Indapamide Sustained-release Capsules

Indapamide Sustained-release Capsules are used for essential hypertension. This medicine increases the excretion of sodium and chloride in the urine, and to a lesser extent, the excretion of potassium and magnesium. As a result, the urine output increases, and it exerts an antihypertensive effect. Phase II and Phase III studies have shown that the antihypertensive effect of single therapy can last for 24 hours. When this therapeutic effect occurs, the dose used only has a mild diuretic effect.

1. National medical insurance Class A, clinical first-line basic medication

2. Low dose, safer, only 1 pill per day is needed

3. Slow release technology, multi-point absorption, 24-hour stable pressure reduction

4. Self-produced raw materials, stable and safe

【Drug Name】
Generic Name: Indapamide Sustained Release Capsules
Trade Name: Yuenanshan
English Name: Indapamide Sustained Release Capsules
【Ingredients】Indapamide
Chemical Name: N-(2-Methyl-2,3-dihydro-1H-indol-1-yl)-3-sulfamoyl-4-chlorobenzamide
Molecular Formula: C16H16ClN3O3S
Molecular Weight: 365.83
【Properties】The contents of this product are white or off-white spherical coated pellets.
【Indications】Essential hypertension.
【Specification】1.5mg.
【Usage and Dosage】Take orally, 1 capsule every 24 hours, preferably in the morning. Increasing the dose does not improve the antihypertensive effect of indapamide, but only increases the diuretic effect.
【Adverse Reactions】Most clinical and laboratory adverse reactions are dose-dependent. Thiazides and related diuretics, including indapamide, may cause the following situations:

Laboratory Parameters

• Potassium deficiency and hypokalemia are more severe in some high-risk groups (see Precautions). In clinical trials, among patients treated for 4-6 weeks, 10% developed hypokalemia (serum potassium < 3.4mmol/L); 4% of patients had serum potassium < 3.2mmol/L. After 12 weeks of treatment, the average serum potassium decreased by 0.23mmol/L.
• Hyponatremia with hypovolemia causes dehydration and orthostatic hypotension. The associated chloride deficiency can lead to secondary compensatory metabolic alkalosis; this situation occurs rarely and is mild in degree.
• During treatment, the levels of uric acid and blood glucose in the plasma increase. When using these diuretics in patients with gout and diabetes, the indications must be carefully considered.
• Hematological disorders are very rare, including thrombocytopenia, leukopenia, agranulocytosis, nutritional anemia, and hemolytic anemia.
• Hypercalcemia is very rare.

Clinical Parameters

• In cases of impaired liver function, hepatic encephalopathy may occur (see Contraindications and Precautions).
• In allergic reactions, mainly skin allergies, it is seen in patients with previous allergies or asthma.
• Maculopapules and purpura may exacerbate the existing acute systemic lupus erythematosus.
• Symptoms such as nausea, constipation, dry mouth, dizziness, fatigue, paresthesia, and headache occur rarely, and most of them are relieved with the reduction of the drug dose.
• Pancreatitis is very rare.

Contraindications

• Hypersensitivity to sulfonamides.
• Severe renal failure.
• Hepatic encephalopathy or severe liver failure.
• Hypokalemia.
• Generally, this drug should not be used in combination with lithium and non-antiarrhythmic drugs that can cause torsade de pointes (refer to Drug Interactions).

Precautions

Warning: When liver function is impaired, thiazides and some diuretics may cause hepatic encephalopathy. If this occurs, the use of diuretics should be stopped immediately.

Water and Electrolyte Balance

• Serum Sodium: Serum sodium must be measured before treatment, and then regular monitoring should be carried out. Any diuretic treatment may lead to hyponatremia, sometimes with serious consequences. The decrease in serum sodium may be asymptomatic at first, so regular monitoring of serum sodium is very necessary; in elderly and cirrhotic patients, the monitoring frequency should be more frequent (see Adverse Reactions and Overdose).
• Serum Potassium: Hypokalemia and potassium deficiency are the main risks of thiazides and their related diuretics. In some high-risk groups, such as the elderly, those with malnutrition and/or multiple drug treatments, as well as patients with cirrhosis with edema and ascites, coronary heart disease, and heart failure patients, the occurrence of hypokalemia (< 3.4mmol/L) must be prevented. In these cases, hypokalemia can increase the cardiotoxicity of digitalis drugs and increase the risk of arrhythmia.

Patients with a long QT interval in the electrocardiogram, whether congenital or iatrogenic, have a certain risk when using this drug. Hypokalemia (and bradycardia) are both inducing factors for severe arrhythmias (especially the life-threatening torsade de pointes). In all the above cases, more frequent monitoring of serum potassium is necessary. The first serum potassium measurement should be carried out within 1 week after the start of treatment. Once hypokalemia is detected, corresponding correction should be carried out.

• Serum Calcium: Thiazides and their related diuretics may reduce the excretion of calcium in the urine, causing a transient and mild increase in serum calcium. Obvious hypercalcemia may be caused by previously undiagnosed hyperparathyroidism. Treatment should be stopped before checking the function of the parathyroid gland.
• Blood Glucose: In diabetic patients, the monitoring of blood glucose is very important, especially when there is hypokalemia.
• Uric Acid: In patients with hyperuricemia, the probability of gout attacks may increase, and the dosage should be adjusted according to the uric acid content in the blood.
• Relationship between Renal Function and the Efficacy of Diuretics: Thiazides and their related diuretics can only fully exert their effects when the renal function is normal or mildly impaired (adult serum creatinine is lower than 25mg/L, that is, 220μmol/L). In the elderly, the serum creatinine value must be adjusted according to age, weight, and gender. The adjustment range can be based on the Cockcroft's formula: Cler=(140 - age)×weight/0.814×serum creatinine (where: age is calculated in "years", weight is in kilograms, and serum creatinine is in μmol/L). This formula is applicable to elderly men. For female patients, the result obtained by the formula should be multiplied by 0.85.

In the initial stage of diuretic treatment, the decrease in glomerular filtration caused by the loss of water and sodium due to diuresis may lead to an increase in blood urea and creatinine. This transient functional renal insufficiency does not cause serious consequences in patients with previously normal renal function; however, for those with previous renal insufficiency, it may further deteriorate the renal function.

• Athletes: The active ingredients contained in this drug may cause a positive reaction in anti-doping tests, and athletes should pay attention to this. Athletes should use it with caution.

Influence on the Ability to Drive Motor Vehicles and Operate Machinery

This product does not affect alertness, but in some patients, due to the decrease in blood pressure, it may cause a decrease in reactivity, especially at the beginning of treatment and when combined with other antihypertensive drugs. Therefore, it may reduce the ability of relevant personnel to drive motor vehicles and operate machinery.

Use in Pregnant and Lactating Women

Pregnancy: Diuretics can cause placental ischemia and lead to fetal malnutrition. The general principle is that pregnant women should avoid using thiazides and related diuretics, and they should never be used to treat physiological edema during pregnancy.
Lactation: Since the drug may enter breast milk, lactating women should avoid taking this product.
【Use in Children】Lack of research data on the application of this product in pediatric patients.
【Use in the Elderly】Elderly patients are more sensitive to the antihypertensive effect and electrolyte changes. When using this product, monitoring should be carried out.

Drug Interactions

1.Association with Antihypertensive Effects: When this drug is used in combination with other antihypertensive drugs, the dosage should be reduced, at least at the beginning of treatment.
2.Inappropriate Combinations

• Lithium: In a sodium-free diet (the excretion of lithium in the urine is reduced), Indapamide increases the blood lithium concentration and leads to the manifestations of lithium overdose. However, if a diuretic is used simultaneously, the blood lithium level should be strictly monitored, and the dosage should be adjusted.
• Non-antiarrhythmic Drugs Causing Torsade de Pointes (including astemizole, bepridil, intravenous erythromycin, halofantrine, pentamidine, sultopride, terfenadine, vincamine). Torsade de pointes may occur (hypokalemia, bradycardia, and QT interval prolongation are the inducing factors). If hypokalemia occurs, do not use drugs that can cause torsade de pointes.

3.Combinations Requiring Attention

• Non steroidal anti-inflammatory drugs (systemic), high-dose sodium salicylate: may weaken the antihypertensive efficacy of indapamide. In dehydrated patients, it can lead to acute renal failure (reduced glomerular filtration). Patients should be given hydration and their kidney function should be monitored from the beginning of treatment.
• Other Compounds Reducing Serum Potassium: Amphotericin B (intravenous injection), glucocorticoids and mineralocorticoids (systemic), ticarcillin, stimulant laxatives: increase the risk of hypokalemia (synergistic effect). Monitor serum potassium and correct it if necessary. When using digitalis drugs, special care should be taken. Use non-stimulant laxatives.
• Baclofen: Strengthens the antihypertensive effect. Rehydrate the patient and monitor renal function at the beginning of treatment.
• Digitalis Drugs: Hypokalemia easily induces the toxic effects of digitalis drugs. Pay attention to monitoring serum potassium and electrocardiogram, and adjust the treatment if necessary.
• Potassium-sparing Diuretics (amiloride, spironolactone, triamterene): This combination may be beneficial for some patients, but the possibility of hypokalemia or hyperkalemia cannot be excluded, especially in patients with renal failure and diabetes, who are more likely to develop hyperkalemia. Monitor serum potassium and electrocardiogram when necessary, and adjust the treatment if necessary.
• Angiotensin-Converting Enzyme (ACE) Inhibitors: In the presence of pre-existing sodium deficiency (especially in renal artery stenosis), the combination of indapamide and ACE inhibitors has the risk of causing sudden hypotension and/or acute renal failure.

In essential hypertension, previous diuretic treatment may lead to sodium deficiency, and attention must be paid to:
(1) Stop using the diuretic 3 days before using the ACE inhibitor; if necessary, the potassium-excreting diuretic can be restarted.
(2) Or when giving the ACE inhibitor, use a low starting dose and gradually increase the dose.
In patients with congestive heart failure, the starting dose of the ACE inhibitor should be very small, and it can be started after reducing the dose of the potassium-losing diuretic. For all patients using ACE inhibitors, renal function (serum creatinine) should be monitored in the first week.

• Antiarrhythmic Drugs Causing Torsade de Pointes

Class Ia antiarrhythmic drugs (quinidine, dihydroquinidine, disopyramide), amiodarone, bretylium, sotalol: Torsade de pointes (hypokalemia, bradycardia, and pre-existing QT interval prolongation are the inducing factors).
Prevent hypokalemia and correct it if necessary; monitor the QT interval. When torsade de pointes occurs, do not use antiarrhythmic drugs (but use a pacemaker for treatment).

• Metformin

The functional renal insufficiency induced by diuretics (especially loop diuretics) can trigger the lactic acidosis caused by metformin.
Do not use metformin when the serum creatinine level in men exceeds 15mg/L (135μmol/L) and in women exceeds 12mg/L (110μmol/L).

• Iodinated Contrast Media

In the case of dehydration caused by diuretics, iodinated contrast media increase the risk of acute renal failure, especially when used in large doses. Before giving iodinated compounds, rehydration treatment must be carried out first.
4.Considerations for Combination Therapy

• Imipramine Antidepressants (tricyclic antidepressants), antipsychotics: Enhance the antihypertensive effect and increase the risk of orthostatic hypotension (synergistic effect).
• Calcium Salts: The risk of hypercalcemia due to reduced calcium excretion in the urine.
• Cyclosporine: In the absence of an increase in the circulating level of cyclosporine, and even in the absence of water/sodium deficiency, there is still a risk of increased serum creatinine when an ACE inhibitor is present.
• Corticosteroids, Tetracosactide (Systemic): Reduce the antihypertensive effect of indapamide (due to the water/sodium retention caused by corticosteroids).

Overdose

When the dose of indapamide reaches 40mg, which is 27 times the therapeutic dose, there is no toxic reaction.
Acute toxicity is mainly manifested as disorders of water and electrolytes (hyponatremia and hypokalemia). Clinical symptoms may include nausea, vomiting, hypotension, painful cramps, dizziness, drowsiness, confusion, polyuria or oliguria, and even anuria (caused by hypovolemia).
The initial treatment methods adopted in specialized medical centers are: to remove the ingested drug as soon as possible through gastric lavage and/or taking activated charcoal. Thereafter, water and electrolytes should be replenished to restore the balance of water and electrolytes.

Pharmacology and Toxicology

Indapamide is a derivative of sulfonamide with an indole ring structure, which is related to the diuretic effect of thiazides. It achieves a diuretic effect by inhibiting the reabsorption of sodium in the cortical diluting segment. This drug increases the excretion of sodium and chloride in the urine and, to a lesser extent, increases the excretion of potassium and magnesium, resulting in an increase in urine output and exerting an antihypertensive effect. Phase II and III clinical studies have shown that the antihypertensive effect of this product used alone can last for 24 hours. When the antihypertensive effect occurs, the dose used only has a mild diuretic effect. The antihypertensive effect of this drug lies in improving the compliance of arteries and reducing the resistance of small arteries and the entire peripheral circulation. Indapamide can reverse left ventricular hypertrophy caused by hypertension. Beyond a certain dose, the efficacy of thiazides and their related diuretics does not increase further, while the side effects continue to increase. If the treatment is ineffective, the drug dose should not be increased.
When indapamide is used to treat hypertensive patients in the short, medium, and long term, it is found that indapamide does not affect lipid metabolism, such as triglycerides, LDL cholesterol, and HDL cholesterol.

Oral administration of a large dose of the drug (40-8000 times higher than the therapeutic dose) to different animal species showed that it can enhance the diuretic effect of indapamide. Acute toxicity tests by intravenous or intraperitoneal injection of indapamide showed that the main symptoms caused were related to the pharmacological effects of indapamide, manifested as bradypnea and peripheral vasodilation.

Absorption: The released indapamide component can be rapidly and completely absorbed by the gastrointestinal tract. Eating can slightly accelerate the absorption of this drug, but it has no effect on the amount of drug absorbed. The blood drug concentration reaches its peak 12 hours after a single dose. Repeated administration can reduce the variation of blood drug concentration between two doses. There are individual differences in absorption.

Distribution: The binding rate of indapamide to plasma proteins is 79%. The plasma elimination half-life is 14-24 hours (average 18 hours). The blood drug concentration reaches a steady state after 7 days of medication. Repeated administration does not cause drug accumulation.

Metabolism: It is mainly excreted in the urine (up to 70% of the administered dose) and feces (22%) in the form of inactive metabolites.

High-risk Groups: In patients with renal failure, the pharmacokinetic parameters do not change.

【Storage】 Protect from light and sealed.

【Package】Packaged in medicinal PVC hard sheets and PTP aluminum foil blister packs. 10 capsules per plate, 1 plate per box; 10 capsules per plate, 3 plates per box.

【Validity】24 months.

【Standard】WS₁-XG-038-2011

【Drug approval number】Guoyao Zhunzi H20051554

【Features】

1. National medical insurance Class A, clinical first-line basic medication

2. Low dose, safer, only 1 pill per day is needed

3. Slow release technology, multi-point absorption, 24-hour stable pressure reduction

4. self-produced raw materials, stable and safe