Indapamide (Page 2 of 3)

Hyperuricemia and Gout

Serum concentrations of uric acid increased by an average of 0.69 mg/100 mL in patients treated with indapamide 1.25 mg, and by an average of 1 mg/100 mL in patients treated with indapamide 2.5 mg and 5 mg, and frank gout may be precipitated in certain patients receiving indapamide (see ADVERSE REACTIONS). Serum concentrations of uric acid should, therefore, be monitored periodically during treatment.

Renal Impairment

Indapamide, like the thiazides, should be used with caution in patients with severe renal disease, as reduced plasma volume may exacerbate or precipitate azotemia. If progressive renal impairment is observed in a patient receiving indapamide, withholding or discontinuing diuretic therapy should be considered. Renal function tests should be performed periodically during treatment with indapamide.

Impaired Hepatic Function

Indapamide, like the thiazides, should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Glucose Tolerance

Latent diabetes may become manifest and insulin requirements in diabetic patients may be altered during thiazide administration. A mean increase in glucose of 6.47 mg/dL was observed in patients treated with indapamide 1.25 mg, which was not considered clinically significant in these trials. Serum concentrations of glucose should be monitored routinely during treatment with indapamide.

Calcium Excretion

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.

Interaction with Systemic Lupus Erythematosus

Thiazides have exacerbated or activated systemic lupus erythematosus and this possibility should be considered with indapamide as well.

Acute Angle-Closure Glaucoma, Acute Myopia, and Choroidal Effusion

Sulfonamide or sulfonamide-derivative drugs, like indapamide, can cause an idiosyncratic reaction resulting in acute angle-closure glaucoma and elevated intraocular pressure with or without a noticeable acute myopic shift and/or choroidal effusions. Symptoms may include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated, the angle-closure glaucoma may result in permanent visual field loss. The primary treatment is to discontinue indapamide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

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.

Nursing Mothers

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.

Pediatric Use

Safety and effectiveness of indapamide in pediatric patients have not been established.

Geriatric Use

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).

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.

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