Glycopyrronium Bromide and Neostigmine Metilsulfate 0.5mg/2.5mg per ml Solution for Injection in Prefilled Syringe Taj Pharma.

  1. Name of the medicinal product

Glycopyrronium Bromide and Neostigmine Metilsulfate 0.5mg/2.5mg per ml Solution for Injection in Prefilled Syringe Taj Pharma

  1. Qualitative and quantitative composition

Each 1ml of solution contains Glycopyrronium Bromide
(Glycopyrrolate)                                  0.5mg
Neostigmine Metilsulfate                    2.5mg

Excipient with known effect:

This medicine contains less than 1 mmol sodium (23 mg) per 1ml essentially ‘sodium free’

For the full list of excipients, see section 6.1.

  1. Pharmaceutical form

A clear and colourless sterile solution for Injection in Prefilled syringe.

  1. Clinical particulars

4.1 Therapeutic indications

Reversal of residual non-depolarising (competitive) Neuromuscular block

4.2 Posology and method of administration

Posology:

Adults and elderly

1-2ml intravenously over a period of 10 to 30 seconds (equivalent to Glycopyrronium Bromide 0.5mg with Neostigmine Metilsulfate 2.5mg to Glycopyrronium Bromide 1mg with Neostigmine Metilsulfate 5mg). Alternatively 0.02ml/kg intravenously over a period of 10 to 30 seconds may be used, (equivalent to Glycopyrronium Bromide 0.01mg/kg with Neostigmine Metilsulfate 0.05mg/kg), dose may be repeated (total maximum 2ml)

Paediatric population:

0.02ml/kg intravenously over a period of 10 to 30 seconds (equivalent to Glycopyrronium Bromide 0.01mg/kg with Neostigmine Metilsulfate 0.05mg/kg).

These doses may be repeated if adequate reversal of neuromuscular blockade is not achieved. Total doses in excess of 2ml are not recommended as this dose of Neostigmine may produce depolarising neuromuscular block.

Method of administration

For intravenous injection

4.3 Contraindications

Hypersensitivity to the Glycopyrronium Bromide or Neostigmine Metilsulfate or to any of the excipients listed in section 6.1.

Glycopyrronium Bromide and Neostigmine Metilsulfate Injection should not be given to patients with known hypersensitivity to either of the two active ingredients or given to patients with mechanical obstruction of the gastrointestinal or urinary tracts. In addition, this product should not be given in conjunction with suxamethonium, as Neostigmine potentiates the depolarising myoneural blocking effects of this agent.

Anticholinesterase-antimuscarinic combinations such as neostigmine plus glycopyrronium should be avoided in patients with a prolonged QT interval.

4.4 Special warnings and precautions for use

Administer with caution to patients with bronchospasm (extreme caution), bradycardia, arrhythmias, recent myocardial infarction, epilepsy, hypotension, parkinsonism, vagotonia, peptic ulceration, hyperthyroidism, renal impairment or glaucoma.

Administration of anticholinesterase agents to patients with intestinal anastomoses may produce rupture of the anastomosis or leakage of intestinal contents.

Although Glycopyrronium Bromide and Neostigmine Metilsulfate Injection has been shown to have less impact on the cardiovascular system than Atropine with Neostigmine Metilsulfate, use with caution in patients with coronary artery disease, congestive heart failure, cardiac dysrhythmias, hypertension or thyrotoxicosis.

Quaternary ammonium compounds in large dose have been shown to block the nicotinic muscle end plate receptors. This must be evaluated prior to its administration in patients with myasthenia gravis.

Use with caution in patients with epilepsy or Parkinson’s disease.

This product should be used cautiously in pyrexial patients due to inhibition of sweating.

This medicinal product contains less than 1 mmol sodium (23mg) per dose, i.e. essentially ‘sodium free’.

4.5 Interaction with other medicinal products and other forms of interaction

Anticholinesterase drugs enhance neuromuscular transmission in voluntary and involuntary muscle in myasthenia gravis.

Non-depolarizing neuromuscular block induced by the muscle relaxants used in anesthesia; neuromuscular block induced by aminoglycoside antibiotics and antiarrhythmic agents.

Aminoglycosides -Effects of Neostigmine antagonised by aminoglycosides

Chloroquine and Hydroxychloroquine – effects of Neostigmine may be diminished because of potential for Chloroquine and Hydroxychloroquine to increase symptoms of myasthenia gravis

Many drugs have antimuscarinic effects; concomitant use of two or more such drugs can increase side-effects such as dry mouth, urine retention, and constipation; concomitant use can also lead to confusion in the elderly.

Clindamycin – Effects of Neostigmine antagonised by Clindamycin

Lithium – Effects of Neostigmine antagonised by lithium

Muscle Relaxants, non-depolarising – Neostigmine antagonises effects of non- depolarising muscle relaxants

Polymyxins – Effects of Neostigmine antagonised by polymyxins

Procainamide – Effects of Neostigmine antagonised by Procainamide

Propafenone -Effects of Neostigmine possibly antagonised by Propafenone

Propranolol -Effects of Neostigmine antagonised by Propranolol

Quinidine -Effects of Neostigmine antagonised by Quinidine

Suxamethonium -Neostigmine enhances effects of Suxamethonium

Antimuscarinics – Effects of parasympathomimetics antagonised by antimuscarinics

4.6 Fertility, pregnancy and lactation

Pregnancy

For use as indicated, animal studies (see section 5.3) are of very limited relevance. Use in human pregnancy has not been systematically evaluated.

The use of Neostigmine in pregnant patients with myasthenia gravis has revealed no untoward effect of the drug on the course of pregnancy.

Breast-feeding:

May reach breast milk but in amounts probably too small to be harmful.

4.7 Effects on ability to drive and use machines

Not applicable.

4.8 Undesirable effects

The Glycopyrronium Bromide component of Glycopyrrolate – Neostigmine Metilsulfate Injection can give rise to a dry mouth, difficulty in micturition, cardiac dysrhythmias, and disturbances of visual accommodation and inhibition of sweating.

The Neostigmine component of Glycopyrronium Bromide and Neostigmine Metilsulfate Injection can give rise to nausea, vomiting, increased salivation, diarrhoea, abdominal cramps (more marked with higher doses); signs of overdosage include bronchoconstriction, increased bronchial secretions, lacrimation, excessive sweating, involuntary defecation and micturition, miosis, nystagmus, bradycardia, photophobia, heart block, arrhythmias, hypotension, agitation, excessive dreaming, and weakness eventually leading to fasciculation and paralysis.

Glycopyrronium-Neostigmine component of injection can give rise to hypersensitivity, angioedema and anaphylactic reaction. Their frequency is not known

Hypersensitivity

If severe Neostigmine induced muscarinic side effects occur (bradycardia, hypotension, increased or pharyngeal secretions, decreased cardiac conduction rate, bronchospasm or increased gastrointestinal activity etc), these may be treated by the intravenous administration of Glycopyrronium Bromide Injection 200 – 600 micrograms (0.2 – 0.6mg) or atropine 400 – 1200 micrograms (0.4 – 1.2mg). Report any Suspected adverse reaction directly.

4.9 Overdose

The treatment of overdosage depends on whether signs of anticholinesterase or anticholinergic overdose is the predominant presenting feature.

Signs of Neostigmine overdosage include those of muscarinic effects (nausea, vomiting, increased salivation, diarrhoea, abdominal cramps (more marked with higher doses); signs of overdosage include bronchoconstriction, increased bronchial secretions, lacrimation, excessive sweating, involuntary defecation and micturition, miosis, nystagmus, bradycardia, heart block, arrhythmias, hypotension, agitation, excessive dreaming, and weakness eventually leading to fasciculation and paralysis.) may be treated by administration of Glycopyrronium Bromide Injection 0.2 – 0.6mg or atropine 0.4 – 1.2mg. In severe cases, respiratory depression may occur, artificial ventilation may be necessary in such patients.

Signs of Glycopyrronium Bromide overdose (tachycardia, ventricular irritability etc.) may be treated by intravenous administration of Neostigmine Metilsulfate 1.0mg for each 1.0mg of Glycopyrronium Bromide known to have been administered. As Glycopyrronium Bromide is a quaternary ammonium agent, symptoms of overdosage are peripheral rather than central in nature. Centrally acting anticholinesterase drugs such as physostigmine are therefore unnecessary to treat Glycopyrronium Bromide overdosage.

  1. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anticholinesterases

Glycopyrronium Bromide is a quaternary ammonium anticholinergic agent. The quaternary ammonium moiety renders Glycopyrronium Bromide highly ionised at physiological pH and it thus penetrates the blood brain and placental barriers poorly. Glycopyrronium Bromide has a more gradual onset and longer duration of action than atropine.

Neostigmine Metilsulfate is a quaternary ammonium anticholinesterase.

Glycopyrronium Bromide and Neostigmine Metilsulfate Injection is associated with less initial tachycardia and better protection against the subsequent cholinergic effects of Neostigmine Metilsulfate than a mixture of Atropine and Neostigmine Metilsulfate.

Neostigmine is used mainly for its effects on skeletal muscle in myasthenia gravis and in anaesthesia for termination of the effects of competitive neuromuscular blocking drugs.

In addition, residual central anticholinergic effects are minimised due to the limited penetration of Glycopyrronium Bromide into the central nervous system. Administration of Glycopyrronium Bromide with Neostigmine Metilsulfate is associated with greater cardiostability than administration of Glycopyrronium Bromide and Neostigmine Metilsulfate separately.

5.2 Pharmacokinetic properties

Absoprtion

Glycopyrronium Bromide and Neostigmine Metilsulfate are routinely administered simultaneously to reverse residual non-depolarising (competitive) neuromuscular block. Numerous clinical studies, which demonstrate this to be a safe and effective combination, have been published.

Over 90% of the Glycopyrronium Bromide disappears from serum within 5 minutes following intravenous administration. The drug is rapidly excreted into bile with highest concentrations being found 30 to 60 minutes after dosing with some product being detected up to 48 hours after administration.

Distribution

Glycopyrronium Bromide is also rapidly excreted into urine with the highest concentrations being found within 3 hours of administration. Over 85% of product is excreted within 48 hours. It has subsequently been confirmed in a single dose pharmacokinetic study using radio immunological assay procedures that Glycopyrronium Bromide was rapidly distributed and/or excreted after intravenous administration. The terminal elimination phase was relatively slow with quantifiable plasma levels remaining up to 8 hours after administration. The elimination half-life was 1.7 hours.

Neostigmine Metilsulfate is extensively hydrolyzed in the blood. In one study, following intravenous administration, the plasma concentration declined to about 8% of its initial value after 5 minutes with a distribution half-life of less than one minute.

Elimination

Elimination half-life ranged from about 15-30 minutes. Trace amounts of Neostigmine Metilsulfate could be detected in the plasma after one hour. In a study in non-myasthenic patients, the plasma half-life was 0.89 hours.

5.3 Preclinical safety data

No further relevant information other than that, which is included in other sections of the Summary of Product Characteristics.

  1. Pharmaceutical particulars

6.1 List of excipients

Citric Acid, Sodium Hydroxide, Citric Acid Solution, Water for Injections, Sodium Phosphate

6.2 Incompatibilities

Do not mix Glycopyrronium Bromide and Neostigmine Metilsulfate Injection with any other preparation.

6.3 Shelf life

12 months.

6.4 Special precautions for storage

Do not store above 25°C.

Keep the container in the outer carton to protect from light.

6.5 Nature and contents of container

A clear and colourless sterile solution for Injection in Prefilled syringe packed accordingly.

6.6 Special precautions for disposal and other handling

If only part of an Prefilled Syringe is used, discard the remaining solution. Keep out of the sight and reach of children.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

  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

 

Glycopyrronium Bromide and Neostigmine Metilsulfate 0.5mg/2.5mg per ml Solution for Injection in prefilled syringe Taj Pharma

PACKAGE LEAFLET: INFORMATION FOR THE USER

Glycopyrronium Bromide

Neostigmine Metilsulfate

(referred to as Glycopyrronium and Neostigmine Injection in this leaflet)

Read this leaflet carefully before you are given 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, pharmacist or nurse.
  • If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet:

  1. What Glycopyrronium and Neostigmine Injection is and what it is used for
    2. What you need to know before you are given Glycopyrronium and Neostigmine Injection.
    3. How Glycopyrronium and Neostigmine Injection is given.
    4. Possible side effects.
    5. How to store Glycopyrronium and Neostigmine Injection.
    6. Contents of the pack and other information
  2. What Glycopyrronium and Neostigmine Injection is and what it is used for

Glycopyrronium-Neostigmine Injection contains two active ingredients:

  • Glycopyrronium Bromide belongs to a group of medicines called anticholinergic drugs. It is used to counteract some unwanted effects that may occur with Neostigmine.
  • Neostigmine belongs to a group of medicines called cholinesterase inhibitors. It can be used to reverse the effects of a type of muscle-relaxing drug used during operations called non-depolarising muscle relaxants.

Glycopyrronium and Neostigmine Injection is used to reverse the muscle relaxation produced by non-depolarising muscle relaxants.

  1. What you need to know before you are given Glycopyrronium and Neostigmine Injection.

You should not be given Glycopyrronium and Neostigmine Injection if:

  • you are allergic to Glycopyrronium Bromide or Neostigmine Metilsulfate, or to any of the other ingredients in this medicine, (listed in section 6).
  • you think you may have a blockage in your intestine or urinary passage.
  • you have been given suxamethonium, a drug used to relax your muscles during surgery.

Warnings and precautions

Take special care with Glycopyrronium and Neostigmine Injection. Tell your doctor if:

  • you are pregnant or breast feeding;
  • you suffer from glaucoma (increased pressure in the eye);
  • you have had a recent operation on your intestines;
  • you suffer from stomach ulcers;
  • you suffer from asthma attacks, wheezing or difficulty breathing;
  • you have a very slow heart beat (less than 60 beats per minute) or you are suffering from coronary artery disease; heart failure, irregular heartbeats or high or low blood pressure;
  • you have recently suffered a heart attack;
  • you have an overactive thyroid gland;
  • you suffer from kidney problems;
  • you suffer from myasthenia gravis (a disease resulting in severe muscle weakness and fatigue);
  • you are suffering from epilepsy or Parkinson’s;
  • you have a fever;
  • you suffer from enlarged prostate gland;
  • you suffer from obstruction of the stomach (pyloric stenosis) or bowel causing vomiting, abdominal pain and swelling (paralytic ileus);
  • you are under the influence of anaesthetics like Cyclopropane or Halothane.

Other medicines and Glycopyrronium and Neostigmine Injection

Tell your doctor or nurse if you are taking, have recently taken or might take any other medicines.

Medicines which may interact with Glycopyrronium and Neostigmine Injection include:

  • suxamethonium, a drug used to relax your muscles during surgery;
  • medicines used to treat bacterial infections known as aminoglycoside antibiotics, such as gentamicin and streptomycin;
  • medicines used to treat bacterial infections known as polymyxins, such as colistimethate sodium;
  • clindamycin, a medicine used to treat bacterial infections;
  • medicines used to treat an irregular heartbeat, such as procainamide, propafenone and quinidine;
  • chloroquine, a medicine used to treat and prevent malaria;
  • lithium, a medicine used to treat bipolar disorder;
  • medicines used to relax your muscles during surgery known as non-depolarising muscle relaxants
  • propranolol, a medicine used to treat a number of conditions including migraines, heart problems and anxiety
  • a type of medicine used to dry body secretions during surgery, known as antimuscarinics
  • medicines to treat depressions (e.g. Tricyclic Antidepressant, MAOIs)
  • Amantadine which is used to treat Parkinson’s disease or viral infections
  • medicines used to treat mental illness (e.g. Nefopam)

Important information about some of the other ingredients in Glycopyrronium-Neostigmine Injection

This injection contains less than 1mmol (23mg) of sodium per 1ml (essentially ‘sodium-free’).

Pregnancy, breast-feeding and fertility.

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before being given this medicine.

Driving and using machines.

After having Glycopyrronium and Neostigmine Injection you should not drive or operate machinery until you have been advised that it is safe to do so because it can cause blurred vision and other effects that may affect your ability to do so. Do not drive or use machinery until these effects have gone

  1. How Glycopyrronium and Neostigmine Injection is given.

Glycopyrronium and Neostigmine Injection is given by injection into a vein.

Your doctor will decide the correct dose for you depending on your circumstances. Your dose may be calculated according to your weight.

Recommended dose:

Adults and elderly patients:

Your doctor will inject 1-2ml into a vein over a period of 10 to 30 seconds. Alternatively, your doctor may inject a dose of 0.02ml per kg body weight into a vein over a period of 10 to 30 seconds, up to a maximum of 2ml.

Paediatric patients:

Your doctor will inject 0.02ml per kg body weight into a vein over a period of 10 to 30 seconds, up to a maximum of 2ml.

If you are given too much Glycopyrronium and Neostigmine Injection

This medicine will be given to you in hospital so it is unlikely you will receive too much, however if you experience any of the following symptoms you should tell your doctor or nurse immediately:

  • difficulty breathing
  • you have too much saliva or increased sweating
  • watering eyes or pinpoint pupils
  • losing control of your bowels or bladder
  • an unusually fast or slow or irregular heartbeat, or low blood pressure (you may feel faint)
  • feeling agitated or an increase in the amount you dream
  • weakness, muscle twitching or paralysis

If you have any further questions about this medicine, ask your doctor or nurse.

  1. Possible side effects

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

Consult a doctor straight away if you notice any of the following symptoms – you may need urgent medical treatment:

Swelling mainly of the face, lips or throat which makes it difficult to swallow or breathe, itching and rashes. This could be a sign of a severe allergic reaction or angioedema (frequency not known, cannot be estimated from the available data).

Tell your doctor or nurse if you notice any of the following symptoms:

  • a dry mouth;
  • difficulty in passing urine;
  • blurred vision;
  • absence of sweating;
  • a very slow heartbeat, palpitations or irregular heartbeats;
  • too much saliva;
  • wheeziness;
  • stomach cramps, feeling sick (nausea), or being sick (vomiting);
  • diarrhoea;
  • hypotension;
  • intolerance to light;
  • weakness;
  • increased lung secretions;
  • increased secretions of stomach;
  • increased sweating;
  • confusion;
  • increased pressure in eye (glaucoma);

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly (see details below). By reporting side effects you can help provide more information on the safety of this medicine.

  1. How to store Glycopyrronium and Neostigmine Injection.

Keep out of the sight and reach of children.

Do not store above 25°C. Keep the container in the outer carton to protect from light.

You should not be given this medicine after the expiry date which is stated on the label and carton after EXP, or if it shows signs of deterioration. The expiry date refers to the last day of that month. The doctor or nurse will check this.

If only part of  prefilled syringe is used the remaining solution should be discarded.

  1. Contents of the pack and other information

What Glycopyrronium and Neostigmine Injection contains.

The active substances are Glycopyrronium Bromide and Neostigmine Metilsulfate. Each 1ml of Glycopyrronium and Neostigmine Injection in prefilled syringe contains 0.5mg of Glycopyrronium Bromide and 2.5mg of Neostigmine Metilsulfate.

The other ingredients are sodium phosphate, citric acid monohydrate, citric acid solution, sodium hydroxide and water for injections.

What Glycopyrronium and Neostigmine Injection looks like and contents of the pack.

Glycopyrronium and Neostigmine Injection is a clear, colourless, sterile solution for injection in prefilled syringe.

Glycopyrronium and Neostigmine Injection is available in prefilled syringe each containing 1ml of solution. Each carton supplied contains ten 1ml  prefilled syringes.

  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