Co-Exforge^® (Tablets) Instructions for Use

ATC Code

C09DX01 (Valsartan, amlodipine and Hydrochlorothiazide)

Active Substances

Hydrochlorothiazide (Rec.INN registered by WHO)

Valsartan (Rec.INN registered by WHO)

Amlodipine (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Antihypertensive combination agent (angiotensin II receptor blocker + CCB)

Pharmacological Action

A combined antihypertensive drug containing three components with complementary mechanisms of blood pressure control: amlodipine (a calcium channel blocker), valsartan (an angiotensin II receptor antagonist), and hydrochlorothiazide (a thiazide diuretic). The combination of these components leads to a more pronounced reduction in blood pressure compared to monotherapy with each drug separately.

Amlodipine is a dihydropyridine derivative, a calcium channel blocker. It has antianginal and hypotensive effects. It inhibits the transmembrane transition of calcium ions into cardiomyocytes and vascular smooth muscle cells. The antihypertensive effect of amlodipine is due to a direct relaxing effect on vascular smooth muscle cells. The mechanism of the antianginal action of amlodipine is not fully understood; it is presumably associated with the following effects: it causes dilation of peripheral arterioles, reducing total peripheral resistance (afterload), which leads to a decrease in myocardial oxygen demand; it causes dilation of coronary arteries and arterioles in both intact and ischemic areas of the myocardium, which increases oxygen delivery to the myocardium, including in patients with Prinzmetal’s angina. Amlodipine reduces the severity of left ventricular hypertrophy. It does not affect myocardial contractility and conductivity, does not cause a reflex increase in heart rate, inhibits platelet aggregation, increases glomerular filtration rate, and has a weak natriuretic effect.

In patients with arterial hypertension, taking amlodipine once a day provides a clinically significant reduction in blood pressure (in supine and standing positions) over 24 hours. The antihypertensive effect develops slowly, so the development of acute arterial hypotension is uncharacteristic. In patients with angina, taking amlodipine once a day increases exercise tolerance, time to onset of angina attack and to ischemic ST-segment depression, and reduces the frequency of angina attacks and the need for nitroglycerin (short-acting forms).

The clinical efficacy of amlodipine has been proven in patients with stable exertional angina, vasospastic angina, and angiographically confirmed coronary artery disease.

Amlodipine does not have an undesirable effect on lipid metabolism and does not cause changes in the plasma lipid profile. Amlodipine can be used in patients with bronchial asthma, diabetes mellitus, and gout.

After a single oral dose, the effect of amlodipine begins within 2-4 hours and lasts for 24 hours. The maximum hypotensive effect is achieved no earlier than 4 weeks from the start of taking the drug. The hemodynamic effects of the drug remain unchanged with long-term use.

Valsartan is a selective oral angiotensin II receptor antagonist (type AT₁). It selectively blocks AT₁ subtype receptors, which are responsible for the effects of angiotensin II. The increase in plasma concentration of angiotensin II due to blockade of AT₁ receptors under the action of valsartan may stimulate unblocked AT₂ subtype receptors, which counteract the effects of AT₁ receptor stimulation. Valsartan does not have agonistic activity towards AT₁ receptors. The affinity of valsartan for AT₁ subtype receptors is approximately 20,000 times higher than for AT₂ subtype receptors.

Valsartan does not interact with or block receptors of other hormones or ion channels involved in the regulation of cardiovascular functions.

Valsartan does not inhibit ACE, also known as kininase II, which converts angiotensin I to angiotensin II and breaks down bradykinin. Due to the lack of effect on ACE, the effects of bradykinin or substance P are not potentiated, so the development of dry cough is unlikely when using angiotensin II receptor antagonists. It has been proven that the incidence of dry cough during treatment with valsartan is significantly lower than with the use of ACE inhibitors. In the treatment of arterial hypertension, Valsartan reduces blood pressure without affecting heart rate.

After a single oral dose of valsartan, the hypotensive effect develops within 2 hours, the maximum reduction in blood pressure is achieved within 4-6 hours. The antihypertensive effect of valsartan persists for 24 hours after its administration. With repeated use of valsartan, the maximum reduction in blood pressure, regardless of the dose, is achieved after 2-4 weeks and is maintained at the achieved level during long-term therapy. Sudden discontinuation of valsartan is not accompanied by a significant increase in blood pressure or other adverse events (withdrawal syndrome).

The use of valsartan in patients with chronic heart failure (NYHA functional class II-IV) leads to a significant reduction in the number of hospitalizations for cardiovascular diseases (which is especially pronounced in patients not receiving ACE inhibitors or beta-blockers). When using valsartan in patients with left ventricular failure (with stable hemodynamic parameters) or with impaired left ventricular function after myocardial infarction, a reduction in cardiovascular mortality is noted.

Hydrochlorothiazide is a thiazide diuretic, the diuretic effect of which is associated with impaired reabsorption of sodium, chloride, potassium, magnesium, and water in the distal nephron; it delays the excretion of calcium ions and uric acid. It has antihypertensive properties; the hypotensive effect develops due to the expansion of arterioles. It has almost no effect on normal blood pressure levels.

Excretion of electrolytes and water begins approximately 2 hours after administration, the maximum effect is achieved in 3-6 hours and lasts for 6-12 hours. The antihypertensive effect is achieved in 3-4 days of treatment and lasts for 1 week after discontinuation of the drug. With long-term treatment, a reduction in blood pressure is achieved with lower doses than those required for a diuretic effect. The reduction in blood pressure is accompanied by a slight increase in glomerular filtration rate, vascular resistance of the renal bed, and plasma renin activity.

Hydrochlorothiazide, when taken in high single doses, leads to a decrease in plasma volume, glomerular filtration rate, renal blood flow, and mean arterial pressure. With long-term use in low doses, plasma volume remains reduced, while minute volume and glomerular filtration rate return to the baseline level prior to the start of treatment. Mean arterial pressure and systemic vascular resistance remain reduced. Thiazide diuretics may interfere with breast milk production.

Pharmacokinetics

The pharmacokinetic parameters of amlodipine, valsartan, and hydrochlorothiazide are linear.

Amlodipine

After oral administration, amlodipine is slowly and almost completely absorbed from the gastrointestinal tract. Simultaneous food intake does not affect the absorption of amlodipine. C_max in plasma is reached 6-12 hours after administration. The mean absolute bioavailability is 64-80%. The mean V_d is 21 L/kg of body weight, indicating that most of the amlodipine is in the tissues, and a smaller part is in the blood. Most of the amlodipine in the blood (97.5%) is bound to plasma proteins. C_ss in plasma are reached after 7-8 days of continuous amlodipine use. Amlodipine crosses the blood-brain barrier and the placental barrier.

Amlodipine undergoes slow but active metabolism in the liver in the absence of a significant first-pass effect. Metabolites do not have significant pharmacological activity.

After a single dose of amlodipine, T_1/2 ranges from 35 to 50 hours; with repeated use, it is approximately 45 hours. About 60% of the orally administered dose is excreted by the kidneys, mainly as metabolites, 10% – unchanged, 20-25% – through the intestine with bile. The total clearance of amlodipine is 0.116 ml/s/kg (7 ml/min/kg, 0.42 L/h/kg). Amlodipine is not removed by hemodialysis.

The prolongation of T_1/2 in patients with hepatic insufficiency suggests that with long-term use, the accumulation of amlodipine in the body will be higher (increases to 60 hours).

Valsartan

After oral administration of valsartan, C_max is reached in 2-3 hours. The mean absolute bioavailability is 23%. When valsartan is taken with food, a decrease in bioavailability (by AUC value) of approximately 40% is noted, and C_max – by approximately 50%. Approximately 8 hours after oral administration, plasma concentrations of valsartan in the group of patients taking the drug with food and in the group taking the drug on an empty stomach level out. The reduction in AUC is not clinically significant, so Valsartan can be taken regardless of food intake.

The V_d of valsartan at steady state after IV administration is about 17 L, indicating no extensive distribution of valsartan in tissues. Valsartan is largely bound to serum proteins (94-97%), mainly to serum albumin.

Valsartan does not undergo significant metabolism. About 20% of the administered dose is determined in plasma as metabolites. The hydroxyl metabolite is determined in plasma in low concentrations (less than 10% of the valsartan AUC). This metabolite is pharmacologically inactive.

Valsartan is eliminated in two phases: an α-phase with T_1/2α of less than 1 hour and a β-phase with T_1/2β of about 9 hours. Valsartan is excreted mainly unchanged through the intestine (about 83%) and by the kidneys (about 13%). After IV administration, the plasma clearance of valsartan is about 2 L/h and its renal clearance is 0.62 L/h (about 30% of total clearance). The T_1/2 of valsartan is 6 hours.

On average, in patients with mild (5-6 points on the Child-Pugh scale) and moderate (7-9 points on the Child-Pugh scale) hepatic impairment, the bioavailability (by AUC value) of valsartan is doubled compared to healthy volunteers of the corresponding age, sex, and body weight.

Hydrochlorothiazide

After oral administration, C_max of hydrochlorothiazide is reached within 1-3 hours. Absolute bioavailability is estimated by cumulative renal excretion of hydrochlorothiazide and is about 60%. Binding to plasma proteins is 40-70%. V_d is 0.8±0.3 L/kg. It is not metabolized in the human body and is excreted in the urine almost unchanged. About 60% of the orally administered dose is excreted within 48 hours. Renal clearance is about 250-300 ml/min. T_1/2 is 10-15 hours. There is a difference in plasma concentrations between men and women. Women tend to have a clinically significant increase in plasma concentration of hydrochlorothiazide. In patients with impaired renal function, the excretion rate of hydrochlorothiazide is reduced. Studies involving patients with a creatinine clearance of 90 ml/min have shown that the T_1/2 of hydrochlorothiazide increases. In patients with reduced renal function, T_1/2 is about 34 hours.

Indications

• Stage II and III arterial hypertension.

ICD codes

Dosage Regimen

Tablets

The drug is taken orally, regardless of meals, preferably in the morning, with a small amount of water.

For convenience, patients receiving therapy with amlodipine, valsartan, and hydrochlorothiazide in separate tablets can be switched to therapy with this combination containing the same doses of active components, as well as in case of insufficient blood pressure control during dual combination therapy (Valsartan+Hydrochlorothiazide, amlodipine+Valsartan and amlodipine+Hydrochlorothiazide), patients can be switched to triple combination therapy with the drug in appropriate doses.

If a patient experiences dose-dependent side effects when using dual combination therapy with any components of the drug, to achieve a similar reduction in blood pressure, patients may be prescribed a drug containing a lower dose of the active component that caused this side effect.

The recommended daily doses of the drug are: 5 mg+160 mg+12.5 mg (1 tablet containing amlodipine+Valsartan+Hydrochlorothiazide in doses of 5 mg+160 mg+12.5 mg); 10 mg+160 mg+12.5 mg (1 tablet containing amlodipine+Valsartan+Hydrochlorothiazide in doses of 10 mg+160 mg+12.5 mg); 10 mg+320 mg+25 mg (2 tablets containing amlodipine+Valsartan+Hydrochlorothiazide in doses of 5 mg+160 mg+12.5 mg).

The maximum antihypertensive effect of the drug is noted 2 weeks after increasing the dose. The maximum dose of the drug is 10 mg+320 mg+25 mg/day.

In patients over 65 years of age, dose adjustment of the drug is not required.

Since the safety and efficacy of the drug in children and adolescents under 18 years of age have not yet been established, the drug is not recommended for use in this category of patients.

In patients with mild to moderate renal impairment (creatinine clearance >30 ml/min) and hepatic impairment (5-9 points on the Child-Pugh scale), dose adjustment of the drug is not required.

Adverse Reactions

Amlodipine+Valsartan+Hydrochlorothiazide

When using the drug, adverse events were mostly mild or moderate in severity. Discontinuation of treatment with the drug due to the development of adverse events was required in rare cases. Most often, the drug was discontinued due to the development of dizziness and pronounced decrease in blood pressure.

No new adverse events were identified with the use of the drug compared to dual combination therapy and monotherapy with individual components.

As with short-term use, good tolerability of the drug was observed with its long-term use (for one year).

The frequency of adverse events was not related to gender, age, or race.

When using the drug, changes in laboratory parameters were minimal and did not differ from those during monotherapy with individual components. With the simultaneous use of hydrochlorothiazide together with valsartan (triple combination therapy), a reduction in the hypokalemic effect of hydrochlorothiazide is noted.

The most frequent adverse events noted in clinical studies (regardless of establishing a causal relationship with the drug use) were dizziness, peripheral edema, headache, dyspepsia, increased fatigue, muscle spasm, back pain, nasopharyngitis, nausea.

The following criteria were used to assess frequency (according to WHO classification): very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000), frequency unknown (insufficient data to estimate frequency).

Metabolism and nutrition disorders: common – hypokalemia; uncommon – hypercalcemia, hyperlipidemia, hyponatremia.

Nervous system disorders: common – dizziness, headache; uncommon – insomnia/sleep disorders, coordination abnormalities, postural dizziness and dizziness on exertion, taste disturbances, lethargy, paresthesia, neuropathy, incl. peripheral, somnolence, syncope.

Eye and ear disorders: uncommon – visual disturbances, vertigo.

Cardiac and vascular disorders: common – pronounced decrease in blood pressure; uncommon – tachycardia, orthostatic hypotension, phlebitis, thrombophlebitis.

Respiratory, thoracic and mediastinal disorders: uncommon – cough, dyspnea, throat irritation.

Gastrointestinal disorders: common – dyspepsia; uncommon – anorexia, abdominal discomfort, upper abdominal pain, halitosis, diarrhea, dry mouth, nausea, vomiting.

Skin and subcutaneous tissue disorders: uncommon – hyperhidrosis, pruritus.

Musculoskeletal and connective tissue disorders: uncommon – back pain, joint swelling, muscle cramps, muscle weakness, myalgia, pain in extremity.

Renal and urinary disorders: common – pollakiuria; uncommon – increased plasma creatinine concentration, acute renal failure.

Reproductive system and breast disorders: uncommon – erectile dysfunction.

General disorders and administration site conditions: common – peripheral edema, increased fatigue; uncommon – abasia, gait disturbance, asthenia, general weakness, chest pain.

Investigations: uncommon – increased blood urea nitrogen, hyperuricemia, increased body weight.

Amlodipine

The following criteria were used to assess frequency (according to WHO classification): very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000), frequency unknown (insufficient data to estimate frequency).

Blood and lymphatic system disorders: very rare – leukopenia, thrombocytopenia.

Immune system disorders: very rare – hypersensitivity reactions.

Metabolism and nutrition disorders: very rare – hyperglycemia.

Nervous system disorders: common – dizziness, headache, somnolence; uncommon – insomnia/sleep disorders, mood swings, paresthesia, syncope, tremor; very rare – muscle hypertonia, peripheral neuropathy, neuropathy; frequency unknown – extrapyramidal disorders.

Eye and ear disorders: uncommon – visual disturbances, tinnitus, taste disturbances.

Cardiac and vascular disorders: common – palpitations, flushing; uncommon – pronounced decrease in blood pressure; very rare – vasculitis, arrhythmias (including bradycardia, ventricular tachycardia, atrial fibrillation).

Respiratory, thoracic and mediastinal disorders: uncommon – dyspnea, rhinitis; very rare – cough.

Gastrointestinal disorders: common – abdominal discomfort, upper abdominal pain, nausea; uncommon – change in bowel habits, diarrhea, dry mouth, dyspepsia, vomiting; very rare – gastritis, gingival hyperplasia, pancreatitis.

Hepatobiliary disorders: very rare – increased liver enzyme activity, increased plasma bilirubin concentration, hepatitis, intrahepatic cholestasis, jaundice.

Dermatological reactions: infrequently – alopecia, increased sweating, pruritus, rash, including exanthema, purpura, skin discoloration; very rarely – angioedema, erythema multiforme, urticaria.

Musculoskeletal and connective tissue disorders: infrequently – arthralgia, back pain, muscle cramps, myalgia.

Urinary system disorders: infrequently – urinary disorders, nocturia, pollakiuria.

Reproductive system disorders: infrequently – erectile dysfunction, gynecomastia.

General disorders: frequently – increased fatigue, edema; infrequently – asthenia, discomfort, general weakness, chest pain, pain of various localization.

Laboratory findings: infrequently – increase or decrease in body weight.

Valsartan

The following criteria were used to assess frequency (according to WHO classification): very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000), frequency unknown (insufficient data to estimate frequency).

Blood and lymphatic system disorders: frequency unknown – decrease in hemoglobin and hematocrit, leukopenia, thrombocytopenia.

Immune system disorders: frequency unknown – hypersensitivity reactions.

Ear and labyrinth disorders: uncommon – vertigo.

Cardiac disorders: frequency unknown – vasculitis.

Respiratory, thoracic and mediastinal disorders: uncommon – cough.

Gastrointestinal disorders: uncommon – abdominal discomfort, upper abdominal pain.

Hepatobiliary disorders: frequency unknown – increased liver enzyme activity, increased plasma bilirubin concentration.

Allergic reactions: frequency unknown – angioedema, pruritus, rash.

Musculoskeletal and connective tissue disorders: frequency unknown – myalgia.

Renal and urinary disorders: frequency unknown – increased plasma creatinine concentration, renal function impairment, including acute renal failure.

General disorders: uncommon – increased fatigue.

Laboratory findings: frequency unknown – increased plasma potassium levels.

In clinical studies with valsartan monotherapy, the following adverse events were observed (regardless of causal relationship to the study drug): viral infections, upper respiratory tract infections, sinusitis, rhinitis, neutropenia, insomnia.

In rare cases, the use of valsartan may be accompanied by a decrease in hemoglobin and hematocrit. In controlled studies, a significant decrease (more than 20%) in hematocrit and hemoglobin was observed in 0.8% and 0.4% of patients receiving Valsartan, respectively. For comparison, in patients receiving placebo, a decrease in both hematocrit and hemoglobin was observed in 0.1% of cases.

Neutropenia was detected in 1.9% of patients receiving Valsartan and in 1.6% of patients receiving an ACE inhibitor.

In controlled studies, an increase in creatinine and blood urea nitrogen concentrations of more than 50% was observed in 3.9% and 16.6% of patients with chronic heart failure receiving Valsartan, respectively. For comparison, in patients receiving placebo, an increase in creatinine and urea nitrogen concentrations was observed in 0.9% and 6.3% of cases.

A doubling of serum creatinine concentration was detected in 4.2% of patients after myocardial infarction receiving Valsartan and in 3.4% receiving captopril.

In controlled studies, an increase in serum potassium of more than 20% was observed in 10% of patients with chronic heart failure. For comparison, in patients receiving placebo, an increase in potassium levels was observed in 5.1% of cases.

Hydrochlorothiazide

The following criteria were used to assess frequency (according to WHO classification): very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000), frequency unknown (insufficient data to estimate frequency).

Blood and lymphatic system disorders: rare – thrombocytopenia; very rare – agranulocytosis, bone marrow depression, hemolytic anemia, leukopenia.

Immune system disorders: very rare – hypersensitivity reactions.

Metabolism and nutrition disorders: common – hypokalemia; uncommon – hyperuricemia, hypomagnesemia, hyponatremia; rare – hypercalcemia, hyperglycemia; very rare – hypochloremic alkalosis.

Nervous system disorders: rare – insomnia/sleep disorders, depression, dizziness, headache, lethargy.

Eye disorders: uncommon – visual disturbances.

Cardiac disorders: uncommon – orthostatic hypotension; rare – arrhythmias (including bradycardia, ventricular tachycardia, atrial fibrillation).

Respiratory, thoracic and mediastinal disorders: very rare – respiratory distress syndrome, pulmonary edema and pneumonitis.

Gastrointestinal disorders: uncommon – decreased appetite, nausea, vomiting; rare – abdominal discomfort, upper abdominal pain, constipation, diarrhea; very rare – pancreatitis.

Hepatobiliary disorders: rare – hepatitis, intrahepatic cholestasis, jaundice.

Dermatological reactions: uncommon – rash, urticaria; rare – increased photosensitivity, purpura; very rare – necrotizing vasculitis, toxic epidermal necrolysis, lupus-like reactions, exacerbation of cutaneous manifestations of systemic lupus erythematosus.

Renal and urinary disorders: rare – renal function impairment, including acute renal failure.

Reproductive system disorders: uncommon – erectile dysfunction.

Laboratory findings: common – hyperlipidemia; rare – glycosuria

Contraindications

• Severe hepatic impairment (more than 9 points on the Child-Pugh scale);
• Biliary cirrhosis and cholestasis;
• Severe renal impairment (CrCl <30 ml/min), anuria, patients on hemodialysis;
• Severe arterial hypotension (systolic BP less than 90 mm Hg);
• Collapse, cardiogenic shock;
• Clinically significant aortic stenosis;
• Hypokalemia, hyponatremia, hypercalcemia refractory to adequate therapy, as well as hyperuricemia with clinical manifestations;
• Hereditary angioedema, or edema in patients during previous therapy with angiotensin II receptor antagonists;
• Pregnancy and pregnancy planning;
• Breastfeeding period;
• Age under 18 years (efficacy and safety not established);
• Hypersensitivity to amlodipine, valsartan, hydrochlorothiazide, other sulfonamide derivatives, dihydropyridine derivatives and other excipients of the drug.

Caution should be exercised when prescribing the drug to patients with unilateral or bilateral renal artery stenosis or stenosis of the artery of a solitary kidney, in conditions accompanied by a decrease in circulating blood volume, in case of water-electrolyte imbalance (including hyponatremia, hyperkalemia), patients with mitral or aortic stenosis, hypertrophic obstructive cardiomyopathy, mild to moderate hepatic impairment, especially against the background of biliary obstruction (less than 9 points on the Child-Pugh scale), diabetes mellitus, SLE.

The safety of the drug in patients after recent kidney transplantation, as well as in patients with heart failure or coronary artery disease has not been established.

Use in Pregnancy and Lactation

It is known that the prescription of ACE inhibitors that affect the RAAS to pregnant women in the II and III trimesters leads to damage or death of the developing fetus. Given the mechanism of action of angiotensin II receptor antagonists, the risk to the fetus cannot be ruled out. According to retrospective analysis, the use of ACE inhibitors in the first trimester of pregnancy was accompanied by the development of fetal and neonatal pathology. Hydrochlorothiazide crosses the placental barrier. When using thiazide diuretics, including Hydrochlorothiazide, during pregnancy, the development of embryonic or neonatal thrombocytopenia, as well as other adverse reactions observed in adult patients, is possible. With unintentional use of valsartan in pregnant women, cases of spontaneous abortions, oligohydramnios and impaired renal function in newborns have been described. Like any other drug that directly affects the RAAS, it should not be prescribed during pregnancy and to women planning pregnancy.

Women of childbearing potential should be informed about the possible risk to the fetus associated with the use of drugs that affect the RAAS. If pregnancy is diagnosed during treatment with the drug, the drug should be discontinued as soon as possible.

It is not known whether Valsartan and/or amlodipine pass into breast milk. In experimental studies, excretion of valsartan in breast milk was noted. Hydrochlorothiazide is excreted in breast milk. The drug should not be used during breastfeeding.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.