Casark® triniti

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT CASARK® TRINITY (Casark Trinity)

Composition:

Active substances: candesartan cilexetil, amlodipine besylate, hydrochlorothiazide;

One hard capsule Casark® Trinity 16 mg/5 mg/12.5 mg contains: candesartan cilexetil – 16 mg, amlodipine (in the form of amlodipine besylate) – 5 mg, hydrochlorothiazide – 12.5 mg;

One hard capsule Casark® Trinity 16 mg/10 mg/12.5 mg contains: candesartan cilexetil – 16 mg, amlodipine (in the form of amlodipine besylate) – 10 mg, hydrochlorothiazide – 12.5 mg;

Excipients: lactose monohydrate; corn starch; hydroxypropylcellulose (type EXF); calcium carmellose; hydroxypropylcellulose (type LF); polyethylene glycol (type 8000); pregelatinized starch, corn; magnesium stearate;

Capsule shell:

Casark® Trinity 16 mg/5 mg/12.5 mg – capsule body: titanium dioxide (E 171), gelatin; capsule cap: yellow sunset FCF (E 110), titanium dioxide (E 171), gelatin;

Casark® Trinity 16 mg/10 mg/12.5 mg – capsule body: titanium dioxide (E 171), gelatin; capsule cap: azorubine, carmoisine (E 122), yellow sunset FCF (E 110), titanium dioxide (E 171), gelatin;

Ink composition: shellac (E 904), iron oxide black (E 172), propylene glycol (E 1520), concentrated ammonia solution (E 527), potassium hydroxide (E 525).

Pharmaceutical form. Hard capsules.

Main physicochemical properties:

Casark® Trinity 16 mg/5 mg/12.5 mg – hard gelatin capsules, size "0", with white body printed in black with the number “1” and orange cap printed in black with the inscription “SAN”, filled with white or almost white powder.

Casark® Trinity 16 mg/10 mg/12.5 mg – hard gelatin capsules, size "0", with white body printed in black with the number “2” and red cap printed in black with the inscription “SAN”, filled with white or almost white powder.

Pharmacotherapeutic group. Agents acting on the renin-angiotensin system. Angiotensin II receptor blockers (ARBs), other combinations. ATC code C09D X06.

Pharmacological Properties

Pharmacodynamics

The medicinal product Casark® Trinity is a combination of candesartan cilexetil – an angiotensin II receptor antagonist, amlodipine besylate – a calcium channel blocker, and hydrochlorothiazide – a thiazide diuretic. This combination exerts an additive antihypertensive effect, reducing arterial pressure to a greater extent than each component alone.

Mechanism of Action

Candesartan cilexetil is a prodrug intended for oral administration. After absorption in the gastrointestinal tract, it is rapidly hydrolyzed to its active metabolite – candesartan. Candesartan is a selective antagonist of angiotensin II type AT1 receptors. Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system (RAAS) and plays a key role in the pathophysiology of arterial hypertension. Its effects include vasoconstriction, stimulation of aldosterone synthesis and release, increased cardiac activity, and renal sodium reabsorption.

Candesartan blocks the vasoconstrictive effects and aldosterone release induced by angiotensin II by inhibiting its binding to AT1 receptors in tissues, including vascular smooth muscle and adrenal glands. The action of candesartan is independent of the source or pathway of angiotensin II synthesis. Selective blockade of AT1 receptors leads to increased plasma concentrations of renin and angiotensin I and II, as well as decreased plasma aldosterone concentration.

Amlodipine is a calcium channel antagonist that inhibits transmembrane influx of calcium ions into cardiac and vascular smooth muscle cells. The antihypertensive mechanism of amlodipine is due to direct vasodilatory action on vascular smooth muscle, resulting in reduced peripheral vascular resistance and decreased arterial pressure. Amlodipine has a more pronounced effect on vascular smooth muscle cells than on cardiac muscle cells.

Hydrochlorothiazide is a thiazide diuretic. The antihypertensive mechanism of thiazide diuretics is not fully understood. Thiazides affect electrolyte reabsorption in renal tubules, increasing excretion of sodium and chloride in approximately equimolar amounts. The diuretic effect of hydrochlorothiazide leads to a reduction in plasma volume, increased plasma renin activity, and enhanced aldosterone secretion, resulting in increased urinary loss of potassium and bicarbonate and decreased serum potassium concentration. The renin-aldosterone relationship is mediated by angiotensin II; therefore, concomitant use of angiotensin II receptor antagonists counteracts potassium loss associated with thiazide diuretic therapy.

Pharmacodynamic Effects

Candesartan does not inhibit angiotensin-converting enzyme (ACE), which converts angiotensin I to angiotensin II and mediates bradykinin breakdown. It does not affect ACE activity and does not potentiate the effects of bradykinin or substance P. In controlled clinical trials comparing candesartan cilexetil with ACE inhibitors, the incidence of cough was lower in patients receiving candesartan cilexetil. Candesartan does not bind to or block other hormonal receptors or ion channels important for cardiovascular regulation. Antagonism at angiotensin II (AT1) receptors leads to dose-dependent increases in plasma renin, angiotensin I, and angiotensin II concentrations, and a decrease in plasma aldosterone concentration.

Candesartan and hydrochlorothiazide exhibit additive antihypertensive effects.

In patients with arterial hypertension, amlodipine produces dose-dependent, long-lasting reduction in arterial pressure. There is no evidence of postural hypotension after the first dose, tachyphylaxis during long-term treatment, or rebound hypertension after abrupt discontinuation. At therapeutic doses, amlodipine effectively reduces arterial pressure in supine, sitting, and standing positions.

Long-term use of amlodipine does not cause significant changes in heart rate or plasma catecholamine concentrations. In hypertensive patients with normal renal function, therapeutic doses of amlodipine reduce renal vascular resistance and increase glomerular filtration rate and effective renal plasma flow without changes in filtration fraction or proteinuria. Hemodynamic studies in patients with heart failure and clinical trials based on exercise testing in patients with NYHA class II–IV heart failure have shown that amlodipine does not clinically worsen exercise tolerance, left ventricular ejection fraction, or clinical signs and symptoms.

Hydrochlorothiazide inhibits active sodium reabsorption, primarily in the distal renal tubules, and increases excretion of sodium, chloride, and water. Renal excretion of potassium and magnesium increases in a dose-dependent manner, while calcium is more extensively reabsorbed. Hydrochlorothiazide reduces plasma volume and extracellular fluid volume, cardiac output, and lowers arterial pressure. With prolonged therapy, reduced peripheral vascular resistance contributes to blood pressure reduction.

Clinical Efficacy and Safety of Candesartan Cilexetil

Arterial Hypertension

In arterial hypertension, candesartan produces dose-dependent, sustained reduction in arterial pressure. The antihypertensive effect is due to decreased peripheral vascular resistance without reflex tachycardia. There are no data indicating occurrence of severe or excessive hypotension after the first dose or withdrawal syndrome upon discontinuation.

After a single dose of candesartan cilexetil, the antihypertensive effect typically begins within 2 hours. With long-term treatment, the main blood pressure-lowering effect is usually achieved within four weeks and is maintained during continued therapy. According to meta-analysis data, the average additional effect of increasing the dose from 16 mg to 32 mg once daily was minimal. However, due to individual differences, a greater than average effect may be expected in some patients.

The antihypertensive effect of candesartan lasts more than 24 hours after a single dose, with minimal differences between peak and trough effects over the dosing interval.

In two randomized, double-blind studies involving 1268 patients with mild to moderate arterial hypertension, the antihypertensive efficacy and tolerability of candesartan and losartan were compared. The mean reduction in arterial pressure (systolic/diastolic) was 13.1/10.5 mm Hg with candesartan cilexetil 32 mg once daily and 10.0/8.7 mm Hg with potassium losartan 100 mg once daily (difference in blood pressure reduction: 3.1/1.8 mm Hg, p<0.0001/p<0.0001).

An additive antihypertensive effect was observed when candesartan cilexetil was used in combination with hydrochlorothiazide. Enhanced effects were also observed when used in combination with amlodipine or felodipine.

Medicinal products that block the RAAS have a weaker antihypertensive effect in patients of non-Black race (due to typically low renin activity) compared to patients of other races. In an open-label clinical study involving 5165 patients with elevated diastolic blood pressure, blood pressure reduction during candesartan treatment was significantly lower in Black patients compared to patients of other races (14.4/10.3 mm Hg vs. 19.0/12.7 mm Hg, p<0.0001/p<0.0001).

Candesartan increases renal blood flow and either does not affect or increases glomerular filtration rate (GFR), while renal vascular resistance and filtration fraction decrease. In a 3-month clinical study involving patients with arterial hypertension, type 2 diabetes, and microalbuminuria, antihypertensive treatment with candesartan cilexetil reduced urinary albumin excretion (albumin/creatinine ratio, mean 30%, 95% confidence interval (CI): 15–42%). Currently, there are no data on the effect of candesartan on the development of diabetic nephropathy.

The effect of candesartan cilexetil at doses of 8–16 mg (mean dose 12 mg) once daily on cardiovascular morbidity and mortality was evaluated in a randomized clinical trial involving 4937 elderly individuals (70–89 years, 21% older than 80 years) with mild to moderate arterial hypertension. Patients were followed for 3.7 years (Study of Cognition and Prognosis in the Elderly). Patients received candesartan cilexetil or placebo in combination with other antihypertensive agents as needed. Blood pressure decreased from 166/90 to 145/80 mm Hg in the candesartan group and from 167/90 to 149/82 mm Hg in the control group. There was no statistically significant difference in the primary endpoint – major cardiovascular events (cardiovascular death, non-fatal stroke, or myocardial infarction). The event rate was 26.7 events per 1000 patient-years in the candesartan group compared to 30.0 events per 1000 patient-years in the control group (relative risk 0.89, 95% CI: 0.75–1.06, p = 0.19).

Dual Blockade of the Renin-Angiotensin-Aldosterone System (RAAS)

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

The ONTARGET trial included patients with prior cardiovascular or cerebrovascular disease or type 2 diabetes with confirmed 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 outcomes or mortality; instead, they showed an increased risk of hyperkalemia, acute kidney injury, and/or hypotension compared to monotherapy. Due to the similarity in pharmacodynamic properties, these findings also apply to other ACE inhibitors and angiotensin II receptor antagonists. Therefore, ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients with diabetic nephropathy.

The ALTITUDE trial (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was designed to evaluate the benefits of adding aliskiren to standard therapy with 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 an increased risk of adverse events. Cardiovascular death and stroke occurred more frequently in the aliskiren group than in the placebo group, and adverse reactions and serious adverse events of special interest (hyperkalemia, hypotension, and renal failure) were reported more frequently in the aliskiren group than in the placebo group.

Clinical Efficacy and Safety of Amlodipine in Patients with Ischemic Heart Disease (IHD)

The efficacy of amlodipine in preventing clinical events in patients with IHD was evaluated in an independent, multicenter, randomized, double-blind, placebo-controlled trial involving 1997 patients (CAMELOT study – Comparison of Amlodipine versus Enalapril for Limitation of Thrombosis). Of these, 663 patients received amlodipine 5–10 mg, 673 patients received enalapril 10–20 mg, and 655 patients received placebo, in addition to standard therapy with statins, beta-blockers, diuretics, and acetylsalicylic acid, over 2 years. The primary efficacy outcomes are presented in Table 1. The results indicate that amlodipine treatment was associated with fewer hospitalizations for angina and revascularization procedures in patients with IHD.

Table 1

Incidence of significant clinical endpoints in the CAMELOT study CAMELOT
	Incidence of cardiovascular events, number (%)			Amlodipine vs placebo
Outcomes	Amlodipine	Placebo	Enalapril	Relative risk (95% CI)	P-value
Adverse cardiovascular events	110 (16.6)	151 (23.1)	136 (20.2)	0.69 (0.54–0.88)	0.003
Individual components
Coronary revascularization	78 (11.8)	103 (15.7)	95 (14.1)	0.73 (0.54–0.98)	0.03
Hospitalization due to angina	51 (7.7)	84 (12.8)	86 (12.8)	0.58 (0.41–0.82)	0.002
Non-fatal myocardial infarction	14 (2.1)	19 (2.9)	11 (1.6)	0.73 (0.37–1.46)	0.37
Stroke or transient ischemic attack	6 (0.9)	12 (1.8)	8 (1.2)	0.50 (0.19–1.32)	0.15
Cardiovascular death	5 (0.8)	2 (0.3)	5 (0.7)	2.46 (0.48–12.7)	0.27
Hospitalization due to congestive heart failure	3 (0.5)	5 (0.8)	4 (0.6)	0.59 (0.14–2.47)	0.46
Cardiac arrest with successful resuscitation	0	4 (0.6)	1 (0.1)	Not applicable	0.04
New onset of peripheral vascular disease	5 (0.8)	2 (0.3)	8 (1.2)	2.6 (0.50–13.4)	0.24

Clinical efficacy and safety of hydrochlorothiazide

Non-melanoma skin cancer (NMSC)

Epidemiological data have shown an association between cumulative hydrochlorothiazide dose and the incidence of NMSC. The study included a population of 71,533 patients with basal cell carcinoma and 8,629 patients with squamous cell carcinoma, compared with 1,430,833 and 172,462 control subjects, respectively. Use of high-dose hydrochlorothiazide (cumulative dose ≥50,000 mg) was associated with an adjusted relative risk 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 clear cumulative dose-response relationship was observed for both basal cell carcinoma and squamous cell carcinoma. Another study indicated a possible association between lip cancer and exposure to hydrochlorothiazide: 633 cases of lip cancer were matched with 63,067 control subjects using a population-based risk-set sampling strategy. A relationship between cumulative dose and risk of lip cancer was observed, with an adjusted relative risk of 2.1 (95 % CI: 1.7–2.6), increasing to 3.9 (95 % CI: 3.0–4.9) with high cumulative doses (~25,000 mg) and to 7.7 (95 % CI: 5.7–10.5) for the highest cumulative dose (~100,000 mg) (see section "Special precautions for use").

Efficacy and safety of the combination candesartan + amlodipine + hydrochlorothiazide

A multicenter study evaluated the efficacy of candesartan cilexetil used as monotherapy or in combination with amlodipine, or in combination with amlodipine and hydrochlorothiazide, in the treatment of patients with moderate to severe primary hypertension. After a 2-week placebo run-in period under single-blind conditions, patients entered a 12-week open-label dose-titration period. The dose of candesartan cilexetil was increased from 8 to 16 mg once daily; amlodipine (5 mg once daily) and hydrochlorothiazide (25 mg once daily) were added as needed; additional antihypertensive agents were permitted if required. Patients then entered a final 4-week double-blind, placebo-controlled, randomized withdrawal phase in parallel groups. A total of 216 patients participated in the study. After the 2-week placebo run-in period, mean seated blood pressure was 175/108 mm Hg. At the end of the 12-week dose-titration or maintenance period, mean seated blood pressure had decreased to 141/88 mm Hg. Overall, 29 patients received candesartan cilexetil (16 mg) in combination with amlodipine (5 mg) and hydrochlorothiazide (25 mg). In 67 patients randomized to the placebo group, a significant increase in mean systolic/diastolic blood pressure (13/6 mm Hg) was observed after discontinuation of candesartan compared to patients who continued candesartan treatment (ANCOVA, p<0.0001).

Candesartan cilexetil was effective as an antihypertensive agent both as monotherapy and in combination with amlodipine or with amlodipine and hydrochlorothiazide for the treatment of moderate to severe primary hypertension. The medicinal product was well tolerated throughout the clinical study.

Pharmacokinetics

Absorption and distribution

Candesartan cilexetil

After oral administration, candesartan cilexetil is converted to its active substance, candesartan. The absolute bioavailability of candesartan after oral administration of a solution of candesartan cilexetil is approximately 40%. The relative bioavailability of candesartan cilexetil in tablet form, compared to the same oral solution, is approximately 34% with very low variability. Mean peak serum concentration (Cmax) is reached within 3–4 hours after capsule intake. The serum concentration of candesartan increases linearly with increasing dose within the therapeutic dose range. No clinically relevant differences in pharmacokinetic parameters of candesartan related to gender have been identified. Food intake does not significantly affect the area under the serum concentration-time curve (AUC) of candesartan. Candesartan is highly bound to plasma proteins (over 99%). The apparent volume of distribution of candesartan is 0.1 L/kg.

Amlodipine

After oral administration of therapeutic doses, amlodipine is well absorbed, reaching peak plasma concentration within 6–12 hours after intake. Absolute bioavailability is estimated to be between 64% and 80%. The volume of distribution is approximately 21 L/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins. Concomitant food intake does not affect the absorption of amlodipine.

Hydrochlorothiazide

After oral administration of hydrochlorothiazide in combination with an angiotensin II receptor antagonist, the mean time to reach maximum hydrochlorothiazide concentration ranged from 2 to 5 hours after intake. Hydrochlorothiazide is 64% bound to plasma proteins and has an apparent volume of distribution of 0.5–1.1 L/kg.

Metabolism and elimination

Candesartan cilexetil

Candesartan is excreted predominantly unchanged in urine and bile, with only minor hepatic metabolism (CYP2C9). Available drug interaction data indicate no effect on the isoenzymes CYP2C9 and CYP3A4. Based on in vitro data, no in vivo interaction is expected with drugs whose metabolism depends on cytochrome P450 isoenzymes, specifically CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4. The elimination half-life (t½) of candesartan is approximately 9 hours. No accumulation occurs after multiple dosing. The half-life of candesartan remains unchanged (approximately 9 hours) when candesartan cilexetil is administered in combination with hydrochlorothiazide. No additional accumulation of candesartan occurs with repeated administration in combination compared to isolated administration. Total plasma clearance of candesartan is approximately 0.37 mL/min/kg, and renal clearance is approximately 0.19 mL/min/kg. Renal excretion of candesartan occurs via glomerular filtration and active tubular secretion. After oral administration of 14C-labeled candesartan cilexetil, approximately 26% of the administered dose is excreted in urine as candesartan and 7% as inactive metabolite, while approximately 56% of the dose is excreted in feces as candesartan and 10% as inactive metabolite of candesartan.

Amlodipine

The elimination half-life after single doses is approximately 35–50 hours. Amlodipine is extensively metabolized in the liver to inactive metabolites, with 10% of the parent compound and 60% of metabolites excreted in urine.

Hydrochlorothiazide

Hydrochlorothiazide is not metabolized in the human body and is excreted almost unchanged in urine. Approximately 60% of an orally administered dose is excreted unchanged within 48 hours. Renal clearance is approximately 250–300 mL/min. The elimination half-life of hydrochlorothiazide is 10–15 hours.

Combination of candesartan cilexetil, amlodipine besylate, and hydrochlorothiazide

In a pharmacokinetic interaction study after single-dose administration under fasting conditions, no significant pharmacokinetic interaction was observed between candesartan cilexetil, amlodipine besylate, and hydrochlorothiazide.

Pharmacokinetics in special patient populations

Elderly patients

In elderly patients (aged 65 years and older), Cmax and AUC values of candesartan are increased by approximately 50% and 80%, respectively, compared to younger patients. However, the antihypertensive effect and incidence of adverse events are similar when the same doses of candesartan cilexetil with hydrochlorothiazide are administered to younger patients and elderly patients (see section "Dosage and administration").

Time to reach peak plasma concentration of amlodipine is similar in elderly and younger patients. Amlodipine clearance is generally reduced, leading to increased AUC and prolonged elimination half-life in elderly patients. Increased AUC and half-life in patients with congestive heart failure were expected for the studied age group.

Renal impairment

In patients with mild to moderate renal impairment, Cmax and AUC values of candesartan increased by approximately 50% and 70%, respectively, after multiple dosing compared to patients with normal renal function, but t½ remained unchanged. Changes in these parameters in patients with severe renal impairment were approximately 50% and 110%, respectively. The terminal elimination half-life of candesartan was approximately twice as long in patients with severe renal impairment. The pharmacokinetic profile in patients on hemodialysis was similar to that in patients with severe renal impairment.

Amlodipine is extensively metabolized to inactive metabolites. 10% of the drug is excreted unchanged in urine. Plasma concentrations of amlodipine do not correlate with the degree of renal impairment. Amlodipine can be administered at usual doses to these patients. Amlodipine is not dialyzable.

The elimination half-life of hydrochlorothiazide is prolonged in patients with renal impairment.

Hepatic impairment

In two studies involving patients with mild to moderate hepatic impairment, an increase in mean AUC of candesartan of approximately 20% was observed in one study and 80% in another (see section "Dosage and administration"). Experience with the use of the medicinal product in patients with severe hepatic impairment is lacking.

Clinical data on amlodipine use in patients with hepatic impairment are very limited. In patients with hepatic impairment, amlodipine clearance is reduced, leading to prolonged elimination half-life and increased AUC by approximately 40–60%. Hepatic impairment does not significantly affect the pharmacokinetics of hydrochlorothiazide.

Clinical Characteristics

Indications

Treatment of essential arterial hypertension in adult patients whose blood pressure is adequately controlled with the combination of candesartan cilexetil, amlodipine, and hydrochlorothiazide administered at the same doses as in the fixed-dose combination medicinal product.

Contraindications

• Hypersensitivity to the active substances, dihydropyridine derivatives, or sulfonamide derivatives, or to any of the excipients of the medicinal product.
• Pregnancy or planned pregnancy (see sections "Special precautions for use" and "Use in pregnancy or breastfeeding").
• Severe arterial hypotension.
• Shock, including cardiogenic shock.
• Left ventricular outflow tract obstruction (e.g., severe aortic stenosis).
• Hypovolemia.
• Hemodynamically unstable heart failure following acute myocardial infarction.
• Severe renal impairment (creatinine clearance <30 mL/min).
• Anuria.
• Severe hepatic impairment and/or cholestasis, precoma associated with hepatic insufficiency.
• Persistent hypokalemia, hyponatremia, and hypercalcemia.
• Symptomatic hyperuricemia, gout.
• Concomitant use of Casark® Trinity with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (eGFR <60 mL/min/1.73 m²) (see sections "Pharmacological properties" and "Interaction with other medicinal products and other forms of interaction").
• Age under 18 years.

Interaction with other medicinal products and other forms of interaction

No specific studies on interactions between Casark® Trinity and other medicinal products have been conducted. This section provides information only on interactions known for the individual active substances.

However, it should be noted that Casark® Trinity may potentiate the hypotensive effect of other antihypertensive agents.

Based on pharmacological properties, the following medicinal products may be expected to potentiate the hypotensive effect of all antihypertensive agents, including Casark® Trinity: baclofen, amifostine, neuroleptics, or antidepressants.

Potential interactions related to candesartan cilexetil

Substances studied in clinical pharmacokinetic interaction trials include: hydrochlorothiazide, warfarin, digoxin, oral contraceptives (e.g., ethinylestradiol/levonorgestrel), glyburide, nifedipine, and enalapril. No clinically significant interactions with these medicinal products were observed.

Concomitant use with potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, and other medicinal products (e.g., heparin) may lead to increased potassium levels. Potassium levels should be monitored when necessary (see section "Special precautions for use").

Dual blockade of the RAS due to concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren

Clinical trial data indicate that dual blockade of the RAS by concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is associated with a higher incidence of adverse events such as arterial hypotension, hyperkalemia, and renal dysfunction (including acute renal failure), compared to treatment with a single RAS blocker as monotherapy (see sections "Pharmacodynamics", "Contraindications", and "Special precautions for use").

Transient increases in serum lithium concentrations and increased lithium toxicity have been reported with concomitant use of lithium and ACE inhibitors.

A similar effect has also been observed with angiotensin II receptor antagonists. Concomitant use of candesartan with lithium is not recommended. If such a combination is necessary, careful monitoring of serum lithium levels is recommended.

When angiotensin II receptor antagonists are used concomitantly with nonsteroidal anti-inflammatory drugs (NSAIDs) (i.e., selective COX-2 inhibitors, acetylsalicylic acid (>3 g/day), and nonselective NSAIDs), a reduction in antihypertensive effect may occur.

As with ACE inhibitors, concomitant use of angiotensin II receptor antagonists and NSAIDs may increase the risk of renal dysfunction, including possible development of acute renal failure, and may also increase serum potassium levels, particularly in patients with pre-existing renal impairment. Such combinations should be used with caution, especially in elderly patients. Patients should receive adequate fluid intake, and monitoring of renal function should be considered both at the start of concomitant therapy and periodically thereafter.

Potential interactions related to amlodipine

Effects of other medicinal products on amlodipine

CYP3A4 inhibitors

Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil, or diltiazem) may result in a significant increase in amlodipine exposure, leading to an increased risk of arterial hypotension. The clinical significance of these pharmacokinetic changes may be more pronounced in elderly patients. Therefore, clinical monitoring and dose adjustment may be necessary.

CYP3A4 inducers

Concomitant use of amlodipine with known CYP3A4 inducers may alter its plasma concentration. Therefore, blood pressure should be monitored and dose adjustments considered both during and after co-administration of amlodipine with other medicinal products, especially strong CYP3A4 inducers (e.g., rifampicin, St. John's wort).

Grapefruit

It is not recommended to take amlodipine with grapefruit or grapefruit juice due to the potential for increased bioavailability of the drug in some patients, which may enhance blood pressure reduction.

Dantrolene (infusion)

In animals, fatal cases of ventricular fibrillation and circulatory collapse with hyperkalemia have been observed after intravenous administration of verapamil and dantrolene. Due to the risk of hyperkalemia, concomitant use of calcium channel blockers such as amlodipine should be avoided in patients predisposed to malignant hyperthermia and during treatment of malignant hyperthermia.

Effects of amlodipine on other medicinal products

Amlodipine enhances the antihypertensive effect of other medicinal products with antihypertensive properties.

Tacrolimus

Concomitant use of amlodipine carries a risk of increased tacrolimus blood concentration, although the pharmacokinetic mechanism of this interaction is not fully understood. To avoid tacrolimus toxicity, patients receiving tacrolimus should have their blood concentration monitored during amlodipine treatment, and dose adjustments made if necessary.

mTOR inhibitors (mammalian target of rapamycin)

mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are substrates of CYP3A isoenzymes, and amlodipine is a weak inhibitor of CYP3A isoenzymes. Amlodipine may be used concomitantly with mTOR inhibitors, potentially increasing their exposure.

Cyclosporine

Interaction studies between cyclosporine and amlodipine have not been conducted in healthy volunteers or other populations, except in kidney transplant patients, in whom variable increases in cyclosporine trough concentrations (on average from 0 to 40%) were observed. Monitoring of cyclosporine concentration should be considered in kidney transplant patients receiving amlodipine, and cyclosporine dose reduction may be necessary.

Simvastatin

Repeated co-administration of 10 mg amlodipine and 80 mg simvastatin resulted in a 77% increase in simvastatin exposure compared to simvastatin alone. The simvastatin dose should be limited to 20 mg daily in patients taking amlodipine.

Potential interactions related to hydrochlorothiazide

Medicinal products whose concomitant use is not recommended

Medicinal products affecting potassium levels

The potassium-wasting effect of hydrochlorothiazide (see section "Special precautions for use") may be enhanced by concomitant use of other medicinal products associated with potassium loss and hypokalemia (e.g., other potassium-wasting diuretics, laxatives, corticosteroids, adrenocorticotropic hormone (ACTH), amphotericin, carbenoxolone, sodium penicillin G, or salicylate derivatives).

Lithium preparations

Thiazides reduce renal excretion of lithium. Transient increases in serum lithium concentration and lithium toxicity have been reported with concomitant use of lithium and thiazides, including hydrochlorothiazide.

Concomitant use requiring caution

Calcium salts

Thiazide diuretics may increase serum calcium levels due to reduced excretion. When calcium supplements are prescribed, serum calcium concentration should be monitored and dosage adjusted accordingly.

Cholestyramine and colestipol

Absorption of hydrochlorothiazide may be impaired in the presence of anion-exchange resins.

Cardiac glycosides

Hypokalemia or hypomagnesemia induced by thiazides may predispose to cardiac arrhythmias caused by cardiac glycosides.

Medicinal products affecting serum potassium levels

Regular monitoring of serum potassium levels and ECG is recommended when Casark® Trinity is used concomitantly with medicinal products that affect serum potassium levels (e.g., cardiac glycosides and antiarrhythmics) and with the following medicinal products that may cause torsades de pointes ventricular tachycardia (including some antiarrhythmics), when hypokalemia is a contributing factor:

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

Medicinal products affecting serum sodium levels

The hyponatremic effect of diuretics may be enhanced when used concomitantly with antidepressants, antipsychotics, or antiepileptic agents. Caution should be exercised with long-term use of these medicinal products (see section "Special precautions for use").

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

Hydrochlorothiazide may potentiate the effect of non-depolarizing skeletal muscle relaxants.

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

Bioavailability of thiazide diuretics may be increased due to reduced gastrointestinal motility and delayed gastric emptying.

Antidiabetic agents (oral medications and insulin)

Thiazide treatment may affect glucose tolerance. Dose adjustment of antidiabetic agents may be required (see section "Special precautions for use").

Metformin

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

Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid (>3 g/day), and nonselective NSAIDs

NSAIDs may reduce the antihypertensive effect of hydrochlorothiazide when used concomitantly. Additionally, concomitant use of hydrochlorothiazide and NSAIDs may lead to impaired renal function and increased serum potassium levels. Therefore, monitoring of renal function at the start of treatment and adequate patient hydration are recommended.

Beta-blockers and diazoxide

Thiazides may enhance the hyperglycemic effect of beta-blockers and diazoxide.

Pressor amines (e.g., noradrenaline)

The effect of pressor amines may be reduced.

Medicinal products used in the treatment of gout (e.g., probenecid, sulfinpyrazone, allopurinol)

Dosage adjustment of uricosuric agents may be required, as hydrochlorothiazide may increase serum uric acid concentration. Increased doses of probenecid or sulfinpyrazone may be needed. Concomitant use of thiazides may increase the frequency of hypersensitivity reactions to allopurinol.

Amantadine

Thiazides may increase the risk of adverse reactions caused by amantadine.

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

Thiazides may reduce renal excretion of cytotoxic drugs and enhance their myelosuppressive effects.

Salicylates

When high doses of salicylates are used, hydrochlorothiazide may enhance the toxic effects of salicylates on the central nervous system.

Methyldopa

Isolated cases of hemolytic anemia have been reported with concomitant use of hydrochlorothiazide and methyldopa.

Cyclosporine

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

Special precautions for use

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 function impairment (including acute renal failure). Therefore, dual RAAS blockade via concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is not recommended (see sections "Pharmacodynamics" and "Interaction with other medicinal products and other forms of interaction"). If dual RAAS blockade is considered absolutely necessary, treatment should be conducted only under specialist supervision and accompanied by frequent and careful monitoring of renal function, electrolyte levels, and blood pressure. ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients with diabetic nephropathy.

Renal impairment

As with other medicinal products that inhibit the RAAS, changes in renal function may be expected during treatment with candesartan cilexetil in combination with hydrochlorothiazide in susceptible patients (see section "Contraindications"). Treatment should be conducted only under specialist supervision with careful and frequent monitoring of renal function, electrolyte levels, creatinine, and blood pressure. Changes in plasma concentrations of amlodipine do not correlate with the degree of renal function impairment. Amlodipine is not removed by dialysis. Due to the risk of hyperkalemia in patients with renal impairment, serum electrolyte and blood urea levels should be carefully monitored.

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 or hours after hydrochlorothiazide intake. Initial symptoms include dyspnea, fever, worsening of lung condition, and arterial hypotension. If ARDS is suspected, this medicinal product should be discontinued immediately and appropriate treatment initiated. Hydrochlorothiazide should not be prescribed to patients who previously experienced ARDS after hydrochlorothiazide intake.

Renal transplantation

Clinical data on the use of candesartan cilexetil in combination with hydrochlorothiazide in patients with transplanted kidneys are limited.

Renal artery stenosis

In patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney, medicinal products affecting the RAAS, including angiotensin II receptor antagonists, may increase blood urea and serum creatinine levels.

Reduced intravascular volume

Symptomatic hypotension may occur in patients with reduced intravascular volume and/or sodium deficiency, as with other RAAS-acting medicinal products. Therefore, candesartan cilexetil/hydrochlorothiazide is not recommended until this condition is corrected.

Anesthesia and surgery

Arterial hypotension may occur during anesthesia and surgical procedures in patients receiving treatment with angiotensin II receptor antagonists due to RAAS blockade. Very rarely, arterial hypotension may be severe enough to require intravenous fluid infusion and/or vasopressor agents.

Aortic and mitral stenosis (obstructive hypertrophic cardiomyopathy)

As with other vasodilators, this medicinal product should be used with particular caution in patients with hemodynamically significant aortic or mitral stenosis or obstructive hypertrophic cardiomyopathy.

Hepatic impairment

Caution should be exercised when administering thiazides to patients with hepatic insufficiency or progressive liver disease, as minor disturbances in fluid and electrolyte balance may precipitate hepatic coma. There is no clinical experience with the use of candesartan cilexetil in combination with hydrochlorothiazide in patients with hepatic insufficiency. In patients with hepatic impairment, the elimination half-life of amlodipine is prolonged and AUC values are higher; dosage recommendations have not been established. Therefore, treatment with amlodipine should be initiated at the lower end of the dose range, with caution both at the beginning of treatment and during dose escalation. Patients with severe hepatic impairment may require gradual dose titration and careful monitoring.

Intestinal angioedema

Cases of intestinal angioedema have been reported in patients taking angiotensin II receptor blockers, including candesartan (see section "Adverse reactions"). These patients experienced abdominal pain, nausea, vomiting, and diarrhea. Symptoms resolved after discontinuation of angiotensin II receptor blockers. If intestinal angioedema is diagnosed, candesartan should be discontinued and appropriate monitoring initiated until complete symptom resolution.

Heart failure

Amlodipine should be prescribed with caution in patients with heart failure. In a long-term placebo-controlled study involving patients with severe heart failure (NYHA class III and IV), the incidence of pulmonary edema was higher in the amlodipine group compared to the placebo group. Calcium antagonists, including amlodipine, should be used cautiously in patients with congestive heart failure, as they may increase the risk of cardiovascular complications and death.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism usually do not respond to antihypertensive agents acting via RAAS blockade. Therefore, candesartan cilexetil in combination with hydrochlorothiazide is not recommended in this population.

Electrolyte imbalance

Regular assessment of serum electrolyte levels should be performed at appropriate intervals. Thiazide derivatives, including hydrochlorothiazide, may cause disturbances in fluid and electrolyte balance (hypercalcemia, hypokalemia, hyponatremia, hypomagnesemia, and hypochloremic alkalosis). Thiazide diuretics may reduce urinary calcium excretion and cause transient and slight increases in serum calcium concentration. Marked hypercalcemia may indicate latent hyperparathyroidism.

Thiazide use should be discontinued prior to testing parathyroid function. Thiazide diuretics may cause or exacerbate existing hyponatremia. In isolated cases, hyponatremia with corresponding neurological symptoms (nausea, progressive disorientation, apathy) has been observed. Sodium levels should be corrected and/or dehydration eliminated before initiating thiazide diuretic therapy.

Hydrochlorothiazide increases urinary potassium excretion in a dose-dependent manner, potentially leading to hypokalemia. This effect of hydrochlorothiazide is less pronounced when used in combination with candesartan cilexetil. The risk of hypokalemia may be increased in patients with liver cirrhosis, those undergoing rapid diuresis, those with inadequate dietary electrolyte intake, and those concurrently treated with corticosteroids or ACTH. Treatment with candesartan cilexetil may cause hyperkalemia, especially in the presence of heart failure and/or renal impairment.

Hyperkalemia

Concomitant use of candesartan cilexetil with ACE inhibitors, aliskiren, potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other medicinal products that may increase serum potassium concentration (e.g., sodium heparin) may lead to elevated serum potassium levels. Serum potassium monitoring should be performed when necessary.

Thiazides have been shown to increase urinary magnesium excretion, potentially leading to hypomagnesemia.

Metabolic and endocrine effects

Therapy with thiazide diuretics may affect glucose tolerance. Adjustment of antidiabetic medicinal product doses, including insulin, may be required. Latent diabetes mellitus may become apparent during thiazide treatment.

Treatment with thiazide diuretics is associated with increased cholesterol and triglyceride levels. With doses contained in the candesartan cilexetil/hydrochlorothiazide combination, only minimal effects have been observed.

Thiazide diuretics increase serum uric acid concentration and may trigger gout in susceptible patients.

Hemodialysis

During dialysis, blood pressure may be particularly sensitive to AT1-receptor blockade due to reduced plasma volume and RAAS activation. Therefore, the dose of candesartan cilexetil should be carefully adjusted in patients undergoing hemodialysis, with close monitoring of blood pressure.

Photosensitivity

Cases of photosensitivity reactions have been reported with thiazide diuretics (see section "Adverse reactions"). 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 recommended.

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

Sulfonamide derivatives, including hydrochlorothiazide, may cause an idiosyncratic reaction leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and usually occur within hours or weeks after starting treatment. Untreated acute angle-closure glaucoma may lead to irreversible vision loss. Initial treatment includes prompt discontinuation of the medicinal product. If intraocular pressure remains uncontrolled, prompt medical or surgical intervention may be required. Risk factors for acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.

Non-melanoma skin cancer (NMSC)

An increased risk of NMSC (basal cell carcinoma and squamous cell carcinoma) with increasing cumulative exposure to hydrochlorothiazide has been observed in two epidemiological studies based on data from the Danish National Cancer Registry. The photosensitizing effect of hydrochlorothiazide may be a possible mechanism for NMSC development. Patients taking hydrochlorothiazide should be informed about the risk of NMSC, advised to regularly check their skin for new lesions, and promptly report any suspicious skin changes. To reduce the risk of skin cancer, patients should be advised to take preventive measures such as limiting exposure to sunlight and ultraviolet radiation or using appropriate protective measures when exposed to solar or ultraviolet rays. Suspicious skin lesions should be promptly evaluated with histological examination of biopsy material. Re-evaluation of hydrochlorothiazide use may be necessary in patients with a history of NMSC (see section "Adverse reactions").

Elderly patients

Dose escalation should be performed cautiously in elderly patients (see sections "Pharmacokinetics" and "Posology and method of administration").

General information

The safety and efficacy of amlodipine in hypertensive crisis have not been established. In patients in whom vascular tone and renal function depend predominantly on RAAS activity (e.g., patients with severe congestive heart failure or renal disease, including renal artery stenosis), treatment with other agents affecting this system, including angiotensin II receptor antagonists, has been associated with acute arterial hypotension, azotemia, oliguria, or, rarely, acute renal failure. As with any other antihypertensive agent, excessive reduction in blood pressure in patients with ischemic heart disease or atherosclerotic cerebrovascular disease may lead to myocardial infarction or stroke. Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with a history of atopy. Exacerbation or activation of systemic lupus erythematosus has been reported during treatment with thiazide diuretics.

Pregnancy

Angiotensin II receptor antagonists should not be initiated during pregnancy. Women of childbearing potential who are planning pregnancy should be switched to alternative antihypertensive agents with a well-established safety profile in pregnancy. Angiotensin II receptor antagonists should be discontinued immediately upon confirmation of pregnancy, and alternative therapy initiated if necessary (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Important information on excipients

Lactose

This medicinal product contains lactose as an excipient and therefore should not be used in patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Yellow sunset FCF (E 110)

The medicinal product Casar® Trinity contains yellow sunset FCF (E 110), which may cause allergic reactions.

Use during pregnancy or breastfeeding

Pregnancy

The medicinal product is contraindicated in pregnant women or women who may become pregnant. If pregnancy is confirmed during treatment with this product, its use must be discontinued immediately and replaced with another medicinal product approved for use during pregnancy (see sections "Contraindications" and "Special precautions for use").

Angiotensin II receptor antagonists

Use of angiotensin II receptor antagonists, such as candesartan cilexetil, is contraindicated during pregnancy (see sections "Contraindications" and "Special instructions").

Epidemiological data on the risk of teratogenic effects associated with the use of angiotensin-converting enzyme (ACE) inhibitors during the first trimester of pregnancy are inconclusive; however, a small increased risk cannot be excluded. Although controlled epidemiological data on risks associated with the use of angiotensin II receptor antagonists are lacking, similar risks may exist for this class of drugs. Except for cases requiring continued use of angiotensin II receptor antagonists, patients planning pregnancy should receive alternative antihypertensive therapy with a well-established safety profile in pregnant women. If pregnancy is confirmed, treatment with an angiotensin II receptor antagonist should be discontinued immediately and, if necessary, alternative therapy initiated.

It is known that the use of angiotensin II receptor antagonists during the second and third trimesters of pregnancy has toxic effects on fetal development (renal dysfunction, thrombocytopenia, delayed skull ossification) and on the newborn (renal failure, arterial hypotension, hyperkalemia).

If exposure to angiotensin II receptor antagonists occurs from the second trimester of pregnancy onward, ultrasound examination of the fetal skull and assessment of renal function are recommended.

Newborns whose mothers have taken angiotensin II receptor antagonists should be closely monitored for signs of arterial hypotension (see sections "Contraindications" and "Special precautions").

Amlodipine

The safety of amlodipine use during human pregnancy has not been established. Reproductive toxicity was observed in animal studies with high doses.

Hydrochlorothiazide

Clinical experience with hydrochlorothiazide use during pregnancy, especially in the first trimester, is limited. Animal data are insufficient. Hydrochlorothiazide crosses the placenta. Based on its mechanism of action, hydrochlorothiazide use during the second and third trimesters of pregnancy may adversely affect fetoplacental perfusion and may cause the following effects in the fetus and newborn: jaundice, electrolyte imbalance, and thrombocytopenia.

Hydrochlorothiazide should not be used to treat gestational edema, gestational hypertension, or preeclampsia due to the risk of reduced plasma volume and placental hypoperfusion without beneficial effects on disease course.

Breastfeeding

The use of Casarck® Triniti is not recommended during breastfeeding. Alternative medicinal products with a better-established safety profile should be preferred during this period, particularly when nursing newborns or preterm infants.

Hydrochlorothiazide passes into breast milk in small amounts. Thiazides in high doses, causing pronounced diuresis, may suppress milk production. Amlodipine also passes into breast milk. It has been estimated that the percentage of the dose received by the infant from a breastfeeding mother lies within the interquartile range of 3 to 7%, with a maximum of 15%. The effect of amlodipine on infants is unknown. It is not known whether candesartan cilexetil passes into breast milk.

Fertility

Candesartan cilexetil had no adverse effect on fertility in rats.

In some patients receiving calcium antagonists such as amlodipine, reversible biochemical changes in sperm heads have been observed. Clinical data on the potential effect of amlodipine on fertility are limited. One study in rats reported adverse effects on male fertility.

In animal studies, hydrochlorothiazide had no effect on fertility or fertilization.

Ability to affect reaction speed when driving or operating machinery

Studies on the effect on the ability to drive vehicles or operate machinery have not been conducted.

Amlodipine may have a minor or moderate effect on the ability to drive vehicles and operate machinery. When driving vehicles or operating machinery, it should be considered that dizziness, headache, fatigue, or nausea may occur during treatment with Casarck® Triniti, and reaction time may be impaired. Caution is recommended, especially at the beginning of treatment.

Dosage and Administration

Dosage

The recommended dose of the medicinal product Casark® Trinity is 1 capsule daily.

Casark® Trinity is not intended for initial therapy. If dose adjustment is required, the dose of each component should be adjusted separately. After appropriate doses have been established, switching to a new fixed-dose combination may be considered.

For patients who have achieved blood pressure control with fixed doses of candesartan cilexetil, amlodipine, and hydrochlorothiazide taken concomitantly, treatment may be switched to Casark® Trinity containing the same doses of the components.

Special Patient Groups

Elderly patients

Casark® Trinity should be used with caution in elderly patients due to their susceptibility to electrolyte disturbances. Caution should be exercised when increasing the dose of the medicinal product (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use").

Renal impairment

When using Casark® Trinity in patients with mild to moderate renal impairment (creatinine clearance 30–60 mL/min), periodic monitoring of renal function is recommended (see section "Special Warnings and Precautions for Use").

Casark® Trinity is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see section "Contraindications").

Hepatic impairment

Patients with hepatic impairment should be closely monitored for blood pressure and renal function.

Casark® Trinity is contraindicated in patients with severe hepatic impairment (see sections "Pharmacological Properties" and "Contraindications").

Administration

The capsule should be swallowed whole with sufficient liquid (e.g., a glass of water). The capsule must not be chewed and should be taken at the same time each day.

Casark® Trinity may be taken independently of food intake.

Children

Casark® Trinity is not recommended for use in children under 18 years of age, as safety and efficacy in this patient population have not been established.

Overdose

Symptoms

Based on the pharmacological properties, the main manifestation of candesartan cilexetil overdose is likely to be symptomatic hypotension and dizziness. Isolated cases of overdose (up to 672 mg of candesartan cilexetil) have been reported, with patients recovering without complications.

Available data indicate that significant overdose of amlodipine may cause excessive peripheral vasodilation and reflex tachycardia. Profound and potentially prolonged systemic hypotension has been reported, which may lead to shock and fatal outcomes. Rare cases of non-cardiogenic pulmonary edema have been reported after amlodipine overdose, which may occur with delayed onset (up to 24–48 hours after ingestion) and may require respiratory support. Early resuscitation measures (including fluid loading) to maintain perfusion and cardiac output may be beneficial.

The main symptom of hydrochlorothiazide overdose is rapid loss of fluid and electrolytes. Other symptoms may include dizziness, hypotension, thirst, tachycardia, ventricular arrhythmias, lethargy/unconsciousness, and muscle cramps.

Treatment

In case of overdose with Casark® Trinity, symptomatic and supportive treatment should be administered. Treatment depends on the time elapsed since drug ingestion and the severity of symptoms.

If drug ingestion occurred recently, gastric lavage should be considered. Administration of activated charcoal immediately or within 2 hours after amlodipine intake has been shown to significantly reduce its absorption in healthy subjects.

Clinically significant hypotension due to overdose of Casark® Trinity requires active cardiovascular support, including careful monitoring of cardiac and pulmonary function, elevation of the legs, and monitoring of circulating fluid volume and diuresis. Vasoconstrictors may be useful to restore normal vascular tone and blood pressure, provided there are no contraindications to their use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade.

Serum electrolytes and creatinine levels should be frequently monitored. In case of arterial hypotension, the patient should be placed in a supine position and prompt restoration of lost salts and fluids should be initiated. Candesartan cannot be removed from the body by hemodialysis. Since amlodipine is highly protein-bound, dialysis is unlikely to be beneficial. The extent to which hydrochlorothiazide is removed by hemodialysis is unknown.

Adverse reactions

Adverse reactions observed during the use of the active substances separately have been classified by frequency as follows: 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

System Organ Class	Adverse Reactions	Frequency *
		Candesartan cilexetil	Amlodipine	Hydrochlorothiazide
Benign, malignant and unspecified neoplasms (including cysts and polyps)	non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma)			unknown
Infections and infestations	respiratory infection	common
Blood and lymphatic system disorders	neutropenia	very rare
	agranulocytosis	very rare		very rare
	leukopenia	very rare	very rare	very rare
	thrombocytopenia		very rare	rare
	aplastic anemia			unknown
	bone marrow depression			very rare
	hemolytic anemia			very rare
Immune system disorders	allergic reactions		very rare
	hypersensitivity reactions			very rare
Metabolism and nutrition disorders	hyperkalemia	very rare
	hyponatremia	very rare		uncommon
	hyperglycemia		very rare	common
	hypokalemia, hyperuricemia, increased serum lipid levels (especially during treatment with high doses)			common
	hypomagnesemia, hypercalcemia, hypochloremic alkalosis, hypophosphatemia			uncommon
Psychiatric disorders	depression		uncommon	rare
	mood changes (including anxiety), insomnia		uncommon
	confusion		rare
	sleep disorders			rare
Nervous system disorders	drowsiness		common
	dizziness	common	common	rare
	vertigo	common
	headache (especially at the beginning of treatment)	common	common	common
	tremor, dysgeusia, loss of consciousness, paresthesia		uncommon
	increased muscle tone, peripheral neuropathy		very rare
	extrapyramidal disorders		unknown
	paraesthesia		uncommon	rare
Eye disorders	visual disturbance		common	rare
	choroidal effusion, acute myopia, acute angle-closure glaucoma			unknown
Ear and labyrinth disorders	tinnitus		uncommon
Cardiac disorders	cardiac arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation)		uncommon	rare
	palpitations		common
	myocardial infarction		very rare
Vascular disorders	flushing		common
	arterial hypotension		uncommon
	vasculitis		very rare
	orthostatic hypotension			uncommon
Respiratory, thoracic and mediastinal disorders	cough	very rare	uncommon
	rhinitis		uncommon
	dyspnea		common
	respiratory disorder, including pneumonitis and pulmonary edema			rare
	acute respiratory distress syndrome (ARDS) (see section "Special precautions")			very rare
Gastrointestinal disorders	nausea	very rare	common	common
	abdominal pain, dyspepsia		common
	anorexia			uncommon
	gastrointestinal disorder			rare
	constipation			uncommon
	change in bowel frequency (including diarrhea and constipation)		common
	diarrhea	unknown	common	uncommon
	vomiting		uncommon	uncommon
	dry mouth		uncommon
	pancreatitis		very rare	rare
	gastritis, gingival hyperplasia		very rare
	intestinal angioedema	very rare
Hepatobiliary disorders	elevated liver enzymes	very rare	very rare
	liver function disorders	very rare
	hepatitis	very rare	very rare
	skin yellowing, jaundice (intrahepatic cholestatic jaundice)		very rare	rare
Skin and subcutaneous tissue disorders	angioedema	very rare	very rare
	rash, urticaria	very rare	uncommon	common
	pruritus	very rare	uncommon
	alopecia, purpura, skin discoloration, hyperhidrosis, exanthema		uncommon
	exfoliative dermatitis, Stevens-Johnson syndrome, Quincke's edema		very rare
	multiform erythema		very rare	unknown
	photosensitivity reactions		very rare	uncommon
	toxic epidermal necrolysis		unknown	very rare
	necrotizing vasculitis			rare
	toxic epidermal necrolysis, lupus-like skin reactions, activation of cutaneous lupus			very rare
Musculoskeletal and connective tissue disorders	back pain, joint pain, muscle pain	very rare	uncommon
	ankle swelling		common
	muscle cramps		common	unknown
Renal and urinary disorders	renal function disorders, including renal failure in susceptible patients	very rare		rare
	urinary disorders, nocturia, increased frequency of urination		uncommon
	acute renal failure			unknown
Reproductive system and breast disorders	impotence		uncommon	rare
	gynecomastia		uncommon
General disorders and administration site conditions	edema		very common
	fatigue, exhaustion		common
	asthenia		common	unknown
	chest pain, pain, malaise		uncommon
	fever			rare
Investigations	increased body weight, decreased body weight		uncommon

* Most frequently associated with cholestasis.

Description of individual adverse reactions

Cases of choroidal effusion with visual field defects have been reported following the use of thiazide and thiazide-like diuretics.

Laboratory test findings

As with other RAAS inhibitors, a slight decrease in hemoglobin concentration has been observed during treatment with candesartan.

Routine laboratory monitoring is generally not required for patients receiving candesartan. However, periodic monitoring of serum potassium and creatinine levels is recommended in patients with renal impairment (see section "Special precautions for use").

Non-melanoma skin cancer

Available epidemiological data suggest a cumulative, dose-dependent association between the use of hydrochlorothiazide and the occurrence of non-melanoma skin cancer (NMSC) (see sections "Pharmacological properties" and "Special precautions for use").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life

3 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 30 °C.

Keep out of reach of children.

Packaging

10 capsules in a blister, 3 blisters per pack.

Prescription status

Prescription only.

Manufacturer

Adamed Pharma S.A., Poland

Manufacturer's address and place of business

5 Józefa Piłsudskiego Street, Pabianice, 95–200, Poland.