Isoket is a concentrated solution of Isosorbide dinitrate 1mg/1ml (0.1%) in sterile isotonic saline. It is supplied in 10 ml ampoules. The solution contains no alcohol or potassium.
Excipients/Inactive Ingredients: Sodium chloride, water for injections, sodium hydroxide (for pH-adjustment), hydrochloric acid (for pH-adjustment).
Pharmacotherapeutic Group: Vasodilators used in cardiac diseases; organic nitrates. ATC Code: C01DA08.
Pharmacology: Pharmacodynamics: Mechanism of Action: Isosorbide dinitrate is an organic nitrate, which in 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 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 dilatation of large epicardial vessels.
It reduces the requirement 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 (ISDN) is eliminated from plasma with a short half-life (about 0.7h). 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 metabolised to isosorbide 5-mononitrate-2-glucuronide (IS-5-MN-2-GLU). The half-life of this metabolite (about 2.5h) is shorter than that of IS-5-MN (about 5.1h). The half-life of ISDN is the shortest of all and that of IS-2-MN (about 3.2h) lies in between.
Non-Clinical Information: Acute toxicity: Acute toxicity of isosorbide dinitrate was related to an exaggerated pharmacodynamic effect. Animal studies showed good local tolerability of the undiluted isosorbide dinitrate solution.
Chronic toxicity: In chronic oral toxicity studies in rats and dogs, toxic effects including CNS symptoms and an increase in 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. At high maternally toxic oral doses, isosorbide dinitrate 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.
Isoket is indicated in the treatment of unresponsive left ventricular failure secondary to acute myocardial infarction, unresponsive left ventricular failure of various aetiology and severe or unstable angina pectoris.
This medicinal product is a concentrated solution and must be diluted prior use. The diluted solution should never be injected directly in the form of a bolus.
Isosorbide dinitrate solution for infusion or injection, can be administered as an intravenous admixture with a suitable vehicle (see Use and Handling under Cautions for Usage).
Prepared isosorbide dinitrate 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.
Adults: A dose of between 2 mg and 12 mg per hour is usually satisfactory.
However, dosages up to 20 mg per hour administered should be adjusted to the patient response.
Children: The safety and efficacy of isosorbide dinitrate solution for infusion or injection has not yet been established in children.
Elderly: No dose adjustment is necessary.
Renal and Hepatic impairment: Isosorbide dinitrate should be used with caution in patients with severely impaired renal or hepatic function (see Precautions).
Route of Administration: For intravenous use.
Symptoms and signs: The following symptoms were observed: fall of blood pressure ≤ 90 mmHg, pallor, sweating, weak pulse, tachycardia, postural dizziness, headache, asthenia, dizziness, nausea, vomiting, diarrhoea.
Methaemoglobinaemia has been reported in patients receiving other organic nitrates. During isosorbide dinitrate biotransformation nitrite ions are released, which may induce methaemoglobinaemia and cyanosis with subsequent tachypnoea, anxiety, loss of consciousness and cardiac arrest. It cannot be excluded that an overdose of isosorbide dinitrate 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; additional administration of noradrenaline or other vasoconstrictors.
Treatment of methaemoglobinaemia: 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 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), constrictive 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 90mmHg), head trauma, cerebral haemorrhage, diseases associated with an increased intracranial pressure, marked anaemia, hypovolaemia, closed angle glaucoma, patients receiving phosphodiesterase-5 inhibitors (e.g. sildenafil, tadalafil, vardenafil) (see Interactions).
Medical supervision required: Isosorbide dinitrate should be used with caution and under medical supervision in patients who are suffering from: hypothyroidism, hypothermia, malnutrition, severe liver 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, 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 (see Adverse Reactions).
Excipients: As this medicinal product contains 3.54 mg of sodium per ml, it should be taken into consideration by patients on a controlled sodium diet.
Effects on Ability to Drive and Use Machines: As for other drugs which produce changes in blood pressure, patients taking isosorbide dinitrate should be warned not to drive or operate machinery if they experience dizziness or related symptoms.
Fertility: No data on fertility are available.
Pregnancy and Lactation: No data have been reported which would indicate the possibility of adverse effects resulting from the use of isosorbide dinitrate in pregnancy. Safety in pregnancy, however, has not been established.
Isosorbide dinitrate should only be used in pregnancy and 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.
Adverse drug reactions (ADRs) are listed as follows by MedDRA system organ class and by frequency. Frequencies are defined as: Very common ≥1/10; Common ≥1/100 to <1/10; Uncommon ≥1/1000 to <1/100; Rare ≥1/10000 to <1/1000; Very rare <1/10000; Not known (cannot be estimated from the available data).
Nervous system disorders:
Not known: headache, dizziness, somnolence.
Not known: tachycardia, angina pectoris aggravated.
Not known: orthostatic hypotension, flushing, collapse (sometimes accompanied by bradyarrhythmia and syncope).
Severe hypotensive responses have been reported for organic nitrates including nausea, vomiting, restlessness, pallor, and excessive perspiration.
Respiratory, thoracic and mediastinal disorders:
Not known: hypoxia (see Precautions).
Not known: nausea, vomiting, heartburn.
Skin and subcutaneous tissue disorders:
Not known: allergic skin reactions (e.g.rash), angioedema, Stevens - Johnson Syndrome, exfoliative dermatitis.
General disorders and administration site conditions:
Not known: asthenia.
Phosphodiesterase-5 inhibitors: Phosphodiesterase-5 inhibitors e.g. sildenafil, potentiate the hypotensive effects of isosorbide dinitrate. This might lead to life-threatening cardiovascular complications. Therefore, isosorbide dinitrate must not be given to patients receiving phosphodiesterase-5-inhibitors (see Contraindications).
Blood pressure lowering drugs: Concurrent intake of drugs with blood pressure lowering properties, e.g. beta-blockers, calcium antagonists, vasodilators etc. and/or alcohol may potentiate the hypotensive effect of isosorbide dinitrate. This might also occur with neuroleptics and tricyclic antidepressants.
Dihydroergotamine: Reports suggest that, when administered concomitantly, isosorbide dinitrate may increase the blood level of dihydroergotamine and its hypertensive effect.
Use and Handling: Isosorbide dinitrate 1mg/ml solution for infusion or injection 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 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 polyethylene (PE), polypropylene (PP) or polytetrafluoroethylene (PTFE). Isosorbide dinitrate may be infused slowly using a syringe pump with glass or plastic syringe.
Example of admixture preparation: To obtain a dose of 6 mg per hour, add 50 ml of isosorbide dinitrate solution for infusion or injection 1 mg/ml to 450 ml of a suitable vehicle, under aseptic conditions. The resultant admixture (500ml) contains 100 μg/ml (1mg/10ml) isosorbide dinitrate. 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 6mg per hour.
Should it be necessary to reduce fluid intake, 100 ml of isosorbide dinitrate solution for infusion or injection 1 mg/ml may be diluted to 500 ml using a suitable vehicle. The resultant solution now contains 200 μg/ml (2mg/10ml) isosorbide dinitrate. An infusion rate of 30ml 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 the active 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 in Use and Handling.
Store below 30°C.
Shelf-Life: Once diluted, chemical and physical in-use stability for 24 hours at 2-8°C has been demonstrated.
From a microbiological point of view, the product must be used immediately once opened/diluted. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.
C01DA08 - isosorbide dinitrate ; Belongs to the class of organic nitrate vasodilators. Used in the treatment of cardiac disease.
Soln for infusion (amp) 10 mg/10 mL (clear, colourless and odourless liquid) x 10's.