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ISOSORBIDE DINITRATE INJECTION CONCENTRATE 1MG/ML 10ML

Active substance(s): ISOSORBIDE DINITRATE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Isosorbide Dinitrate Injection Concentrate 1mg/ml, 10ml.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION
Isosorbide Dinitrate 10mg in 10ml.

3.

PHARMACEUTICAL FORM
Clear, colourless, sterile aqueous
administration to human beings.

4.

CLINICAL PARTICULARS

4.1.

Therapeutic Indications

solution

intended

for

parenteral

Isosorbide dinitrate is indicated in the treatment of unresponsive left
ventricular failure of various aetiology, including left ventricular failure
secondary to acute myocardial infarction. It is also indicated in the
management of severe or unstable angina pectoris.

4.2.

Posology and Method of Administration
Recommended Route : Intravenously, after dilution.
Adults, including the elderly: The dose must be adjusted according to the
patients response. A dose of between 2 and 12mg per hour is generally
suitable, although doses as high as 20mg per hour may be necessary.
Children: The safety and efficacy of isosorbide dinitrate injection has not
been established in children.
Administration: This is a concentrated solution and should never be
administered in bolus form. It should be administered only as an admixture,
intravenously, with a suitable vehicle such as Sodium Chloride Injection B.P.
or Dextrose Injection B.P. Admixtures are prepared by exchanging the

required volume of Isosorbide Dinitrate Injection Concentrate with an equal
volume of the infusion vehicle. For example, if the dose requirement is 6mg
per hour, 50ml of Isosorbide Dinitrate Injection Concentrate should be added
to 450ml of the infusion vehicle. The admixture now contains 1mg in 10ml
and the required dosage can be achieved by administering 60ml per hour
(equivalent to 20 standard drops or 60 paediatric microdrops per minute).
If further reduction in fluid intake is required, 100ml of Isosorbide Dinitrate
Injection Concentrate made up to 500ml with a suitable infusion vehicle
produces an admixture containing 2mg in 10ml which may be infused at a drip
rate of 30ml per hour for a required dosage of 6mg per hour.
Where fluid intake is strictly limited, a dilution of 50% is advocated to
produce a solution containing 0.5mg in 1ml.
Admixtures should be made up under aseptic conditions. Loss of potency will
occur on contact with PVC and the use of PVC infusion bags or administration
sets should, therefore, be avoided.

4.3

Contraindications
These are common to all nitrates: hypersensitivity to isosorbide dinitrate, other
nitrates or any of the excipients, marked anaemia, cerebral haemorrhage, head
trauma, diseases associated with an increased intracranial pressure, hypovolaemia,
severe hypotension (systolic blood pressure less than 90mmHg), aortic and/or mitral
valve stenosis, closed angle glaucoma.
Use in circulatory collapse or low filling pressure is also contraindicated.
Isosorbide Dinitrate Injection Concentrate 1mg/ml should not be used in the treatment
of cardiogenic shock (unless some means of maintaining an adequate diastolic
pressure are undertaken), hypertrophic obstructive cardiomyopathy, cardiac
tamponade, or constrictive pericarditis.
Phosphodiesterase type-5 inhibitors (e.g. sildenafil, tadalafil and vardenafil) have
been shown to potentiate the hypotensive effects of nitrates. Therefore, Isosorbide
Dinitrate Injection Concentrate 1mg/ml must not be given to patients receiving
phosphodiesterase-5 inhibitors (see section 4.5).

4.4

Special warnings and precautions for use
Isosorbide dinitrate should be used with caution and under medical supervision in
patients who are suffering from:
• hypothyroidism,
• hypothermia,
• malnutrition,
• severe hepatic or renal disease
• orthostatic syndrome

The development of tolerance (decrease in efficacy) as well as cross tolerance
towards other nitrate-type drugs (decrease in effect incase 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 should always be monitored and the dose adjusted
according to the patient's response.

4.5

Interaction with other medicinal products and other forms of interaction
Concurrent intake of drugs with blood pressure lowering properties e.g. betablockers, calcium antagonists, vasodilators etc. and /or alcohol may potentiate the
hypotensive effect of Isosorbide Dinitrate Injection Concentrate 1mg/ml. This might
also occur with neuroleptics and tricyclic antidepressants.
Also phosphodiesterase-5 inhibitors e.g. sildenafil, potentiate the hypotensive effect
of Isosorbide Dinitrate Injection Concentrate 1mg/ml. This might lead to lifethreatening cardiovascular complications, see section 4.3.
Reports suggest that, when administered concomitantly, Isosorbide Dinitrate Injection
Concentrate 1mg/ml may increase the blood level of dihydroergotamine and its
hypertensive effect.

4.6.

Pregnancy and Lactation
Although there are no reported data to indicate the possibility of adverse
effects resulting from administration of isosorbide dinitrate in pregnancy,
safety in pregnancy has not been established. Isosorbide dinitrate should only
be used in pregnancy or lactation if, in the opinion of the physician, the
possible benefits outweigh the possible risks.

4.7

Effects on ability to drive and use machines
As for other drugs which produce changes in blood pressure, patients taking
Isosorbide Dinitrate Injection Concentrate 1mg/ml should be warned not to drive or
operate machinery if they experience dizziness or related symptoms.

4.8.

Undesirable Effects
As with all nitrates, the vasodilatory effects may cause a fall in systemic
arterial pressure which could give rise to symptoms of cerebral flow
insufficiency or decreased coronary perfusion. In common with other nitrates,
headache, severe hypotension, nausea and retching, excessive sweating,

apprehension, restlessness, muscle twitching, retrosternal discomfort,
palpitations, abdominal pain, syncope and bradycardia may occur during
therapy with isosorbide dinitrate (particularly if infused too rapidly).
Methaemoglobinaemia has been known to occur, rarely.
If
methaemoglobinaemia is diagnosed, treatment with methylene blue at a dose
of 1 to 2 mg/kg intravenously may be administered, depending on the degree
and rapidity of methaemoglobin formation.

4.9.

Overdose
Toxic effects of overdose include: vomiting, restlessness, cyanosis,
hypertension, tachycardia and syncope.
Overdosage or too rapid infusion, especially in heart failure will result in
excessively reduced filling pressures, hypotension, decreased ventricular
performance and decreased perfusion of tissues. If the arterial systolic blood
pressure drops below 90mm Hg and if the heart rate increases above 10% of
its initial value, the infusion should be discontinued. Where necessary,
hypotension may be treated by keeping the patient recumbent in a shock
position and/or use hypertensive agents such as methoxamine or
phenylephrine.

5.

PHARMACOLOGICAL PROPERTIES

5.1.

Pharmacodynamic Properties
Isosorbide dinitrate is a member of the organic nitrate group of vasodilators. It
decreases both preload and afterload as a result of respective dilatation of
venous capacitance and arteriolar resistance vessels. In left ventricular failure,
isosorbide dinitrate produces a significant increase in the ejection fraction,
stroke volume, cardiac output and tissue perfusion.
Isosorbide dinitrate decreases myocardial oxygen demand by increasing the
venous capacitance and thereby reducing ventricular end-diastolic pressure
and volume. It also influences oxygen supply, by improving the distribution
of the myocardial blood flow to the subendocardial regions.

5.2.

Pharmacokinetic Properties
The biotransformation of organic nitrates is the result of reductive hydrolysis
catalysed by the hepatic enzyme glucathione-organic nitrate reductase. The
major route of metabolism of isosorbide dinitrate in man is by enzymatic
denitration followed by formation of glucuronides. The primary initial

metabolites, isosorbide-2-mononitrate and isosorbide-5-mononitrate, have
longer half lives (2 - 5 hours) and are presumed to be responsible, at least in
part, for the therapeutic efficacy of isosorbide dinitrate.
Denitration markedly reduces its activity. Hepatic denitration is also
influenced by hepatic disease and blood flow. The terminal elimination half
life is 54.7 minutes following intravenous injection. The total plasma
clearance is 136 litres per hour.

5.3.

Pre-clinical Safety Data
No further relevant information other than that which is included in other
sections of the Summary of Product Characteristics.

6.

PHARMACEUTICAL PARTICULARS

6.1.

List of Excipients
Sodium Chloride B.P.
Sodium Hydroxide B.P.
Water for Injections B.P.

6.2.

Incompatibilities
Isosorbide dinitrate is incompatible with infusion bags and giving sets made
from PVC - loss of potency will occur on contact with PVC.

6.3.

Shelf-Life
3 years (36 months).

6.4.

Special Precautions for Storage
Protect from light.
Store below 30°C.

6.5.

Nature and Contents of Container
10ml, clear glass ampoules, glass type 1 Ph.Eur., packed in cardboard cartons
to contain 10 x 10ml ampoules.

6.6.

Instructions for Use/Handling
Solutions containing visible solid particles should not be used.
Dilute before use with a suitable vehicle such as Sodium Chloride Intravenous
Infusion.
Not for direct injection.
For administration by I.V. Infusion only.
Use by slow infusion only, with haemodynamic monitoring of the patient.
Use as directed by the physician.
Keep out of reach of children.
If only part used, discard the remaining solution.

7

MARKETING AUTHORISATION HOLDER

Mercury Pharma International Ltd
4045, Kingswood Road,
City West Business Park,
Co Dublin, Ireland
8.
MARKETING AUTHORISATION NUMBER
PL 02848/0160

9.
DATE OF FIRST AUTHORISATION/RENEWAL OF
AUTHORISATION
11/06/2010

10

DATE OF REVISION OF THE TEXT
23/08/2012

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Source: Medicines and Healthcare Products Regulatory Agency

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