Isosorbide Dinitrate

Registered South African indications:

• Angina pectoris
• Congestive cardiac failure

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to other nitrates
• Circulatory collapse
• Acute circulatory failure (shock, vascular collapse)
• Hypertrophic obstructive cardiomyopathy (inj, IR tab)
• Low filling pressure
• Severe anaemia
• Cerebral haemorrhage
• Head trauma
• Hypovolaemia
• Severe hypotension (systolic blood pressure <90mmHg)
• Haemorrhage
• Volume depletion
• Cardiac tamponade (inj, IR tab)
• Aortic and/or mitral valve stenosis (inj, IR tab)
• Closed-angle glaucoma
• Constrictive pericarditis (inj, IR tab)
• Inferior myocardial infarction with right ventricular involvement
• Myocardial infarction with low filling pressure
• Diseases associated with raised intracranial pressure (inj, IR tab)
• Cor pulmonale
• Cardiogenic shock (unless some means of maintaining an adequate diastolic pressure is undertaken)
• Coadministration with phosphodiesterase inhibitors (e.g. sildenafil, tadalafil, vardenafil)
• Coadministration with riociguat

Cautions

• Pregnancy
• Breastfeeding
• Severe renal impairment
• Severe hepatic impairment
• Elderly
• Hypothyroidism
• Malnutrition
• Hypothermia
• Orthostatic syndrome
• Continuous high doses
• Hypoxaemia or ventilation/ perfusion imbalance due to lung disease or ischaemic heart failure
• Seriously damaged myocardia
• Labile circulation
• Sodium-controlled diet
• Hypertrophic obstructive cardiomyopathy (HOCM) (ER tab)
• Constrictive pericarditis (ER tab)
• Cardiac tamponade (ER tab)
• Aortic/mitral valve stenosis (ER tab)
• Diseases associated with raised intracranial pressure (ER tab)
• G6PD deficiency
• Galactose intolerance (certain formulations)
• Lapp lactase deficiency (certain formulations)
• Glucose-galactose malabsorption (certain formulations)
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: IR tab, SL tab, ER tab, inj

Angina pectoris - prophylaxis and treatment

• Oral (SL tab): 2.5-10mg, every 2-3hrs
• Oral (IR tab): 30-120mg, dly in divided doses according to response
• Oral (ER tab): 40mg, 12-24hrly

Tab: Dosage should be gradually increased to minimise the possibility of nitrate headache and/or tolerance

Congestive cardiac failure 

• Oral (SL tab): 5-15mg, 2-3hrly

Dosage level determined by the supervising physician

For treatment of acute congestive heart failure, the sublingual form is preferable

• Oral (IR tab): 40-160mg, dly in divided doses according to response  

The optimum dosage is best determined by continuous haemodynamic monitoring. The use of isosorbide dinitrate tablets in severe congestive cardiac failure should be regarded as an adjunctive therapy to more conventional treatment (such as cardiac glycosides, diuretics)

For treatment of chronic congestive heart failure, the rapid acting sublingual form should be administered initially to stabilise the patient’s symptoms or to determine the magnitude of haemodynamic response, followed by the oral form for maintenance

Unresponsive left ventricular failure secondary to acute myocardial infarction or of various aetiology
Severe or unstable angina pectoris

• IV: 2-12mg/hr; Adjusted according to patient response; May require up to 20mg/hr
• Intracoronary: 1mg, as a bolus injection prior to balloon inflation; Max: 5mg/30min

Prepared admixtures should be given by IV infusion or with the aid of a syringe pump incorporating a glass or rigid plastic syringe

The diluted solution should never be injected directly in the form of a bolus except via the intracoronary route prior to balloon inflation. A dilution of 50% is advocated for intracoronary administration

Not established for use in children 

Pregnancy

• Caution
• No data have been reported which would indicate the possibility of adverse effect 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 if, in the opinion of the physician, the possible benefits of treatment outweigh the possible hazards

Breastfeeding

• Caution
• 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 methemoglobinemia 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 breastfeeding women

Fertility

• There is no data available on the effect on fertility in humans

Renal Impairment

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no dose adjustment recommended

Hepatic impairment

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no dose adjustment recommended

Elderly

• Caution; no dose adjustment recommended
  Dosage may be reduced in the elderly, especially where there is impairment of renal or hepatic function (tab)
  Elderly patients should be given lowest recommended adult daily doses initially and titrate upward

Porphyria Information

• Not porphyrinogenic (NP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache
• Dizziness
• Somnolence
• Asthenia
• Cerebral ischaemia
  - Drowsiness
  - Weakness

Cardiovascular Disorders

• Aggravated angina pectoris
• Tachycardia
• Circulatory collapse
  - Bradyarrhythmia
  - Syncope
  - Cardiac rhythm disturbances
• Orthostatic hypotension
• Hypotension
• Severe hypotensive responses
  - Nausea and vomiting
  - Restlessness
  - Pallor
  - Excessive perspiration
• Myocardial hypoxia
• Myocardial infarction
• Peripheral oedema

Respiratory Disorders

• Alveolar hypoventilation

Gastrointestinal Disorders

• Nausea and vomiting
• Heartburn

Endocrine and Metabolic System Disorders

• Pituitary apoplexy (in patients with undiagnosed pituitary tumours)
• Temporary hypoxaemia

Skin and Subcutaneous Tissue Disorders

• Cutaneous vasodilation, including flushing
• Allergic skin reactions
  - Rash
• Exfoliative dermatitis
• Stevens-Johnson Syndrome
• Angioedema

Sensory Disorders

• Angle-closure glaucoma

Others

• Tolerance and cross tolerance 

• Phosphodiesterase inhibitors
• Sildenafil
• Vardenafil
• Tadalafil
• Antihypertensive agents
• Beta-blockers
• Calcium channel blockers
• Vasodilators
• Angiotensin-converting enzyme inhibitors 
• Phenothiazines
• Monoamine oxidase inhibitors
• Neuroleptics
• Tricyclic antidepressants
• Dihyrdoergotamine
• Sapropterin
• Riociguat

Other interactions

• Alcohol
• Noradrenaline (norepinephrine)
• Acetylcholine  
• Histamine

None routine. Specific cases may require

• Blood pressure
• Heart rate
• Haemodynamic parameters
   

Development of tolerance and cross-tolerance

• The development of tolerance (decrease in efficacy) as well as cross tolerance towards other nitrate-type agents (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
• If the tablets are not taken as indicated with the appropriate dosing interval tolerance to the medication could develop

Incompatibilities (IV)

• Isosorbide dinitrate is 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
• 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
• 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

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. 

Tablet sublingual 5mg

• Isordil sublingual (Pharmacare) originator
• Sandoz Isosorbide Dinitrate (Sandoz)

Tablet 10mg

• Isordil (Pharmacare) originator
• Sandoz Isosorbide Dinitrate (Sandoz)

Tablet 30mg

• Isordil (Pharmacare) originator
• Sandoz Isosorbide Dinitrate (Sandoz)

Tablet tembids 40mg

• Isordil (Pharmacare) originator

Injection (per ml) 1mg

• Isoket 0.1 Solution (GSK) originator