ISOSORBIDE DINITRATE- is os orbide dinitrate tablet

Wes t-ward Pharmaceutical Corp

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ISOSORBIDE DINITRATE SUBLINGUAL TABLETS, USP

Rev 11/07
Rx Only

DESCRIPTION
Isosorbide dinitrate (ISDN) is 1,4:3,6-dianhydro-D-glucitol 2,5-dinitrate, an organic nitrate whose
structural formula is:

and whose molecular weight is 236.14. The organic nitrates are vasodilators, active on both arteries
and veins.
ISDN is a white, crystalline, odorless compound which is stable in air and in solution, has a melting
point of 70°C and has an optical rotation of +134° (c=1.0, alcohol. 20°C). ISDN is freely soluble in
organic solvents such as acetone, alcohol, and ether, but is only sparingly soluble in water.
Each isosorbide dinitrate sublingual tablet contains 2.5 mg or 5 mg of ISDN.
Inactive ingredients are as follows:
2.5 mg Sublingual: Ammonium phosphate dibasic, anhydrous lactose, colloidal silicon dioxide, corn
starch, D&C Yellow No. 10 Lake, FD&C Yellow No. 6 Lake, magnesium stearate, microcrystalline
cellulose, sodium starch glycolate.
5 mg Sublingual: Ammonium phosphate dibasic, anhydrous lactose, colloidal silicon dioxide, corn
starch, magnesium stearate, microcrystalline cellulose.

CLINICAL PHARMACOLOGY
The principal pharmacological action of ISDN is relaxation of vascular smooth muscle and consequent
dilatation of peripheral arteries and veins, especially the latter. Dilatation 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 (preload). Arteriolar relaxation reduces
systemic vascular lesistance, systolic arterial pressure, and mean arterial pressure (afterload). Dilatation
of the coronary arteries also occurs. The relative importance of preload reduction, afterload reduction,
and coronary dilatation remains undefined.
Dosing 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. Several well-controlled clinical trials have used exercise testing to assess the anti-
anginal efficacy of continuously-delivered nitrates. In the large majority of these trials, active agents
were no more effective than placebo after 24 hours (or less) of continuous therapy. Attempts to
overcome nitrate 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 anti-
anginal efficacy been restored.

Pharmacokinetics
Bioavailability of ISDN after single sublingual doses is 40 to 50%. Multiple-dose studies of
sublingual ISDN pharmacokinetics have not been reported; multiple-dose studies of ingested ISDN
have observed progressive increases in bioavailability during chronic therapy. Serum levels of ISDN
reach their maxima 10 to 15 minutes after sublingual dosing.
Once absorbed, the distribution volume of ISDN is 2 to 4 L/kg, and this volume is cleared at the rate of
2 to 4 L/min, so ISDN's half-life in serum is about an hour. Since the clearance exceeds hepatic blood
flow, considerable extrahepatic metabolism must also occur. Clearance is affected primarily by
denitration to the 2-mononitrate (15 to 25%) and the 5-mononitrate (75 to 85%).
Both metabolites have biological activity, especially the 5-mononitrate. With an overall half-life of
about 5 hours, the 5-mononitrate is cleared from the serum by denitration to isosorbide; glucuronidation
to the 5-mononitrate glucuronide; and denitration/hydration to sorbitol. The 2-mononitrate has been less
well studied, but it appears to participate in the same metabolic pathways, with a half-life of about 2
hours.
The daily dose-free interval sufficient to avoid tolerance to organic nitrates has not been well defined.
Studies of nitroglycerin (an organic nitrate with a very short half-life) have shown that daily dose-free
intervals of 10 to 12 hours are usually sufficient to minimize tolerance. Daily dose-free intervals that
have succeeded in avoiding tolerance during trials of moderate doses (e.g., 30 mg) of immediate-
release ISDN have generally been somewhat longer (at least 14 hours), but this is consistent with the
longer half-lives of ISDN and its active metabolites.
Few well-controlled clinical trials of organic nitrates have been designed to detect rebound or
withdrawal effects. In one such trial, however, subjects receiving nitroglycerin had less exercise
tolerance at the end of the daily dose-fiee interval than the parallel group receiving placebo. The
incidence, magnitude, and clinical significance of similar phenomena in patients receiving ISDN have
not been studied.

Clinical trials
In a controlled trial in which 0.4 mg of sublingual nitroglycerin took 1.9 minutes to begin to produce an
anti-anginal effect, 5 mg of sublingual ISDN took 3.4 minutes to begin to produce a similar effect. In the
same trial, the anti-anginal effect of the sublingual nitroglycerin was evident for about an hour, while
that of the sublingual ISDN lasted about 2 hours.
In other controlled trials, the anti-anginal efficacy of sublingual ISDN has persisted for periods ranging
from 30 minutes up to 4 hours.
Multiple-dose trials of sublingual ISDN have not been reported. Multiple-dose trials of ingested
formulations of ISDN have shown that ISDN's anti-anginal efficacy is substantially attenuated by
tolerance unless the daily regimen includes a dose-free interval of at least 14 hours. The daily dose-
free interval necessary in any chronic regimen using sublingual ISDN is not known.
From large, well-controlled studies of other nitrates, it is reasonable to believe that the maximal
achievable daily duration of anti-anginal effect from ISDN is about 12 hours. No dosing regimen for
ISDN has, however, ever actually been shown to achieve this duration of effect. In the absence of data
from multiple-dose trials, and considering the capacity of organic nitrates to induce tolerance, it is not
reasonable to assume that multiple sublingual ISDN tablets taken during the course of a day will all have
similar effects.

INDICATIONS AND USAGE

Isosorbide dinitrate sublingual tablets are indicated for the prevention and treatment of angina pectoris
due to coronary artery disease. However, because the onset of action of sublingual ISDN is
significantly slower than that of sublingual nitroglycerin, sublingual ISDN is not the drug of first
choice for abortion of an acute anginal episode.

CONTRAINDICATIONS
Allergic reactions to organic nitrates are extremely rare, but they do occur. The isosorbide dinitrate
sublingual tablet is contraindicated in patients who are allergic to ISDN or any of its other ingredients.

WARNINGS
Amplification of the vas odilatory effects of is os orbide dinitrate by s ildenafil can res ult in s evere
hypotens ion. The time cours e and dos e dependence of this interaction have not been s tudied.
Appropriate s upportive care has not been s tudied, but it s eems reas onable to treat this as a
nitrate overdos e, with elevation of the extremities and with central volume expans ion.
The benefits of sublingual ISDN in patients with acute myocardial infarction or congestive heart failure
have not been established. If one elects to use ISDN in these conditions, careful clinical or
hemodynamic monitoring must be used to avoid the hazards of hypotension and tachycardia.

PRECAUTIONS

General
Severe hypotension, particularly with upright posture, may occur with even small doses of ISDN. This
drug should therefore be used with caution in patients who may be volume depleted or who, for
whatever reason, are already hypotensive. Hypotension induced by ISDN may be accompanied by
paradoxical bradycardia and increased angina pectoris.
Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy.
As tolerance to ISDN develops, the effect of sublingual nitroglycerin on exercise tolerance, although
still observable, is somewhat blunted.
Some clinical trials in angina patients have provided nitroglycerin for about 12 continuous hours of
every 24-hour day. During the daily dose-free interval in some of these trials, anginal attacks have been
more easily provoked than before treatment, and patients have demonstrated hemodynamic rebound and
decreased exercise tolerance. The importance of these observations to the routine, clinical use of
sublingual ISDN is not known.
In industrial workers who have had long-term exposure to unknown (presumably high) doses of organic
nitrates, tolerance clearly occurs. Chest pain, acute myocardial infarction, and even sudden death have
occurred during temporary withdrawal of nitrates from these workers, demonstrating the existence of
true physical dependence.

Information for Patients

Patients should be told that the anti-anginal efficacy of ISDN is strongly related to its dosing regimen,
so the prescribed schedule of dosing should be followed carefully. In particular, daily headaches
sometimes accompany treatment with ISDN. In patients who get these headaches, the headaches are a
marker of the activity of the drug. Patients should resist the temptation to avoid headaches by altering
the schedule of their treatment with ISDN, since loss of headache may be associated with simultaneous
loss of anti-anginal efficacy. Aspirin and/or acetaminophen, on the other hand, often successfully
relieve ISDN-induced headaches with no deleterious effect on ISDN'S anti-anginal efficacy.
Treatment with ISDN may be associated with lightheadedness on standing, especially just after rising
from a recumbent or seated position. This effect may be more frequent in patients who have also
consumed alcohol.

Drug Interactions
The vasodilating effects of ISDN may be additive with those of other vasodilators. Alcohol, in
particular, has been found to exhibit additive effects of this variety.

Carcinogenes is . Mutagenes is . Impairment of Fertility

No long-term studies in animals have been performed to evaluate the carcinogenic potential of ISDN. In
a modified two-litter reproduction study, there was no remarkable gross pathology and no altered
fertility or gestation among rats fed ISDN at 25 or 100 mg/kg/day.

Pregnancy Category C
At oral doses 35 and 150 times the maximum recommended human daily dose. ISDN has been shown to
cause a dose-related increase in embryotoxicity (increase in mummified pups) in rabbits. There are no
adequate, well-controlled studies in pregnant women. ISDN should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.

Nurs ing Mothers

It is not known whether ISDN is excreted in human milk. Because many drugs are excreted in human
milk, caution should be exercised when ISDN is administered to a nursing woman.

Pediatric Us e
Safety and effectiveness in pediatric patients have not been established.

Geriatric Us e
Clinical studies of sublingual ISDN 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.

ADVERSE REACTIONS
Adverse reactions to ISDN are generally dose-related, and almost all of these reactions are the result
of ISDN's activity as a vasodilator. Headache, which may be severe, is the most commonly reported
side effect. Headache may be recurrent with each daily dose, especially at higher doses. Transient
episodes of lightheadedness, occasionally related to blood pressure changes, may also occur.
Hypotension occurs infrequently, but in some patients it may be severe enough to warrant
discontinuation of therapy. Syncope, crescendo angina, and rebound hypertension have been reported
but are uncommon.
Extremely rarely, ordinary doses of organic nitrates have caused methemoglobinemia in normal-
seeming patients. Methemoglobinemia is so infrequent at these doses that further discussion of its
diagnosis and treatment is deferred (see OVERDOSAGE).
Data are not available to allow estimation of the frequency of adverse reactions during treatment of
isosorbide dinitrate sublingual tablets.

OVERDOSAGE

Hemodynamic Effects
The ill effects of ISDN overdose are generally the results of ISDN's capacity to induce vasodilatation,
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.
Laboratory determinations of serum levels of ISDN and it metabolites are not widely available, and such
determinations have, in any event, no established role in the management of ISDN overdose.
There are no data suggesting what dose of ISDN is likely to be life-threatening in humans. In rats, the
median acute lethal dose (LD 50 ) was found to be 1100 mg/kg.
No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the
urine) that might accelerate elimination of ISDN and its active metabolites. Similarly, it is not known
which, if any, of these substances can usefully be removed from the body by hemodialysis.
No specific antagonist to the vasodilator effects of ISDN is known, and no intervention has been subject
to controlled studies as a therapy for ISDN overdose. Because the hypotension associated with ISDN
overdose is the result of venodilatation and arterial hypovolemia, prudent therapy in this situation
should be directed toward increase in central fluid volume. Passive elevation of the patient's legs may
be sufficient, but intravenous infusion of normal saline or similar fluid may also be necessary.
The use of epinephrine or other arterial vasoconstrictors in this setting is likely to do more harm than
good.
In patients with renal disease or congestive heart failure, therapy resulting in central volume expansion
is not without hazard. Treatment of ISDN overdose in these patients may be subtle and difficult, and
invasive monitoring may be required.

Methemoglobinemia
Nitrate ions liberated during metabolism of ISDN can oxidize hemoglobin into methemoglobin. Even in
patients totally without cytochrome b5 reductase activity, however and even assuming that the nitrate
moieties of ISDN are quantitatively applied to oxidation of hemoglobin, about 1 mg/kg of ISDN should
be required before any of these patients manifests clinically significant (≥10%) methemoglobinemia. In
patients with normal reductase function, significant production of methemoglobin should require even
larger doses of ISDN. In one study in which 36 patients received 2 to 4 weeks of continuous
nitroglycerin therapy at 3.1 to 4.4 mg/hr (equivalent, in total administered dose of nitrate ions, to 4.8 to
6.9 mg of bioavailable ISDN per hour), the average methemoglobin level measured was 0.2%; this was
comparable to that observed in parallel patients who received placebo.
Notwithstanding these observations, there are case reports of significant methemoglobinemia in
association with moderate overdoses of organic nitrates. None of the affected patients had been thought
to be unusually susceptible.
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 pO 2 . Classically, methemoglobinemic blood is described as chocolate brown, without color
change on exposure to air.
When methemoglobinemia is diagnosed, the treatment of choice is methylene blue, 1 to 2 mg/kg
intravenously.

DOSAGE AND ADMINISTRATION

As noted under CLINICAL PHARMACOLOGY, multiple studies with ISDN and other nitrates have
shown that maintenance of continuous 24-hour plasma levels results in refractory tolerance. Every
dosing regimen for ISDN must provide a daily dose-free interval to minimize the development of this
tolerance. In the case of sublingual tablets, it is probably true that one of the daily dose-free intervals
must be somewhat longer than 14 hours.
As also noted under CLINICAL PHARMACOLOGY, the efficacy of daily doses after the first has
never been demonstrated.
Large controlled studies with other nitrates suggest that no dosing regimen with Isosorbide Dinitrate
Sublingual Tablets should be expected to provide more than about 12 hours of continuous anti-anginal
efficacy per day.
A patient anticipating activity likely to cause angina should take one isosorbide dinitrate sublingual
tablet (2.5 to 5 mg) about 15 minutes before the activity is expected to begin. Isosorbide dinitrate
sublingual tablets may be used to abort an acute anginal episode, but its use is recommended only in
patients who fail to respond to sublingual nitroglycerin.

HOW SUPPLIED
Isosorbide Dinitrate Sublingual Tablets USP 2.5 mg: Yellow, round, compressed tablet imprinted "W1".
Bottles of 100 tablets.
Bottles of 1000 tablets.
Unit Dose Boxes of 100 tablets.

Isosorbide Dinitrate Sublingual Tablets USP 5 mg: White, round, compressed tablet engraved
with "W3".
Bottles of 100 tablets.
Bottles of 1000 tablets.
Unit Dose Boxes of 100 tablets.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
Store at 20-25°C (68-77°F) [See USP Controlled Room Temperature]. Protect from light and moisture.
Also available: Isosorbide Dinitrate Oral Tablets in the following dosage strengths:
5 mg; in bottles of 100, 500, 1000 or unit dose boxes of 100 tablets.
10 mg; in bottles of 100, 500, 1000 or unit dose boxes of 100 tablets.
20 mg; in bottles of 100, 1000 or unit dose boxes of 100 tablets.
Manufactured by:
Wes t-ward Pharmaceutical Corp.
Eatontown, NJ 07724
Revised November 2007

PRINCIPAL DISPLAY PANEL

Isosorbide Dinitrate Sublingual Tablets, USP
NDC 0143-1765-01
2.5 mg/100 Tablets

PRINCIPAL DISPLAY PANEL

Isosorbide Dinitrate Subligual Tablets, USP
NDC 0143-1767-01
5 mg/100 Tablets

ISOSORBIDE DINITRATE
isosorbide dinitrate tablet

Product Information
Prod uct T yp e HUMAN PRESCRIPTIO N DRUG Ite m Cod e (S ource ) NDC:0 143-176 5

Route of Ad minis tration SUBLINGUAL

Active Ing redient/Active Moiety

Ing redient Name Basis o f Streng th Streng th
ISO SO RBIDE DINITRATE (UNII: IA730 6 519 N) (ISO SO RBIDE DINITRATE - UNII:IA730 6 519 N) ISO SO RBIDE DINITRATE 2.5 mg

Inactive Ing redients

 Ing redient Name Streng th
AMMO NIUM PHO SPHATE, DIBASIC (UNII: 10 LGE70 FSU)
ANHYDRO US LACTO SE (UNII: 3SY5LH9 PMK)
SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)
STARCH, CO RN (UNII: O 8 232NY3SJ)
D&C YELLO W NO . 10 (UNII: 35SW5USQ 3G)
FD&C YELLO W NO . 6 (UNII: H77VEI9 3A8 )
MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )
CELLULO SE, MICRO CRYSTALLINE (UNII: O P1R32D6 1U)
SO DIUM STARCH GLYCO LATE TYPE A PO TATO (UNII: 58 56 J3G2A2)

Product Characteristics
Color YELLO W S core no sc o re
S hap e RO UND S iz e 9 mm
Flavor Imp rint Cod e W1
Contains

Packag ing
# Item Co de Packag e Descriptio n Marketing Start Date Marketing End Date
1 NDC:0 143-176 5-0 1 10 0 in 1 BO TTLE
2 NDC:0 143-176 5-10 10 0 0 in 1 BO TTLE
3 NDC:0 143-176 5-25 10 0 in 1 BO X, UNIT-DO SE

Marketing Information
Marke ting Cate gory Ap p lication Numb e r or Monograp h Citation Marke ting S tart Date Marke ting End Date
ANDA ANDA0 8 6 0 54 12/0 1/19 78

ISOSORBIDE DINITRATE
isosorbide dinitrate tablet

Product Information
Prod uct T yp e HUMAN PRESCRIPTIO N DRUG Ite m Cod e (S ource ) NDC:0 143-176 7

Route of Ad minis tration SUBLINGUAL

Active Ing redient/Active Moiety

Ing redient Name Basis o f Streng th Streng th
ISO SO RBIDE DINITRATE (UNII: IA730 6 519 N) (ISO SO RBIDE DINITRATE - UNII:IA730 6 519 N) ISO SO RBIDE DINITRATE 5 mg

Inactive Ing redients

Ing redient Name Streng th
AMMO NIUM PHO SPHATE, DIBASIC (UNII: 10 LGE70 FSU)
 ANHYDRO US LACTO SE (UNII: 3SY5LH9 PMK)
SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)
STARCH, CO RN (UNII: O 8 232NY3SJ)
MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )
CELLULO SE, MICRO CRYSTALLINE (UNII: O P1R32D6 1U)

Product Characteristics
Color WHITE S core no sc o re
S hap e RO UND S iz e 10 mm
Flavor Imp rint Cod e W3
Contains

Packag ing
# Item Co de Packag e Descriptio n Marketing Start Date Marketing End Date
1 NDC:0 143-176 7-0 1 10 0 in 1 BO TTLE
2 NDC:0 143-176 7-10 10 0 0 in 1 BO TTLE
3 NDC:0 143-176 7-25 10 0 in 1 BO X, UNIT-DO SE

Marketing Information
Marke ting Cate gory Ap p lication Numb e r or Monograp h Citation Marke ting S tart Date Marke ting End Date
ANDA ANDA0 8 6 0 55 12/0 1/19 78

Labeler - Wes t-ward Pharmaceutical Corp (001230762)

Establishment
Name Ad d re s s ID/FEI Bus ine s s Op e rations
We st-wa rd Pha rma c e utic a l Co rp 0 0 1230 76 2 MANUFACTURE(0 143-176 5, 0 143-176 7)

Revised: 5/2012 West-ward Pharmaceutical Corp