Imdur®
Isosorbide-5-mononitrate
Antianginal
AstraZeneca
http://www.astrazeneca-us.com/default.asp
Imdur Monograph PDF download here.
CPS:PIS_m260000
Pharmacology
As with other organic nitrates, the principal
pharmacological action of isosorbide-5-mononitrate, the major active metabolite
of isosorbide dinitrate (ISDN), is relaxation of vascular smooth muscle and
consequent dilation of peripheral arteries and veins, especially the latter.
Dilation of the veins promotes peripheral pooling of blood and decreases venous
return to the heart, thereby reducing left ventricular end-diastolic pressure
and pulmonary capillary wedge pressure (pre-load). Arteriolar relaxation
reduces systemic vascular resistance, systolic arterial pressure, and mean
arterial pressure (after-load). Dilation of the coronary arteries also occurs.
The hemodynamic responses to isosorbide-5-mononitrate are similar to those
produced by other nitrates.
Pharmacodynamics: Dosage regimens for most
chronically used drugs are designed to provide plasma concentrations that are
continuously greater than a minimally effective concentration. This strategy is
inappropriate for organic nitrates. Prolonged administration of nitrate drugs
according to traditionally recommended dosage regimens has been shown to
produce tolerance. Tolerance results in a loss of efficacy. Several
well-controlled clinical trials have used exercise testing to assess the
antianginal efficacy of continuously delivered nitrates. In the large majority
of these trials, nitrate effectiveness was indistinguishable from placebo after
24 hours (or less) of continuous therapy. Attempts to overcome tolerance
by dose escalation, even to doses far in excess of those used acutely, have
consistently failed. Only after nitrates have been absent from the body for
several hours has their antianginal efficacy been restored. Drug-free intervals
of 10 to 12 hours are known to be sufficient to restore response. The
drug-free interval sufficient to avoid tolerance to isosorbide-5-mononitrate
has not been completely defined. Imdur tablets during long-term use over
42 days dosed at 120 mg once daily continued to improve exercise
performance at 4 hours and 12 hours after dosing but its effects (although
better than placebo) are less than or at best equal to the effects of the first
dose of 60 mg. Considering the pharmacokinetic profile of
isosorbide-5-mononitrate and its long half-life (see Pharmacokinetics),
clinical efficacy is consistent with that observed for other organic nitrates.
Pharmacokinetics
After oral administration of
isosorbide-5-mononitrate as a solution or immediate-release tablets, maximum
plasma concentrations of isosorbide-5-mononitrate are achieved in 30 to
60 minutes with an absolute bioavailability of approximately 100%. After
i.v. administration, isosorbide-5-mononitrate is distributed into total body
water in about 9 minutes with a volume of distribution of approximately
0.6 to 0.7 L/kg. Isosorbide-5-mononitrate is approximately 5% bound
to human plasma proteins and is distributed into blood cells and saliva.
Isosorbide-5-mononitrate is primarily metabolized by the liver, but unlike oral
isosorbide dinitrate, it is not subject to first-pass metabolism.
Isosorbide-5-mononitrate is cleared by denitration to isosorbide and
glucuronidation as the mononitrate, with 96% of the administered dose excreted
in the urine within 5 days and only about 1% eliminated in the feces. At
least 6 different compounds have been detected in urine, with about 2% of
the dose excreted as the unchanged drug and at least 5 metabolites. The
metabolites are not pharmacologically active. Renal clearance accounts for only
about 4% of total body clearance. The mean plasma elimination half-life of
isosorbide-5-mononitrate is approximately 5 hours.
The disposition of
isosorbide-5-mononitrate in patients with various degrees of renal
insufficiency, liver cirrhosis or cardiac dysfunction was evaluated and found
to be similar to that observed in healthy subjects.
The elimination
half-life of isosorbide-5-mononitrate was not prolonged, and there was no drug
accumulation in patients with chronic renal failure after multiple oral dosing.
Impaired liver or
kidney function has no major influence on the pharmacokinetic properties.
Food intake may
decrease the rate (increase in Tmax) but not the extent (AUC) of
absorption of isosorbide-5-mononitrate.
With the extended
release formulation of Imdur, isosorbide-5-mononitrate is gradually released,
independent of pH, over a 10 hour period, according to a first order process.
This prolongation of the absorption phase results in reduced and delayed peak
plasma levels compared to conventional tablets of isosorbide-5-mononitrate.
After administration of 60 mg of isosorbide-5-mononitrate extended release
tablets, peak plasma levels of around 3000 nmol/L are usually obtained
within approximately 4 hours. The plasma concentrations then gradually
fall to around 500 nmol/L at the end of the dosage interval (24 hours
after dose intake).
Indications
For the prevention of anginal attacks in
patients with chronic stable angina pectoris associated with coronary artery
disease.
Not intended for the
immediate relief of acute attacks of angina pectoris.
Contraindications
Known hypersensitivity to
isosorbide-5-mononitrate or to other nitrates or nitrites. Acute circulatory
failure associated with marked hypotension (shock and states of collapse).
Postural hypotension. Myocardial insufficiency due to obstruction (e.g., in the
presence of aortic or mitral stenosis or of constrictive pericarditis).
Increased intracranial pressure. Severe anemia. Concomitant use of nitrates,
either regularly and/or intermittently, with sildenafil citrate is absolutely
contraindicated.
Warnings
The benefits and safety of
isosorbide-5-mononitrate in anginal patients with acute myocardial infarction
or congestive heart failure have not been established. Because the effects of
isosorbide-5-mononitrate are difficult to terminate rapidly, this drug is not
recommended in these settings.
Abrupt withdrawal may
occasionally aggravate anginal symptoms. To avoid possible withdrawal effects,
the administration of isosorbide-5-mononitrate should be gradually reduced and
not abruptly discontinued.
Caution should be observed
in patients with severe cerebral arteriosclerosis or severe hypotension.
Precautions
Headaches or symptoms of severe hypotension,
such as weakness or dizziness, particularly when arising suddenly from a
recumbent position, may occur.
Caution should be
exercised when using nitrates in patients prone to, or who might be affected
by, hypotension. Isosorbide-5-mononitrate should therefore be used with caution
in patients who may have volume depletion from diuretic therapy or in patients
who have low systolic blood pressure (e.g., below 90 mmHg). Paradoxical
bradycardia and increased angina pectoris may accompany nitrate-induced
hypotension.
Nitrate therapy may
aggravate the angina caused by hypertrophic cardiomyopathy.
In industrial workers
who have had long-term exposure to unknown (presumably high) doses of organic
nitrates, tolerance clearly occurs. There is, moreover, physical dependence
since chest pain, acute myocardial infarction, and even sudden death have
occurred during temporary withdrawal of nitrates from these workers. In
clinical trials of angina patients, there are reports of anginal attacks being
more easily provoked and of rebound in the hemodynamic effects soon after
nitrate withdrawal. The importance of these observations to the routine,
clinical use of oral isosorbide-5-mononitrate has not been fully elucidated.
Caution should be
exercised in patients with arterial hypoxemia due to anemia (see
Contraindications). Similarly, caution is called for in patients with hypoxemia
and a ventilation/perfusion imbalance due to lung disease or ischemic heart
failure. Patients with angina pectoris, myocardial infarction, or cerebral
ischemia frequently suffer from abnormalities of the small airways (especially
alveolar hypoxia). Under these circumstances vasoconstriction occurs within the
lung to shift perfusion from areas of alveolar hypoxia to better ventilated
regions of the lung. As a potent vasodilator, isosorbide-5-mononitrate could
reverse this protective vasoconstriction and thus result in increased perfusion
to poorly ventilated areas, worsening of the ventilation/perfusion imbalance,
and a further decrease in the arterial partial pressure of oxygen.
Tolerance to
isosorbide-5-mononitrate with cross tolerance to other nitrates or nitrites may
occur (see Pharmacology). As tolerance to isosorbide-5-mononitrate develops,
the effect of sublingual nitroglycerin on exercise tolerance, although still
observable, is somewhat blunted.
Occupational Hazards
As patients may experience faintness and/or
dizziness, reaction time when driving or operating machinery may be impaired,
especially at the start of treatment.
Pregnancy
Teratogenic Effects: In studies designed to
detect effects of isosorbide-5-mononitrate on embryo-fetal development, doses
of up to 240 to 248 mg/kg/day, administered to pregnant rats and
rabbits, were unassociated with evidence of such effects. No adverse effects on
reproduction or fetal development were reported. These animal doses are about
100 times the maximum recommended human dose when comparison is based on
body weight; when comparison is based on body surface area, the rat dose is
about 17 times the human dose and the rabbit dose is about 38 times
the human dose. There are no studies in pregnant women. Because animal
reproduction studies are not always predictive of human response,
isosorbide-5-mononitrate should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
Nonteratogenic Effects: Neonatal survival and development
and incidence of stillbirths were adversely affected when pregnant rats were
administered oral doses of 750 (but not 300) mg
isosorbide-5-mononitrate/kg/day during late gestation and lactation. This dose
(about 312 times the human dose when comparison is based on body weight
and 54 times the human dose when comparison is based on body surface area)
was associated with decreases in maternal weight gain and motor activity and
evidence of impaired lactation.
Lactation
It is not known whether isosorbide-5-mononitrate
is excreted in human milk. Because many drugs are excreted in human milk,
caution should be exercised when isosorbide-5-mononitrate is administered to a
nursing mother.
Children
The safety and efficacy of
isosorbide-5-mononitrate in children have not been established. Therefore, its
use is not recommended.
Drug Interactions
Concomitant treatment with other vasodilators,
calcium antagonists, ACE inhibitors, beta-blockers, diuretics,
antihypertensives, tricyclic antidepressants, and major tranquilizers may
potentiate the blood pressure lowering effect of isosorbide-5-mononitrate.
Marked symptomatic
orthostatic hypotension has been reported when calcium channel blockers and
organic nitrates were used in combination. Dose adjustments of either class of
agents may be necessary.
Concomitant use of
isosorbide-5-mononitrate and sildenafil citrate can potentiate the hypotensive
effect of isosorbide-5-mononitrate. This could result in life-threatening
hypotension with syncope or myocardial infarction and death. Therefore,
sildenafil citrate should not be given to patients receiving
isosorbide-5-mononitrate therapy.
Alcohol may enhance
sensitivity to the hypotensive effects of nitrates.
Adverse Effects
In 17 clinical trials, both controlled and
uncontrolled, 861 patients were treated with isosorbide-5-mononitrate 30
to 240 mg once daily, alone or in combination with β -adrenergic
blocking agents. Adverse events were reported in 71% of the patients.
Discontinuation of therapy due to adverse reactions was required in 8% of the
patients. Most of these were discontinued because of headaches. Dizziness,
myocardial infarction, nausea, and vertigo were also associated with withdrawal
from these studies. The most common adverse events were headache, dizziness,
fatigue, nausea and flushing.
The following adverse
events were reported by >1 to 3% of patients: myocardial
infarction, postural hypotension, tachycardia, angina pectoris, somnolence,
coughing, paresthesia, vertigo, abdominal pain, diarrhea, flatulence, extra
systoles, palpitation, aggravated angina, insomnia, dyspnea, respiratory
infection, increased sweating, vasospasm, abnormal vision, back pain,
musculoskeletal pain, dyspepsia, chest pain, rhinitis, constipation.
The following adverse
events were reported in ≤ 1% of the patients:
Cardiovascular
bundle branch block, cardiac failure,
circulatory failure, hypotension, hypertension, syncope, arrhythmia, AV block,
bradycardia, atrial fibrillation, heart murmur, abnormal heart sound, Q-wave
abnormality, T-wave changes, ECG abnormal.
Dermatological
rash, pruritus, eczema, acne, rash erythematous,
rash psoriaform, abnormal hair texture, skin disorder.
Gastrointestinal
duodenal ulcer, eructation, hemorrhagic gastric
ulcer, gastritis, hemorrhoids, intestinal obstruction, melena, dry mouth,
pharynx disorder, tooth disorder, vomiting, loose stools, glossitis.
Genitourinary
atrophic vaginitis, prostatic disorder, renal
calculus, urinary bladder diverticulum, urinary tract infection, polyuria.
Miscellaneous
allergic reaction, asthenia, female breast pain,
edema, feeling of warmth, fever, flu-like symptoms, malaise, rigors, earache,
biliary pain, cholecystitis, hepatomegaly, diabetes mellitus, gout, weight
decrease, weight increase, peripheral edema, tinnitus, epistaxis, purpura,
infection, bacterial infection, cerebrovascular disorder, intermittent
claudication, leg ulcer, peripheral ischemia, varicose vein, amaurosis fugax,
conjunctivitis, diplopia, photophobia, moniliasis, skin nodule, tympanic
membrane perforation, allergy, pain.
Musculoskeletal
arthralgia, arthritis, arthropathy, arthrosis,
frozen shoulder, muscle weakness, myalgia, myositis, torticollis, tendon
disorder.
Neurological
hypoesthesia, migraine, neuritis, tremor,
agitation, amnesia, impaired concentration, depression, decreased libido,
nervousness, paroniria, confusion, anxiety, paresis, ptosis, impotence.
Respiratory
bronchitis, bronchospasm, pharyngitis,
pneumonia, rales, respiratory disorder, pulmonary infiltration, increased
sputum, sinusitis, nasal congestion.
Laboratory Changes
albuminuria, hematuria, gamma GT increased, AST
increased, ALT increased, hypercholesterolemia, hyperlipemia,
hyperuricemia, hypocalcemia, hypokalemia, increased non-protein nitrogen,
thrombocytopenia, anemia, leukopenia, leukocytosis, glycosuria.
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
Hemodynamic Effects: Symptoms of
isosorbide-5-mononitrate overdose are generally the results of vasodilation,
venous pooling, reduced cardiac output and hypotension. These hemodynamic
changes may have protean manifestations, including increased intracranial
pressure, with any or all of persistent throbbing headache, confusion, and
moderate fever; vertigo; palpitations; visual disturbances; nausea and vomiting
(possibly with colic and even bloody diarrhea); syncope (especially in the
upright posture); air hunger and dyspnea, later followed by reduced ventilatory
effort; diaphoresis, with the skin either flushed or cold and clammy; heart
block and bradycardia; paralysis; coma; seizures and death.
No specific antagonist
to the vasodilator effects of isosorbide-5-mononitrate is known, and no
intervention has been subject to controlled study as a therapy of
isosorbide-5-mononitrate overdose. Because the hypotension associated with
isosorbide-5-mononitrate overdose is the result of venodilation and arterial
hypovolemia, prudent therapy in this situation should be directed toward an
increase in central fluid volume. Passive elevation of the patient's legs may
be sufficient, but i.v. infusion of normal saline or similar fluid may also be
necessary.
In patients with renal
disease or congestive heart failure, therapy resulting in central volume
expansion is not without hazard. Treatment of isosorbide-5-mononitrate overdose
in these patients may be subtle and difficult, and invasive monitoring may be
required.
The use of epinephrine
or other vasoconstrictors is ineffective in reversing the severe hypotensive
effects of overdose and is therefore contraindicated in this situation.
Dialysis is known to be
ineffective in removing isosorbide-5-mononitrate from the body.
Methemoglobinemia: Methemoglobinemia has been
reported in patients receiving other organic nitrates, and it may occur as a
side effect of isosorbide-5-mononitrate. Nitrate ions liberated during
metabolism of isosorbide-5-mononitrate can oxidize hemoglobin into methemoglobin.
In patients totally without cytochrome b5 reductase activity, about
2 mg/kg of isosorbide-5-mononitrate would be required before any of these
patients manifests clinically significant (≥ 10%)
methemoglobinemia. In patients with normal reductase function, significant
production of methemoglobin would require even larger doses of
isosorbide-5-mononitrate.
Methemoglobin levels
are available from most clinical laboratories. The diagnosis should be
suspected in patients who exhibit signs of impaired oxygen delivery despite
adequate cardiac output and adequate arterial pO2. Classically,
methemoglobinemic blood is described as chocolate brown without color change on
exposure to air. When methemoglobinemia is diagnosed, administration of
methylene blue, 1 to 2 mg/kg i.v. may be required.
Treatment
See Symptoms.
Dosage
Isosorbide-5-mononitrate, administered once
daily, provides efficacy for up to 12 hours. This formulation is designed
to avoid or attenuate the development of tolerance.
The recommended
starting dose, for those patients who are active during the day, is 60 mg
(1 tablet) once daily to be taken in the morning on arising. The dose may
be increased to 120 mg (2 tablets) once daily. Rarely 240 mg may
be required. To minimize the possibility of headache the dose can be titrated
by initiating treatment with 30 mg (½ a tablet) for the first 2 to
4 days.
Dosage adjustments are
not necessary for elderly patients or patients with altered renal or hepatic
function.
The tablet may be taken
whole or as divided halves.
The tablets should not
be chewed or crushed, and should be swallowed together with half a glass of
water. Whole tablets may sometimes seem to appear in the stool; these will only
be the matrices which have remained intact after the active substance has been
leached out.
Note: Isosorbide-5-mononitrate is not indicated
for the relief of acute anginal attacks; in these situations sublingual or
buccal nitroglycerin should be used.
Supplied
Each oval, yellow, biconvex, film-coated,
extended release tablet, scored on both sides and engraved 
on one side, contains:
isosorbide-5-mononitrate 60 mg. Nonmedicinal ingredients: tablet core:
colloidal silicon dioxide, hydroxypropylcellulose, magnesium stearate, paraffin
and sodium aluminum silicate; coating: hydroxypropylmethylcellulose, iron oxide
yellow, paraffin, polyethylene glycol and titanium dioxide. Blister packs of
30. Bottles of 100. Store between 15 and 30°C.
