Lozide (Indapamide)

LOZIDE®

Servier

Indapamide Hemihydrate

Diuretic – Antihypertensive Agent

Action And Clinical Pharmacology: Indapamide is a diuretic antihypertensive agent. The mechanism whereby indapamide exerts its action in the control of hypertension is not completely elucidated: both renal and extrarenal actions may be involved. The renal site of action is the proximal part of the distal tubule and the ascending part of Henle’s loop. Sodium and chloride ions are excreted in approximately equivalent amounts. The increased delivery of sodium to the distal tubular exchange site results in increased potassium excretion and hypokalemia.

Pharmacokinetics: Indapamide is rapidly and completely absorbed after oral administration. Peak blood levels are obtained after 1 to 2 hours. Indapamide is concentrated in the erythrocytes and is 79% bound to plasma proteins and to erythrocytes.

It is taken up by the vascular wall in smooth vascular muscle according to its high lipid solubility. Seventy per cent of a single oral dose is eliminated by the kidneys and 23% by the gastrointestinal tract. Indapamide is metabolized to a marked degree, the unchanged product representing approximately 5% of the total dose found in the urine during the 48 hours following administration. Elimination of indapamide from the plasma is biphasic with half-lives of 14 and 25 hours respectively.

Indications And Clinical Uses: The management of essential hypertension. It may be tried as a sole therapeutic agent in the treatment of mild to moderate hypertension. Normally indapamide, as other diuretics, is used as the initial agent in multiple drug regimens.

Contra-Indications: Anuria, progressive and severe oliguria, hepatic coma. Known hypersensitivity to indapamide or to other sulfonamide derivatives.

Manufacturers’ Warnings In Clinical States: Electrolyte changes observed with indapamide become severe at doses above 2.5 mg/day. Therefore the maximum daily dose should not exceed this dose.

Hypokalemia may occur at all doses with consequent weakness, cramps, and cardiac dysrhythmias. Hypokalemia is a particular hazard in digitalized patients; dangerous or fatal arrhythmias may be precipitated.

Hypokalemia occurs commonly with diuretics; electrolyte monitoring is essential particularly in patients who would be at increased risk from hypokalemia, such as patients with cardiac arrhythmias or those who are receiving concomitant cardiac glycosides.

Patients with renal insufficiency receiving indapamide should be carefully monitored. If increasing azotemia and oliguria occur during treatment, the diuretic should be discontinued.

Hyperuricemia may occur during administration of indapamide. Rarely gout has been reported. Blood uric acid levels should be monitored, particularly in patients with a history of gout who should continue to receive appropriate treatment.

Precautions: Patients receiving indapamide should be carefully observed and serum electrolytes monitored for signs and symptoms of fluid or electrolyte imbalance; namely hyponatremia, hypochloremia and hypokalemia. BUN, uric acid, and glucose levels should also be assessed during therapy. Hypokalemia, an ever present hazard with most diuretics, will be more common in association with concomitant steroid or ACTH therapy and with inadequate electrolyte intake. The serum potassium should be determined at regular intervals and potassium supplementation instituted when indicated (see Warnings).

The signs of electrolyte imbalance are: dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscle fatigue, hypotension, oliguria, gastrointestinal disturbances such as nausea and vomiting, tachycardia and ECG changes.

Special caution should be used in treating patients with severe hepatic disease since diuretics may induce metabolic alkalosis in cases of potassium depletion which may precipitate episodes of hepatic encephalopathy.

Orthostatic hypotension may occur and may be potentiated by alcohol, barbiturates, narcotics or concurrent therapy with other antihypertensives.

When indapamide is given with other nondiuretic antihypertensive agents, the effects on blood pressure are additive.

Sulfonamide derivatives have been reported to exacerbate or activate systemic lupus erythematosus. These possibilities should be kept in mind with the use of indapamide although no case has been reported to date.

Severe dermatological adverse reactions, some accompanied by systemic manifestations, have been rarely reported with the use of indapamide. In the majority of cases, the condition subsided within 14 days following discontinuation of indapamide therapy (see Adverse Effects).

Caution should be observed when administering the drug to patients with severely impaired renal function, since the drug is excreted primarily by the renal route.

Although indapamide exerts minimal effect on glucose metabolism, insulin requirements may be affected in diabetics and hyperglycemia and glycosuria may occur in patients with latent diabetes.

Calcium excretion is decreased by diuretics pharmacologically related to indapamide. After 6 to 8 weeks of indapamide 1.25 mg treatment and in long-term studies of hypertensive patients with higher doses of indapamide, however, serum concentrations of calcium increased only slightly with indapamide. Prolonged treatment with drugs pharmacologically related to indapamide may in rare instances be associated with hypercalcemia and hypophosphatemia secondary to physiologic changes in the parathyroid gland; however, the common complications of hyperparathyroidism, such as renal lithiasis, bone resorption, and peptic ulcer, have not been seen. Treatment should be discontinued before tests for parathyroid function are performed. Like the thiazides, indapamide may decrease serum PBI levels without signs of thyroid disturbance.

The antihypertensive effect of the drug may be enhanced in the patient postsympathectomy.

Pregnancy: Since indapamide has not been studied in human pregnancy, the drug should not be given to pregnant women. The use in patients of childbearing potential requires that the anticipated benefit be weighed against possible hazards.

Lactation: It is unknown whether or not indapamide appears in breast milk. Indapamide should not be administered to nursing mothers. If use of the drug is deemed essential, the patient should stop nursing.

Children: The safety and effectiveness have not been established.

Adverse Reactions: The safety data presented under this section involves 2 different databases and was obtained at 2 different time periods. For the earliest database (indapamide 2.5 mg), consisting mainly of European studies performed before 1980, adverse events were collected with respect to a possible causal relationship to treatment, whereas for the most recent database (indapamide 1.25 mg), consisting exclusively of North American studies, adverse events were collected irrespective of such a causal relationship. This explains why the overall incidence of adverse events at the 2.5 mg dose appears to be lower than at the 1.25 mg dose (see below).

Most adverse events for both dosages, 1.25 mg and 2.5 mg, have been mild or moderate.

The adverse reactions represent data from clinical studies involving a total of 992 patients given indapamide 2.5 mg: 349 patients from 4 placebo controlled studies treated for 8 to 12 weeks; 356 patients from 6 active controlled studies treated for 6 up to more than 52 weeks; 287 patients from 4 uncontrolled studies treated for 6 up to 40 weeks.

The overall rate of adverse events, with respect to a possible causal relationship to the drug, was 29% and discontinuation of therapy due to adverse events was required in 5.6% of patients.

The most severe and common adverse event is the electrolyte imbalance. Electrolyte changes reported include hypokalemia (14.2%; requiring potassium supplementation 6%; with clinical symptoms 1.2%), hypochloremia (9.4%) and hyponatremia (3.1%).

The other changes observed in laboratory parameters are minor and infrequent: elevation in blood uric acid (8.6%), blood glucose (6.0%), BUN (5.7%) and blood creatinine (3.6%).

The most frequent adverse events (incidence ³1%) reported for patients treated with indapamide 2.5 mg were: headache (3.4%), vertigo (2.2%), dizziness (1.9%), asthenia (1.7%) and muscle cramps (1.2%).

All other adverse events occured at an incidence of less than 1% and included by body system:

Central Nervous: drowsiness, sleepiness, insomnia, weakness, lethargy and visual disturbance.

Gastrointestinal: nausea, anorexia, dryness of mouth, gastralgia, vomiting, diarrhea and constipation.

Musculoskeletal: joint pain, back pain and weakness of legs.

Cardiovascular: orthostatic hypotension, tachycardia and ECG changes (nonspecific ST-T change, U waves, left ventricular strain).

Urogenital: impotence, modification of libido and polyuria.

Dermatological: rash and pruritus.

Endocrine: gout.

Other: tinnitus, malaise, fainting and sweat.

In placebo-controlled studies involving 306 patients given indapamide 1.25 mg and 319 given placebo for up to 8 weeks, the overall incidence of adverse events, irrespective of causal relationship, was about 50% in both indapamide and placebo groups. In the indapamide 1.25 mg group, 4.2% of patients discontinued treatment because of adverse events.

In these studies, 20% of patients treated with indapamide 1.25 mg had at least 1 potassium value below 3.4 mEq/L.

The most frequently reported adverse events (incidence ³1%) in the indapamide 1.25 mg group were: headache (17%), infection (12%), pain (8%), dizziness (7%), back pain (5%), rhinitis (5%), asthenia (4%), dyspepsia (4%), flu syndrome (3%), hypertonia (3%), sinusitis (3%), chest pain (2%), constipation (2%), cough (2%), diarrhea (2%), edema (2%), nausea (2%), pharyngitis (2%), conjunctivitis (1%), nervousness (1%) and ECG abnormalities (nonspecific ST-T changes (7%), sinus bradycardia (3%), arrhythmia (2%) or tachycardia (2%)).

All other clinical adverse events occured at an incidence of less than 1%. These are the following:

Central Nervous: agitation, amnesia, anxiety, ataxia, coordination abnormality, depression, dream abnormality, hyperesthesia, insomnia, migraine, paresthesia, somnolence, twitching and vertigo.

Gastrointestinal: increased appetite, dry mouth, GI carcinoma, GI disorders, duodenitis, dysphagia, esophagitis, flatulence, gastritis, gastroenteritis, oral moniliasis, proctitis, rectal disorders, rectal hemorroids, stomatitis, tooth disorders and vomiting.

Musculoskeletal: arthralgia, arthritis, bone disorders, joint disorders, bone fracture, bone pain, chondrodystrophy, myalgia, myasthenia and myopathy.

Cardiovascular: angina pectoris, bundle branch block, ventricular extrasystoles, atrial fibrillation, atrial flutter, hypertension, postural hypotension, palpitations, syncope, supraventricular tachycardia and vasodilation.

Urogenital: dysmenorrhea, dysuria, impotence, urinary tract infection, nocturia, oliguria, urinary frequency or urgency, renal pain or calculus, prostate disorders and vaginitis.

Respiratory: bronchitis, dyspnea, laryngitis, lung disorder and sputum increase.

Dermatological: acne, application site reaction, exfoliative dermatitis, nail disorder, skin nodule, rash, bullous eruption and sweat.

Metabolic and nutritional: diabetes mellitus and gout.

Special senses: amblyopia, ear disorders, ear pain, otitis, photophobia, taste perversion, tinnitus and vision abnormality.

Other: thyroid disorder, ecchymosis, allergic reaction, edema face, fever, hernia, malaise and monilia.

Postmarketing experience: Among the less common suspected adverse reactions reported, the following, which are not included elsewhere in the product monograph, have been published in the medical literature and/or are classified as serious or potentially serious: Stevens-Johnson syndrome, bullous eruption, photosensitivity with bullae, erythroderma, purpura, epidermal necrolysis, erythema multiforme, angioedema, cataract, acute myopia, optic neuritis, ventricular arrhythmia, torsades de pointe, stroke, acute hypersensitivity reaction leading to interstitial nephritis and renal failure, anemia, agranulocytosis, metabolic alcalosis, hyperosmolar coma, dehydration, hepatitis, pancreatitis, lithium toxicity, rhabdomyolysis, vasculitis, fever.

One case of synergetic effect of clofibrate with indapamide leading to hyponatremia, hypokalemia, hypoosmolarity, nausea and progressive loss of consciousness.

Relationship with the administration of indapamide has not been proved in all cases.

Symptoms And Treatment Of Overdose: Symptoms: There have been no reports of overdosage. Based on the pharmacological activities of indapamide, overdosage may lead to excessive diuresis with electrolyte depletion. In cirrhotic patients, overdosage might precipitate hepatic coma.

Treatment: There is no specific antidote. Treatment is symptomatic and supportive. Discontinue drug. Induce emesis or perform gastric lavage. Correct dehydration, electrolyte imbalance, hepatic coma and hypotension by established procedures.

Dosage And Administration: One 1.25 mg tablet/day taken in the morning as a single dose. If the response is not satisfactory after 4 to 8 weeks, the dose may be increased to a maximum of 2.5 mg as a single dose taken in the morning. If the antihypertensive response to indapamide is insufficient, an increase in dosage is not recommended (see Warnings).

Instead a nondiuretic antihypertensive agent should be added to the drug regimen. Alternatively if in the opinion of the physician, an important diuretic effect is desirable for the patient’s control, a different diuretic which allows for dose titration could be tried instead of indapamide.

Availability And Storage: 1.25 mg: Each round, orange, film-coated tablet, with S embossed on one side, contains: indapamide hemihydrate 1.25 mg. Blister-packs of 30 and 100.

2.5 mg: Each pink sugar-coated tablet contains: indapamide hemihydrate 2.5 mg. Tartrazine-free. Blister-packs of 30 and 100. (Shown in Product Recognition Section)

LOZIDE® Servier Indapamide Hemihydrate Diuretic – Antihypertensive Agent

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