Isoket 0.5 mg/ml Solution for Infusion or Injection

Each ml contains 0.5 mg of isosorbide dinitrate.

Each 10 ml pre-filled syringe contains 5 mg of isosorbide dinitrate.

Each 50 ml bottle contains 25 mg of isosorbide dinitrate.

Excipients:

Each ml contains 3.54 mg (0.154 mmol) sodium (as sodium chloride).

Each 10 ml pre-filled syringe also contains 35.4 mg (1.54 mmol) sodium (as sodium chloride).

Each 50 ml bottle also contains 177 mg (7.7 mmol) sodium (as sodium chloride).

For a full list of excipients, see section 6.1

Solution for infusion or injection.

Clear, colourless solution.

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 to 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.

Adults, including the elderly

Intravenous route

Isoket 0.5 mg/ml (undiluted) is intended for intravenous administration by slow infusion via a syringe pump. Alternatively it can be administered as an admixture with a suitable vehicle such as Sodium Chloride Injection B.P. or Dextrose Injection B.P.

A dose of between 2mg and 12mg per hour is usually satisfactory. However, dosages up to 20mg per hour may be required. In all cases the dose administered should be adjusted to the patient response.

Intra-coronary Route

Isoket 0.5 mg/ml 10ml prefilled syringes may be used for direct administration (through a catheter by means of an adaptor, if necessary) during percutaneous transluminal coronary angioplasty.

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

Children

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

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 90 mmHg), 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).

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.

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 antagonists, vasodilators etc. and/or alcohol may potentiate the hypotensive effect of Isoket. This might also occur with neuroleptics and tricyclic antidepressants.

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.

Reports suggest that, when administered concomitantly, Isoket may increase the blood level of dihydroergotamine and its hypertensive effect.

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

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.

During administration of Isoket the following undesirable effects may be observed:

Nervous system disorders: headache, dizziness, somnolence.

Cardiac disorders: tachycardia, angina pectoris aggravated.

Vascular disorders: orthostatic hypotension, collapse (sometimes accompanied by bradyarrhythmia and syncope).

Gastrointestinal disorders: nausea, vomiting, heartburn.

Skin and subcutaneous tissue disorders: allergic skin reactions (e.g. rash), flush, angioedema, Stevens-Johnson-Syndrome, in single cases: exfoliative dermatitis.

General disorders and administration site conditions: 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.

o 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:

- 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.

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 0.7h). 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 0.57h^-1 followed by isosorbide-2-mononitrate (IS-2-MN) with 0.27h^-1and isosorbide (IS) with 0.16h^-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.

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 injection

Hydrochloric acid for pH adjustment

Sodium hydroxide 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 been shown to be suitable for infusing Isoket 0.5 mg/ml.

This medicinal product must not be mixed with other medicinal products except those mentioned in Section 6.6.

50ml glass bottles (glass type 1): 5 years as packaged for sale.

50ml glass bottles (glass type 2): 2 years as packaged for sale.

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

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 are 2-8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.

Prefilled glass syringes: 3 years

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.

50 ml glass bottles (glass type 1 or 2) with a laminated rubber stopper. The stopper consists of butyl rubber. The inner side of the stopper, coming into contact with the product is laminated with a film, consisting of a copolymer of tetrafluorethylene, ethylene and a fluorine containing vinyl monomer.

10 ml prefilled glass syringes with rubber plunger, stopper and cap and polystyrene plunger rod.

Not all pack sizes may be marketed.

Isoket contains isosorbide dinitrate in isotonic solution and is compatible with commonly employed infusion fluids, such as sodium chloride 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.

Merus Labs Luxco II S.à r.l.

26-28, rue Edward Steichen

L-2540 Luxembourg

PL 44374/0020

October 2003

August 2016