Avalide™
Irbesartan--Hydrochlorothiazide
Angiotensin II AT1 Receptor Blocker--Diuretic
Bristol-Myers Squibb
http://www.bms.com/landing/data/index.html
Avalide Monograph PDF download here.
Sanofi-Synthelabo
CPS:PIS_m074100
Pharmacology
Avalide combines the actions of irbesartan, an
angiotensin II AT1 receptor blocker, and that of a thiazide
diuretic, hydrochlorothiazide.
Irbesartan: Irbesartan antagonizes angiotensin
II by blocking AT1 receptors.
Angiotensin II is the
primary vasoactive hormone in the renin-angiotensin system. Its effects include
vasoconstriction and the stimulation of aldosterone secretion by the adrenal
cortex.
Irbesartan blocks the
vasoconstrictor and aldosterone-secreting effects of angiotensin II by
selectively blocking in a noncompetitive manner the binding of angiotensin II
to the AT1 receptor found in many tissues. Irbesartan has no agonist
activity at the AT1 receptor. AT2 receptors have been
found in many tissues, but to date they have not been associated with
cardiovascular homeostasis. Irbesartan has essentially no affinity for the AT2
receptors.
Irbesartan does not inhibit
angiotensin converting enzyme, also known as kininase II, the enzyme that
converts angiotensin I to angiotensin II and degrades bradykinin, nor does it
affect renin or other hormone receptors or ion channels involved in
cardiovascular regulation of blood pressure and sodium homeostasis.
Hydrochlorothiazide: Hydrochlorothiazide is a
thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte
reabsorption, directly increasing excretion of sodium and chloride in
approximately equivalent amounts. Indirectly, the diuretic action of
hydrochlorothiazide reduces plasma volume, with consequent increases in plasma
renin activity, increases in aldosterone secretion, increases in urinary
potassium loss, and decreases in serum potassium. The renin-aldosterone link is
mediated by angiotensin II, so coadministration of an angiotensin II AT1
receptor blocker tends to reverse the potassium loss associated with these
diuretics.
The mechanism of the
antihypertensive effect of thiazides is not fully understood.
Pharmacokinetics
Irbesartan: Irbesartan is an orally active
agent. The oral absorption of irbesartan is rapid and complete with an average
absolute bioavailability of 60 to 80%. Irbesartan exhibits linear
pharmacokinetics over the therapeutic dose range with an average terminal
elimination half-life of 11 to 15 hours. Following oral administration, peak
plasma concentrations are attained at 1.5 to 2 hours after dosing. Steady-state
concentrations are achieved within 3 days.
Irbesartan is approximately
96% protein-bound in the plasma, primarily to albumin and α1-acid
glycoprotein.
The average volume of
distribution of irbesartan is 53 to 93 L. Total plasma and renal clearances are
in the range of 157 to 176 and 3 to 3.5 mL/min, respectively.
Irbesartan is
metabolized via glucuronide conjugation, and oxidation by the cytochrome P450
system. Following either oral or i.v. administration of 14C-labeled
irbesartan, more than 80% of the circulating plasma radioactivity is
attributable to unchanged irbesartan. The primary circulating metabolite is the
inactive irbesartan glucuronide (approximately 6%). The remaining oxidative
metabolites do not add appreciably to the pharmacologic activity.
Irbesartan and its
metabolites are excreted by both biliary and renal routes. Following either
oral or i.v. administration of 14C-labeled irbesartan, about 20% of
radioactivity is recovered in the urine and the remainder in the feces. Less
than 2% of the dose is excreted in urine as unchanged irbesartan.
In vitro studies of
irbesartan indicate that the oxidation of irbesartan is primarily by cytochrome
P450 isoenzyme CYP2C9. Metabolism of irbesartan by CYP3A4 is negligible.
Irbesartan is neither metabolized, nor does it substantially induce or inhibit
the following isoenzymes: CYP1A1, 1A2, 2A6, 2B6, 2D6, 2E1. There was no
induction or inhibition of CYP3A4.
In subjects over the
age of 65 years, irbesartan elimination half-life was not significantly
altered, but AUC and Cmax values were about 20 to 50% greater than
those of young subjects.
The mean AUC and Cmax
were not altered in patients with any degree of renal impairment, including
patients on hemodialysis. However, a wide variance was seen in patients with
severe renal impairment.
The pharmacokinetics of
irbesartan following repeated oral administration were not significantly
affected in patients with mild to moderate cirrhosis of the liver. No data are
available in patients with severe liver disease.
Hydrochlorothiazide: Hydrochlorothiazide is not
metabolized but is eliminated rapidly by the kidney. The plasma half-life has
been observed to vary between 5.6 and 14.8 hours when the plasma levels can be
followed for at least 24 hours. At least 61% of the oral dose is eliminated unchanged
within 24 hours. Hydrochlorothiazide crosses the placental but not the
blood-brain barrier and is excreted in breast milk.
Pharmacodynamics
Irbesartan: In healthy subjects, single oral
doses of irbesartan up to 300 mg produced dose-dependent inhibition of the
pressor effect of angiotensin II infusions. The inhibition was complete (100%)
4 hours following oral doses of 150 mg or 300 mg. Partial inhibition
of 40% and 60% was still present 24 hours post dose with 150 mg and
300 mg irbesartan respectively.
In hypertensive
patients, angiotensin II receptor inhibition following chronic administration
of irbesartan causes a 1.5- to 2-fold rise in angiotensin II plasma
concentration and a 2- to 3-fold increase in plasma renin levels. Aldosterone
plasma concentrations generally decline following irbesartan administration,
however serum potassium levels are not significantly affected at recommended
doses.
During clinical trials,
minimal incremental blood pressure response was observed at doses greater than
300 mg.
The blood pressure
lowering effect of irbesartan is apparent after the first dose and
substantially present within 1 to 2 weeks, with the maximal effect occurring by
4 to 6 weeks. In long-term studies, the effect of irbesartan appeared to be
maintained for more than 1 year. There was essentially no change in average
heart rate in patients treated with irbesartan in controlled trials.
There is no rebound
effect after withdrawal of irbesartan.
Black hypertensive
patients had a smaller blood pressure response to irbesartan monotherapy than
Caucasians.
Hydrochlorothiazide: Onset of the diuretic
action following oral administration occurs in 2 hours and the peak action in
about 4 hours. Diuretic activity lasts about 6 to 12 hours.
Irbesartan/Hydrochlorothiazide: The components
of Avalide have been shown to have an additive effect on blood pressure
reduction, reducing blood pressure to a greater degree than either component
alone.
The blood pressure
lowering effect of irbesartan in combination with hydrochlorothiazide was
apparent after the first dose and substantially present within 1 to 2 weeks,
with the maximal effect occurring by 6 to 8 weeks. In long-term follow-up
studies, the effect of irbesartan/hydrochlorothiazide was maintained for over 1
year.
There was no
significant difference in blood pressure response based on age or gender.
Indications
Treatment of essential hypertension in patients
for whom combination therapy is appropriate.
Avalide is not
indicated for initial therapy (see Dosage).
Irbesartan should
normally be used in those patients in whom treatment with diuretic or α
-blocker was found ineffective or has been associated with unacceptable adverse
effects.
Contraindications
In patients who are hypersensitive to any
component of this product.
Because of the
hydrochlorothiazide component, this product is contraindicated in patients with
anuria, and in patients who are hypersensitive to other sulfonamide-derived
drugs.
Warnings
Pregnancy
Drugs that act directly on the renin-angiotensin
system can cause fetal and neonatal morbidity and death when administered to
pregnant women. When pregnancy is detected, irbesartan should be discontinued
as soon as possible.
The use of drugs that
act directly on the renin-angiotensin system during the second and third
trimesters of pregnancy has been associated with fetal and neonatal injury,
including hypotension, neonatal skull hypoplasia, anuria, reversible or
irreversible renal failure, and death. Oligohydramnios has also been reported,
presumably resulting from decreased fetal renal function; oligohydramnios in
this setting has been associated with fetal limb contractures, craniofacial
deformation, and hypoplastic lung development. Prematurity, intrauterine growth
retardation, and patent ductus arteriosus have also been reported, although it
is not clear whether these occurrences were due to exposure to the drug. These
adverse effects do not appear to have resulted from intrauterine drug exposure
that has been limited to the first trimester.
Mothers whose embryos
and fetuses are exposed to an angiotensin Il receptor antagonist only during
the first trimester should be so informed. Nonetheless, when patients become
pregnant, physicians should have the patient discontinue the use of irbesartan
as soon as possible.
Rarely (probably less
often than once in every 1000 pregnancies), no alternative to an angiotensin II
receptor antagonist will be found. In these rare cases, the mothers should be
apprised of the potential hazards to their fetuses, and serial ultrasound
examinations should be performed to assess the intra-amniotic environment.
If oligohydramnios is
observed, irbesartan should be discontinued unless it is considered life-saving
for the mother. Contraction stress testing (CST), a non-stress test (NST), or
biophysical profiling (BPP) may be appropriate, depending upon the week of
pregnancy. Patients and physicians should be aware, however, that
oligohydramnios may not appear until after the fetus has sustained irreversible
injury.
Infants with histories
of in utero exposure to an angiotensin II receptor antagonist should be closely
observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs,
attention should be directed toward support of blood pressure and renal
perfusion. Exchange transfusion may be required as means of reversing
hypotension and/or substituting for disordered renal function. Irbesartan is
not removed by hemodialysis.
Thiazides cross the
placental barrier and appear in cord blood. The routine use of diuretics in
otherwise healthy pregnant women is not recommended and exposes mother and
fetus to unnecessary hazard, including fetal or neonatal jaundice,
thrombocytopenia, and possibly other adverse reactions that have occurred in
adults. Diuretics do not prevent development of toxemia of pregnancy and there
is no satisfactory evidence that they are useful in the treatment of toxemia.
Hypotension
Occasionally, symptomatic hypotension has
occurred after administration of irbesartan, in some cases after the first
dose. It is more likely to occur in patients who are volume depleted by
diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. In
these patients, because of the potential fall in blood pressure, therapy should
be started under close medical supervision (see Dosage). Similar
considerations apply to patients with ischemic heart or cerebrovascular
disease, in whom an excessive fall in blood pressure could result in myocardial
infarction or cerebrovascular accident.
Hypersensitivity Reaction
Sensitivity reactions to hydrochlorothiazide may
occur in patients with or without a history of allergy or bronchial asthma.
Systemic Lupus Erythematosus
Thiazide diuretics have been reported to cause exacerbation
or activation of systemic lupus erythematosus.
Azotemia
Azotemia may be precipitated or increased by
hydrochlorothiazide. Cumulative effects of the drug may develop in patients
with impaired renal function.
If increasing azotemia
and oliguria occur during treatment of severe progressive renal disease the
diuretic should be discontinued.
Precautions
Renal Impairment
As a consequence of inhibiting the
renin-angiotensin-aldosterone system, changes in renal function have been seen
in susceptible individuals. In patients whose renal function may depend on the
activity of the renin-angiotensin-aldosterone system, such as patients with
bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary
kidney, or severe congestive heart failure, treatment with agents that inhibit
this system has been associated with oliguria, progressive azotemia, and
rarely, acute renal failure and/or death. In susceptible patients, concomitant
diuretic use may further increase risk.
Use of irbesartan
should include appropriate assessment of renal function.
Thiazides should be
used with caution.
Because of the
hydrochlorothiazide component, Avalide is not recommended in patients with
severe renal impairment (creatinine clearance ≤ 30 mL/min).
Hepatic Impairment
Thiazides should be used with caution in
patients with impaired hepatic function or progressive liver disease, since
minor alterations in fluid and electrolyte balance may precipitate hepatic
coma.
Electrolyte and Metabolic Imbalances
Thiazides, including hydrochlorothiazide, can
cause fluid or electrolyte imbalance (hypokalemia, hyponatremia and
hypochloremic alkalosis).
Calcium excretion is
decreased by thiazides which may cause intermittent and slight elevation of
serum calcium. If calcium or a calcium sparing drug (e.g., vitamin D therapy)
is prescribed, serum calcium levels should be monitored and calcium dosage
adjusted accordingly. Marked hypercalcemia suggests the possibility of
hyperparathyroidism. Thiazides should be discontinued before carrying out tests
for parathyroid function.
Thiazides have been
shown to increase the urinary excretion of magnesium, which may result in
hypomagnesemia.
Hyperuricemia may
occur, and an acute attack of gout may be precipitated in certain patients
receiving thiazide therapy.
Insulin requirements in
diabetic patients may be altered and latent diabetes mellitus may become
manifest during thiazide diuretic therapy.
Increases in
cholesterol and triglyceride levels may be associated with thiazide diuretic
therapy.
Thiazides may decrease
serum PB1 levels without signs of thyroid disturbance.
Valvular Stenosis
There is concern on theoretical grounds that
patients with aortic stenosis might be at particular risk of decreased coronary
perfusion when treated with vasodilators because they do not develop as much
afterload reduction.
Lactation
It is not known whether irbesartan is excreted
in human milk, but measurable levels of radioactivity were shown to be present
in milk of lactating rats. Thiazides appear in human milk. A decision should be
made whether to discontinue nursing or discontinue the drug, taking into
account the importance of the drug to the mother.
Children
Safety and effectiveness have not been
established.
Geriatrics
Of the 2650 hypertensive patients receiving
irbesartan/hydrochlorothiazide in clinical studies, 618 patients were 65 years
of age and over. No overall age-related differences were seen in the adverse
effect profile but greater sensitivity in some older individuals cannot be
ruled out.
General
Occupational Hazards: The effect of irbesartan
on ability to drive and use machines has not been studied, but based on its
pharmacodynamic properties, irbesartan is unlikely to affect this ability. When
driving vehicles or operating machines, it should be taken into account that
occasionally dizziness or weariness may occur during treatment of hypertension.
Drug Interactions
Diuretics: Patients on diuretics, and especially
those in whom diuretic therapy was recently instituted, may occasionally
experience an excessive reduction of blood pressure after initiation of therapy
with irbesartan. The possibility of symptomatic hypotension with the use of
irbesartan can be minimized by discontinuing the diuretic prior to initiation
of treatment and/or lowering the initial dose of irbesartan (see Warnings,
Hypotension and Dosage). No drug interaction of clinical significance has been
identified with thiazide diuretics.
Agents Increasing Serum Potassium: Since irbesartan
decreases the production of aldosterone, potassium-sparing diuretics or
potassium supplements should be given only for documented hypokalemia and with
frequent monitoring of serum potassium. Potassium-containing salt substitutes
should also be used with caution. Concomitant thiazide diuretic use may
attenuate any effect that irbesartan may have on serum potassium.
Lithium Salts: As with other drugs that
eliminate sodium, lithium clearance may be reduced in the presence of
irbesartan. Therefore, serum lithium levels should be monitored carefully if
lithium salts are to be administered with irbesartan.
Lithium generally
should not be given with diuretics. Diuretic agents reduce the renal clearance
of lithium and increase risk of lithium toxicity.
Warfarin: When irbesartan was administered as
300 mg once daily under steady-state conditions, no pharmacodynamic effect on
PT was demonstrated in subjects stabilized on warfarin.
Digoxin: When irbesartan was administered as 150
mg once daily under steady-state conditions, no effect was seen on the
pharmacokinetics of digoxin at steady state. Thiazide-induced electrolyte
disturbances may predispose to digitalis-induced arrhythmias.
Simvastatin: When irbesartan was administered in
a small single-dose study with 12 young, healthy males aged 19 to 39, the
single-dose pharmacokinetics of simvastatin were not affected by the
concomitant administration of 300 mg irbesartan. Simvastatin values were
highly variable whether simvastatin was administered alone or in combination
with irbesartan.
Nifedipine: The pharmacokinetics of irbesartan
were not affected by coadministration of nifedipine.
Alcohol, Barbiturates, or Narcotics: Diuretic
potentiation of orthostatic hypotension may occur.
Antidiabetic Drugs (oral agents and insulin): In
the presence of diuretics, dosage adjustment of the antidiabetic drug may be
required.
Other Antihypertensive Drugs: Diuretic additive
effect or potentiation may occur.
Cholestyramine and Colestipol Resins: Absorption
of hydrochlorothiazide is impaired in the presence of anionic exchange resins.
Avalide should be taken at least 1 hour before or 4 hours after these
medications.
Corticosteroids, ACTH: Intensified electrolyte
depletion, particularly hypokalemia, may occur when given concomitantly with
diuretics.
Pressor Amines (e.g., norepinephrine): In the
presence of diuretics, possible decreased response to pressor amines may be
seen but not sufficient to preclude their use.
Skeletal Muscle Relaxants, Nondepolarizing
(e.g., tubocurarine): In the presence of diuretics, possible increased
responsiveness to the muscle relaxant may occur.
NSAIDs: In some patients, the administration of
a nonsteroidal anti-inflammatory agent can reduce the diuretic, natriuretic,
and antihypertensive effects of loop, potassium-sparing and thiazide diuretics.
Therefore, when Avalide and nonsteroidal anti-inflammatory agents are used
concomitantly, the patient should be observed closely to determine if the
desired effect of the diuretic is obtained.
Adverse Effects
Avalide has been evaluated for safety in 2746
patients with essential hypertension including 968 patients for 1 year or more.
In placebo-controlled
clinical trials, therapy was discontinued due to a clinical or laboratory
adverse event in 3.6% of patients treated with irbesartan/hydrochlorothiazide,
vs 6.8% of patients given placebo.
The following
potentially serious adverse reactions have been reported rarely with irbesartan
in controlled clinical trials: syncope, hypotension.
Adverse events regardless
of drug relationship, occurring in ≥ 1% of the
irbesartan/hydrochlorothiazide patients in placebo-controlled clinical trials
are included in Table 1.
CPS:Avalide_t1Click here for Table 1
Table 1: Avalide
Adverse Events Regardless of Relationship,
Occurring in ≥% of
the Avalide Patients
|
|
Irbesartan/HCTZ
n=898
(%)
|
Irbesartan
n=400
(%)
|
HCTZ
n=380
(%)
|
Placebo
n=236
(%)
|
|
|
General
|
|
Chest Pain
|
1.8
|
1.5
|
1.6
|
1.3
|
|
|
Fatigue
|
6.5
|
4.0
|
3.2
|
3.0
|
|
|
Influenza
|
2.8
|
2.0
|
1.8
|
1.3
|
|
|
Cardiovascular
|
|
Edema
|
3.1
|
1.5
|
1.6
|
2.5
|
|
|
Tachycardia
|
1.2
|
0.5
|
0.5
|
0.4
|
|
|
Gastrointestinal
|
|
Abdominal Pain
|
1.7
|
1.5
|
1.6
|
0.8
|
|
|
Dyspepsia/Heartburn
|
2.1
|
0.3
|
1.6
|
0.8
|
|
|
Nausea/Vomiting
|
3.2
|
1.5
|
2.4
|
0.4
|
|
|
Diarrhea
|
2.1
|
2.8
|
1.1
|
3.4
|
|
|
Immunology
|
|
Allergy
|
1.1
|
0.5
|
0.5
|
0
|
|
|
Musculoskeletal
|
|
Musculoskeletal Pain
|
6.5
|
6.0
|
9.7
|
4.7
|
|
|
Muscle Cramp
|
1.0
|
0.8
|
2.1
|
1.3
|
|
|
NervousSystem
|
|
Dizziness
|
7.6
|
5.5
|
4.7
|
4.2
|
|
|
Dizziness Orthostatic
|
1.1
|
1.0
|
0.8
|
0.4
|
|
|
Anxiety/Nervousness
|
1.0
|
1.0
|
0.5
|
1.7
|
|
|
Headache
|
11.0
|
9.3
|
11.6
|
16.1
|
|
|
Renal/Genitourinary
|
|
Abnormality Urination
|
1.9
|
0.5
|
2.1
|
0.8
|
|
|
Urinary Tract Infection
|
1.6
|
1.5
|
2.4
|
2.5
|
|
|
Respiratory
|
|
Sinus Abnormality
|
2.9
|
4.5
|
3.2
|
4.7
|
|
|
Cough
|
2.2
|
2.3
|
2.6
|
3.0
|
|
|
Upper Respiratory Tract Infection
|
5.6
|
8.3
|
7.1
|
5.5
|
|
|
Pharyngitis
|
2.1
|
2.3
|
2.9
|
1.7
|
|
|
Rhinitis
|
1.9
|
2.0
|
1.6
|
2.5
|
|
|
Dermatologic
|
|
Rash
|
1.2
|
1.8
|
3.2
|
1.7
|
|
Irbesartan Alone: In addition, the following
potentially important events occurred in less than 1% of patients receiving
irbesartan, regardless of drug relationship:
Body as a Whole
fever.
Cardiovascular
flushing, hypertension, myocardial infarction,
angina pectoris, arrhythmic/conduction disorder, cardiorespiratory arrest,
heart failure, hypertensive crisis.
Dermatologic
pruritus, dermatitis, ecchymosis, erythema,
urticaria, photosensitivity.
Endocrine
sexual dysfunction, libido change, gout.
Gastrointestinal
constipation, gastroenteritis, flatulence,
distention abdomen, hepatitis.
Musculoskeletal
muscle cramp, arthritis, myalgia, muscle
weakness.
Nervous System
sleep disturbance, numbness, somnolence,
vertigo, depression, paresthesia, tremor, transient ischemic attack,
cerebrovascular accident.
Renal/Genitourinary
abnormal urination.
Respiratory
epistaxis, tracheobronchitis, pulmonary
congestion, dyspnea, wheezing.
Special Senses
visual disturbance, hearing abnormality,
conjunctivitis, taste disturbance.
Postmarketing Experience
angioedema (involving swelling of the face,
lips, and/or tongue) has been reported rarely in postmarketing use. The
following adverse reactions, regardless of drug relationship, were reported
very rarely in postmarketing use: syncope, asthenia, jaundice, myalgia,
elevated liver function tests and impaired renal function including occasional
cases of renal failure in patients at risk (see Precautions, Renal Impairment).
Laboratory Test Findings
Avalide
Liver Function Tests
Occasional elevations of liver enzymes and/or
serum bilirubin have occurred. In patients with essential hypertension treated
with Avalide alone, 1 patient was discontinued due to elevated liver enzymes.
Creatinine, Blood Urea Nitrogen
Minor increases in blood urea nitrogen (BUN) or
serum creatinine were observed in 2.3% of patients. No patient was discontinued
due to increased BUN. One patient was discontinued due to a minor increase in
serum creatinine.
Irbesartan
Liver Function Tests
In placebo-controlled trials, elevations of AST
and ALT ≥ 3× ULN occurred in 0.1% and 0.2%, respectively, of
irbesartan-treated patients compared to 0.3% and 0.3%, respectively, of
patients receiving placebo. The cumulative incidence of AST and/or ALT
elevations ≥ 3× ULN was 0.4% in patients treated with irbesartan for a
mean duration of over 1 year.
Hyperkalemia
In placebo-controlled trials, greater than a 10%
increase in serum potassium was observed in 0.4% of irbesartan-treated patients
compared to 0.5% of patients receiving placebo.
Creatinine, Blood Urea Nitrogen
Minor increases in blood urea nitrogen (BUN) or
serum creatinine were observed in less than 0.7% of patients with essential
hypertension treated with irbesartan alone vs 0.9% on placebo.
Hemoglobin
Mean decreases in hemoglobin of 0.16 g/dL were
observed in patients receiving irbesartan. No patients were discontinued due to
anemia.
Neutropenia
Neutropenia (<1000 cells/mm3) was
observed in 0.3% of irbesartan-treated patients compared to 0.5% of patients
receiving placebo.
In clinical trials, the
following were noted to occur with an incidence of <1%, regardless of drug
relationship: anemia, thrombocytopenia, lymphocytopenia, and increased CPK.
Overdose
For management of a
suspected drug overdose, CPhA recommends that you contact your regional
Poison Control Centre. See the CPS Directory section for a list of
Poison Control Centres.
Symptoms
No specific information is available on the
treatment of overdosage with Avalide. The patient should be closely monitored,
and the treatment should be symptomatic and supportive, including fluid and
electrolyte replacement.
Irbesartan: No data are available in regard to
overdosage in humans. The most likely manifestations of overdosage would be
hypotension and/or tachycardia; bradycardia might also occur in this setting.
Irbesartan is not removed by hemodialysis.
Hydrochlorothiazide: The most common signs and
symptoms observed are those caused by electrolyte depletion (hypokalemia,
hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis.
If digitalis has also been administered, hypokalemia may accentuate cardiac
arrhythmias.
The degree to which
hydrochlorothiazide is removed by hemodialysis has not been established.
Treatment
See Symptoms.
Dosage
Must be individualized. The fixed combination is
not for initial therapy. The dose should be determined by the titration of the
individual components.
Once the patient has
been stabilized on the individual components as described below, either one
tablet of Avalide 150/12.5 mg or 300/12.5 mg once daily may be substituted if
the doses on which the patient was stabilized are the same as those in the
fixed combination.
Avalide may be
administered with or without food; however, it should be taken consistently
with respect to food intake.
