallowed whole with water, at the same time each day, preferably in the morning.

Dosage

The recommended dose of Exforge HCT is 1 tablet daily, preferably in the morning.

Prior to switching to Exforge HCT, the patient's condition should be controlled with stable doses of the individual monotherapy components currently being used. The dose of Exforge HCT should correspond to the doses of the individual components of the combination therapy being used at the time of the switch.

The maximum recommended dose of Exforge HCT is 10 mg/320 mg/25 mg.

Special Patient Populations

Renal Impairment

Since hydrochlorothiazide is a component of the medicinal product, Exforge HCT is contraindicated in patients with anuria and severe renal impairment (glomerular filtration rate (GFR) <30 mL/min/1.73 m²).

Dose adjustment is not required in patients with mild to moderate renal impairment.

Hepatic Impairment

Since valsartan is a component of the medicinal product, Exforge HCT is contraindicated in patients with severe hepatic impairment. In patients with mild to moderate hepatic impairment not associated with cholestasis, the maximum recommended dose of valsartan is 80 mg; therefore, Exforge HCT is not recommended for this patient group. Dosage recommendations for amlodipine in patients with mild to moderate hepatic impairment have not been established. When switching hypertensive patients with hepatic impairment to Exforge HCT, the lowest available dose of amlodipine should be used.

Heart Failure and Coronary Artery Disease

Experience with Exforge HCT, particularly at maximum doses, in patients with heart failure and coronary artery disease is limited. The use of Exforge HCT, especially the maximum dose of 10 mg/320 mg/25 mg, should be approached with caution in such patients.

Elderly Patients (aged 65 years and older)

Exforge HCT should be prescribed with caution in elderly patients, particularly with frequent monitoring of blood pressure, especially when using the maximum dose of 10 mg/320 mg/25 mg, as data in this patient group are limited. When switching elderly patients to Exforge HCT, the lowest available dose of amlodipine should be used.

Pediatric Population

There are no adequate data on the use of Exforge HCT in pediatric patients (patients under 18 years of age) for the indication of arterial hypertension.

Children

Safety and efficacy in children have not been established; therefore, the medicinal product is not recommended for use in this age group.

Overdose

Symptoms

There are no data on overdose with Exforge HCT. The main symptom of overdose is likely to be pronounced arterial hypotension accompanied by dizziness. Overdose with amlodipine may lead to marked peripheral vasodilation and possibly reflex tachycardia. Cases of severe and potentially prolonged systemic hypotension, including shock with fatal outcome, have been reported.

Rare cases of non-cardiogenic pulmonary edema following amlodipine overdose have been reported, which may present with delayed onset (24–48 hours after ingestion) and may require mechanical ventilation. Contributing factors to the development of non-cardiogenic pulmonary edema may include early resuscitation measures (including fluid overload) aimed at maintaining perfusion and cardiac output.

Treatment

Amlodipine/Valsartan/Hydrochlorothiazide

Clinically significant arterial hypotension following overdose with Exforge HCT requires active cardiovascular support, including continuous monitoring of cardiac and respiratory function, elevation of the lower limbs, monitoring of circulating blood volume and diuresis. Vasoconstrictor agents may be appropriate to restore vascular tone and blood pressure, provided there are no contraindications to their use. Intravenous administration of calcium gluconate may be effective in reversing the effects of calcium channel blockade.

Amlodipine

If ingestion was recent, induction of emesis or gastric lavage should be considered. Administration of activated charcoal to healthy volunteers immediately or 2 hours after amlodipine intake significantly reduced amlodipine absorption.

Amlodipine is unlikely to be removed by hemodialysis.

Valsartan

Valsartan is unlikely to be removed by hemodialysis.

Hydrochlorothiazide

Hydrochlorothiazide overdose is associated with electrolyte depletion (hypokalemia, hypochloremia) and hypovolemia due to excessive diuresis. The most common symptoms of overdose are nausea and drowsiness. Hypokalemia may lead to muscle cramps and/or exacerbation of arrhythmias, particularly in patients receiving concomitant digoxin or certain antiarrhythmic drugs.

The extent to which hydrochlorothiazide is removed by hemodialysis has not been established.

Adverse reactions

The safety profile of Exforge HCT presented below is based on clinical studies of the medicinal product and the known safety profile of its individual components: amlodipine, valsartan, and hydrochlorothiazide.

Summary of safety profile

The safety of Exforge HCT was evaluated at the maximum dose of 10 mg/320 mg/25 mg in a controlled short-term (8-week) clinical study involving 2271 patients, of whom 582 received valsartan in combination with amlodipine and hydrochlorothiazide. Adverse reactions were generally mild and transient, and only rarely required discontinuation of therapy. In this active-controlled clinical study, the most common reasons for discontinuation with Exforge HCT were dizziness and hypotension (0.7%).

In the 8-week controlled clinical study, no significant new or unexpected adverse effects were observed with triple therapy compared to the known effects of monotherapy or dual therapy with the individual components of the medicinal product.

In the 8-week controlled clinical study, laboratory test changes observed with Exforge HCT were minor and consistent with the pharmacological mechanisms of action of the individual monotherapies. The presence of valsartan in the triple combination attenuates the hypokalemic effect of hydrochlorothiazide.

Adverse reactions listed in Table 2 by organ system classes (MedDRA) and frequency are presented for Exforge HCT (amlodipine/valsartan/hydrochlorothiazide) and separately for amlodipine, valsartan, and hydrochlorothiazide.

Very common: ≥1/10; common: ≥1/100 to <1/10; uncommon: ≥1/1,000 to <1/100; rare: ≥1/10,000 to <1/1,000; very rare: <1/10,000; not known (cannot be estimated from the available data).

Table 2

*More associated with cholestasis.

Non-melanoma skin cancer: based on available epidemiological data, there is a cumulative dose-response relationship between the use of hydrochlorothiazide and the development of NMSC.

Shelf life. 2 years.

Storage conditions.

Store at a temperature not exceeding 30°C in a place protected from moisture.

Keep out of the reach of children.

Packaging.

14 tablets in a blister; 1 or 2 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Novartis Pharma S.p.A.

Manufacturer's address and location of business activity.

Via Provinciale Scauri 131, 80058 Torre Annunziata (Province of Naples), Italy