Both mouse and rat lifetime carcinogenicity studies were conducted. There was no significant difference in the incidence of tumors between the indapamide-treated animals and the control groups.
Pregnancy category B. 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 pre-treatment 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.
It is not known whether this drug is excreted in human milk. Because most drugs are excreted in human milk, if use of this drug is deemed essential, the patient should stop nursing.
Safety and effectiveness of indapamide in pediatric patients have not been established.
Clinical studies of indapamide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Severe cases of hyponatremia, accompanied by hypokalemia have been reported with recommended doses of indapamide in elderly females (see WARNINGS).
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.
|Incidence ≥ 5%||Incidence < 5%*|
|BODY AS A WHOLE|
|Back Pain||Chest Pain|
|METABOLIC SYSTEM||Peripheral Edema|
|CENTRAL NERVOUS SYSTEM||Nervousness|
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 eight weeks because of adverse reactions.
In controlled clinical trials of six to eight 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.
|Incidence ≥ 5%||Incidence < 5%|
|CENTRAL NERVOUS SYSTEM / NEUROMUSCULAR|
|Fatique, weakness, loss of energy, lethargy, tiredness, or malaise||Vertigo / Insomnia|
|Muscle cramps or spasm, or numbness of the extremities||Depression /Blurred Vision|
|Nervousness, tension, anxiety, irritability or agitation|
|Abdominal pain or cramps|
|CARDIOVASCULAR SYSTEM||Orthostatic hypotension|
|Premature ventricular contractions|
|Irregular heart beat|
|GENITOURINARY SYSTEM||Frequency of urination|
|OTHER||Impotence or reduced libido|
|Increase in serum urea nitrogen (BUN) or creatinine|
|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 six to eight 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||BUN|
|Indapamide||– 0.28||– 0.63||– 2.60||0.69||1.46|
|Placebo||0.00||– 0.11||– 0.21||0.06||0.06|
|(n=263 to 266)|
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||BUN|
|Indapamide||– 0.4||– 0.6||– 3.6||0.7||– 0.1|
|2.5 mg (n=76)|
|Indapamide||– 0.6||– 0.7||– 5.1||1.1||1.4|
|5 mg (n=81)|
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.
To report SUSPECTED ADVERSE REACTIONS contact AvKARE, Inc. at 1-855-361-3993; email firstname.lastname@example.org ; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
Symptoms of overdosage include nausea, vomiting, weakness, gastrointestinal disorders and disturbances of electrolyte balance. In severe instances, hypotension and depressed respiration may be observed. If this occurs, support of respiration and cardiac circulation should be instituted. There is no specific antidote. An evacuation of the stomach is recommended by emesis and gastric lavage after which the electrolyte and fluid balance should be evaluated carefully.
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