Indapamide

DOSAGE AND ADMINISTRATION Hypertension The adult starting indapamide dose for hypertension is 1.25 mg as a single daily dose taken in the morning. If the response to 1.25 mg is not satisfactory after 4 weeks, the daily dose may be increased to 2.5 mg taken once daily. If the response to 2.5 mg is not satisfactory after 4 weeks, the daily dose may be increased to 5 mg taken once daily, but adding another antihypertensive should be considered. Edema of Congestive Heart Failure The adult starting indapamide dose for edema of congestive heart failure is 2.5 mg as a single daily dose taken in the morning. If the response to 2.5 mg is not satisfactory after one week, the daily dose may be increased to 5 mg taken once daily. If the antihypertensive response to indapamide is insufficient, indapamide may be combined with other antihypertensive drugs, with careful monitoring of blood pressure. It is recommended that the usual dose of other agents be reduced by 50% during initial combination therapy. As the blood pressure response becomes evident, further dosage adjustments may be necessary. In general, doses of 5 mg and larger have not appeared to provide additional effects on blood pressure or heart failure, but are associated with a greater degree of hypokalemia. There is minimal clinical trial experience in patients with doses greater than 5 mg once a day.

CONTRAINDICATIONS Anuria. Known hypersensitivity to indapamide or to other sulfonamide-derived drugs.

WARNINGS Severe cases of hyponatremia, accompanied by hypokalemia have been reported with recommended doses of indapamide. This occurred primarily in elderly females. (See PRECAUTIONS, Geriatric Use .) This appears to be dose related. Also, a large case-controlled pharmacoepidemiology study indicates that there is an increased risk of hyponatremia with indapamide 2.5 mg and 5 mg doses. Hyponatremia considered possibly clinically significant (< 125 mEq/L) has not been observed in clinical trials with the 1.25 mg dosage (see PRECAUTIONS ). Thus, patients should be started at the 1.25 mg dose and maintained at the lowest possible dose. (See DOSAGE AND ADMINISTRATION .) Hypokalemia occurs commonly with diuretics (see ADVERSE REACTIONS, Hypokalemia ), and electrolyte monitoring is essential, particularly in patients who would be at increased risk from hypokalemia, such as those with cardiac arrhythmias or who are receiving concomitant cardiac glycosides. In general, diuretics should not be given concomitantly with lithium because they reduce its renal clearance and add a high risk of lithium toxicity. Read prescribing information for lithium preparations before use of such concomitant therapy.

Drug Interactions Other Antihypertensives Indapamide may add to or potentiate the action of other antihypertensive drugs. In limited controlled trials that compared the effect of indapamide combined with other antihypertensive drugs with the effect of the other drugs administered alone, there was no notable change in the nature or frequency of adverse reactions associated with the combined therapy. Lithium See WARNINGS . Post-Sympathectomy Patient The antihypertensive effect of the drug may be enhanced in the post-sympathectomized patient. Norepinephrine Indapamide, like the thiazides, may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use.

ADVERSE REACTIONS Most adverse effects have been mild and transient. The clinical adverse reactions listed in Table 1 represent data from Phase II/III placebo-controlled studies (306 patients given indapamide 1.25 mg). The clinical adverse reactions listed in Table 2 represent data from Phase II placebo-controlled studies and long-term controlled clinical trials (426 patients given indapamide 2.5 mg or 5 mg). The reactions are arranged into two groups: 1) a cumulative incidence equal to or greater than 5%; 2) a cumulative incidence less than 5%. Reactions are counted regardless of relation to drug. TABLE 1: Adverse Reactions from Studies of 1.25 mg Incidence ≥ 5% Incidence < 5% 1 BODY AS A WHOLE Headache Infection Pain Back Pain Asthenia Flu Syndrome Abdominal Pain Chest Pain GASTROINTESTINAL SYSTEM Constipation Diarrhea Dyspepsia Nausea METABOLIC SYSTEM Peripheral Edema CENTRAL NERVOUS SYSTEM Dizziness Nervousness Hypertonia RESPIRATORY SYSTEM Rhinitis Cough Pharyngitis Sinusitis SPECIAL SENSES Conjunctivitis 1 OTHER All other clinical adverse reactions occurred at an incidence of < 1%. Approximately 4% of patients given indapamide 1.25 mg compared to 5% of the patients given placebo discontinued treatment in the trials of up to 8 weeks because of adverse reactions. In controlled clinical trials of 6 to 8 weeks in duration, 20% of patients receiving indapamide 1.25 mg, 61% of patients receiving indapamide 5 mg, and 80% of patients receiving indapamide 10 mg had at least one potassium value below 3.4 mEq/L. In the indapamide 1.25 mg group, about 40% of those patients who reported hypokalemia as a laboratory adverse event returned to normal serum potassium values without intervention. Hypokalemia with concomitant clinical signs or symptoms occurred in 2% of patients receiving indapamide 1.25 mg. TABLE 2: Adverse Reactions from Studies of 2.5 mg and 5 mg Incidence ≥ 5% Incidence < 5% CENTRAL NERVOUS SYSTEM/NEUROMUSCULAR Headache Dizziness Fatigue, weakness, loss of energy, lethargy, tiredness, or malaise Muscle cramps or spasm, or numbness of the extremities Nervousness, tension, anxiety, irritability, or agitation Lightheadedness Drowsiness Vertigo Insomnia Depression Blurred Vision GASTROINTESTINAL SYSTEM Constipation Nausea Vomiting Diarrhea Gastric irritation Abdominal pain or cramps Anorexia CARDIOVASCULAR SYSTEM Orthostatic hypotension Premature ventricular contractions Irregular heart beat Palpitations GENITOURINARY SYSTEM Frequency of urination Nocturia Polyuria DERMATOLOGIC/HYPERSENSITIVITY Rash Hives Pruritus Vasculitis OTHER Impotence or reduced libido Rhinorrhea Flushing Hyperuricemia Hyperglycemia Hyponatremia Hypochloremia Increase in serum urea nitrogen (BUN) or creatinine Glycosuria Weight loss Dry mouth Tingling of extremities Because most of these data are from long-term studies (up to 40 weeks of treatment), it is probable that many of the adverse experiences reported are due to causes other than the drug. Approximately 10% of patients given indapamide discontinued treatment in long-term trials because of reactions either related or unrelated to the drug. Hypokalemia with concomitant clinical signs or symptoms occurred in 3% of patients receiving indapamide 2.5 mg q.d. and 7% of patients receiving indapamide 5 mg q.d. In long-term controlled clinical trials comparing the hypokalemic effects of daily doses of indapamide and hydrochlorothiazide, however, 47% of patients receiving indapamide 2.5 mg, 72% of patients receiving indapamide 5 mg, and 44% of patients receiving hydrochlorothiazide 50 mg had at least one potassium value (out of a total of 11 taken during the study) below 3.5 mEq/L. In the indapamide 2.5 mg group, over 50% of those patients returned to normal serum potassium values without intervention. In clinical trials of 6 to 8 weeks, the mean changes in selected values were as shown in the tables below. Mean Changes from Baseline after 8 Weeks of Treatment - 1.25 mg Serum Electrolytes (mEq/L) Serum Uric Acid (mg/dL) BUN (mg/dL) Potassium Sodium Chloride Indapamide 1.25 mg (n=255 to 257) -0.28 -0.63 -2.60 0.69 1.46 Placebo (n=263 to 266) 0.00 -0.11 -0.21 0.06 0.06 No patients receiving indapamide 1.25 mg experienced hyponatremia considered possibly clinically significant (< 125 mEq/L). Indapamide had no adverse effects on lipids. Mean Changes from Baseline after 40 Weeks of Treatment - 2.5 mg and 5 mg Serum Electrolytes (mEq/L) Serum Uric Acid (mg/dL) BUN (mg/dL) Potassium Sodium Chloride Indapamide 2.5 mg (n=76) -0.4 -0.6 -3.6 0.7 -0.1 Indapamide 5 mg (n=81) -0.6 -0.7 -5.1 1.1 1.4 The following reactions have been reported with clinical usage of indapamide: jaundice (intrahepatic cholestatic jaundice), hepatitis, pancreatitis, and abnormal liver function tests. These reactions were reversible with discontinuance of the drug. Also reported are erythema multiforme, Stevens-Johnson Syndrome, bullous eruptions, purpura, photosensitivity, fever, pneumonitis, anaphylactic reactions, agranulocytosis, leukopenia, thrombocytopenia, and aplastic anemia. Other adverse reactions reported with antihypertensive/diuretics are necrotizing angiitis, respiratory distress, sialadenitis, xanthopsia. Postmarketing Experience Eye Disorders Choroidal effusion, acute myopia, and angle-closure glaucoma (frequency not known). 1 1 Module 2.5 SER-indapamide-choroidal effusion-acute myopia and angle-closure glaucoma-Jul2020.

Pregnancy Teratogenic Effects Reproduction studies have been performed in rats, mice and rabbits at doses up to 6,250 times the therapeutic human dose and have revealed no evidence of impaired fertility or harm to the fetus due to indapamide. Postnatal development in rats and mice was unaffected by pretreatment of parent animals during gestation. There are, however, no adequate and well controlled studies in pregnant women. Moreover, diuretics are known to cross the placental barrier and appear in cord blood. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. There may be hazards associated with this use such as fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in the adult.