Isoket 1 mg/ml concentrate for solution for injection or infusion

1. Intravenous

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.

2. Intra-coronary

Isoket is indicated during percutaneous transluminal coronary angioplasty to facilitate prolongation of balloon inflation and to prevent or relieve coronary spasm.

Posology

Adults, including the elderly population

Intravenous route

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.

Intra-coronary Route

The usual dose is 1 mg given as a bolus injection prior to balloon inflation. Further doses maybe given not exceeding 5 mg within a 30 minute period.

Paediatric population

The safety and efficacy of Isoket has not yet been established in children.

Method of administration:

Isoket is a concentrated solution and must be diluted prior use. The diluted solution should never be injected directly in the form of a bolus except via the intra-coronary route prior to balloon inflation. A dilution of 50% is advocated for intracoronary administration.

Isoket can be administered as an intravenous admixture with a suitable vehicle, see Section 6.6.

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.

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:

• hypothyroidism

• malnutrition

• severe liver or renal disease

• hypothermia

• orthostatic syndrome

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).

Hypoxaemia

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.

Pregnancy and lactation

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.

Fertility

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:

Nervous system disorders:

very common: headache

common: dizziness, somnolence.

Cardiac disorders:

common: tachycardia

uncommon: angina pectoris aggravated.

Vascular disorders:

common: orthostatic hypotension

uncommon: collapse (sometimes accompanied by bradyarrhythmia and syncope).

not known: hypotension

Gastrointestinal disorders:

uncommon: nausea, vomiting

very rare: heartburn.

Skin and subcutaneous tissue disorders:

uncommon: allergic skin reactions (e.g. 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.

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 of suspected adverse reactions

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.

Symptoms:

• 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 Isoket may cause this adverse reaction.

• In very high doses the intracranial pressure may be increased. This might lead to cerebral symptoms.

General procedure:

• Stop delivery of the drug

• General procedures in the event of nitrate-related hypotension:

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

• Resuscitation measures

In case of signs of respiratory and circulatory arrest, initiate resuscitation measures immediately.

Pharmacotherapeutic group: Vasodilators used in cardiac diseases, organic nitrates, ATC Code: CO1D A08

Pharmacodynamics:

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.

Isosorbide dinitrate (ISDN) 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 rates 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 2.5 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.

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 and carcinogenicity:

No evidence for mutagenic effect was found in both in vitro and in vivo tests.

A long-term study in rats did not provide any evidence for carcinogenicity.

Sodium chloride

Water for injections

Sodium hydroxide (for pH-adjustment)

Hydrochloric acid solution (for pH-adjustment)

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 proven 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.

5 years, as packaged for sale.

Open ampoules should be used immediately and any unused drug discarded.

Once diluted, chemical and physical in-use stability for 24 hours at 2-8ºC 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 2-8ºC, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.

Unopened: There are no special precautions for storage of the product as packaged for sale.

Once diluted: See Section 6.3 for storage conditions of the diluted solution.

Ten 10 ml clear glass ampoules.

Isoket 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.

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.

Isoket may be infused slowly using a syringe pump with glass or plastic syringe, see Section 6.2 for suitable materials.

Example of admixture preparation

To obtain a dose of 6 mg per hour, add 50 ml of Isoket 1 mg/ml to 450 ml of a suitable vehicle, under aseptic conditions. The resultant admixture (500 ml) contains 100 µg/ml (1mg/10ml) isosorbide dinitrate. An infusion rate of 60ml 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, 100ml of Isoket 1 mg/ml may be diluted to 500ml 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.