Expiration date: 10/2025
The composition and form of issue:
Tablets, film-coated. 1 tablet contains:
valsartan 80 or 160 mg
hydrochlorothiazide 12.5 or 25 mg
excipients: silica colloidal anhydrous crospovidone magnesium stearate MCC
shell tablets 80 + 12.5 mg: hypromellose macrogol 8000 talc titanium dioxide (E171) iron oxide red (E172) iron oxide yellow (E172)
shell tablets 160 + 12.5 mg: hypromellose macrogol 8000 talc titanium dioxide (E171) iron oxide red (E172)
shell tablets 160 + 25 mg: hypromellose macrogol 8000 talc titanium dioxide (E171) iron oxide red (E172) iron oxide yellow (E172) iron oxide black (E172)
blistere in 14 PCs. in cardboard pack 1, 2 or 7 blisters.
Description pharmaceutical form:
Tablets, film-coated, 80 + 12.5 mg: light orange color, oval, lenticular, on one side marked with "HGH" on the other — CG.
Tablets, film-coated, 160 + 12.5 mg: from dark red to brownish-red, oval-shaped, on one side of the tablet marking "NNN", the other "CG".
Tablets, film-coated, 160 x 25 mg: brown-orange, oval, biconvex, one side marked "NHN", on the other "NVR".
Pharmacokinetics:
Valsartan
After taking the drug inside the absorption of valsartan occurs rapidly, but the degree of absorption varies widely. Average bioavailability of 23%. The pharmacokinetic curve is downward valsartan multiexponential character (T1/2&alpha <1 h and T1/2&beta about 9 hours).
In the range of doses studied kinetics valsartan is linear. If you re-use valsartan changes of the kinetic parameters was observed. When taking valsartan 1 time per day accumulation is negligible. The concentration of valsartan in plasma in women and men were the same. Valsartan largely (94-97%) is associated with serum proteins, mainly to albumin. Equilibrium VSS low (about 17 l). Compared with hepatic blood flow (about 30 l/h) plasma Cl is relatively slow valsartan (about 2 l/h). Valsartan is excreted primarily in unchanged form, valsartan excretion with the feces is 70% of the value of absorbirowawrzayasa of dose in urine and about 30%.
In the appointment of valsartan with food decreases AUC by 48% although, from about the eighth hour after drug administration the concentration of valsartan in plasma as in case of taking it on an empty stomach and when taken with food, the same. Reduction in AUC, however, is not accompanied by a clinically significant decrease in therapeutic effect.
Hydrochlorothiazide
After oral absorption of hydrochlorothiazide is fast (Tmax about 2 h). Pharmacokinetics gidrohlorotiazida in the phases of distribution and excretion is described in General bieksponencialny downward curve T1/2 the final phase of 6-15 h
In the therapeutic dose range average AUC increases with the increase in dose. When re-appointments pharmacokinetics of hydrochlorothiazide is not changed. In the appointment, 1 time per day accumulation is negligible.
When administered, the absolute bioavailability of hydrochlorothiazide is 60-80%. Excretion occurs in the urine: more than 95% absorbirowawrzayasa dose is excreted unchanged and about 4% in the form of a hydrolysate — 2-amino-4-chloro-m-benzenedisulfonamide.
In concurrent use of hydrochlorothiazide with food were observed both increase and reduction of its systemic bioavailability (as compared to the corresponding period in the fasting). The range of these changes are small and clinically insignificant.
Valsartan/hydrochlorothiazide
Combined with a lower systemic bioavailability of hydrochlorothiazide is reduced by about 30%. Co-administration of hydrochlorothiazide, for its part, has no significant effect on the kinetics of valsartan. Observed interaction has no impact on the effectiveness of the combined use of valsartan and hydrochlorothiazide. In controlled clinical trials has revealed a clear antihypertensive effect of this combination, which exceeded the effect of each component separately, as well as the placebo effect.
Pharmacokinetics in specific groups of patients
Elderly patients. Some elderly patients valsartan AUC was slightly higher than in young patients, however, this was not clinically significant.
A few data suggest that in elderly patients (both healthy and with arterial hypertension), systemic Cl of hydrochlorothiazide lower than in healthy young volunteers.
Patients with impaired liver function. AUC valsartan in patients with mild (n=6) and moderately severe (n=5) liver dysfunction was 2 times more than in healthy volunteers.
Description pharmacological action:
Co-Diovan — antihypertensive drug, which comprises an antagonist of angiotensin II receptor and thiazide diuretic.
Active hormone of the renin-angiotensin-aldosterone system (RAAS) is angiotensin II formed from angiotensin I with the participation of the APF. Angiotensin II binds to specific receptors located on cell membranes in various tissues. It has a wide range of physiological effects, including in the first place as a direct and indirect part in regulating blood pressure. Being a powerful vasoconstrictor substance, angiotensin II causes direct Pressor response. In addition, it stimulates secretion of aldosterone and promotes sodium retention.
Valsartan is an active and specific antagonist of angiotensin II receptor. Acts selectively on the receptor subtype AT1, which is responsible for the known effects of angiotensin II. Increased serum levels of angiotensin II as a consequence of the blockade AT1-receptor by valsartan may stimulate the availability of the AT2 receptors, which balances the effects associated with the blockade of AT1-receptors. Any pronounced agonistic activity with respect to receptor subtype AT1 valsartan does not show. The affinity of valsartan for the AT1 receptor subtype approximately 20,000 times higher than for the AT2 receptor subtype.
Valsartan is not ingibiruet agents, also known as kininase II, which converts angiotensin I to angiotensin II and destroys bradykinin. When comparing valsartan with an ACE inhibitor, the incidence of dry cough was significantly (p<0.05) lower in patients treated with valsartan than in patients treated with ACE inhibitor (2.6 vs. 7.9%, respectively). In a clinical study involving patients earlier in the treatment of ACE inhibitor developed a dry cough, the treatment with valsartan, this complication was noted in 19.5% of cases, and in the treatment of thiazide diuretic — in 19% of cases, while in the group of patients treated with ACE inhibitor, cough was observed in 68.5% of cases (p<0.05). Valsartan does not enter into interaction and does not block other hormone receptors or ion channels of importance for the regulation of the functions of the cardiovascular system.
The treatment with valsartan in patients with arterial hypertension there is a decrease in AD, is not accompanied by changes in heart rate.
After ingestion of a single dose of the drug, most patients start antihypertensive effect observed within 2 h, the maximum decrease in blood pressure is achieved within 4-6 h. the Antihypertensive effect persisted for more than 24 hours after taking the drug. With repeated prescriptions maximum decrease in blood pressure, regardless of the dose, is usually achieved within 2-4 weeks and maintained at that level during long-term therapy. The presence of the drug hydrochlorothiazide provide a significant additional decrease in blood pressure.
The point of application of the effect of thiazide diuretics is the division of cortical distal convoluted renal tubules, where it is located is highly sensitive to the action of diuretics receptors, and where there is a suppression of the transport of ions Na+ and C1-. The mechanism of action of thiazides is associated with suppression pump Na+Cl-, which presumably occurs by competition for space transport CL-. As a result, excretion of sodium and chlorine ions increases approximately to the same extent. The result is diuretic effect a decrease in volume, resulting in increased renin activity, aldosterone secretion, the urinary excretion of potassium and hence reduce the concentration of potassium in the blood serum. The relationship between renin and aldosterone is mediated by angiotensin II, so the appointment of an antagonist of the angiotensin II receptor will reduce the potassium loss associated with thiazide diuretic use.
Indications:
Hypertension.
Contraindications:
- hypersensitivity to any component of the drug
- pregnancy
- severe violations of the liver, biliary cirrhosis and cholestasis
- anuria, severe violations of kidney function (Cl creatinine <30 ml/min)
- refractory to adequate therapy hypokalemia, hyponatremia, hypercalcemia, and hyperuricemia with clinical manifestations.
- The safety and efficacy of the drug Co-Diovan in children has so far not established.
Caution — renal artery stenosis.
The safety of the drug Co-Diovan in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery only kidneys are not installed.
Application of pregnancy and breast-feeding:
Given the mechanism of action of antagonists of angiotensin II cannot exclude the risk to the fetus. It is known that the effect of ACE inhibitors on the uterus, in case of their appointment in the II and III trimester of pregnancy, causes damage or death to the developing fetus. Introduction thiazide diuretics in the uterus led to the development of thrombocytopenia in the fetus or in the neonatal period, as well as to the development of other adverse effects that have been observed in the subsequent adults. Therefore, the drug Co-Diovan, like any other drug that has a direct impact on the RAAS, should not be used during pregnancy and lactation. If pregnancy is detected during treatment with the drug Co-Diovan, it should be abolished as soon as possible.
It is unknown if valsartan penetrates into breast milk in humans. In experimental studies it was shown that valsartan is excreted in breast milk.
Hydrochlorothiazide crosses the placenta, excreted in breast milk in humans. Therefore, it is not recommended to use the drug Co-Diovan in breast-feeding.
Side effects:
Adverse events observed when using the drug Co-Diovan, were generally mild and transient in nature.
The data given in the table below, based on the results of 3 controlled studies. In these studies it was included 2159 patients, 2066 of them received valsartan in combination with hydrochlorothiazide. The overall frequency of adverse events observed when using the drug Co-Diovan, were the same as when using a placebo.
In the table included all adverse events, registered in the group of patients receiving the drug Co-Diovan (regardless of their causal relationship with the intake of study drug), and met with a frequency of 1% or more.
Table
Adverse reactions are encountered with a frequency of 1% or more
| Adverse events | Drug Co-Diovan (n=2066), % | Placebo (n=93), % |
| Headache | 5,1 | 17,2 |
| Dizziness (excluding vertigo) | 3,9 | 6,5 |
| Nasopharyngitis | 2,7 | 1,1 |
| Feeling tired | 2,0 | 1,1 |
| Back pain | 1,5 | 3,2 |
| Cough | 1,4 | - |
| Infections of the upper respiratory tract | 1,4 | 2,2 |
| Sinusitis | 1,3 | 3,2 |
| Diarrhea | 1,2 | - |
| Chest pain | 1,1 | 1,1 |
| Pain in the extremities | 1,1 | - |
| Nausea | 1,0 | 1,1 |
With a frequency of less than 1% of observed adverse events such as abdominal pain, visual disturbances, anxiety, arthralgia, arthritis, bronchitis, indigestion, shortness of breath, impotence, insomnia, muscle cramps of the lower extremities, frequent urination, palpitations, rash, sprains, urinary tract infection, viral infection, swelling, asthenia, vertigo. A causal relationship of these phenomena with the use of drug Co-Diovan is not installed.
Post-marketing data revealed very rare cases of angioedema, rash, pruritus and other hypersensitivity reactions/allergic reactions including serum sickness and vasculitis. Also very rarely reported impaired renal function.
The laboratory parameters. In 2.2% of patients receiving the drug Co-Diovan, potassium concentrations in serum fell by more than 20% (the decrease of this index in the group of patients treated with placebo, 3.3%).
In controlled clinical trials in 1.4% of patients treated with the drug Co-Diovan, increased concentration of serum creatinine (compared with 1.1% for the group of patients treated with placebo).
In those clinical trials where valsartan was used as monotherapy was also observed for other adverse events (a causal relationship of these phenomena with the use of valsartan has not been established): with a frequency of more than 1% — arthralgia with a frequency of less than 1% — swelling, asthenia, insomnia, rash, decreased libido, vertigo.
Hydrochlorothiazide is widely used for many years, and often in doses higher than that which is part of the drug Co-Diovan. It was reported the following adverse events during the monotherapy of thiazide diuretics, including hydrochlorothiazide: often — urticaria and other types of rash, loss of appetite, nausea and vomiting postural hypotension, the severity of which increases with intake of alcohol, use of drugs for anesthesia or sedatives impotence. Rarely — photosensitivity, abdominal pain, constipation, diarrhea, gastrointestinal discomfort, intrahepatic cholestasis, jaundice, arrhythmia, headache, dizziness, sleep disturbance, depression, paresthesia, visual disturbances thrombocytopenia, sometimes with purpura. Very rarely necrotizing vasculitis, toxic epidermal necrolysis volchanochnopodobny reactions exacerbation of cutaneous manifestations of systemic lupus erythematosus, pancreatitis, leukopenia, agranulocytosis, bone marrow depression, haemolytic anaemia, hypersensitivity reactions, disorders of the respiratory system, including pneumonitis and pulmonary edema. It is also possible water and electrolyte and metabolic disorders (see "Special instructions").
Drug interactions:
May increase the antihypertensive effect when used together with other antihypertensive agents.
The simultaneous use of potassium salts, potassium-sparing diuretics, potassium-containing substitutes for salt or any other drugs that may cause increased concentration of potassium in the blood (e.g. heparin) requires compliance with the precautionary measures and, in particular, often determine the concentration of potassium in the blood.
While the appointment drugs lithium with ACE inhibitors or thiazide diuretics was observed a reversible increase of lithium concentration in serum and strengthening, in this regard, the toxic manifestations. Experience of joint use of valsartan and lithium preparations is not yet available, so in this case it is recommended to control the concentration of lithium in the blood serum.
Was not observed clinically significant interactions during the monotherapy with valsartan with application of the following drugs: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide.
Part of the drug Co-Diovan includes a thiazide diuretic, so potentially possible drug interactions.
Thiazides potentiate the action of curare-like muscle relaxants.
May decrease the diuretic and antihypertensive effect of thiazide component of the drug Co-Diovan while the use of NSAIDs, such as derivatives of salicylic acid, indomethacin. Concomitant hypovolemia can lead to acute renal failure.
The risk of hypokalemia is increased with concomitant administration of saluretikov, corticosteroids, ACTH, amphotericin, carbenoxolone, penicillin G and derivatives of salicylic acid.
Thiazide diuretics can cause such undesirable effects as hypokalemia or hypomagnesemia data status increase the risk of arrhythmias with concomitant use of digitalis preparations.
May require dose adjustment of insulin or oral hypoglycemic agents.
Coadministration of thiazide diuretics may lead to increased frequency of hypersensitivity reactions to allopurinol, increase the risk of side effects of amantadine, strengthening the hyperglycemic action of diazoxide, reduced excretion by the kidneys cytotoxic drugs (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive action.
May increase the bioavailability of thiazide diuretics concurrent use of anticholinergics (e.g. atropine, biperiden), which appears to be associated with a reduction in motor activity of the gastrointestinal tract and delayed gastric emptying.
Reported cases of hemolytic anemia with concomitant administration of thiazide diuretics and methyldopa.
Cholestyramine reduces the absorption of thiazide diuretics.
In a joint application of thiazide diuretics with vitamin D or with calcium salts may potentiate the increase in the concentration of calcium in serum.
Coadministration with cyclosporine may increase the risk of developing hyperuricemia and the onset of symptoms, resembling exacerbation of gout.
Method of application and dose:
Inside, 1 tab. 1 time a day every day. Depending on the clinical situation, the daily recommended dose is 1 table. 80 + 12.5 or 160 + 12,5 mg. If necessary, appoint 1 table. 160 + 25 mg a day.
Patients with mild or moderate violations of the kidney (Cl creatinine >30 ml/min) changes in dose is not required. Also do not want to change the dose in patients with mild or moderate hepatic insufficiency debelyanovo aneurysm without concomitant phenomena of cholestasis.
Overdose:
Symptoms: although to date information about overdose are absent, the main manifestation that you would expect, is a marked reduction in blood pressure.
Treatment: if the drug had been recently adopted, it should be cause vomiting. Hypotension common method of therapy is in/in a physiological solution.
Valsartan is not displayed by hemodialysis because of its significant binding to blood plasma proteins. At the same time for elimination from the body hydrochlorothiazide hemodialysis effective.
Special instructions:
Changes in the concentration of serum electrolytes. Caution should be exercised with simultaneous use of drug Co-Diovan with salts of potassium, kalisberegatmi dioretikami, kalisoderjasimi substitutes for salt, as well as with drugs that may cause increased concentration of potassium in the blood (e.g. heparin).
There are reports about the development of hypokalemia in the treatment of thiazide diuretics. It is recommended frequent monitoring of potassium in the blood.
With the use of a thiazide diuretic may develop hyponatremia and gipohloremichesky alkaloz. Thiazides increase urinary excretion of magnesium, which can lead to gipomagniemii.
A deficiency of sodium and/or BCC. Patients with severe deficiency of sodium and/or BCC, for example, receiving high doses of diuretics, in rare cases at the beginning of treatment Co-Diovan can occur hypotension with clinical manifestations. Before treatment should be correction of sodium in the body and/or BCC.
In the case of arterial hypotension patients should be laid and, if necessary, in/in infusion of saline solution. After stabilization of blood pressure treatment Co-Diovan can be continued.
The impairment of renal function. Patients with impaired renal function, when creatinine Cl is more than 30 ml/min, is not required correction doses of the drug.
Currently, there are no data on the use of drug Co-Diovan in patients with severe renal impairment (Cl creatinine <30 ml/min) and patients undergoing hemodialysis.
The liver dysfunction. Is not required correction doses of the drug Co-Diovan in patients with mild or moderate disorders of liver function in the absence of the phenomena of cholestasis, although we recommend caution. Liver disease does not have a significant effect on the pharmacokinetics of hydrochlorothiazide, so reducing the dose is not required.
Currently, there are no data on the use of valsartan in patients with severe liver dysfunction.
Other metabolic disorders. Thiazide diuretics can cause changes in glucose tolerance and increased concentrations of cholesterol, triglycerides and uric acid in serum.
Effects on ability to drive a car and operate machinery. Patients receiving Co-Diovan should be used with caution when driving a car and management mechanisms.
Storage conditions:
In a closed package.
