Isosorbide Dinitrate Solution for Injection 0.05% w/v (5mg/10ml) Taj Pharma

  1. NAME OF THE MEDICINAL PRODUCT

Isosorbide Dinitrate Solution for Injection 0.05% w/v (5mg/10ml) Taj Pharma
Isosorbide Dinitrate Solution for Injection 0.1% w/v (10mg/10ml) Taj Pharma

  1. QUALITATIVE AND QUANTITATIVE COMPOSITIONa) Each ml of injection contains:
    Isosorbide dinitrate……………….0.5mg (0.05% w/v)
    b) Each ml of injection contains:

    Isosorbide dinitrate……………….1mg (0.1% w/v)

Each 10mL ampoule contains 10mg of isosorbide dinitrate and 36mg of sodium.

  1. PHARMACEUTICAL FORM

solution for injection or infusion.

  1. CLINICAL PARTICULARS

4.1 Therapeutic indications

  • Treatment of unresponsive left ventricular failure, secondary to acute myocardial infarction.
  • Unresponsive left ventricular failure of various aetiologies.
  • Severe or unstable angina pectoris.
  • To facilitate or prolong balloon inflation and to prevent or relieve coronary spasm during percutaneous transluminal coronary angioplasty.

4.2 Posology and method of administration

Dosage: Adults, including the elderly.

Isosorbide Dinitrate is a concentrated solution. It should never be injected directly and must be diluted.

Avoid administration through PVC or PU tubing and giving sets, because of adsorption of ISDN onto plastic.

Intravenous administration: Dosage should be adjusted according to patient response. Typically, a dose of between 2mg and 12mg per hour is suitable, although doses of up to 20mg per hour may be necessary.

Prepared admixtures are always given by intravenous infusion or using a syringe pump incorporating a glass or rigid plastic syringe (see section 6.6). The patient’s blood pressure and pulse should be monitored closely during administration.

Intracoronary administration: A dilution of 50% is recommended. The usual dose is 1mg given as a bolus injection prior to balloon inflation. Additional doses may be given, not exceeding 5mg over 30 minutes.

The safety and efficacy of Isosorbide Dinitrate has not been established in children.

Isosorbide Dinitrate is presented in 10mL ampoules and 50mL vials intended for single use only.

4.3 Contraindications

Use of Isosorbide Dinitrate is contraindicated in patients with known hypersensitivity to nitrates, marked anaemia, cerebral haemorrhage, head trauma, diseases associated with an increased intracranial pressure, hypovolaemia, severe hypotension (systolic blood pressure less than 90mm Hg), aortic and/or mitral valve stenosis, closed angle glaucoma.

Isosorbide Dinitrate must not be used in cases of circulatory collapse or low filling pressure.

Treatment of cardiogenic shock with Isosorbide Dinitrate should only be undertaken if means of maintaining an adequate diastolic pressure is available.

Isosorbide Dinitrate should not be used in the treatment of 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, and its co-administration with nitrates or nitric oxide donors is therefore contraindicated (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
  • 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.

Isosorbide Dinitrate contains 0.15mmol (3.6mg) of sodium per mL and should be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

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 isosorbide dinitrate. This might also occur with neuroleptics and tricyclic antidepressants.

Also phosphodiesterase-5 inhibitors e.g. sildenafil, potentiate the hypotensive effects of isosorbide dinitrate. This might lead to life-threatening cardiovascular complications, see section 4.3.

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

4.6 Pregnancy and lactation

The safety of this medicinal product for human use in pregnancy has not been established. However, no data have been reported that suggest adverse effects occur as a result of using isosorbide dinitrate during pregnancy. Isosorbide dinitrate should only be used during pregnancy and lactation if the benefits of treatment outweigh the possible hazards.

4.7 Effects on ability to drive and use machines

As for other drugs which produce changes in blood pressure, patients taking Isosorbide Dinitrate should be warned not to drive or operate machinery if they experience dizziness or related symptoms.

4.8 Undesirable effects

During administration of Isosorbide Dinitrate 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 Isosorbide Dinitrate 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 at: Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

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 isosorbide dinitrate 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.
  • 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.

  1. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Vasodilators used in cardiac diseases – organic nitrates

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.

5.2 Pharmacokinetic properties

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 rate of formation of the metabolites has been calculated for isosorbide-5- mononitrate (IS-5-MN) with 0.57 h-1 followed by isosorbide-2-mononitrate (IS-2-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.

5.3 Preclinical safety data

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.

  1. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium Chloride

Water for Injections

6.2 Incompatibilities

The use of polyvinyl chloride (PVC) or polyurethane (PU) giving sets and containers should be avoided as significant losses of the active ingredient by adsorption can occur.

Materials made of polyethylene (PE), Polypropylene (PP) or polytetrafluroethylene (PTFE) have been proven to be suitable for infusing this medicine.

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

6.3 Shelf life

Unopened: 24 months.

After first opening: once opened, the product should be used immediately and any unused drug discarded.

Isosorbide dinitrate solutions diluted with sodium chloride or glucose have been shown to be chemically and physically stable for 72 hours at 25°C, when stored in polypropylene or glass containers, protected from light.

From a microbiological point of view, the product should be used immediately. 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 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Keep container (ampoules or vials) in the outer carton to protect from light. Store vials upright.

6.5 Nature and contents of container

Isosorbide Dinitrate 0.1% w/v Concentrate for Solution for Injection or Infusion is presented in 10mL clear Type I glass ampoules and in 50mL vials made from clear Type II glass, sealed with a bromobutyl rubber stopper and an aluminium tamper proof flip-top cap. The product is packed into cartons containing 10 ampoules, 1 vial or 10 vials. Both pack sizes of vials may not be available at the same time.

6.6 Special precautions for disposal and other handling

The injection is for single dose use only.

The injection should not be used if particles are present.

Isosorbide Dinitrate is a concentrate. Once opened, the product should be used immediately and any unused drug discarded.

Isosorbide Dinitrate is compatible with commonly employed infusion fluids. It is compatible with glass infusion bottles and infusion packs made from polyethylene (PE), Polypropylene (PP) or polytetrafluroethylene (PTFE). A syringe pump with a glass or plastic syringe may also be used for infusion.

Example of admixture preparation

To obtain a dose of 6 mg per hour, add 50 mL of Isosorbide Dinitrate 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 Isosorbide Dinitrate 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.

  1. MANUFACTURED IN INDIA BY:


TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

ISOSORBIDE DINITRATE SOLUTION FOR INJECTION
0.1% W/V / 0.05% W/V
TAJ PHARMA

PACKAGE LEAFLET: INFORMATION FOR THE USER

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

  • Keep this leaflet. You may need to read it again
  • If you have any further questions, ask your doctor or pharmacist.
  • If you get any side effects, talk to your doctor or pharmacist.
    This includes any possible side effects not listed in this leaflet.

WHAT IS IN THIS LEAFLET:

  1. What Isosorbide Dinitrate is and what it is used for
  2. What you need to know before you are given Isosorbide Dinitrate
  3. How to use Isosorbide Dinitrate
  4. Possible Side Effects
  5. How to store Isosorbide Dinitrate
  6. Contents of the pack and other information1. WHAT ISOSORBIDE DINITRATE IS AND WHAT IT IS USED FOR

Isosorbide dinitrate, the active ingredient, belongs to a group of medicines called vasodilators used in the treatment of heart disease. It works by widening the arteries and veins so decreasing the resistance to blood flow and lowering blood pressure.

This medicine is a concentrated solution for injection or infusion and is used for the treatment of heart problems. It is specifically used for:

  • Treatment of severe chest pain (angina) which may start suddenly and gets increasingly worse
  • Treatment of heart failure, which may have occurred after a heart attack
  • Surgical procedures treating narrowing of heart arteries
  1. WHAT YOU NEED TO KNOW BEFORE YOU USE ISOSORBIDE DINITRATE

Please tell your doctor if you are taking any other medication.

DO NOT use Isosorbide Dinitrate 0.1% w/v Concentrate for Solution for Injection or Infusion if:

  • You are allergic to isosorbide dinitrate or any other medication containing nitrate, mononitrate or dinitrate or any of the other ingredients listed in this medicine (listed in section 6)
  • You have ever had a ruptured blood vessel in your brain (cerebral haemorrhage)
  • You have had a head injury (head trauma) or raised intracranial pressure (high pressure within your skull)
  • You suffer from anaemia (reduced number of red blood cells or iron level)
  • You have low blood pressure
  • Your blood has stopped circulating around your body properly (circulatory failure)
  • You have cardiogenic shock (your heart is not delivering enough oxygen around your body)
  • You have constrictive pericarditis (inflammation of the sack-like covering of the heart)
  • You have cardiac tamponade or hypertrophic obstructive cardiomyopathy (conditions which affect the ability of your heart to function as a pump)
  • You have aortic or mitral valve stenosis (narrowing of the heart valves)
  • You have a low blood volume because of injury or another reason
  • You have an eye disease called glaucoma
  • You have been taking sildenafil or any other phosphodiesterase inhibitor

If any of the above applies to you talk to your doctor or pharmacist.

Warnings and Precautions

Talk to your doctor or pharmacist before using Isosorbide Dinitrate 0.1% w/v Concentrate for Solution for Injection or Infusion if:

  • You are pregnant or breastfeeding
  • You have hypothyroidism (an underactive thyroid gland which can cause tiredness or weight gain)
  • You are malnourished (severely underfed)
  • You suffer from hypothermia (a very low body temperature)
  • You suffer from liver or kidney disease
  • You have other heart problems or a family history of heart problems
  • You suffer from orthostatic syndrome (where you may have a rapid heart rate and light-headedness on standing)

Other medicines and Isosorbide Dinitrate 0.1% w/v Concentrate for Solution for Injection or Infusion

Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines.

You should not be given Isosorbide Dinitrate with phosphodiesterase inhibitors such as Sildenafil (“Viagra”) used for impotence. Using Isosorbide Dinitrate with these medicines could cause your blood pressure to fall to a dangerously low level.

It is especially important to tell your doctor or pharmacist if you are taking any of the following medicines:

  • Medicines to lower your blood pressure. They could increase the effect of Isosorbide Dinitrate and lower your blood pressure too much.
  • Tricyclic antidepressants (used to treat depression) and neuroleptics (used to treat anxiety). These may also increase the effect of Isosorbide Dinitrate.
  • Dihydroergotamine (used to treat migraine). This could increase your blood pressure too much.
  • Any other medicine, including medicines obtained without a prescription.
  • Sapropterin used for phenylketonuria (PKU).

Using Isosorbide Dinitrate 0.1% w/v Concentrate for Solution for Injection or Infusion with alcohol

Do not drink alcohol. It could increase the effect of Isosorbide Dinitrate and lower your blood pressure too much. If this happens, you may feel dizzy or faint.

Pregnancy and breast-feeding

If you are pregnant, trying to become pregnant or breast-feeding, ask your doctor or pharmacist for advice before being given Isosorbide Dinitrate 0.1% w/v Concentrate for Solution for Injection or Infusion. Your doctor will decide whether you should be given this medicine.

Driving and using machines

Isosorbide Dinitrate may give you a headache, or make you feel dizzy or tired. If this happens to you, do not drive or operate machinery.

Isosorbide Dinitrate 0.1% w/v Concentrate for Solution for Injection or Infusion contains Sodium Chloride

This medicine contains less than 1mmol sodium (23mg) per 1mg per 1mL, that is to say it is essentially ‘sodium-free’.

  1. HOW TO USE ISOSORBIDE DINITRATE

Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

The doctor will decide what dose of this medicine you should be given. Check the label carefully. If you are not sure, ask your doctor, nurse or pharmacist.

This medicine must be diluted before use with sodium chloride or glucose. It should never be used undiluted.

The recommended dose is:

Adults

This medicine is either given by infusion into a vein or by direct injection into the coronary artery. Doses will be adjusted by your doctor, but the usual dose is between 2mg and 12mg per hour, although sometimes as much as 20mg per hour is necessary. The normal dose for direct injection into the coronary artery is 1mg. Further doses may be given if your doctor thinks it necessary.

The injection is for single use only, so once the ampoule or vial is opened the medicine should be used immediately and any unused medicine discarded.

As this medicine is used in hospital, your heartbeat (pulse) and blood pressure will be carefully monitored whilst you are being given Isosorbide Dinitrate. This is to make sure that your medicine is working properly and that the dose you are taking is right for you.

Use in Children

This medicine is not suitable for children. If you have any further questions about the use of this medicine, ask your doctor or pharmacist.

If you are given more Isosorbide Dinitrate 0.1% w/v Concentrate for Solution for Injection or Infusion than you should

Tell your doctor as soon as possible. If you are a medical practitioner administering this medicine please refer to the Summary of Product Characteristics.

An overdose of Isosorbide Dinitrate may cause your blood pressure to be too low resulting in paleness, sweating, weak pulse, fast heartbeat, light-headedness on standing, headache, weakness, dizziness, feeling sick, being sick and diarrhoea. If you have any concerns about this tell your doctor or nurse.

If a dose of Isosorbide Dinitrate 0.1% w/v Concentrate for Solution for Injection or Infusion is not given at the correct time

The dose should be given as soon as it is remembered. The next dose should be given at the usual time. Do not take a double dose to make up for a forgotten dose.

  1. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.

Stop taking this medicine and tell your doctor immediately if you experience:

  • Swelling of the face, lips or throat which makes it difficult to swallow or breathe, as well as itching and rashes. This could be a sign of severe allergic reaction.
  • Fainting which is sometimes accompanied by a slowing heartbeat
  • Swelling of the face or blistering of the skin, mouth, eyes or genitals (Stevens-Johnson syndrome)

Other side effects

  • Headache
  • Drowsiness
  • Weakness
  • Nausea
  • Feeling faint or dizzy as this may be caused by a reduced blood flow to the brain and heart
  • Skin rash or flushing
  • Dizziness
  • Increased heartbeat
  • Light-headedness on standing
  • Vomiting
  • Worsening symptoms of angina (chest pain)
  • Heartburn

Your pulse and blood pressure may be monitored during administration (because of these effects).

Tell your doctor, nurse or pharmacist immediately if you think you have any of these, or other problems.

Reporting of Side Effects

If you get any side effects, talk to your doctor, nurse or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme at: Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects you can help provide more information on the safety of this medicine.

  1. HOW TO STORE ISOSORBIDE DINITRATE
  • Keep this medicine out of the sight and reach of children.
  • The medicine has an expiry date printed on the ampoule or vial and carton label. Do not use the medicine after the expiry date. Before use the doctor or nurse will check the medicine has not passed this date and that the medicine does not show any sign of deterioration. The expiry date refers to the last day of the month.
  • After the expiry date, return any unused medicine to a pharmacy.
  • Only use this medicine if it is particle free.
  • This medicine is for single use only, so once the ampoule or vial is opened the medicine should be used immediately and any unused medicine discarded.
  • Keep the container in the outer carton to protect it from light.
  • Do not throw away any medicines via waste water. These measures will help to protect the environment.
  1. CONTENTS OF THE PACK AND OTHER INFORMATIONa) Each ml of injection contains:
    Isosorbide dinitrate……………….0.5mg (0.05% w/v)b) Each ml of injection contains:
    Isosorbide dinitrate……………….1mg (0.1% w/v)

Each 10mL ampoule contains 10mg of isosorbide dinitrate and 36mg of sodium.

The other ingredients are sodium chloride and Water for Injections.

What Isosorbide Dinitrate 0.1% w/v Concentrate for Solution for Injection or Infusion looks like and contents of the pack

This medicine is a clear and colourless solution. This medicine comes in 10mL single use ampoules and 50mL single use vials. The medicine is packed into cartons containing 10 ampoules, 1 vial or 10 vials. Both pack sizes of vials may not be available at the same time.

  1. MANUFACTURED IN INDIA BY:

TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

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