Prescription Drug Information: ISOSORBIDE DINITRATE (Page 2 of 2)

ADVERSE REACTIONS

Adverse reactions to isosorbide dinitrate are generally dose-related, and almost all of these reactions are the result of isosorbide dinitrate’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 with isosorbide dinitrate tablets.

OVERDOSAGE

Hemodynamic Effects

The ill effects of isosorbide dinitrate overdose are generally the results of isosorbide dinitrate’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 isosorbide dinitrate and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of isosorbide dinitrate overdose.

There are no data suggesting what dose of isosorbide dinitrate 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 isosorbide dinitrate 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 isosorbide dinitrate is known, and no intervention has been subject to controlled studies as a therapy for isosorbide dinitrate overdose. Because the hypotension associated with isosorbide dinitrate 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 isosorbide dinitrate overdose in these patients may be subtle and difficult, and invasive monitoring may be required.

Methemoglobinemia

Nitrate ions liberated during metabolism of isosorbide dinitrate can oxidize hemoglobin into methemoglobin. Even in patients totally without cytochrome b 5 reductase activity, however, and even assuming that the nitrate moieties of isosorbide dinitrate are quantitatively applied to oxidation of hemoglobin, about 1 mg/kg of isosorbide dinitrate 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 isosorbide dinitrate. 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 isosorbide dinitrate 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-dose studies with ISDN and other nitrates have shown that maintenance of continuous 24-hour plasma levels results in refractory tolerance. Every dosing regimen for isosorbide dinitrate tablets must provide a daily dose-free interval to minimize the development of this tolerance. With immediate-release ISDN, it appears that one daily dose-free interval must be at least 14 hours long.

As also noted under CLINICAL PHARMACOLOGY, the effects of the second and later doses have been smaller and shorter-lasting than the effects of the first.

Large controlled studies with other nitrates suggest that no dosing regimen with isosorbide dinitrate tablets should be expected to provide more than about 12 hours of continuous anti-anginal efficacy per day.

As with all titratable drugs, it is important to administer the minimum dose which produces the desired clinical effect. The usual starting dose of isosorbide dinitrate is 5 mg to 20 mg, two or three times daily. For maintenance therapy, 10 mg to 40 mg, two or three times daily is recommended. Some patients may require higher doses. A daily dose-free interval of at least 14 hours is advisable to minimize tolerance. The optimal interval will vary with the individual patient, dose and regimen.

HOW SUPPLIED

Isosorbide dinitrate Tablets are available as follows:

5 mg, Light pink to pink round tablets, debossed with, “Λ” on one side and score line on the other side.
21

NDC 72888-081-01, bottles of 100.
NDC 72888-081-00, bottles of 1000.

10 mg, Light green to green mottled round tablets, debossed with, “Λ” on one side and score line on the other side.
22

NDC 72888-082-01, bottles of 100
NDC 72888-082-00, bottles of 1000.

20 mg, Light green to green mottled round tablets, debossed with, “Λ” on one side and score line on the other side.
23

NDC 72888-083-01, bottles of 100
NDC 72888-083-00, bottles of 1000.

30 mg, Light green to green mottled round tablets, debossed with, “Λ” on one side and score line on the other side.
24

NDC 72888-084-01, bottles of 100
NDC 72888-084-00, bottles of 1000.

40 mg, Light green to green mottled round tablets, debossed with, “Λ” on one side and score line on the other side.
45

NDC 72888-085-01, bottles of 100
NDC 72888-085-00, bottles of 1000.

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Protect from light.

Keep bottles tightly closed.

Dispense in a light-resistant, tight container.

All trademarks are the property of their respective owners.

Manufactured by:
Rubicon Research Private Limited
Ambernath, Dist: Thane, 421506 India

Distributed by:
Advagen Pharma Ltd
666 Plainsboro Road Suite 605Plainsboro, NJ 08536, US

Revision: 06/22

PRINCIPAL DISPLAY PANEL

Isosorbide Dinitrate Tablets 5 mg — NDC 72888-081-01 — 100 Tablets Bottle

Isosorbide Dinitrate Tablets 5 mg -- NDC 72888-081-01 -- 100 Tablets Bottle
(click image for full-size original)

Isosorbide Dinitrate Tablets 5 mg — NDC 72888-081-00 — 1000 Tablets Bottle

Isosorbide Dinitrate Tablets 5 mg -- NDC 72888-081-00 -- 1000 Tablets Bottle
(click image for full-size original)

Isosorbide Dinitrate Tablets 10 mg — NDC 72888-082-01 — 100 Tablets Bottle

Isosorbide Dinitrate Tablets 10 mg -- NDC 72888-082-01 -- 100 Tablets Bottle
(click image for full-size original)

Isosorbide Dinitrate Tablets 10 mg — NDC 72888-082-00 — 1000 Tablets Bottle

Isosorbide Dinitrate Tablets 10 mg -- NDC 72888-082-00 -- 1000 Tablets Bottle
(click image for full-size original)

Isosorbide Dinitrate Tablets 20 mg — NDC 72888-083-01 — 100 Tablets Bottle

Isosorbide Dinitrate Tablets 20 mg -- NDC 72888-083-01 -- 100 Tablets Bottle
(click image for full-size original)

Isosorbide Dinitrate Tablets 20 mg — NDC 72888-083-00 — 1000 Tablets Bottle

Isosorbide Dinitrate Tablets 20 mg -- NDC 72888-083-00 -- 1000 Tablets Bottle
(click image for full-size original)

Isosorbide Dinitrate Tablets 30 mg — NDC 72888-084-01 — 100 Tablets Bottle

Isosorbide Dinitrate Tablets 30 mg -- NDC 72888-084-01 -- 100 Tablets Bottle
(click image for full-size original)

Isosorbide Dinitrate Tablets 30 mg — NDC 72888-084-00 — 1000 Tablets Bottle

Isosorbide Dinitrate Tablets 30 mg -- NDC 72888-084-00 -- 1000 Tablets Bottle
(click image for full-size original)

Isosorbide Dinitrate Tablets 40 mg — NDC 72888-085-01 — 100 Tablets Bottle

Isosorbide Dinitrate Tablets 40 mg -- NDC 72888-085-01 -- 100 Tablets Bottle
(click image for full-size original)

Isosorbide Dinitrate Tablets 40 mg — NDC 72888-085-00 — 1000 Tablets Bottle

Isosorbide Dinitrate Tablets 40 mg -- NDC 72888-085-00 -- 1000 Tablets Bottle
(click image for full-size original)
ISOSORBIDE DINITRATE isosorbide dinitrate tablet
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:72888-081
Route of Administration ORAL DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
ISOSORBIDE DINITRATE (ISOSORBIDE DINITRATE) ISOSORBIDE DINITRATE 5 mg
Inactive Ingredients
Ingredient Name Strength
MICROCRYSTALLINE CELLULOSE
SILICON DIOXIDE
MAGNESIUM STEARATE
ANHYDROUS LACTOSE
SODIUM STARCH GLYCOLATE TYPE A
FD&C RED NO. 40
Product Characteristics
Color pink (Light pink to pink) Score 2 pieces
Shape ROUND Size 6mm
Flavor Imprint Code UpArrowhead21
Contains
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:72888-081-01 100 TABLET in 1 BOTTLE None
2 NDC:72888-081-00 1000 TABLET in 1 BOTTLE None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA215723 07/08/2022
ISOSORBIDE DINITRATE isosorbide dinitrate tablet
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:72888-082
Route of Administration ORAL DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
ISOSORBIDE DINITRATE (ISOSORBIDE DINITRATE) ISOSORBIDE DINITRATE 10 mg
Inactive Ingredients
Ingredient Name Strength
MICROCRYSTALLINE CELLULOSE
SILICON DIOXIDE
MAGNESIUM STEARATE
ANHYDROUS LACTOSE
SODIUM STARCH GLYCOLATE TYPE A
FD&C BLUE NO. 1 ALUMINUM LAKE
D&C YELLOW NO. 10 ALUMINUM LAKE
Product Characteristics
Color green (Light green to green) Score 2 pieces
Shape ROUND Size 6mm
Flavor Imprint Code UpArrowhead22
Contains
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:72888-082-01 100 TABLET in 1 BOTTLE None
2 NDC:72888-082-00 1000 TABLET in 1 BOTTLE None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA215723 07/08/2022
ISOSORBIDE DINITRATE isosorbide dinitrate tablet
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:72888-083
Route of Administration ORAL DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
ISOSORBIDE DINITRATE (ISOSORBIDE DINITRATE) ISOSORBIDE DINITRATE 20 mg
Inactive Ingredients
Ingredient Name Strength
MICROCRYSTALLINE CELLULOSE
SILICON DIOXIDE
MAGNESIUM STEARATE
ANHYDROUS LACTOSE
SODIUM STARCH GLYCOLATE TYPE A
FD&C BLUE NO. 1 ALUMINUM LAKE
D&C YELLOW NO. 10 ALUMINUM LAKE
Product Characteristics
Color green (Light green to green) Score 2 pieces
Shape ROUND Size 7mm
Flavor Imprint Code UpArrowhead23
Contains
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:72888-083-01 100 TABLET in 1 BOTTLE None
2 NDC:72888-083-00 1000 TABLET in 1 BOTTLE None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA215723 07/08/2022
ISOSORBIDE DINITRATE isosorbide dinitrate tablet
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:72888-084
Route of Administration ORAL DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
ISOSORBIDE DINITRATE (ISOSORBIDE DINITRATE) ISOSORBIDE DINITRATE 30 mg
Inactive Ingredients
Ingredient Name Strength
MICROCRYSTALLINE CELLULOSE
SILICON DIOXIDE
MAGNESIUM STEARATE
ANHYDROUS LACTOSE
SODIUM STARCH GLYCOLATE TYPE A
FD&C BLUE NO. 1 ALUMINUM LAKE
D&C YELLOW NO. 10 ALUMINUM LAKE
Product Characteristics
Color green (Light green to green) Score 2 pieces
Shape ROUND Size 8mm
Flavor Imprint Code UpArrowhead24
Contains
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:72888-084-01 100 TABLET in 1 BOTTLE None
2 NDC:72888-084-00 1000 TABLET in 1 BOTTLE None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA215723 07/08/2022
ISOSORBIDE DINITRATE isosorbide dinitrate tablet
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:72888-085
Route of Administration ORAL DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
ISOSORBIDE DINITRATE (ISOSORBIDE DINITRATE) ISOSORBIDE DINITRATE 40 mg
Inactive Ingredients
Ingredient Name Strength
MICROCRYSTALLINE CELLULOSE
SILICON DIOXIDE
MAGNESIUM STEARATE
FD&C BLUE NO. 1 ALUMINUM LAKE
D&C YELLOW NO. 10 ALUMINUM LAKE
Product Characteristics
Color green (Light green to green) Score 2 pieces
Shape ROUND Size 10mm
Flavor Imprint Code UpArrowhead45
Contains
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:72888-085-01 100 TABLET in 1 BOTTLE None
2 NDC:72888-085-00 1000 TABLET in 1 BOTTLE None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA215723 07/08/2022
Labeler — Advagen Pharma Ltd (051627256)
Establishment
Name Address ID/FEI Operations
Rubicon Research Private Limited 677604197 manufacture (72888-081), analysis (72888-081), label (72888-081), manufacture (72888-082), analysis (72888-082), label (72888-082), manufacture (72888-083), analysis (72888-083), label (72888-083), manufacture (72888-084), analysis (72888-084), label (72888-084), manufacture (72888-085), analysis (72888-085), label (72888-085)

Revised: 07/2022 Advagen Pharma Ltd

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