Approval date: 2007-2-20
Modification date: 2012-4-16
2013-2-19
2014-2-21
XXXX-XX-XX
Indapamide Extended Release Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician.
This drug contains active ingredients that may cause a positive doping test and should be used with caution by athletes.
Drug Name]
Generic name: indapamide extended-release tablets
Trade name: Natrilix® SR
(Natrilix®SR)
English name: lndapamide Sustained Release Tablets
Hanyu Pinyin: Yindapa’an Huanshipian
Ingredients
The active ingredient of this product is indapamide, its chemical name: N-(2-methyl-2, 3-dihydro-1H-indolyl)-3-(aminosulfonyl)-4-chloro-benzamide.
Chemical structure formula.
Molecular formula: C16H16ClN3O3S
Molecular weight: 365.8
Properties]: This product is a film-coated tablet, which appears white after removing the coating.
Indications】For the treatment of adult essential hypertension.
Specification】1.5mg
Dosage and Administration
Method of administration.
Take 1 tablet every 24 hours, preferably in the morning. The tablet must be swallowed whole with water and not chewed.
Increasing the dose does not improve the antihypertensive efficacy of indapamide, but only increases the diuretic effect.
Special Populations.
Renal failure (see [Contraindications] and [Precautions]).
Thiazides and thiazide-like diuretics are fully effective only when renal function is normal or mildly impaired.
Hepatic impairment (see [Contraindications] and [Precautions]).
[Adverse reactions].
Summary of safety characteristics
The most frequently reported adverse reaction was hypersensitivity reactions (skin-based), which occurred mainly in patients with allergic tendencies and susceptibility to asthmatic reactions or maculopapular rash.
During clinical trials, hypokalemia (blood potassium < 3.4 mmol/l) was observed in 10% of patients after 4 to 6 weeks of treatment, and 4% of patients had blood potassium levels < 3.2 mmol/l. After 12 weeks of treatment, blood potassium decreased by a mean of 0.23 mmol/l.
Biological and clinical adverse reactions were largely dose-dependent.
Summary of adverse reactions in tabular form
The following adverse reactions were observed during indapamide treatment and are listed in the following order of frequency.
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), unknown (cannot be inferred from known data).
MedDRA
System Organ Classification Adverse Reaction Frequency Blood and Lymphatic System Disorders Granulocyte Deficiency Extremely Rare Aplastic Anemia Extremely Rare Hemolytic Anemia Extremely Rare Leukopenia Extremely Rare Thrombocytopenia Extremely Rare Metabolic and Nutritional Disorders Hypercalcemia Extremely Rare Potassium Deficiency with Hypokalemia, Particularly Severe in Certain High-Risk Populations (see [Precautions]) Unknown Hyponatremia (see [Precautions]) Unknown Neurological disordersDizziness rare fatigue rare headache rare sensory abnormalities rare syncope unknown Eye disordersMyopia unknown blurred vision unknown visual impairment unknown Cardiac disordersArrhythmia very rare tip-twist ventricular tachycardia (possibly fatal) (see [Precautions] and [Drug Interactions]) unknown Vascular disordersLow blood pressure very rare Gastrointestinal disordersVomiting
Uncommon nausea rare constipation rare dry mouth rare pancreatitis very rare hepatobiliary disease impaired liver function very rare hepatic encephalopathy may occur in hepatic insufficiency (see [Contraindications] and [Precautions]) unknown hepatitis unknown skin and subcutaneous tissue disorders hypersensitivity reactions common maculopapular rash common purpura uncommon angioedema very rare urticaria very rare toxic epidermal necrolysis relaxation very rare Stevens- Johnson syndrome extremely rare may exacerbate existing acute SLE unknown photosensitivity reaction (see [Precautions]) unknown renal and urinary disorders renal failure extremely rare laboratory tests ECG prolonged QT interval (see [Precautions] and [Drug Interactions]) unknown increased blood glucose (see [Precautions]) unknown increased blood uric acid (see [Precautions]) Unknown elevated liver enzyme levels unknown
[Contraindications
– High sensitivity to the active ingredient or hypersensitivity to other sulfonamides or any of the excipients.
– Severe renal failure (creatinine clearance less than 30 ml/min).
– Hepatic encephalopathy or severe hepatic impairment.
– Hypokalemia.
【Caution】.
Special warning.
When liver function is impaired, thiazide-like diuretics may cause hepatic encephalopathy, especially in the case of electrolyte disturbance. If hepatic encephalopathy occurs, diuretics should be discontinued immediately.
Photosensitivity.
Photosensitivity reactions have been reported with thiazides and thiazide-like diuretics (see [Adverse Reactions]). If photosensitivity reactions occur during treatment, it is recommended that treatment be discontinued. If this diuretic must be taken again, it is recommended that the patient’s exposed body surface areas be protected from sunlight or artificial UVA exposure.
Excipients.
This product contains lactose. This drug is contraindicated in patients with rare congenital galactose intolerance, lactase deficiency, or impaired glucose and galactose absorption.
Precautions in use :
Water and electrolyte balance
– Blood sodium
Blood sodium must be measured prior to treatment and should be monitored regularly thereafter. Decreased blood sodium can be asymptomatic at first, so regular monitoring is essential; in high-risk groups such as the elderly and patients with cirrhosis, monitoring should be more frequent (see [ADVERSE REACTIONS] and [OVERDOSAGE]). Any diuretic therapy can lead to hyponatremia, sometimes with very serious consequences. Hyponatremia with hypovolemia may lead to dehydration and upright hypotension. Combined loss of chloride ions may lead to secondary compensatory metabolic alkalosis: the incidence of this effect is low and mild.
– Blood potassium
Hypokalemia due to potassium deficiency is the main risk due to thiazide and thiazide-like diuretics. Hypokalemia must be prevented in certain high-risk groups, such as in the elderly, in people with malnutrition and/or multiple drug therapy, and in patients with edema, cirrhosis with ascites, coronary artery disease and heart failure (<3.4 mmol/l). In these cases, hypokalemia can increase the toxicity of digitalis drugs to the heart and increase the risk of arrhythmias.
Patients with prolonged QT intervals in the ECG, either congenital or of medical origin, are at risk with this drug. Both hypokalemia and bradycardia are predisposing factors for severe arrhythmias (especially the fatal risk of tip-twist ventricular tachycardia).
In all of the above cases, more frequent potassium monitoring must be performed. The first blood potassium measurement should be performed within 1 week after the start of treatment.
When low blood potassium is determined, it should be corrected accordingly.
– Blood calcium
Thiazides and thiazide-like diuretics may reduce urinary calcium excretion, causing a transient, mild elevation of blood calcium. Significant hypercalcemia may be due to previously unrecognized hyperparathyroidism.
Treatment should be discontinued until parathyroid function is checked.
Blood glucose
In patients with diabetes, monitoring of blood glucose is important, especially if hypokalemia is present.
Uric acid
In patients with hyperuricemia, the chance of a gout attack may be increased.
Renal function and diuretics
Thiazides and thiazide-like diuretics are only fully effective when renal function is normal or only mildly impaired (blood creatinine below 25 mg/L, i.e. 220 μmol/L in adults). In the elderly, blood creatinine must be adjusted according to age, weight and gender.
At the beginning of diuretic therapy, glomerular filtration is reduced by the hypovolemia caused by the loss of water and sodium, which may lead to an increase in blood urea and creatinine. This transient functional renal insufficiency has no effect on those with normal renal function; however, in those with pre-existing renal insufficiency, it may lead to further deterioration of renal function.
Athletes
This drug contains active ingredients that may cause positive doping tests and athletes should be aware of this. Use with caution in athletes.
Effects on the ability to drive motor vehicles and operate machinery
This product does not affect alertness, but individual reactions associated with lowered blood pressure may occur in some patients, especially at the beginning of treatment and in combination with other antihypertensive drugs.
As a result, it can cause a decrease in the ability of the person concerned to drive a motor vehicle and operate machinery.
Pregnant women and nursing mothers
Pregnancy
Data on the use of indapamide in pregnant women are limited (less than 300 pregnancy outcomes). Prolonged exposure to thiazides at the end of pregnancy may reduce maternal plasma volume and uteroplacental blood flow, which in turn may lead to fetal-placental ischemia and growth retardation.
Animal studies have not suggested direct or indirect harmful effects in terms of reproductive toxicity (see [Pharmacological Toxicology]).
As a precaution, indapamide is best avoided during pregnancy.
Lactation
Insufficient information is available on the secretion of indapamide/metabolites via human milk. Hypersensitivity to drugs of sulfonamide origin and hypokalemia may occur. Risk to the newborn/infant cannot be excluded.
Indapamide is structurally very similar to thiazide diuretics, and the latter have been associated with reduced milk production and even suppression of lactation during breastfeeding.
Indapamide should not be used during breastfeeding.
Fertility
Reproductive toxicity studies have shown no effect on fertility in female and male rats (see [Pharmacologic Toxicology]). No effect on human fertility is expected.
Pediatric Use]
The safety and efficacy of this product in children and adolescents have not been established and no data are available.
[Geriatric Use].
Normal blood creatinine values in the elderly must be adjusted for age, weight and gender. This product can be used in elderly patients with normal or mildly impaired renal function (see [Precautions]).
Drug Interactions]
Drugs not recommended to be used in combination
+ Lithium
In a sodium-free diet (reduced urinary excretion of lithium), indapamide can increase blood lithium concentrations and lead to lithium overdose. However, if a diuretic must be used, blood lithium levels should be strictly monitored and the dosage adjusted.
Drugs to be used in combination with caution
+ Drugs that cause tip-twisting ventricular tachycardia
Class Ia antiarrhythmics (quinidine, dihydroquinidine, propiamine)
Class III antiarrhythmics (amiodarone, sotalol, dofetilide, ibupilide)
Some antipsychotics.
phenothiazines (chlorpromazine, cyromazine, levomepromazine, thioridazine, trifluoperazine), the
Benzamides (amisulpride, sulpiride, sultopride, thiopride), the
butylphenols (haloperidol, haloperidol)
Others: bepridil, cisapride, diphenhydramine, intravenous erythromycin, halofantrine, imipramine, pentoxifylline, sparfloxacin, moxifloxacin, intravenous vincristine.
Combinations increase the risk of ventricular arrhythmias, especially causing tip-twist ventricular tachycardia (hypokalemia is a risk factor)
Hypokalemia should be monitored and corrected if necessary prior to co-administration. Monitoring of clinical signs, plasma electrolyte levels and electrocardiogram should be performed.
In case of hypokalemia, choose a drug that does not have the risk of causing tip-twisting ventricular tachycardia.
+ Non-steroidal anti-inflammatory drugs. (systemic), including selective COX-2 inhibitors, and high doses of salicylates (>3 g daily)
May reduce the antihypertensive effect of indapamide
Risk of acute renal failure (reduced glomerular filtration rate) in dehydrated patients. Hydrate and monitor renal function prior to initiation of therapy
+ Angiotensin-converting enzyme (ACE) inhibitors
Risk of sudden hypotension and/or acute renal failure with indapamide in combination with angiotensin-converting enzyme inhibitors in the presence of prior sodium deficiency (seen particularly in renal artery stenosis).
In essential hypertension, prior application of diuretic therapy may lead to sodium deficiency and care must be taken.
Discontinuing diuretics 3 days prior to the application of angiotensin-converting enzyme inhibitors and restarting potassium-depleting diuretics if necessary.
or when giving angiotensin-converting enzyme inhibitors, use a low starting dose and gradually increase the dose.
In patients with congestive heart failure, the starting dose of angiotensin-converting enzyme inhibitors should be very small and may be started with a reduced dose of potassium-removing diuretics.
In all patients, monitor renal function (creatinine) during the first few weeks of angiotensin-converting enzyme inhibitor administration
+ Other compounds causing hypokalemia.
Amphotericin B (sedation), glucocorticoids and salicorticoids (systemic administration), ticlopidine, stimulant laxatives.
Increase the risk of hypokalemia (synergistic effect).
Monitor blood potassium and correct if necessary. Take special care when co-administering digitalis analogues. Apply non-stimulant laxatives.
+ Baclofen:
Enhance the hypotensive effect. Rehydrate the patient; monitor renal function at the start of therapy.
+ Digitalis analogues.
Hypokalemia predisposes to toxic effects of digitalis drugs. Monitor potassium and electrocardiogram and adjust therapy if necessary.
Additional combinations to be considered
+ Potassium-protective diuretics (amiloride, spironolactone, aminoglutethimide)
This combination may be beneficial in some patients, but hypokalemia or hyperkalemia may still occur (especially in patients with renal failure and diabetes). Monitoring of blood potassium and electrocardiogram is required, and therapy should be adjusted if necessary.
+ Metformin
Diuretics (especially medullary collaterals) may induce renal insufficiency, thereby increasing the risk of metformin-induced lactic acidosis. Do not apply metformin if blood creatinine levels exceed 15 mg/L (135 μmol/L) in men and 12 mg/L (110 μmol/L) in women.
+ Iodine contrast agents
In cases of dehydration caused by diuretics, iodine contrast agents increase the risk of acute renal failure, especially when applied in high doses. Iodine compounds must be treated with rehydration before administration.
+ Class promethazine antidepressants (tricyclics), psychostimulants
Anti-hypertensive effect and increased risk of upright hypotension (synergistic effect).
+ Calcium salts
Risk of hypercalcemia due to decreased calcium excretion in urine.
+ Cyclosporine, tacrolimus
Risk of elevated blood creatinine without increasing circulating cyclosporine levels, even in the absence of water/sodium deficiency.
+ Corticosteroids, ticlopidine (systemic administration)
Reduces the anti-hypertensive efficacy of indapamide (due to water/sodium retention caused by corticosteroids).
[Drug overdose].
Symptoms
There were no toxic reactions to indapamide at doses up to 40 mg, i.e., equivalent to 27 times the therapeutic amount.
Acute toxicity is mainly manifested by water and electrolyte disturbances (hyponatremia and hypokalemia). Clinical signs may be nausea, vomiting, hypotension, painful cramps, dizziness, drowsiness, confusion, polyuria or oliguria or possibly even anuria (due to hypovolemia).
Treatment
The initial treatment used in specialized medical centers is to remove the ingested drug as soon as possible by gastric lavage and/or administration of activated charcoal. Thereafter, water and electrolytes should be replenished to restore the water and electrolyte balance.
Pharmacology and Toxicology
Diuretic effect acting on the diluted segment of the renal cortex (cardiovascular system)
Mechanism of action.
Indapamide is a sulfonamide derivative with an indole ring structure, pharmacologically related to thiazide diuretics, and achieves diuretic effect by inhibiting sodium reabsorption in the dilute segment of the renal cortex. This drug increases the excretion of urinary sodium and urinary chloride and, to a lesser extent, potassium and magnesium, resulting in an increase in urine output, which exerts an antihypertensive effect.
Pharmacodynamic effects
Phase II and III studies have shown that the antihypertensive effect of monotherapy with this drug lasts up to 24 hours. At the time of this effect, the dose used had only a mild diuretic effect.
The antihypertensive effect of this drug is associated with improved arterial compliance and reduced resistance of small arteries and the entire peripheral circulation.
Indapamide reduces left ventricular hypertrophy.
Above a certain dose, the efficacy of thiazide-type and thiazide-like diuretics does not further improve, while the side effects keep increasing. If treatment is ineffective, the drug dose should not be increased.
In short-, medium- and long-term application of indapamide in the treatment of hypertensive patients, it was found that indapamide.
– Does not affect lipid metabolism: e.g. triglycerides, LDL-cholesterol and HDL-cholesterol.
– Does not affect carbohydrate metabolism, even when used to treat patients with diabetic hypertension.
Preclinical safety data
Available trials have not confirmed the mutagenicity and carcinogenicity of indapamide.
Oral administration of large doses (40 to 8000 times higher than therapeutic doses) to animals of different species has been shown to enhance the diuretic effect of indapamide. Acute toxicity tests with intravenous or intraperitoneal administration of indapamide showed that the main symptoms induced were related to the pharmacological effects of indapamide and were characterized by bradycardia and peripheral vasodilation.
Reproductive toxicity studies did not show embryotoxicity or teratogenicity.
Fertility was not impaired in male or female rats.
Pharmacokinetics]
The product contains indapamide in a sustained-release dose in a matrix that acts as a support for the active ingredient to allow slow release of the drug.
Absorption
The released indapamide component is rapidly and completely absorbed into the gastrointestinal tract.
The absorption of the drug is mildly accelerated by eating, but has no effect on the amount of drug absorbed.
Peak blood levels are reached 12 hours after a single dose. Repeated dosing may reduce the variation in blood concentration between doses.
There are inter-individual differences in absorption.
Distribution
Indapamide binds to plasma proteins at a rate of 79%.
The half-life of plasma elimination is 14-24 hours (mean 18 hours).
Steady-state blood levels are achieved after 7 days of dosing.
Repeated dosing does not cause drug accumulation.
Metabolism
Mainly excreted as inactive metabolites in urine (up to 70% of the administered dose) and feces (22%).
High risk groups
In patients with renal failure, there is no change in pharmacokinetic parameters.
Storage】Seal and store in a cool and dry place.
Package】Aluminum package, 10, 30 tablets/box
Expiration date】24 months.
Execution Standard】JX20110038
Imported drug registration number】H20130140
Manufacturer
French pharmaceutical company
Les Laboratoires Servier – France
Production enterprise.
Company name: Les Laboratoires Servier Industrie
Production address: 905, route de Saran, 45520 Gidy – France
Telephone number: 33 1 55 72 75 73
Fax number: 33 1 55 72 57 65
Domestic contact.
Svea (Tianjin) Pharmaceutical Co.
No.1 Dongsanhuan Middle Road, Chaoyang District, Beijing
6/F, West Building, World Financial Center
Postal Code: 100020
Tel: (8610) 65610341
Fax: (8610) 65610348
Website: www.servier.com.cn