Xipamide
Adverse Effects, Treatment, and Precautions as for Hydrochlorothiazide whose record is discussed below :
PRECAUTIONS:
General
All patients receiving diuretic therapy should be observed for evidence of fluid
or electrolyte imbalance: namely, hyponatremia, hypochloremic alkalosis, and
hypokalemia. Serum and urine electrolyte determinations are particularly
important when the patient is vomiting excessively or receiving parenteral
fluids. Warning signs or symptoms of fluid and electrolyte imbalance,
irrespective of cause, include dryness of mouth, thirst, weakness, lethargy,
drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular
fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances
such as nausea and vomiting.
Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis
is present or after prolonged therapy.
Interference with adequate oral electrolyte intake will also contribute to
hypokalemia. Hypokalemia may cause cardiac arrhythmia and may also sensitize or
exaggerate the response of the heart to the toxic effects of digitalis (e.g.,
increased ventricular irritability). Hypokalemia may be avoided or treated by
use of potassium sparing diuretics or potassium supplements such as foods with a
high potassium content.
Although any chloride deficit is generally mild and usually does not require
specific treatment except under extraordinary circumstances (as in liver disease
or renal disease), chloride replacement may be required in the treatment of
metabolic alkalosis.
Dilutional hyponatremia may occur in edematous patients in hot weather;
appropriate therapy is water restriction, rather than administration of salt,
except in rare instances when the hyponatremia is life threatening. In actual
salt depletion, appropriate replacement is the therapy of choice.
Hyperuricemia may occur or acute gout may be precipitated in certain patients
receiving thiazides.
In diabetic patients dosage adjustments of insulin or oral hypoglycemic agents
may be required. Hyperglycemia may occur with thiazide diuretics. Thus latent
diabetes mellitus may become manifest during thiazide therapy.
The antihypertensive effects of the drug may be enhanced in the post-
sympathectomy patient.
If progressive renal impairment becomes evident, consider withholding or
discontinuing diuretic therapy.
Thiazides have been shown to increase the urinary excretion of magnesium; this
may result in hypomagnesemia.
Thiazides may decrease urinary calcium excretion. Thiazides may cause
intermittent and slight elevation of serum calcium in the absence of known
disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden
hyperparathyroidism. Thiazides should be discontinued before carrying out tests
for parathyroid function.
Increases in cholesterol and triglyceride levels may be associated with thiazide
diuretic therapy.
Laboratory Tests
Periodic determination of serum electrolytes to detect possible electrolyte
imbalance should be done at appropriate intervals.
Drug Interactions
When given concurrently the following drugs may interact with thiazide
diuretics.
Alcohol, Barbiturates, Or Narcotics--potentiation of orthostatic hypotension may
occur.
Antidiabetic Drugs--(oral agents and insulin)--dosage adjustment of the
antidiabetic drug may be required.
Other Antihypertensive Drugs--additive effect or potentiation.
Cholestyramine And Colestipol Resins--Absorption of hydrochlorothiazide is
impaired in the presence of anionic exchange resins. Single doses of either
cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its
absorption from the gastrointestinal tract by up to 85 and 43 percent,
respectively.
Corticosteroids, ACTH--intensified electrolyte depletion, particularly
hypokalemia.
Pressor Amines (e.g., Norepinephrine)--possible decreased response to pressor
amines but not sufficient to preclude their use.
Skeletal Muscle Relaxants, Nondepolarizing (e.g., Tubocurarine)--possible
increased responsiveness to the muscle relaxant.
Lithium--generally should not be given with diuretics. Diuretic agents reduce
the renal clearance of lithium and add a high risk of lithium toxicity. Refer to
the package insert for lithium preparations before use of such preparations with
ESIDREX.
Non-Steroidal Anti-Inflammatory Drugs--In some patients, the administration of a
non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and
antihypertensive effects of loop, potassium-sparing and thiazide diuretics.
Therefore, when ESIDREX and non-steroidal anti-inflammatory agents are used
concomitantly, the patient should be observed closely to determine if the
desired effect of the diuretic is obtained.
Drug/Laboratory Test Interactions
Thiazides should be discontinued before carrying out tests for parathyroid
function (see PRECAUTIONS, General).
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Two-year feeding studies in mice and rats conducted under the auspices of the
National Toxicology Program (NTP) uncovered no evidence of a carcinogenic
potential of hydrochlorothiazide in female mice (at doses of up to approximately
600 mg/kg/day) or in male and female rats (at doses of up to approximately 100
mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity
in male mice.
Hydrochlorothiazide was not genotoxic In Vitro in the Ames mutagenicity assay of
Salmonella Typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 and
in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or In Vivo
in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow
chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive
test results were obtained only in the In Vitro CHO Sister Chromatid Exchange
(clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, using
concentrations of hydrochlorothiazide from 43 to 1300 mcgm/mL, and in the
Aspergillus Nidulans non-disjunction assay at an unspecified concentration.
Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of
either sex in studies wherein these species were exposed, via their diet, to
doses of up to 100 and 4 mg/kg, respectively, prior to conception and throughout
gestation.
Pregnancy
Teratogenic Effects--Pregnancy Category B: Studies in which hydrochlorothiazide
was orally administered to pregnant mice and rats during their respective
periods of major organogenesis at doses up to 3000 and 1000 mg
hydrochlorothiazide/kg, respectively, provided no evidence of harm to the fetus.
There are, however, no adequate and well- controlled studies in pregnant women.
Because animal reproduction studies are not always predictive of human response,
this drug should be used during pregnancy only if clearly needed.
Nonteratogenic Effects: Thiazides cross the placental barrier and appear in cord
blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia, and
possibly other adverse reactions that have occurred in adults.
Nursing Mothers
Thiazides are excreted in breast milk. Because of the potential for serious
adverse reactions in nursing infants, a decision should be made whether to
discontinue nursing or to discontinue hydrochlorothiazide, taking into account
the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in children have not been established.
DRUG INTERACTIONS:
When given concurrently the following drugs may interact with thiazide
diuretics.
Alcohol, Barbiturates, Or Narcotics--potentiation of orthostatic hypotension may
occur.
Antidiabetic Drugs--(oral agents and insulin)--dosage adjustment of the
antidiabetic drug may be required.
Other Antihypertensive Drugs--additive effect or potentiation.
Cholestyramine And Colestipol Resins--Absorption of hydrochlorothiazide is
impaired in the presence of anionic exchange resins. Single doses of either
cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its
absorption from the gastrointestinal tract by up to 85 and 43 percent,
respectively.
Corticosteroids, ACTH--intensified electrolyte depletion, particularly
hypokalemia.
Pressor Amines (e.g., Norepinephrine)--possible decreased response to pressor
amines but not sufficient to preclude their use.
Skeletal Muscle Relaxants, Nondepolarizing (e.g., Tubocurarine)--possible
increased responsiveness to the muscle relaxant.
Lithium--generally should not be given with diuretics. Diuretic agents reduce
the renal clearance of lithium and add a high risk of lithium toxicity. Refer to
the package insert for lithium preparations before use of such preparations with
ESIDREX.
Non-Steroidal Anti-Inflammatory Drugs--In some patients, the administration of a
non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and
antihypertensive effects of loop, potassium-sparing and thiazide diuretics.
Therefore, when ESIDREX and non-steroidal anti-inflammatory agents are used
concomitantly, the patient should be observed closely to determine if the
desired effect of the diuretic is obtained.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
The following adverse reactions have been reported and, within each category,
are listed in order of decreasing severity.
Body As A Whole: Weakness.
Cardiovascular: Hypotension including orthostatic hypotension (may be aggravated
by alcohol, barbiturates, narcotics or antihypertensive drugs).
Digestive: Pancreatitis, jaundice (intrahepatic cholestatic jaundice), diarrhea,
vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea,
anorexia.
Hematologic: Aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia,
thrombocytopenia.
Hypersensitivity: Anaphylactic reactions, necrotizing angiitis (vasculitis and
cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary
edema, photosensitivity, fever, urticaria, rash, purpura.
Metabolic: Electrolyte imbalance (see PRECAUTIONS), hyperglycemia, glycosuria,
hyperuricemia.
Musculoskeletal: Muscle spasm.
Nervous System/Psychiatric: Vertigo, paresthesias, dizziness, headache,
restlessness.
Renal: Renal failure, renal dysfunction, interstitial nephritis. (See WARNINGS.)
Skin: Erythema multiforme including Stevens- Johnson syndrome, exfoliative
dermatitis including toxic epidermal necrolysis, alopecia.
Special Senses: Transient blurred vision, xanthopsia.
Urogenital: Impotence.
Whenever adverse reactions are moderate or severe, thiazide dosage should be
reduced or therapy withdrawn.
Effects on the electrolyte balance. Although reductions
in plasma-potassium concentrations with xipamide have been
shown to be on average comparable with those produced by
thiazide and loop diuretics at equipotent doses. there have
been several reports of marked hypokalaemia in individual
patients. Asymptomatic hypokalaemia was reported in 4 of 5
patients (scrum-potassium concentrations of less than
3.4 mmol per litre) by Weissberg and Kendall and in 3 of 13
patients (serum-potassium concentrations of less than
3.0 mmol per litre) by Raftery. Severe hypokalaemia result-
ing in ventricular arrhythmias has been reported following xi-
pamide alone or in combination with indapamide. Profound
electrolyte disturbances with altered consciousness and ven-
tricular extrasystoles occurred in a patient taking digoxin fol-
lowing the addition of xipamide for 10 days. Boulton and
Hardisty have also reported a case of hypokalaemic periodic
paralysis associated with xipamide administration.
Hepatic impairement. For a recommendation that xipa
mide should be given with caution to patients with liver dis
ease. see under Pharmacokinetics- below.
Pharmacokinetics
Xipamide has been reported to be well absorbed
from the gastro-intestinal tract. Absorption is fairly
rapid with peak plasma concentrations occurring
within I or 2 hours of oral administration. It is 99%
bound to plasma proteins, and is excreted in the
urine, partly unchanged and partly in the form of the
glucuronide metabolite. It is reported to have a plas-
ma half-life of about 5 to 8 hours. In patients with
renal impairment excretion in the bile become
more prominent.
Hepatic impairment. Xipamide was present in the plasma
and in ascitic fluid in patients with liver cirrhosis in propor-
tion to the protein content of the respective compartments.
The amount of drug excreted into the urine was much greater
in patients with liver disease than in healthy control subjects.
This was attributed to a diminution in hepatic elimination.
which could result in significant effects on the clinical re-
sponse to xipamide. Thus patients with cholestasis could have
an enhanced response to xipamide. On the other hand cirrhot-
ic patients with the hepatorenal syndrome may be resistant to
diuretics. Xipamide should be administered with caution to
patients with liver disease.
Renal Impairment. Following single oral and intravenous
doses of xipamide 20 mg the drug appeared to be completely
absorbed from the gastro-intestinal tract. The mean elimina-
tion half-life in healthy subjects was 7 hours and two-thirds of
the clearance was by extrarenal routes. There was some accu-
mulation in patients with chronic renal failure, with a calcu-
lated elimination half-life of 9 hours in end-stage renal
disease.
Uses and Administration
Xipamide is a diuretic, structurally related to inda-
pamide, with actions and uses similar to those of the
thiazide diuretics (see Hydrochlorothiazide).
It is used for oedema, including that associated with
heart failure and for hypertension .
Diuresis is initiated in about I or 2 hours, reaches a
peak at 4 to 6 hours, and lasts for about 12 hours.
In the treatment of oedema the usual initial dose is
40 mg by mouth daily, subsequently reduced to
20 mg daily, according to the patient's response; in
resistant cases doses of 80 mg daily may be re-
quired. In the treatment of hypertension the usual
dose is 20 mg daily, as a single morning dose, either
alone, or in conjunction with other antihyperten-
sives. In some patients a dose of 10 mg daily may be
adequate.
In susceptible patients potassium supplements or a
potassium-sparing diuretic may be necessary, but
see hydrochlorothiazide.