Each ampoule of Isosorbide Dinitrate (Isoket) 1 mg/mL (10 mg/10 mL) Solution for I.V. Infusion contains 10 mg of Isosorbide Dinitrate in 10 mL sterile isotonic sodium chloride solution.
Pharmacology: Mechanism of Action and Pharmacodynamic Effects: Isosorbide dinitrate (ISDN) is an organic nitrate, which is common with other cardioactive nitrates, is a vasodilator.
It produces decreased left and right ventricular end- diastolic pressures to a greater extent than the decrease in systemic arterial pressure, thereby reducing afterload and especially the preload of the heart.
Isosorbide Dinitrate (Isoket) influences the oxygen supply to ischaemic myocardium by causing the redistribution of blood flow along collateral channels and from epicardial to endocardial regions by selective dilation of large epicardial vessels.
It reduces the requirements of the myocardium for oxygen by increasing venous capacitance, causing a pooling of blood in peripheral veins, thereby reducing ventricular volume and heart wall distension.
Pharmacokinetics: Metabolism and Elimination: Isosorbide dinitrate (Isoket) is eliminated from plasma with a short half-life (about 0.7 h). The metabolic degradation of ISDN occurs via denitration and glucuronidation, like all organic nitrates. The rate of formation of the metabolites has been calculated for isosorbide-5-mononitrate (IS-5-MN) with 0.27 h-1 and isosorbide (IS) with 0.16 h-1. IS-5 MN and IS-2-MN are the primary metabolites which are also pharmacologically active.
IS-5-MN is metabolized to isosorbide 5-mononitrate-2-glucuronide (IS-5-MN-2-GLU). The half-life of this metabolite (about 2.5 h) is shorter than that of IS-5-MN (about 5.1 h). The half-life of ISDN is the shortest of all and that of IS-2-MN (about 3.2 h) lies in between.
Toxicology: Preclinical Safety Data: Acute toxicity: Acute toxicity of Isosorbide dinitrate (Isoket) was related to an exaggerated pharmacodynamic effect. Animal studies showed good local tolerability of the undiluted Isosorbide dinitrate (Isoket) solution.
Chronic toxicity: In chronic toxicity studies in rats and dogs, toxic effects CNS symptoms and an increase of liver weight, were observed at exposures considered sufficiently in excess of the maximum human exposure levels indicating little relevance to clinical use.
Reproduction studies: There is no evidence from animal studies suggesting a teratogenic effect of Isosorbide dinitrate (Isoket). At high maternally toxic oral doses, Isosorbide dinitrate (Isoket) was associated with increased post-implantation loss and reduced survival of offspring.
Mutagenicity: No evidence for mutagenic effects was found in several tests undertaken both in vitro and in vivo.
Carcinogenicity: A long-term study in rats did not provide any evidence for carcinogenicity.
Severe or unstable angina pectoris; unresponsive left ventricle failure secondary to acute myocardial infarction; unresponsive left ventricular failure of various aetiology; during percutaneous transluminal coronary angioplasty to facilitate prolongation of balloon inflation and to prevent or receive coronary spasm.
Intravenous: Adult: A dose of between 2 mg and 12 mg per hour is usually satisfactory. However, dosages up to 20 mg/hr administered should be adjusted to the patient response.
Intracoronary: The usual dose is 1 mg given as a bolus injection prior to balloon inflation. Further doses may be given not exceeding 5 mg within a 30 minute period.
Children: The safety and efficacy of Isosorbide Dinitrate (Isoket) solution for I.V. infusion has not yet been established in children.
Elderly: No dose adjustment is necessary.
Renal and Hepatic Impairment: Isosorbide Dinitrate (Isoket) should be used with caution in patients with severely impaired renal or hepatic function (see Precautions).
Administration: Isoket is a concentrated solution and must be diluted prior use. The diluted solution should never be injected in the form of a bolus except via the intracoronary route prior to balloon inflation. A dilution of 50% is advocated for intracoronary administration.
Isosorbide Dinitrate (Isoket) solution for infusion can be administered as an intravenous admixture with a suitable vehicle (see Use and Handling under Cautions for Usage).
Prepared Isoket admixtures should be given by intravenous infusion or with the aid of a syringe pump incorporating a glass or rigid plastic syringe. During administration the patient's blood pressure and pulse should be closely monitored.
For IV or intracoronary use.
Symptoms: The following symptoms were observed: fall of blood pressure ≤90 mmHg, pallor, sweating, weak pulse, tachycardia, postural dizziness, headache, asthenia, dizziness, nausea, vomiting, diarrhea.
Methemoglobinemia has been reported in patients receiving other organic nitrates. During Isosorbide Dinitrate (Isoket) biotransformation, nitrite ions are released, which may induce methemoglobinemia and cyanosis with subsequent tachypnea, anxiety, loss of consciousness and cardiac arrest. It cannot be excluded that an overdose of Isoket may cause this adverse reaction.
In very high doses, the intracranial pressure may be increased. This might lead to cerebral symptoms.
Treatment: General Procedure: Stop delivery of the drug.
General Procedures in the Event of Nitrate-Related Hypotension: The patient must be laid down with lowered head and raised legs; supply oxygen; expand plasma volume (I.V. fluids), specific shock treatment (admit patient to intensive care unit).
Special Procedure: Raise the blood pressure if the blood pressure is very low; vasopressors should be used only in patients who do not respond to adequate fluid resuscitation.
Treatment of Methemoglobinemia: Reduction therapy of choice with vitamin C, methylene-blue, or toluidine-blue; administer oxygen (if necessary); initiate artificial ventilation.
Resuscitation Measures: In case of signs of respiratory and circulatory arrest, initiate resuscitation measures immediately.
Further management should be as clinically indicated or as recommended by the national poisons centre, where available.
Isosorbide Dinitrate (Isoket) is contraindicated in: known hypersensitivity to the active substance, to any of the excipients or to other nitrates or nitrites; low filling pressure; hypertrophic obstructive cardiomyopathy (HOCM); constructive pericarditis; cardiac tamponade; cardiogenic shock (unless some means of maintaining an adequate diastolic pressure is undertaken); circulatory collapse; aortic and/or mitral valve stenosis; severe hypotension (systolic blood pressure less than 90 mmHg); head trauma; cerebral hemorrhage; diseases associated with an increased intracranial pressure; marked anemia; hypovolemia; closed angle glaucoma; patients receiving phosphodiesterase-5 inhibitors (eg, sildenafil, tadalafil, vardenafil) (see Precautions; Interactions); patients receiving the soluble guanylate cyclase stimulator riociguat (see Interactions).
Medical Supervision required: Isosorbide Dinitrate (Isoket) should be used with caution and under medical supervision in patients who are suffering from: hypothyroidism, hypothermia, malnutrition, severe liver disease or renal disease, orthostatic syndrome.
Tolerance: The development of tolerance (decrease in efficacy) as well as cross tolerance towards other nitrate-type drugs (decrease in effect in case of a prior therapy with another nitrate drug) has been described. For a decrease in, or loss of, effect to be prevented, continuously high dosages must be avoided.
Blood pressure and pulse rate monitoring: Blood pressure and pulse rate should always be monitored and the dose adjusted according to the patient's response.
Hypoxia: During treatment with Isosorbide Dinitrate (Isoket), temporary hypoxemia may occur due to a relative redistribution of the blood flow in hypoventilated alveolar areas. Particularly in patients with coronary artery disease this may lead to myocardial hypoxia.
Phosphodiesterase inhibitors containing products: Patients who undergo a maintenance treatment with Isosorbide Dinitrate (Isoket) should be informed that they must not use phosphodiesterase inhibitors containing products (eg, sildenafil, tadalafil, vardenafil). Isosorbide Dinitrate (Isoket) therapy should not be interrupted to take phosphodiesterase inhibitors containing products (eg, sildenafil, tadalafil, vardenafil), because the risk of inducing an attack of angina pectoris could increase by doing so (see Contraindications; Drug Interactions).
Acute therapy with isosorbide dinitrate must not be used in patients who have recently taken phosphodiesterase inhibitors (eg, sildenafil, tadalafil, vardenafil). Patients who receive Isosorbide Dinitrate (Isoket) as acute therapy must be warned not to take phosphodiesterase inhibitors containing products (eg, sildenafil, vardenafil, tadalafil).
Effects on ability to drive and use machines: As for other drugs which produce changes in blood pressure, patients taking Isosorbide Dinitrate (Isoket) should be warned not to drive or operate machinery if they experience dizziness or related symptoms.
Isosorbide Dinitrate (Isoket) may affect the patient's reactivity to an extent that her/his ability to drive or to operate machinery is impaired. This effect is increased in combination with alcohol.
Use in Pregnancy & Lactation: Isosorbide Dinitrate (Isoket) should only be used in pregnancy if, in the opinion of the physician, the possible benefits of treatment outweigh the possible hazards.
No data have been reported which would indicate the possibility of adverse effects resulting from the use of Isosorbide Dinitrate (Isoket) in pregnancy. Safety in pregnancy, however, has not been established.
Isosorbide Dinitrate (Isoket) should only be used during lactation if, in the opinion of the physician, the possible benefits of treatment outweigh the possible hazards.
Available evidence is inconclusive or inadequate for determining infant risk when used during breastfeeding. There is data that nitrates are excreted in breast milk and may cause methaemoglobinemia in infants. The extent of excretion of isosorbide dinitrate and its metabolites in human breast milk has not been determined. Therefore, caution is appropriate when administering this agent to lactating women.
Fertility: There are no relevant data available.
Use in Pregnancy: Isosorbide Dinitrate (Isoket) should only be used in pregnancy if, in the opinion of the physician, the possible benefits of treatment outweigh the possible hazards.
No data have been reported which would indicate the possibility of adverse effects resulting from the use of Isosorbide Dinitrate (Isoket) in pregnancy. Safety in pregnancy, however, has not been established.
Use in Lactation: Isosorbide Dinitrate (Isoket) should only be used during lactation if, in the opinion of the physician, the possible benefits of treatment outweigh the possible hazards.
Available evidence is inconclusive or inadequate for determining infant risk when used during breastfeeding. There is data that nitrates are excreted in breast milk and may cause methaemoglobinemia in infants. The extent of excretion of isosorbide dinitrate and its metabolites in human breast milk has not been determined. Therefore, caution is appropriate when administering this agent to lactating women.
Post-Marketing Data: Adverse drug reactions (ADRs) are listed below by MedDRA system organ class and by frequency.
Frequencies are defined as: Very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000) or very rare (<1/10,000); not known (cannot be estimated from the available data).
Nervous System Disorders: Very common: Headache. Common: Dizziness, somnolence.
Cardiac Disorders: Common: Tachycardia. Uncommon: Aggravated angina pectoris.
Vascular Disorders: Common: Orthostatic hypotension. Uncommon: Circulatory collapse (sometimes accompanied by bradyarrhythmia and syncope). Not known: Hypotension.
Gastrointestinal Disorders: Uncommon: Nausea, vomiting, heartburn. Very rare: Heartburn.
Skin and Subcutaneous Tissue Disorders: Uncommon: Allergic skin reactions (eg, rash), flushing. Very rare: Angioedema, Stevens-Johnson syndrome. Not known: Exfoliative dermatitis.
General Disorders and Administration Site Conditions: Common: Asthenia.
Severe hypotensive responses have been reported for organic nitrates including nausea, vomiting, restlessness, pallor, and excessive perspiration.
Phosphodiesterase-5 Inhibitors: Phosphodiesterase-5 inhibitors eg, sildenafil potentiate the hypotensive effects of Isosorbide Dinitrate (Isoket). This might lead to life-threatening cardiovascular complications. Therefore Isosorbide Dinitrate (Isoket) must not be given to patients receiving phosphodiesterase-5-inhibitors (see Contraindications; Precautions).
Blood Pressure Lowering Drugs: Concurrent intake of drugs with blood pressure lowering properties eg, beta-blockers, calcium antagonists vasodilators etc and/or alcohol may potentiate the hypotensive effect of Isosorbide Dinitrate (Isoket). This might also occur with neuroleptics and tricyclic antidepressants.
Dihydroergotamine: Reports suggest that, when administered concomitantly, Isosorbide Dinitrate (Isoket) may increase the blood level of dihydroergotamine and its hypertensive effect.
Riociguat: The use of isosorbide dinitrate (ISDN) with riociguat, a soluble guanylate cyclase stimulator, is contraindicated (see Contraindications) since concomitant use can cause hypotension.
Use and Handling: Isosorbide Dinitrate (Isoket) solution 1 mg/mL solution for I.V infusion is oversaturated with the active substance, therefore, crystallisation may occur in undiluted form. If crystals are observed, it is safer not to use the solution, although under normal conditions, efficacy is not impaired.
Isosorbide Dinitrate (Isoket) must be diluted under aseptic conditions immediately after opening. The diluted solution is to be used immediately. Any unused contents of the container should be discarded.
This medicinal product contains Isosorbide Dinitrate in isotonic solution and is compatible with commonly employed infusion fluids such as sodium chloride solution, dextrose solution, 5-30% glucose solution, Ringer's solution and solutions containing albumin. No incompatibilities have so far been demonstrated.
This product is compatible with glass infusion bottles and infusion packs made from polyethylenepylene (PE), polypropylene (PP) or polytetraflouroethylene (PTFE). Isosorbide Dinitrate (Isoket) may be infused slowly using a syringe pump with a glass or plastic syringe.
Example of admixture preparation: To obtain a dose of 6 mg per hour, add 50 mL of Isosorbide Dinitrate (Isoket) solution for infusion 1 mg/mL to 450 mL of a suitable vehicle, under aseptic conditions. The resultant admixture (500 mL) contains 100 µg/mL (1 mg/10 mL) Isosorbide Dinitrate (Isoket), An infusion rate of 60 mL per hour (equivalent to 60 paediatric microdrops per minute or 20 standard drops per minute) will deliver the required dose of 6 mg per hour.
Should it be necessary to reduce fluid intake, 100 mL of Isosorbide Dinitrate (Isoket) solution for infusion 1 mg/mL may be diluted to 500 mL using a suitable vehicle. The resultant solution now contains 200 µg/mL (2 mg/10 mL) Isosorbide Dinitrate (Isoket). An infusion rate of 30 mL per hour (equivalent to 30 paediatric microdrops per minute or 10 standard drops per minute), will deliver the required dose of 6 mg per hour.
A dilution of 50% is advocated to produce a solution containing 0.5 mg/mL where fluid intake is strictly limited.
Incompatibilities: Polyvinyl chloride (PVC) or polyurethane (PU) giving sets and containers should not be used since significant losses of theactive ingredient by adsorption occur and it has not been verified how the dose can be adjusted to suit the patient's needs to account for this adsorption.
This medicinal product must not be mixed with other medicinal products except those mentioned previously.
Store at temperatures not exceeding 25°C.
C01DA08 - isosorbide dinitrate ; Belongs to the class of organic nitrate vasodilators. Used in the treatment of cardiac disease.
Isoket IV soln for IV infusion 1 mg/mL
10 mL x 10 × 1's
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