Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Norgine Pharmaceuticals Limited, Norgine House, Widewater place, Moorhall Road, Harefield, Middlesex, UB9 6NS, UK
Hypersensitivity to the active substance, other nitrates or to any of the excipients listed in section 6.1.
These are common to all nitrates: 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.
Isoket should not be used in the treatment of cardiogenic shock (unless some means of maintaining an adequate diastolic pressure is undertaken), hypertrophic obstructive cardiomyopathy, constrictive pericarditis or cardiac tamponade.
Phosphodiesterase type-5 inhibitors (e.g. sildenafil, tadalafil and vardenafil) have been shown to potentiate the hypotensive effects of nitrates. Therefore, Isoket must not be given to patients receiving phosphodiesterase-5 inhibitors (see section 4.5).
During nitrate therapy, the soluble guanylate cyclase stimulator riociguat must not be used (see section 4.5).
Isoket should be used with caution and under medical supervision in patients who are suffering from:
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 should always be monitored and the dose adjusted according to the patient’s response.
Acute therapy with ISDN (i.v. 0.05% and 0.1%, tablets 5 and 10mg, or oromucosal spray) must not be used in patients who have recently taken phosphodiesterase inhibitors (e.g., sildenafil, tadalafil, vardenafil) the intervening 24 hours (48 hours for tadalafil).
Caution should be exercised in patients with hypoxaemia and ventilation/perfusion imbalance due to lung disease or ischaemic heart failure. As a potent vasodilator, ISDN could result in increased perfusion of poorly ventilated areas, worsening of the ventilation/perfusion imbalance, and a further decrease in the arterial partial pressure of oxygen.
During treatment with ISDN alcohol should be avoided as it may potentiate the hypotensive and vasodilating effect of ISDN (see Section 4.5).
Isoket contains 0.15mmol (3.54mg) of sodium per ml and should be taken into consideration by patients on a controlled sodium diet.
Concurrent intake of drugs with blood pressure lowering properties e.g. beta-blockers, calcium channel antagonists, vasodilators, ACE-inhibitors, monoamine oxidase inhibitors etc. and/or alcohol may potentiate the hypotensive effect of Isoket. This might also occur with neuroleptics and tricyclic antidepressants.
The concurrent intake of ISDN with ACE-inhibitors or arterial vasodilators could be a desirable interaction, unless the antihypertensive effects are excessive in which case consider reducing the dose of one or both drugs.
Also phosphodiesterase-5 inhibitors e.g. sildenafil, potentiate the hypotensive effects of Isoket. This might lead to life-threatening cardiovascular complications, see section 4.3.
Patients who have recently taken phosphodiesterase inhibitors (e.g., sildenafil, vardenafil, tadalafil) therefore must not receive acute ISDN therapy within the next 24 hours for sildenafil and vardenafil, or within the next 48 hours for tadalafil.
Reports suggest that, when administered concomitantly, Isoket may increase the blood level of dihydroergotamine and its hypertensive effect.
Sapropterin (Tetrahydrobiopterine, BH4) is a cofactor for nitric oxide synthetase. Caution is recommended during concomitant use of sapropterin-containing medicine with all agents that cause vasodilation by affecting nitric oxide (NO) metabolism or action, including classical NO donors (e.g. glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN), isosorbide 5-mononitrate (5-ISMN) and others).
The use of isosorbide dinitrate with riociguat, a soluble guanylate cyclase stimulator, is contraindicated (see section 4.3) since concomitant use can cause hypotension.
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 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 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 lactating women.
There is no data available on the effect of ISDN on fertility in humans.
As for other drugs which produce changes in blood pressure, patients taking Isoket should be warned not to drive or operate machinery if they experience dizziness or related symptoms.
Undesirable effects frequencies are defined as: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).
During administration of Isoket the following undesirable effects may be observed:
Very common: headache
Common: dizziness, somnolence
Common: tachycardia
Uncommon: angina pectoris aggravated
Common: orthostatic hypotension
Uncommon: collapse (sometimes accompanied by bradyarrhythmia and syncope).
Not known: hypotension
Uncommon: nausea, vomiting
Very rare: heartburn
Uncommon: allergic skin reactions (e.g. rash), flushing
Very rare: angioedema, Stevens-Johnson-Syndrome
Not known: exfoliative dermatitis
Common: asthenia
Severe hypotensive responses have been reported for organic nitrates including nausea, vomiting, restlessness, pallor, and excessive perspiration.
During treatment with Isoket a 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 a myocardial hypoxia.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
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.
Materials made of glass, polyethylene (PE), polypropylene (PP) or polytetrafluoroethylene (PTFE) have been shown to be suitable for infusing Isoket 1 mg/ml.
This medicinal product must not be mixed with other medicinal products except those mentioned in Section 6.6.
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