Zocardis® [Hydrochlorothiazide, zofenopril]

Pharmacological properties

Zocardis plus 30 / 12.5 is a combined preparation consisting of zofenopril, a substance that suppresses apf, and hydrochlorothiazide - a diuretic agent of the thiazide series. the mechanisms of action of both substances complement each other, and their antihypertensive effect is enhanced. zofenopril is a sulfhydryl inhibitor of APF, an inhibitory enzyme that catalyzes the conversion of angiotensin i to angiotensin ii, a peptide with a vasoconstrictor effect. this leads to a weakening of vasoconstrictor activity and a decrease in the secretion of aldosterone. the latter can lead to an increase in the concentration of potassium in the blood plasma with the simultaneous removal of sodium and water from the body. elimination of the negative inverse effect of angiotensin ii on renin secretion leads to its activation in plasma. The mechanism of decreasing adofenopril ad is based on the primary inhibition of the renin-angiotensin-aldosterone system. apf is identical to kininase ii, an enzyme that catalyzes the breakdown of bradykinin, a peptide with a potential vasodilating effect. this, obviously, plays a role in the implementation of the therapeutic effect of APF inhibitors.

The simultaneous use of ACE inhibitors and angiotensin II receptor blockers has been studied in two large-scale randomized controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes). ONTARGET is a study conducted with a history of cardiovascular or cerebrovascular diseases or type II diabetes mellitus with signs of target organ damage. VA NEPHRON-D is a study in patients with type II diabetes mellitus and diabetic nephropathy. The studies did not reveal a significant beneficial effect on the outcome of renal and / or cardiovascular diseases and mortality from them, whereas compared with monotherapy, there was an increased risk of developing hyperkalemia, acute kidney damage and / or hypotension. Given the similar pharmacodynamic properties, these results are also applicable to other ACE inhibitors and angiotensin II receptor blockers. The combined use of ACE inhibitors and angiotensin II receptor blockers is contraindicated in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) - a study conducted to identify the positive effect of adding aliskiren to standard therapy with ACE inhibitors or angiotensin II receptor blockers, involving patients with type II diabetes and chronic kidney disease, cardiovascular disease or with the presence of both diseases. The study was terminated earlier due to an increased risk of undesirable consequences. Mortality from cardiovascular disease and the development of stroke was more often observed in the aliskiren group compared with the placebo group. Serious adverse reactions (hyperkalemia, hypotension, and impaired renal function) were more often reported in the aliskiren group compared with the placebo group.

Hydrochlorothiazide has a diuretic and hypotensive effect. It affects the reabsorption of electrolytes in the distal part of the renal tubules. Hydrochlorothiazide enhances the excretion of sodium and chlorine in approximately the same way. Natriuresis may be accompanied by the loss of a certain amount of potassium and bicarbonate. The simultaneous administration of hydrochlorothiazide with zofenopril leads to the restoration of potassium losses associated with the action of a diuretic. Diuresis begins 2 hours after taking the latter, reaches a maximum after 4 hours and lasts about 6-12 hours.

Pharmacokinetics The combined use of zofenopril and hydrochlorothiazide slightly or practically does not affect the bioavailability of the active substances separately.The combined preparation is bioequivalent to both mono-substances taken simultaneously.

Zofenopril is a prodrug, since the active component is zofenoprilat, a free thiol compound obtained by thioupher hydrolysis.

Suction. When taken orally, zofenopril is rapidly and completely absorbed and is almost completely converted into zofenopril. C_max in blood is reached after 1.5 hours. The kinetics of a single dose is linear in the dose range of 10–80 mg of zofenopril calcium. After taking 15-60 mg of zofenopril calcium for 3 weeks, there is no cumulation. Eating reduces the rate, but not the amount of absorption, the AUC of zofenoprilat before and after eating is almost identical.

Distribution. Approximately 88% of the circulating radioactive substance, measured ex vivo after administration of labeled zofenopril, binds to blood plasma proteins, and the distribution volume in the equilibrium state is 96 l.

Metabolism. In human urine after taking labeled zofenopril, 8 metabolites were identified, accounting for 76% of the total radioactive substance in the urine. The main metabolite is zofenoprilat (22%), which is then metabolized in several ways, including conjugation with glucuronic acid (17%), cyclization and conjugation with glucuronic acid (13%), conjugation with cysteine ​​(9%) and S-methylation of the thiol group ( 8%).

Excretion. After administration, radiolabeled zofenoprilat is excreted in urine (76%) and feces (16%), and after oral administration in urine and feces, 69 and 26% of the total content of the radioactive substance are detected, respectively, which indicates the presence of two routes of withdrawal, namely, through kidneys and liver. T_½ zofenoprilat after oral administration of zofenopril is 5.5 hours, and its total clearance in the body is 1300 ml / min.

Elderly patients with normal renal function do not require dose adjustment.

Impaired renal function. A study of the pharmacokinetics of radiolabeled zofenopril for oral administration in patients with mild renal impairment (creatinine clearance 45 and 90 ml / min) suggests that it is excreted at the same rate as in patients with normal renal function (creatinine clearance 90 ml / min). In patients with moderate or severe renal impairment (7–44 ml / min), the excretion rate is reduced to about 50% of the norm. In patients with end-stage renal failure receiving hemodialysis and peritoneal dialysis, clearance is reduced to 25% of the norm.

Impaired liver function. In patients with impaired liver function of mild or moderate degree, who used radiolabeled zofenopril once, the values ​​of Tmax and C_max for zofenoprilat were similar to the values ​​obtained in individuals with normal liver function. However, the AUC values ​​in patients with cirrhosis were approximately 2 times higher than the AUC values ​​in patients with normal liver function. Thus, patients with impaired liver function of mild to moderate severity should use half the initial dose, which is recommended for patients with normal liver function. Pharmacokinetics of zofenopril and zofenoprilat are not available in persons with severe impaired liver function, therefore, zofenopril is contraindicated in such patients.

When taken orally, hydrochlorothiazide is well absorbed (65–75%). Plasma concentration is linearly dependent on the dose of the drug. The absorption of hydrochlorothiazide varies depending on the time of passage through the intestine, increasing with a longer passage, for example, with food. T_½ from blood plasma ranges from 5.6 to 14.8 hours and C_max in blood plasma is achieved 1-5 hours after administration.

Distribution. Thiazides are widely distributed in body fluids and bind to plasma proteins by 92%, mainly with albumin. This leads to lower renal clearance and, thus, to a longer action.The relationship between the concentration of hydrochlorothiazide in blood plasma and the severity of arterial hypotension has not been established.

Excretion. Hydrochlorothiazide is excreted mainly by the kidneys. The main part of the drug is excreted unchanged and 3–6 hours after ingestion, 95% of unchanged hydrochlorothiazide is determined in the urine. With impaired renal function, the level of hydrochlorothiazide in the blood increases, as does T_½. Hydrochlorothiazide passes through the placental barrier, but does not pass through the BBB.

Indications

Essential ag to mild to moderate severity. the combined drug is indicated for patients with an insufficient reaction to zofenopril monotherapy.

Application

The drug Zokardis plus 30 / 12.5 is used once a day, regardless of food intake.

Before using the combined drug with a fixed content of zofenopril and hydrochlorothiazide, it is recommended to establish their optimal doses separately. If necessary, a direct replacement of single drugs with a combined drug is possible. To facilitate swallowing, the tablet can be divided into two halves and swallow them in turn at the appointed time. The risk is intended to be divided into tablets for easier swallowing, and not to be divided into dosage levels.

Adults (18–65 years old). Patients without disturbances in water-electrolyte metabolism should use 1 tablet per day. For patients with impaired water-electrolyte metabolism, the drug is not recommended.

Patients of advanced age (over 65 years). Elderly patients with normal creatinine clearance do not require dose adjustment. The drug is not recommended for patients with reduced creatinine clearance. Creatinine clearance can be calculated based on the level of serum creatinine according to the Cockroft-Gault formula:

The above formula allows you to calculate creatinine clearance for men. For women, the resulting value must be multiplied by 0.85.

Children (under 18 years old). The use of the drug Zokardis Plus 30 / 12.5 in children is not recommended due to the lack of data on safety and effectiveness.

Patients with impaired renal function or receiving hemodialysis sessions. Patients with mild impaired renal function (creatinine clearance 45 ml / min) do not require dose adjustment. For persons with moderate or severe impaired renal function (creatinine clearance 45 ml / min), the use of the drug Zokardis plus 30 / 12.5 is not recommended. Patients with severe impaired renal function (creatinine clearance 30 ml / min) drug Zokardis plus 30 / 12.5 is contraindicated. Patients receiving hemodialysis sessions, Zokardis plus 30 / 12.5 is not recommended.

Patients with impaired liver function. For patients with mild or moderate impaired liver function, dose adjustment is not required. Zokardis plus 30 / 12.5 is contraindicated in patients with severe hepatic impairment.

Contraindications

Pregnancy, pregnancy planning. hypersensitivity to zofenopril or to any other apf inhibitor. hypersensitivity to hydrochlorothiazide or to other sulfonamide derivatives. hypersensitivity to excipients of the drug. a history of angioedema associated with previous treatment with an apt inhibitor. history of hereditary or idiopathic angioneurotic edema. severe liver dysfunction. severe renal impairment (creatinine clearance 30 ml / min). bilateral renal artery stenosis or renal artery stenosis of a single kidney. the simultaneous use of the drug zokardis plus 30 / 12.5 and drugs containing aliskiren is contraindicated in patients with diabetes mellitus or impaired renal function (glomerular filtration rate of 60 ml / min / 1.73 m2).

Side effects

In controlled clinical trials involving 597 patients who received zofenopril and hydrochlorothiazide in the randomization order, there were no adverse reactions specific to this combination drug. only adverse reactions previously identified for zofenopril calcium and hydrochlorothiazide were noted. the frequency of adverse reactions is not related to the gender or age of the patient.

Adverse reactions that occurred during clinical trials, and those that had an equally probable or possible relationship with the treatment of Zokardis Plus 30 / 12.5, are given below. These reactions are classified by organ systems and frequency of occurrence: very often: ≥1 / 10; often: ≥1 / 100, 1/10; sometimes: ≥1 / 1000, ≤1 / 100; rarely: ≥1 / 10,000, 1/1000; very rare: ≤1 / 10,000.

Infections and infections: sometimes - infection, bronchitis, pharyngitis.

Violation of nutrition and metabolism: sometimes - hypercholesterolemia, hyperglycemia, hyperlipidemia, hypokalemia, hyperkalemia, hyperuricemia.

Mental disorders: sometimes - insomnia.

From the nervous system: often - dizziness, headache; sometimes - drowsiness, fainting, hypertension.

From the side of the heart: sometimes - angina pectoris, atrial fibrillation, myocardial infarction, palpitation.

From the vessels: sometimes - hot flashes, arterial hypotension, hypertension.

On the part of the respiratory system, chest and mediastinum: often - cough; sometimes shortness of breath.

From the digestive tract: sometimes - nausea, dyspeptic symptoms, gastritis, gingivitis, dry mouth, abdominal pain.

On the part of the skin and subcutaneous tissue: sometimes - angioedema, psoriasis, acne, dry skin, itching, urticaria.

From the musculoskeletal system: sometimes - back pain.

From the kidneys and urinary tract: sometimes - polyuria.

General disorders: sometimes - asthenia, flu-like symptoms, peripheral edema.

From the reproductive system and mammary glands: sometimes - erectile dysfunction.

Data from additional research methods: sometimes - increased levels of creatinine and functional liver samples in the blood.

Additional information on individual components

Known adverse reactions characteristic of each