Valsartan and Hydrochlorothiazide Tablets

Indication

Light-to-moderate essential hypertension for the treatment of a single drug that does not adequately control blood pressure. This product is not suitable for the initial treatment of hypertension.

Clinical pharmacology

Valsartan angiotensin I forms angiotensin II (AGII) under the action of angiotensin-converting enzyme (ACE), an important active component of the renin-angiotensin-aldosterone system (RAAS), and the cell membrane of various tissues. The specific receptor binding on it exerts a wide range of physiological effects, including direct or indirect involvement in blood pressure regulation. Angiotensin II is a strong vasoconstrictor that exerts a direct boosting effect and promotes sodium reabsorption and stimulates aldosterone secretion... (see instructions)

Dosage

The recommended dose of valsartan monotherapy is 80 mg once a day. When the antihypertensive effect is unsatisfactory, the daily dose can be increased to 160 mg. The effective dose of hydrochlorothiazide is 12.5-50 mg daily, once a day, in order to reduce the dose-independent adverse reactions, usually only when the single drug treatment can not achieve satisfactory therapeutic effect. (See the instructions for details)

Formulation

tablet

specification

Each tablet contains 80.0 mg of valsartan and 12.5 mg of hydrochlorothiazide.

Instruction manual

Approved date: May 8, 2007

Date of revision: 2015-7-7 (standard to positive) 2016-1-5 (adding packaging specifications)

Valsartan hydrochlorothiazide tablets instructions

Please read the instructions carefully and use them under the guidance of a physician.

【Drug Name】

Common name: valsartan hydrochlorothiazide tablets

Product Name: Fuxin

English name: Valsartan and Hydrochlorothiazide Tablets

Pinyin: Xieshatan Qinglüsaiqin Pian

【Ingredients】 This product is a compound preparation, and its components are: each tablet contains 80 mg of valsartan and 12.5 mg of hydrochlorothiazide.

【Properties】 This product is a white-like film.

【indications】

Light-to-moderate essential hypertension for the treatment of a single drug that does not adequately control blood pressure. This product is not suitable for the initial treatment of hypertension.

【Specifications】 Each tablet contains 80.0 mg of valsartan and 12.5 mg of hydrochlorothiazide.

【Dosage】

The recommended dose of valsartan monotherapy is 80 mg once a day. When the antihypertensive effect is unsatisfactory, the daily dose can be increased to 160 mg. The effective dose of hydrochlorothiazide is 12.5-50 mg daily, once a day, in order to reduce dose-independent adverse reactions, usually only when the single drug treatment can not achieve satisfactory results.

Adverse reactions to valsartan are often rare and independent of dose size. The adverse reaction of hydrochlorothiazide is mainly hypokalemia. This adverse reaction is dose-related, and the dose-independent adverse reaction is mainly pancreatitis.

In the combination of valsartan and hydrochlorothiazide, the dose of each drug needs to be adjusted. When the dose adjustment is satisfactory, the same dose of this product can be used instead of the combination.

Dose adjustment:

Each tablet contains 80 mg of valsartan and 12.5 mg of hydrochlorothiazide. When the single treatment with valsartan can not satisfactorily control blood pressure, hydrochlorothiazide 25mg once daily can not be satisfactorily controlled blood pressure or hypokalemia, you can use this product (containing valsartan 80mg / hydrochlorothiazide 12.5mg) each time, Once a day, the maximum antihypertensive effect can be achieved within 2-4 weeks of taking the drug.

The use of this product has nothing to do with the meal time.

For patients with mild to moderate renal failure (creatinine clearance ≥ 30 ml/min) or mild to moderate liver failure, no dose adjustment is required.

【Adverse reactions】In two controlled clinical trials involving a total of 1,570 patients, 730 patients received a combination of valsartan and hydrochlorothiazide. The reported adverse events were as follows:

Central Nervous System

Common (>5%): headache (10.8%: 17.2% of placebo), dizziness.

Occasionally (5 to 0.1%): fatigue, depression.

Upper respiratory tract

Occasionally (5 to 0.1%): cough, rhinitis, sinusitis, pharyngitis, upper respiratory tract infection, nosebleeds.

Gastrointestinal

Occasionally (5 to 0.1%): nausea, diarrhea, indigestion, abdominal pain.

Lower urethra

Occasionally (5 ~ 0.1%): frequent urination, urinary tract infection.

Musculoskeletal system

Occasionally (5 to 0.1%): pain in the arms or legs, arthritis, myalgia, sprains and strains, muscle spasms.

other

Occasionally (5 ~ 0.1%): weakness, chest pain, weakness, viral infection, visual impairment, conjunctivitis.

After the product entered the market, there have been some rare reports, including angioedema, rash itching and other allergic reactions such as serum disease and vasculitis.

Laboratory inspection

Among patients treated with the same product, 5.8% of patients observed a decrease in serum potassium of more than 20% and a placebo-treated patient of 3.3%.

The following adverse events were associated with valsartan alone and not with this product.

In rare cases, valsartan causes a decrease in hemoglobin and hematocrit. Clinical controlled trials found that valsartan treatment group significantly reduced hemoglobin and hematocrit (>20%) by 0.8% and 0.4%, respectively. The placebo group accounted for 0.1%.

The clinical control study found that the incidence of neutropenia in the valsartan group and the ACEI group was 1.9% and 1.6%, respectively.

The serum creatinine, serum potassium and total bilirubin were significantly increased in the valsartan group by 0.8%, 4.4%, and 6%, respectively, and in the ACEI group, 1.6%, 6.4%, and 12.9%, respectively.

Occasionally, liver function indicators increased.

For patients with essential hypertension who are treated with valsartan, no special monitoring of laboratory indicators is required.

Valsartan

Other adverse events reported in valsartan clinical trials are:

Occasionally (5 ~ 0.1%): joint pain, gastroenteritis, neuralgia.

Only one case of angioedema was reported.

There is no evidence of a causal relationship with valsartan treatment.

Hydrochlorothiazide

In patients treated with a single thiazide diuretic (including hydrochlorothiazide), the reported adverse effects are as follows, and most patients use doses higher than those in this product:

Electrolytes and metabolic disorders (see [Precautions])

Common (>5%): hypokalemia.

Occasionally (5 to 0.1%): hyponatremia, hypomagnesemia and hyperuricemia.

Rare (<0.1%): Hypercalcemia, elevated blood sugar, worsening of diabetes and diabetes.

Very rare: low chloride alkalosis.

skin

Occasionally (5 to 0.1%): urticaria and other types of rashes.

Rare (<0.1%): Light sensitivity.

Very rare: necrotizing vasculitis, acute toxic epidermolysis, lupus-like reaction, recurrence of cutaneous lupus erythematosus.

Gastrointestinal

Occasionally (5 to 0.1%): loss of appetite, mild nausea and vomiting.

Rare (<0.1%): abdominal symptoms, constipation, diarrhea, gastrointestinal symptoms.

Very rare: pancreatitis.

liver

Rare (<0.1%): intrahepatic cholestasis or jaundice.

Cardiovascular System

Occasionally (5 to 0.1%): orthostatic hypotension, alcohol, anesthesia or sedatives can make it worse.

Rare (<0.1%): arrhythmia.

Central Nervous System

Rare (<0.1%): headache, dizziness or light-headache, sleep disturbance, depression, paresthesia.

Sensory organ

Visual impairment, especially during the first few weeks of treatment.

blood

Rare (<0.1%): thrombocytopenia, occasionally with purpura.

Very rare: leukopenia, neutropenia, myelosuppression, hemolytic anemia.

other

Occasionally (5 ~ 0.1%): impotence.

Very rare: allergic reactions, including respiratory symptoms of pneumonia and pulmonary edema.

【taboo】

Allergic to any of the ingredients in this product or sulfa derivatives.

Pregnancy (see [Pregnant and lactating women medication])

Severe liver failure, biliary cirrhosis or cholestasis.

Severe kidney failure (creatinine clearance <30ml/min) or no urine.

Refractory hypokalemia, hyponatremia or hypercalcemia and symptomatic hyperuricemia (history of gout or uric acid calculi).

【Precautions】

Serum electrolyte changes

Care should be taken in conjunction with potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other drugs that increase blood potassium levels (such as heparin).

Therefore, blood potassium levels should be monitored regularly.

Thiazide diuretics are associated with hyponatremia and hypochlorine alkalosis.

Thiazide drugs can cause hypomagnesemia by increasing the excretion of magnesium in the kidneys.

Sodium and / or insufficient blood volume

In rare cases, in patients with severe sodium deficiency and/or hypovolemia (eg, high-dose diuretics), symptomatic hypotension may occur when starting treatment with this product. Low sodium and/or hypovolemia should be corrected before starting treatment with this product.

If hypotension occurs, the patient should be placed on his or her back and, if necessary, given normal saline. The treatment can be resumed after the blood pressure is stable.

Renal artery stenosis

In patients with unilateral or bilateral renal artery stenosis or isolated renal stenosis, there is no experience in using this product.

Renal insufficiency

Patients with creatinine clearance ≥ 30 ml/min do not need to adjust the dose.

Hepatic insufficiency

This product should be used with caution in patients with mild to moderate hepatic insufficiency who are not cholestasis. However, since the daily dose of valsartan of 80 mg does not exceed the limit, and the pharmacokinetics of hydrochlorothiazide is not significantly affected by liver dysfunction, no dose adjustment is required for such patients.

Systemic lupus erythematosus

Thiazide diuretics can cause or aggravate systemic lupus erythematosus.

Other metabolic disorders

Thiazide diuretics can affect glucose tolerance and increase serum cholesterol, triglycerides and uric acid levels.

Impact on the ability to drive and maneuver the machine

As with other antihypertensive drugs, patients taking medication should be careful when driving and handling the machine.

Athletes use with caution.

【Pregnant women and lactating women】

In the second and third trimesters of pregnancy, the use of drugs that act directly on RAAS can cause fetal damage and death. In humans, the fetus develops renal perfusion from the second trimester of pregnancy, and its renal perfusion is dependent on the development of the RAAS system, so the risk of valsartan is increased during the second and third trimesters of pregnancy.

Similar to other drugs that act directly on RAAS, this product is not suitable for use during pregnancy. If pregnancy is found during medication, discontinue the drug as soon as possible.

All neonates who have been in contact with the drug in the uterus should be closely observed to ensure adequate urine output, prevent hyperkalemia, and monitor blood pressure. If necessary, use appropriate treatments (such as rehydration) to remove circulating medication.

Exposure to thiazide diuretics in the uterus can cause fetal or neonatal thrombocytopenia and other adverse reactions that are different from adults.

It has not been determined whether valsartan can enter human milk. Lactating rats can secrete valsartan into milk.

Hydrochlorothiazide can pass through the placental barrier and secrete into the milk. There is currently no research on lactating women, so this product should not be used for lactation.

【Child medication】 This experiment was not performed and there is no reliable reference.

【Geriatric Use】

Compared with young volunteers, some elderly people (>65 years old) had a slightly higher concentration of valsartan, but no clinical significance.

Compared with young people, the steady-state concentration of hydrochlorothiazide in the elderly is high and the systemic clearance rate is significantly reduced. Therefore, elderly patients receiving hydrochlorothiazide need to be closely monitored.

【medicine interactions】

Combined with other antihypertensive drugs can increase the antihypertensive effect of this product.

Use with potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes, or other drugs that increase serum potassium (such as heparin) requires caution and monitoring blood potassium levels.

It has been reported that the simultaneous use of lithium, ACE inhibitors and/or thiazide diuretics can cause a reversible increase in serum potassium concentration and lithium poisoning. There is no experience in applying valsartan and lithium at the same time.

Therefore, in the case of combined application of lithium and this product, it is recommended to regularly check serum lithium levels.

No clinically significant interactions were observed between valsartan alone and any of the following drugs: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, Hydrochlorothiazide, amlodipine and glibenclamide.

Because this product contains thiazide diuretic ingredients, the following interactions may occur:

Combination with non-steroidal anti-inflammatory drugs (such as salicylic acid derivatives, indomethacin) may reduce the diuretic and antihypertensive activity of thiazide components in this product. If there is insufficient blood volume at the same time, it may lead to acute renal failure.

Simultaneous administration with potassium-sparing diuretics (such as furosemide), corticosteroids, adrenocorticotropic hormone (ACTH), amphotericin B, carbenoxol, penicillin G or salicylic acid derivatives can exacerbate potassium and/or magnesium. Lost.

Low potassium or low magnesium caused by thiazides can increase the risk of arrhythmia in patients taking cardiac glycosides.

Thiazide diuretics increase the role of the arrow poison muscle relaxant.

It may be necessary to adjust the dose of insulin or oral antidiabetic drugs.

Use in combination with a thiazide diuretic may increase the incidence of hypersensitivity to allopurinol.

May increase the risk of side effects caused by amantadine.

Thiazines may also enhance the effect of diazoxide on raising blood sugar.

Thiazides may reduce renal excretion of cytotoxic drugs (such as cyclophosphamide, methotrexate), thus increasing their myelosuppressive effects.

When an anticholinergic drug (such as atropine, biperiden) is administered at the same time, the bioavailability of the thiazide diuretic may increase, which may be the result of a decrease in gastrointestinal motility and a slowing of gastric emptying.

A case report of hemolytic anemia caused by the combined use of hydrochlorothiazide and methyldopa.

Cholestyramine and colestipol reduce the absorption of thiazide diuretics.

The combined use of thiazide diuretics and vitamin D or calcium salts enhances the effect of elevated blood calcium.

The combined use of cyclosporine may increase the risk of hyperuricemia and cause symptoms of gout.

【Drug overdose】

There is currently no experience with this product. The main symptom after overdose may be significant hypotension.

When hydrochlorothiazide is excessive, the following symptoms and signs may also appear: nausea, drowsiness, insufficient blood volume, electrolyte imbalance, arrhythmia, and muscle spasm.

Treatment should be based on the length of medication and the type and severity of symptoms, and should be followed by a stable cycle.

If you take a short time, you can induce vomiting. If the medication has been taken for a long time, an appropriate amount of activated carbon should be given.

If hypotension occurs, the patient should be placed supine and given fluid and electrolyte replacement therapy.

Due to the strong protein binding of valsartan, it cannot be removed by hemodialysis. However, hydrochlorothiazide can be removed by this method.

【Pharmacology and Toxicology】

Pharmacological action

Valsartan

Angiotensin I forms angiotensin II (AGII) under the action of angiotensin-converting enzyme (ACE), an important active component of the renin-angiotensin-aldosterone system (RAAS), and specificity on the cell membrane of various tissues. Receptor binding exerts a wide range of physiological effects, including direct or indirect involvement in blood pressure regulation. Angiotensin II is a strong vasoconstrictor that exerts a direct boosting effect and promotes sodium reabsorption and stimulates aldosterone secretion.

Valsartan is an orally effective specific angiotensin (AT) II receptor antagonist that selectively interacts with the AT1 receptor subtype, has a higher affinity for the AT1 receptor than the AT2 receptor. 20000 times. The AT1 receptor subtype mediates the physiological response of angiotensin II, the AT2 receptor subtype is not associated with cardiovascular effects, and valsartan has no partial agonist activity on the AT1 receptor.

Valsartan does not inhibit ACE (also known as kininase II), which converts angiotensin I to angiotensin II and degrades bradykinin. Valsartan has no inhibitory effect on ACE, and does not cause retention of bradykinin and substance P, so it is not easy to cause cough.

Clinical trials comparing valsartan with ACE inhibitors confirmed that the incidence of dry cough in the valsartan group (2.6%) was significantly lower than in the ACE inhibitor group (7.9%) (P < 0.05). In a clinical trial of patients who developed symptoms of dry cough after treatment with ACE inhibitors, 19.5%, 19.0%, and 68.5% of patients in the valsartan group, diuretic group, and ACEI group developed cough (P<0.05). ). In clinical trials, the incidence of cough in patients treated with valsartan and hydrochlorothiazide was 2.9%.

Valsartan has no effect on other known hormone receptors or ion channels that play important roles in cardiovascular regulation.

Valsartan reduces blood pressure and does not affect heart rate.

For most patients, a single dose of oral hypotensive effect within 2 hours, 4 to 6 hours to reach a peak, the antihypertensive effect is maintained until more than 24 hours after taking the drug. In long-term treatment, the maximum antihypertensive effect is achieved after 2 to 4 weeks of treatment and is maintained. The combination with hydrochlorothiazide significantly enhances the antihypertensive effect of valsartan.

Sudden termination of valsartan treatment does not cause high blood pressure "rebound" or other side effects.

Valsartan does not affect fasting total cholesterol, triglycerides, blood sugar or uric acid levels in hypertensive patients.

Hydrochlorothiazide

The main site of action of thiazide diuretics is the proximal end of the distal convoluted tubule. Studies have shown that there is a high-affinity receptor in the renal cortex, which is the main binding site and site of action of thiazide diuretics, inhibiting the transport of sodium chloride in the proximal end of the distal convoluted tubule. The mode of action of thiazides is to inhibit the co-transport of sodium and chloride ions. Competing for the action of chloride ions can affect the reabsorption of electrolytes, which will directly increase the excretion of sodium and chlorine, and indirectly reduce plasma volume, which in turn increases plasma renin activity. Aldosterone secretion and potassium excretion reduce serum potassium.

Because the renin-aldosterone system is angiotensin II dependent, the combined use of an angiotensin II receptor antagonist reduces potassium loss associated with thiazide diuretics.

【Pharmacokinetics】

Valsartan

Absorption: Valsartan can be rapidly absorbed after oral administration, and its absorption varies widely. The average absolute bioavailability is 23% (23±7). In the dose range studied, the pharmacokinetic curve is linear and taken once a day. When valsartan rarely accumulates, plasma concentrations are similar in men and women.

Taking valsartan at mealtime reduced AUC by 48% and peak plasma concentration (Cmax) by 59%. The blood concentration was similar after 8 hours, whether or not taken with food. The reduction in AUC or Cmax has no significant effect on clinical outcomes, so valsartan can be taken at mealtime or on an empty stomach.

Distribution: Most valsartan (94-97%) binds to serum proteins (mainly albumin), reaching a steady state within 1 week, and the steady state volume is about 17 liters.

Plasma clearance was relatively slow (about 2 L/h) compared to hepatic blood flow (30 L/h).

Clearance: Valsartan is metabolized by multiple exponential decay kinetics (a half-life <1 hour, terminal half-life of about 9 hours). Valsartan is mainly excreted as a prototype, 70% is excreted from the feces and 30% is excreted from the urine.

Hydrochlorothiazide

Absorption: Hydrochlorothiazide is rapidly absorbed after oral administration, and the peak time tmax is about 2 hours.

Distribution and removal: The distribution and elimination kinetics of hydrochlorothiazide are double exponential with a terminal half-life of 6 to 15 hours.

Within the therapeutic dose range, the AUC increases linearly proportional to the dose. Repeated administration did not alter the kinetics of hydrochlorothiazide. The accumulation of once-daily dosing is very small.

The absolute bioavailability of hydrochlorothiazide after oral administration is 60 to 80%. More than 95% of the absorbed dose is excreted from the urine as a prototype.

It has been reported that eating can reduce the bioavailability of hydrochlorothiazide, which has little change and has no significant clinical significance.

Valsartan/hydrochlorothiazide

Co-administration with valsartan reduced the bioavailability of hydrochlorothiazide by approximately 30%; the combination with hydrochlorothiazide did not significantly affect the pharmacokinetics of valsartan. The interaction had no effect on the combined use of valsartan/hydrochlorothiazide. In a controlled clinical trial, the combination of valsartan/hydrochlorothiazide showed a clear antihypertensive effect and was more potent than either drug alone.

Pharmacokinetics in special clinical situations

1. Patients with renal insufficiency

Valsartan/hydrochlorothiazide

In patients with a creatinine clearance of 30 to 70 ml/min, it is not necessary to adjust the dose of this product.

Valsartan

Only 30% of valsartan is excreted from the kidneys, so patients with renal insufficiency do not have to adjust the dose (for contraindications to severe renal failure). No studies have been done on dialysis patients. However, given that valsartan is highly associated with plasma proteins, it is difficult to remove by dialysis.

Hydrochlorothiazide

Renal clearance of hydrochlorothiazide includes passive filtration and active secretion into the renal tubules. Because its clearance is almost entirely through the kidneys, renal function has a large impact on its pharmacokinetic parameters (see [Contraindications]). For patients with renal insufficiency, the mean plasma peak concentration and AUC of hydrochlorothiazide increased. Due to a decrease in renal clearance, the average elimination half-life is approximately doubled in patients with renal failure (creatinine clearance of 30 to 70 ml/min), and hydrochlorothiazide can be removed by dialysis.

2, patients with liver dysfunction

Pharmacokinetic studies in patients with mild to moderate hepatic insufficiency have shown that valsartan is approximately twice as high as healthy volunteers, and no valsartan is available for patients with severe hepatic insufficiency (see [taboo]).

Liver disease does not significantly alter the pharmacokinetics of hydrochlorothiazide, so there is no need to reduce the dose.

【Storage】Protect from light and keep it sealed.

【Packing】aluminum plastic packaging. 12 pieces / box, 14 pieces / box, 28 pieces / box.

【Validity period】 24 months.

【Executive Standards】National Food and Drug Administration National Drug Standard YBH09662006.

【Approval No.】National Drug Standard H20060578.

【manufacturer】

Company Name: Lunan Beite Pharmaceutical Co., Ltd.

Production address: No. 243, Yinqueshan Road, Linyi City, Shandong Province

Postal code: 276006

Phone number: 0539-8336336 (Sales)              8336337 (Quality Management Department)

Fax number: 0539-8336029 (Sales)                   8336338 (Quality Management Department)

Website: www.LUNAN.com.cn

24-hour customer service hotline: 400-0539-310