Excorge h

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EXFORGE H (EXFORGE H)

Composition:

Active substances: amlodipine besylate, valsartan, hydrochlorothiazide;

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

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

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

One 10 mg/160 mg/25 mg tablet contains: amlodipine besylate 13.87 mg, equivalent to 10 mg of 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 – oval, biconvex, film-coated tablets of white color, with beveled edges, without a score mark, imprinted with "NVR" on one side and "VCL" on the other;

Tablets 10 mg/160 mg/12.5 mg – oval, biconvex, film-coated tablets of pale yellow color, with beveled edges, without a score mark, imprinted with "NVR" on one side and "VDL" on the other;

Tablets 5 mg/160 mg/25 mg – oval, biconvex, film-coated tablets of yellow color, with beveled edges, without a score mark, imprinted with "NVR" on one side and "VEL" on the other;

Tablets 10 mg/160 mg/25 mg – oval, biconvex, film-coated tablets of brown-yellow color, with beveled edges, without a score mark, imprinted 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 includes three antihypertensive agents with complementary mechanisms of action for controlling blood pressure in patients with essential hypertension: amlodipine belongs to the class of calcium channel blockers, valsartan belongs to the class of angiotensin II receptor antagonists, and hydrochlorothiazide belongs to the class of thiazide diuretics. The combination of these three components provides 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 amlodipine is due to direct vasodilatory action on vascular smooth muscle, resulting in decreased peripheral vascular resistance and blood pressure.

At therapeutic doses in patients with hypertension, amlodipine causes vasodilation, leading to reduced blood pressure in both supine and standing positions. This blood pressure reduction 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 hypertensive patients with 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 hypertension leads to blood pressure reduction without affecting pulse rate.

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

Hydrochlorothiazide

The primary site of action of thiazide diuretics is the distal convoluted tubules of the kidneys. It has been confirmed that high-affinity binding sites exist in the renal cortex, which serve as the main site for binding thiazide diuretics and inhibition of NaCl transport in the distal convoluted tubules. The mechanism of action of thiazides involves inhibition of the Na+Cl– cotransporter, possibly by competing for Cl– binding sites, thereby affecting electrolyte reabsorption: it directly enhances excretion of sodium and chloride to approximately equivalent degrees and indirectly, via diuresis, reduces plasma volume, leading 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 the 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 potential association between lip cancer and hydrochlorothiazide use: 633 cases of lip cancer were compared with 63,067 population 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), 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 trials 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 for use").

Additionally, the ALTITUDE trial (Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints), which 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, was prematurely terminated due to an increased risk of adverse outcomes. Cardiovascular death 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 common in the aliskiren group than in the placebo group.

Pharmacokinetics.

Linearity

Amlodipine, valsartan, and hydrochlorothiazide exhibit 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 agents.

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 amlodipine bioavailability.

Distribution. The volume of distribution is approximately 21 L/kg. In vitro studies show that approximately 97.5% of circulating amlodipine 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 half-life of approximately 30–50 hours. Steady-state plasma concentrations are achieved after 7–8 days of continuous administration. About 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 peak plasma concentration (Cmax) by approximately 50%, although valsartan concentrations are similar in fasting and postprandial groups approximately 8 hours after dosing. However, this reduction in AUC is not associated with clinically significant reduction in therapeutic effect; therefore, valsartan can be administered regardless of food intake.

Distribution. The volume of distribution at steady state 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 transformation, 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 excreted in feces (approximately 83% of dose) and urine (approximately 13% of dose), mainly as unchanged drug. After intravenous administration, plasma clearance of valsartan is approximately 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. Hydrochlorothiazide is rapidly absorbed after oral administration (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 dosing, and accumulation is minimal with once-daily administration. When administered with food, both increased and decreased systemic availability of hydrochlorothiazide have been observed compared to fasting conditions. The magnitude of these effects is minor and of limited clinical significance. Absolute bioavailability of hydrochlorothiazide is 60–80% after oral administration.

Distribution. The apparent volume of distribution is 4–8 L/kg. Circulating hydrochlorothiazide 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 both passive filtration and active tubular secretion. Elimination half-life is 6–15 hours.

Special Patient Populations

Children (under 18 years of age)

There are no pharmacokinetic data 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 half-life. Mean systemic AUC of valsartan is 70% higher in elderly patients compared to younger patients; therefore, dose escalation should be done cautiously in these patients.

Systemic exposure to valsartan is somewhat 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 hypertensive patients compared to younger healthy volunteers.

Since all three components of the drug are similarly well tolerated in younger and elderly patients, the recommended dosing regimen is the same.

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 started on 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, 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 and 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 yielded negative results.

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 excipient.

• 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 interaction studies have been conducted with Exforge HCT and other medicinal products. Table 1 provides information only on interactions known for each individual active ingredient.

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

Table 1

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

Clinical data have shown that dual blockade of the RAS 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 a RAS-acting agent.

Special precautions for use.

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

Patients with sodium deficiency 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 doses of diuretics upon initiation of Exforge HCT therapy. It is recommended to correct such conditions prior to starting Exforge HCT or to closely monitor patients at the beginning of treatment.

If marked arterial hypotension occurs during treatment with Exforge HCT, the patient should be placed in a supine position with elevated lower extremities. 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 other patients, one or the other effect may predominate.

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

Periodic determination of serum electrolyte and potassium levels should be performed at appropriate intervals to prevent possible electrolyte imbalances, especially in patients with risk factors such as renal impairment, 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 drugs that may increase potassium levels (e.g., heparin) is not recommended. If necessary, 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 therapy with hydrochlorothiazide, 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 present 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 sodium levels normalize. Thiazides, including hydrochlorothiazide, enhance urinary magnesium excretion, which may lead to hypomagnesemia. Thiazide diuretics reduce calcium excretion, which may result in hypercalcemia.

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

Renal impairment

Thiazide diuretics may exacerbate 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 renal impairment.
Exforge HCT is contraindicated in patients with severe renal impairment, anuria, or those on dialysis.

No dose adjustment of Exforge HCT is required in patients with mild to moderate renal impairment (eGFR ≥30 mL/min/1.73m²).

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

Currently, there is no information on the safety of Exforge HCT use 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 indicated for this patient group.

Angioedema.

Angioedema, including laryngeal and glottis 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 patients with heightened sensitivity. 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. Such 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 and IV non-ischemic heart failure, the incidence of pulmonary edema was higher with amlodipine compared to placebo, despite a minimal 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, as data on its use in this patient group are limited.

Aortic and mitral valve stenosis

As with other vasodilators, Exforge HCT should be prescribed with particular caution in patients with low-grade aortic and mitral valve stenosis.

Pregnancy

Treatment with angiotensin II receptor antagonists (ARBs) should not be initiated during pregnancy. If continued ARB therapy is necessary, patients planning pregnancy should be switched to alternative antihypertensive agents with an established safety profile in pregnancy. If pregnancy occurs, ARB 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 adjustment of insulin or oral hypoglycemic agents may be necessary in patients with diabetes mellitus.

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 worsening of hyperuricemia and acute gout attacks in susceptible patients.

Thiazides may reduce urinary calcium excretion and cause transient, slight 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 resumption 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

The use of 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 sudden onset of decreased visual acuity or eye pain and usually occur within hours to the first week after starting treatment. Untreated angle-closure glaucoma may lead to irreversible vision loss.

Hydrochlorothiazide should be discontinued immediately. If intraocular pressure remains uncontrolled, immediate medical or surgical treatment 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 who have previously experienced 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 monitoring of blood pressure, in elderly patients, especially at the maximum dose of 10 mg/320 mg/25 mg, as data on its use in this patient group are limited.

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 and may lead to higher incidences of hypotension, hyperkalemia, and renal impairment (including acute renal failure).

Therefore, dual blockade of the RAAS by 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

An increased risk of non-melanoma skin cancer (NMSC) (basal cell carcinoma and squamous cell carcinoma) with increasing cumulative doses 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. Such patients should be advised to regularly check their skin for new lesions and promptly report any suspicious skin changes. Preventive measures to minimize skin cancer risk, such as limiting exposure to sunlight and ultraviolet radiation and using adequate protection when exposed to sunlight, are recommended. Suspicious skin lesions should be promptly evaluated, including histological examination of biopsies. The use of hydrochlorothiazide 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 intake. Pulmonary edema usually develops within minutes or hours after hydrochlorothiazide administration. 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 have previously experienced ARDS after hydrochlorothiazide intake.

Use during pregnancy or breastfeeding.

Pregnancy

Amlodipine

Studies on the safety of amlodipine during pregnancy have not been conducted. Reproductive toxicity was observed in animal studies at high doses. Amlodipine may be used during pregnancy only if no safer alternative is available and if the disease poses a greater risk to the pregnant woman and fetus.

Valsartan

The drug is contraindicated in pregnant women or women planning pregnancy. If pregnancy is confirmed during treatment with this drug, its use must be discontinued immediately and, if necessary, replaced with another drug approved for use during pregnancy.

Hydrochlorothiazide

Experience with hydrochlorothiazide use during pregnancy, especially in the first trimester, is limited. Data from animal studies are insufficient.

Hydrochlorothiazide crosses the placenta. The pharmacological mechanism of action of hydrochlorothiazide suggests that its 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 reactions observed in adults.

Amlodipine/valsartan/hydrochlorothiazide

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

Breastfeeding period

Amlodipine is excreted in breast milk. The fraction of maternal dose received by the infant 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 the use of valsartan 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

There are no clinical studies on Exforge HCT related to fertility.

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 higher than the maximum recommended human dose based on mg/m² (calculations assume an oral dose of 320 mg/day for a 60 kg patient).

Amlodipine

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

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.

Method of Administration and Dosage

Method of Administration

Exforge HCT can be taken independently of food intake. 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 adequately controlled with unchanged doses of the individual monotherapy components currently being used. The dose of Exforge HCT should correspond to the doses of the individual components in the combination therapy at the time of switching.

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

Special Patient Groups

Renal Impairment

Since hydrochlorothiazide is a component of Exforge HCT, the drug 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 Exforge HCT, the drug is contraindicated in patients with severe hepatic impairment. In patients with mild to moderate hepatic impairment without 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. Caution is recommended when prescribing the drug to such patients, especially the maximum dose of Exforge HCT (10 mg/320 mg/25 mg).

Elderly Patients (aged 65 years and older)

Caution, including frequent monitoring of blood pressure, is recommended when prescribing Exforge HCT to elderly patients, particularly the maximum dose (10 mg/320 mg/25 mg), due to limited data in this population. 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 (under 18 years of age) for the indication of arterial hypertension.

Children

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

Overdose

Symptoms

There are no reported cases of overdose with Exforge HCT. The main symptom of overdose is likely to be pronounced arterial hypotension with dizziness. Overdose with amlodipine may lead to marked peripheral vasodilation and possibly reflex tachycardia. Severe and potentially prolonged systemic hypotension, including shock with fatal outcome, has 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 due to Exforge HCT overdose requires active cardiovascular support, including continuous monitoring of cardiac and respiratory function, elevation of the lower limbs, monitoring of circulating blood volume and diuresis. Vasoconstrictors 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 only a short time has passed since ingestion, 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 when digoxin or certain antiarrhythmic drugs are used concomitantly.

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

Adverse reactions

The safety profile of Exforge HCT described below is based on clinical studies of the medicinal product and the well-known safety profiles 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 drug.

In the 8-week controlled clinical study, laboratory test abnormalities 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 system organ 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 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 hydrochlorothiazide use and the development of NMSC.

Shelf life. 2 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

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

Prescription status.

Prescription only.

Manufacturer.

Novartis Pharma S.p.A.

Manufacturer's address and location of business operation.

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