AMILORIDE
DESCRIPTION:
Amiloride HCl, an antikaliuretic-diuretic agent, is a pyrazine-carbonyl-
guanidine that is unrelated chemically to other known antikaliuretic or diuretic
agents. It is the salt of a moderately strong base (pKa 8.7). It is designated
chemically as 3,5-diamino-6-chloro-N- (diaminomethylene) pyrazinecarboxamide
monohydrochloride, dihydrate and has a molecular weight of 302.12. Its empirical
formula is C6H8ClN7O.HCl.2H2O.
ACTIONS/CLINICAL PHARMACOLOGY:
AMILORIDE HCL is a potassium-conserving (antikaliuretic) drug that possesses weak
(compared with thiazide diuretics) natriuretic, diuretic, and antihypertensive
activity. These effects have been partially additive to the effects of thiazide
diuretics in some clinical studies. When administered with a thiazide or loop
diuretic, AMILORIDE HCL has been shown to decrease the enhanced urinary excretion of
magnesium which occurs when a thiazide or loop diuretic is used alone. AMILORIDE HCL
has potassium-conserving activity in patients receiving kaliuretic-diuretic
agents.
AMILORIDE HCL is not an aldosterone antagonist and its effects are seen even in the
absence of aldosterone.
AMILORIDE HCL exerts its potassium sparing effect through the inhibition of sodium
reabsorption at the distal convoluted tubule, cortical collecting tubule and
collecting duct; this decreases the net negative potential of the tubular lumen
and reduces both potassium and hydrogen secretion and their subsequent
excretion. This mechanism accounts in large part for the potassium sparing
action of amiloride.
AMILORIDE HCL usually begins to act within 2 hours after an oral dose. Its effect on
electrolyte excretion reaches a peak between 6 and 10 hours and lasts about 24
hours. Peak plasma levels are obtained in 3 to 4 hours and the plasma half-life
varies from 6 to 9 hours. Effects on electrolytes increase with single doses of
amiloride HCl up to approximately 15 mg.
Amiloride HCl is not metabolized by the liver but is excreted unchanged by the
kidneys. About 50 percent of a 20 mg dose of AMILORIDE HCL is excreted in the urine
and 40 percent in the stool within 72 hours. AMILORIDE HCL has little effect on
glomerular filtration rate or renal blood flow. Because amiloride HCl is not
metabolized by the liver, drug accumulation is not anticipated in patients with
hepatic dysfunction, but accumulation can occur if the hepatorenal syndrome
develops.
INDICATIONS AND USAGE:
AMILORIDE HCL is indicated as adjunctive treatment with thiazide diuretics or other
kaliuretic-diuretic agents in congestive heart failure or hypertension to:
a. help restore normal serum potassium levels in patients who develop
hypokalemia on the kaliuretic diuretic
b. prevent development of hypokalemia in patients who would be exposed to
particular risk if hypokalemia were to develop, e.g., digitalized patients or
patients with significant cardiac arrhythmias.
The use of potassium-conserving agents is often unnecessary in patients
receiving diuretics for uncomplicated essential hypertension when such patients
have a normal diet. AMILORIDE HCL has little additive diuretic or antihypertensive
effect when added to a thiazide diuretic.
AMILORIDE HCL should rarely be used alone. It has weak (compared with thiazides)
diuretic and antihypertensive effects. Used as single agents, potassium sparing
diuretics, including AMILORIDE HCL, result in an increased risk of hyperkalemia
(approximately 10% with amiloride). AMILORIDE HCL should be used alone only when
persistent hypokalemia has been documented and only with careful titration of
the dose and close monitoring of serum electrolytes.
CONTRAINDICATIONS:
Hyperkalemia
AMILORIDE HCL should not be used in the presence of elevated serum potassium levels
(greater than 5.5 mEq per liter).
Antikaliuretic Therapy Or Potassium Supplementation
AMILORIDE HCL should not be given to patients receiving other potassium-conserving
agents, such as spironolactone or triamterene. Potassium supplementation in the
form of medication, potassium-containing salt substitutes or a potassium-rich
diet should not be used with AMILORIDE HCL except in severe and/or refractory cases of
hypokalemia. Such concomitant therapy can be associated with rapid increases in
serum potassium levels. If potassium supplementation is used, careful monitoring
of the serum potassium level is necessary.
Impaired Renal Function
Anuria, acute or chronic renal insufficiency, and evidence of diabetic
nephropathy are contraindications to the use of AMILORIDE HCL. Patients with evidence
of renal functional impairment (blood urea nitrogen (BUN) levels over 30 mg per
100 mL or serum creatinine levels over 1.5 mg per 100 mL) or diabetes mellitus
should not receive the drug without careful, frequent and continuing monitoring
of serum electrolytes, creatinine, and BUN levels. Potassium retention
associated with the use of an antikaliuretic agent is accentuated in the
presence of renal impairment and may result in the rapid development of
hyperkalemia.
Hypersensitivity
AMILORIDE HCL is contraindicated in patients who are hypersensitive to this product.
WARNINGS:
Hyperkalemia
Like other potassium-conserving agents,
amiloride may cause hyperkalemia (serum
potassium levels greater than 5.5 mEq per
liter) which, if uncorrected, is
potentially fatal. Hyperkalemia occurs
commonly (about 10%) when amiloride is used
without a kaliuretic diuretic. This
incidence is greater in patients with renal
impairment, diabetes mellitus (with or
without recognized renal insufficiency),
and in the elderly. When AMILORIDE HCL is used
concomitantly with a thiazide diuretic in
patients without these complications, the
risk of hyperkalemia is reduced to about
1-2 percent. It is thus essential to
monitor serum potassium levels carefully in
any patient receiving amiloride,
particularly when it is first introduced,
at the time of diuretic dosage adjustments,
and during any illness that could affect
renal function.
The risk of hyperkalemia may be increased when potassium-conserving agents,
including AMILORIDE HCL, are administered concomitantly with an angiotensin-converting
enzyme inhibitor. (See PRECAUTIONS, Drug Interactions.) Warning signs or
symptoms of hyperkalemia include paresthesias, muscular weakness, fatigue,
flaccid paralysis of the extremities, bradycardia, shock, and ECG abnormalities.
Monitoring of the serum potassium level is essential because mild hyperkalemia
is not usually associated with an abnormal ECG.
When abnormal, the ECG in hyperkalemia is characterized primarily by tall,
peaked T waves or elevations from previous tracings. There may also be lowering
of the R wave and increased depth of the S wave, widening and even disappearance
of the P wave, progressive widening of the QRS complex, prolongation of the PR
interval, and ST depression.
Treatment Of Hyperkalemia: If hyperkalemia occurs in patients taking AMILORIDE HCL,
the drug should be discontinued immediately. If the serum potassium level
exceeds 6.5 mEq per liter, active measures should be taken to reduce it. Such
measures include the intravenous administration of sodium bicarbonate solution
or oral or parenteral glucose with a rapid-acting insulin preparation. If
needed, a cation exchange resin such as sodium polystyrene sulfonate may be
given orally or by enema. Patients with persistent hyperkalemia may require
dialysis.
Diabetes Mellitus
In diabetic patients, hyperkalemia has been reported with the use of all
potassium-conserving diuretics, including AMILORIDE HCL, even in patients without
evidence of diabetic nephropathy. Therefore, AMILORIDE HCL should be avoided, if
possible, in diabetic patients and, if it is used, serum electrolytes and renal
function must be monitored frequently.
AMILORIDE HCL should be discontinued at least three days before glucose tolerance
testing.
Metabolic Or Respiratory Acidosis
Antikaliuretic therapy should be instituted only with caution in severely ill
patients in whom respiratory or metabolic acidosis may occur, such as patients
with cardiopulmonary disease or poorly controlled diabetes. If AMILORIDE HCL is given
to these patients, frequent monitoring of acid- base balance is necessary.
Shifts in acid-base balance alter the ratio of extracellular/intracellular
potassium, and the development of acidosis may be associated with rapid
increases in serum potassium levels.
PRECAUTIONS:
General
Electrolyte Imbalance And BUN Increases
Hyponatremia and hypochloremia may occur when AMILORIDE HCL is used with other
diuretics and increases in BUN levels have been reported. These increases
usually have accompanied vigorous fluid elimination, especially when diuretic
therapy was used in seriously ill patients, such as those who had hepatic
cirrhosis with ascites and metabolic alkalosis, or those with resistant edema.
Therefore, when AMILORIDE HCL is given with other diuretics to such patients, careful
monitoring of serum electrolytes and BUN levels is important. In patients with
pre-existing severe liver disease, hepatic encephalopathy, manifested by
tremors, confusion, and coma, and increased jaundice, have been reported in
association with diuretics, including amiloride HCl.
Drug Interactions
When amiloride HCl is administered concomitantly with an angiotensin-converting
enzyme inhibitor, the risk of hyperkalemia may be increased. Therefore, if
concomitant use of these agents is indicated because of demonstrated
hypokalemia, they should be used with caution and with frequent monitoring of
serum potassium. (See WARNINGS.)
Lithium generally should not be given with diuretics because they reduce its
renal clearance and add a high risk of lithium toxicity. Read circulars for
lithium preparations before use of such concomitant therapy.
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 AMILORIDE HCL 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.
Since indomethacin and potassium-sparing diuretics, including AMILORIDE HCL, may each
be associated with increased serum potassium levels, the potential effects on
potassium kinetics and renal function should be considered when these agents are
administered concurrently.
Carcinogenicity, Mutagenicity, Impairment Of Fertility
There was no evidence of a tumorigenic effect when amiloride HCl was
administered for 92 weeks to mice at doses up to 10 mg/kg/day (25 times the
maximum daily human dose). Amiloride HCl has also been administered for 104
weeks to male and female rats at doses up to 6 and 8 mg/kg/day (15 and 20 times
the maximum daily dose for humans, respectively) and showed no evidence of
carcinogenicity.
Amiloride HCl was devoid of mutagenic activity in various strains of Salmonella
Typhimurium with or without a mammalian liver microsomal activation system (Ames
test).
Pregnancy
Pregnancy Category B. Teratogenicity studies with amiloride HCl in rabbits and
mice given 20 and 25 times the maximum human dose, respectively, revealed no
evidence of harm to the fetus, although studies showed that the drug crossed the
placenta in modest amounts. Reproduction studies in rats at 20 times the
expected maximum daily dose for humans showed no evidence of impaired fertility.
At approximately 5 or more times the expected maximum daily dose for humans,
some toxicity was seen in adult rats and rabbits and a decrease in rat pup
growth and survival occurred.
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.
Nursing Mothers
Studies in rats have shown that amiloride is excreted in milk in concentrations
higher than those found in blood, but it is not known whether AMILORIDE HCL is
excreted in human milk. Because many drugs are excreted in human milk and
because of the potential for serious adverse reactions in nursing infants from
AMILORIDE HCL, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the
mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
DRUG INTERACTIONS:
When amiloride HCl is administered concomitantly with an angiotensin-converting
enzyme inhibitor, the risk of hyperkalemia may be increased. Therefore, if
concomitant use of these agents is indicated because of demonstrated
hypokalemia, they should be used with caution and with frequent monitoring of
serum potassium. (See WARNINGS.)
Lithium generally should not be given with diuretics because they reduce its
renal clearance and add a high risk of lithium toxicity. Read circulars for
lithium preparations before use of such concomitant therapy.
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 AMILORIDE HCL 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.
Since indomethacin and potassium-sparing diuretics, including AMILORIDE HCL, may each
be associated with increased serum potassium levels, the potential effects on
potassium kinetics and renal function should be considered when these agents are
administered concurrently.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
AMILORIDE HCL is usually well tolerated and, except for hyperkalemia (serum potassium
levels greater than 5.5 mEq per liter--see WARNINGS), significant adverse
effects have been reported infrequently. Minor adverse reactions were reported
relatively frequently (about 20%) but the relationship of many of the reports to
amiloride HCl is uncertain and the overall frequency was similar in
hydrochlorothiazide treated groups. Nausea/anorexia, abdominal pain, flatulence,
and mild skin rash have been reported and probably are related to amiloride.
Other adverse experiences that have been reported with amiloride are generally
those known to be associated with diuresis, or with the underlying disease being
treated.
The adverse reactions for AMILORIDE HCL listed in the following table have been
arranged into two groups: (1) incidence greater than one percent; and (2)
incidence one percent or less. The incidence for group (1) was determined from
clinical studies conducted in the United States (837 patients treated with
AMILORIDE HCL). The adverse effects listed in group (2) include reports from the same
clinical studies and voluntary reports since marketing. The probability of a
causal relationship exists between AMILORIDE HCL and these adverse reactions, some of
which have been reported only rarely.
Incidence > 1% Incidence = 1%
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Body As A Whole
Headache* Back pain
Weakness Chest pain
Fatigability Neck/shoulder ache
Pain, extremities
Cardiovascular
None Angina pectoris
Orthostatic hypotension
Arrhythmia
Palpitation
Digestive
Nausea/anorexia* Jaundice
Diarrhea* GI bleeding
Vomiting* Abdominal fullness
Abdominal pain GI disturbance
Gas pain Thirst
Appetite changes Heartburn
Constipation Flatulence
Dyspepsia
Metabolic
Elevated serum None
potassium levels
(> 5.5 mEq per liter)**
Skin
None Skin rash
Itching
Dryness of mouth
Pruritus
Alopecia
Musculoskeletal
Muscle cramps Joint pain
Leg ache
Nervous
Dizziness Paresthesia
Encephalopathy Tremors
Vertigo
Psychiatric
None Nervousness
Mental confusion
Insomnia
Decreased libido
Depression
Somnolence
Respiratory
Cough Shortness of breath
Dyspnea
Special Senses
None Visual disturbances
Nasal congestion
Tinnitus
Increased intraocular
pressure
Urogenital
Impotence Polyuria
Dysuria
Urinary frequency
Bladder spasms
Gynecomastia
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* Reactions occurring in 3% to 8% of patients treated with AMILORIDE HCL. (Those
reactions occurring in less than 3% of the patients are unmarked.)
** See WARNINGS.
Causal Relationship Unknown
Other reactions have been reported but occurred under circumstances where a
causal relationship could not be established. However, in these rarely reported
events, that possibility cannot be excluded. Therefore, these observations are
listed to serve as alerting information to physicians.
Activation of probable pre-existing peptic ulcer
Aplastic anemia
Neutropenia
Abnormal liver function
OVERDOSAGE:
No data are available in regard to overdosage in humans.
The oral LD50 of amiloride hydrochloride (calculated as the base) is 56 mg/kg in
mice and 36 to 85 mg/kg in rats, depending on the strain.
It is not known whether the drug is dialyzable.
The most likely signs and symptoms to be expected with overdosage are
dehydration and electrolyte imbalance. These can be treated by established
procedures. Therapy with AMILORIDE HCL should be discontinued and the patient observed
closely. There is no specific antidote. Emesis should be induced or gastric
lavage performed. Treatment is symptomatic and supportive. If hyperkalemia
occurs, active measures should be taken to reduce the serum potassium levels.
DOSAGE AND ADMINISTRATION:
AMILORIDE HCL should be administered with food.
AMILORIDE HCL, one 5 mg tablet daily, should be added to the usual antihypertensive or
diuretic dosage of a kaliuretic diuretic. The dosage may be increased to 10 mg
per day, if necessary. More than two 5 mg tablets of AMILORIDE HCL daily usually are
not needed, and there is little controlled experience with such doses. If
persistent hypokalemia is documented with 10 mg, the dose can be increased to 15
mg, then 20 mg, with careful monitoring of electrolytes.
In treating patients with congestive heart failure after an initial diuresis has
been achieved, potassium loss may also decrease and the need for AMILORIDE HCL should
be reevaluated. Dosage adjustment may be necessary. Maintenance therapy may be
on an intermittent basis.
If it is necessary to use AMILORIDE HCL alone (see INDICATIONS), the starting dosage
should be one 5mg tablet daily. This dosage may be increased to 10 mg per day,
if necessary. More than two 5 mg tablets usually are not needed, and there is
little controlled experience with such doses. If persistent hypokalemia is
documented with 10 mg, the dose can be increased to 15 mg, then 20 mg, with
careful monitoring of electrolytes.
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