1. NAME OF THE MEDICINAL PRODUCT

Glycopyrrolate and Neostigmine 0.5mg+2.5mg/5ml Methylsulfate Injection Taj Pharma

  1. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1ml of solution contains 0.5mg of glycopyrrolate and 2.5mg of neostigmine Methylsulfate.

Excipient with known effect

Each 1 ml contains 3 mg (0.13 mmol) sodium

For the full list of excipients, see section 6.1.

  1. PHARMACEUTICAL FORM

Solution for Injection.

Clear, colourless sterile solution for injection intended for parenteral administration presented in 1ml clear, type 1, Ph. Eur. glass ampoules.

  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: 1-2 ml intravenously over a period of 10-30 seconds [equivalent to neostigmine Methylsulfate 2500 micrograms (2.5mg) with glycopyrrolate 500 micrograms (0.5mg) to neostigmine Methylsulfate 5000 micrograms (5mg) with glycopyrrolate 1000 micrograms (1mg)].

Alternatively 0.02ml/kg intravenously over a period of 10-30 seconds may be used [equivalent to neostigmine Methylsulfate 50 micrograms/kg (0.05mg/kg) with glycopyrrolate 10 micrograms/kg (0.01mg/kg)].

Paediatric population: 0.02ml/kg intravenously over a period of 10-30 seconds [equivalent to neostigmine Methylsulfate 50 micrograms/kg (0.05mg/kg) with glycopyrrolate 10 micrograms/kg (0.01mg/kg)]. Alternatively, dilute to 10ml with Water for Injections BP or Sodium Chloride injection BP 0.9% w/v and administer 1ml per 5kg bodyweight.

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

Glycopyrrolate-Neostigmine injection is for intravenous administration

4.3 Contraindications

Hypersensitivity to the two active substances or to any of the excipients listed in section 6.1.

Glycopyrrolate and Neostigmine Injection should not be given to patients with mechanical obstruction of the gastrointestinal or urinary tracts.

Glycopyrrolate-Neostigmine Injection 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 glycopyrrolate 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), or severe bradycardia arrhythmias, recent myocardial infarction, hypotension, vagotonia, peptic ulceration, hyperthyroidism or renal impairment. Administration of anticholinesterase agents to patients with intestinal anastomosis may produce rupture of the anastomosis or leakage of intestinal contents. Although Glycopyrrolate-Neostigmine Injection has been shown to have less impact on the cardiovascular system than atropine with neostigmine Methylsulfate, use with caution in patients with coronary artery disease, congestive heart failure, cardiac dysrhythmias, hypertension, thyrotoxicosis and cardiac insufficiency. Use with caution in patients with epilepsy or Parkinsonism. As glycopyrrolate inhibitsweating, patients with increased temperature (especially children) should be observed closely.

In common with other antimuscarinic drugs caution is advised in patients with prostatic hypertrophy, paralytic ileus, pyloric stenosis and closed angle glaucoma.

Anticholinergic drugs can cause ventricular arrhythmias when administered during inhalation anaesthesia especially in association with the halogenated hydrocarbons.

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.

Unlike atropine, glycopyrrolate is a quaternary ammonium compound and does not cross the blood-brain barrier. It is therefore less likely to cause postoperative confusion which is a particular concern in the elderly patients. Compared to atropine, glycopyrrolate has reduced cardiovascular and ocular effects.

Neostigmine Methylsulfate: Glycopyrronium or alternatively atropine, given before or with neostigmine, prevents bradycardia, excessive salivation, and other muscarinic effects of neostigmine.

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

Neostigmine potentiates the depolarising myoneural blocking effects of suxamethonium (see contra-indications above).

There is increased risk of antimuscarinic side effects in patients taking drugs with antimuscarinic effects such as MAOIs, amantadine, clozapine, tricyclic antidepressants and nefopam.

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.

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

This medicine may cause your eyesight to become weak and this could interfere with your ability to drive or operate machinery safely.

4.8 Undesirable effects

Adverse events are which have been associated with Glycopyrrolate-Neostigmine injection are given below, listed by system organ class and frequency.

Undesirable effects are especially likely to occur at treatment onset or at dose increase.

The undesirable effects are listed below by organ class and the following frequency convention:

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.”

Tabulated list of adverse reactions for Glycopyrrolate component of Glycopyrrolate-Neostigmine Injection:

System Organ ClassAdverse reactionFrequency
Nervous system disordersConfusion**

Dizziness

Not known
Eye disordersAccommodation disorder, dilatation of the pupils, photophobia, Angle closure glaucomaNot known
Cardiac disordersTransient bradycardia* , Cardiac dysrhythmiasNot known
Respiratory, thoracic and mediastinal disordersBronchial secretion reducedNot known
Gastrointestinal DisordersDry mouth, Constipation

Nausea, vomiting

Not known
Skin and subcutaneous tissue disordersFlushing

Dry skin

Inhibition of sweating

Not known
Renal and urinary disordersDifficulty in micturition

Micturition urgency

Urinary retention

Not known

* Followed by tachycardia, palpitation and arrhythmias

**Particularly in elderly

Tabulated list of adverse reactions for Neostigmine component of Gylcopyrolate-Neostigmine Injection:

System Organ ClassAdverse reactionFrequency
Cardiac disordersBradycardia, cardiac dysrhythmiasNot known
Respiratory, thoracic and mediastinal disordersincreased oropharyngeal secretionsNot known
Gastrointestinal DisordersNausea, vomiting, increased salivation, increased gastrointestinal activity (more marked and higher doses), diarrheaNot known

Glycopyrrolate-Neostigmine component of injection can give rise to hypersensitivity, angioedema and anaphylactic reaction.

If severe neostigmine-induced muscarinic side effects occur (bradycardia, increased oropharyngeal secretions, decreased cardiac conduction rate, increased sweating ,bronchospasm or increased gastrointestinal activity etc), these may be treated by the intravenous administration of Glycopyrrolate Injection 200-600 micrograms (0.2-0.6mg) or atropine 400-1200 micrograms (0.4-1.2mg).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important.

4.9 Overdose

Symptoms

Signs of neostigmine overdosage include nausea, vomiting, diarrhoea, abdominal cramps (more marked with higher doses), increased bronchial secretions, lacrimation, excessive salivation and sweating, involuntary defecation and micturition, increased oropharyngeal secretions, miosis, nystagmus, bradycardia or tachycardia, cardiospasm, bronchospasm, incoordination, muscle cramps, heart block, arrhythmias, hypotension, agitation, excessive dreaming, and weakness eventually leading to fasciculation and paralysis.

Signs of glycopyrrolate overdosage include tachycardia, venticular irritability etc.

Management

The treatment of overdosage depends upon whether signs of anticholinesterase or anticholinergic overdosage are predominant presenting features

Signs of neostigmine overdosage may be treated by the administration of Glycopyrrolate Injection 200-600 micrograms (0.2-0.6mg) or atropine 400-1200 micrograms (0.4-1.2mg). In severe cases, respiratory depression may occur and artificial ventilation may be necessary in such patients.

Signs of glycopyrrolate overdosage may be treated by the administration of neostigmine Methylsulfate 1000 micrograms (1.0mg) for each 1000 micrograms (1.0mg) of glycopyrrolate known to have been administered. As glycopyrrolate 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 glycopyrrolate overdosage.

  1. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Quaternary ammonium antimuscarinic

Mechanism of action:

Glycopyrrolate is a quaternary ammonium anticholinergic agent. Glycopyrrolate has a more gradual onset and longer duration of action than atropine.

Neostigmine Methylsulfate is a quaternary ammonium anticholinesterase.

Glycopyrrolate-Neostigmine Injection is associated with less initial tachycardia and better protection against the subsequent cholinergic effects of neostigmine Methylsulfate than a mixture of atropine and neostigmine Methylsulfate.

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 Glycopyrrolate into the central nervous system. Administration of glycopyrrolate with neostigmine Methylsulfate is associated with greater cardiostability than administration of glycopyrrolate and neostigmine Methylsulfate separately.

Glycopyrrolate-Neostigmine Injection can be used when atropine has been used as a pre-operative anticholinergic.

5.2 Pharmacokinetic properties

Absorption and Biotransformation:

Glycopyrrolate is a quaternary ammonium anti-muscarinic agent. The quaternary ammonium moiety renders glycopyrrolate highly ionised at physiological pH and it thus penetrates the blood brain and placental barriers poorly. Neostigmine Methylsulfate is a quaternary ammonium anticholinesterase. Neostigmine undergoes hydrolysis by cholinesterases and is also metabolised in the liver.

Elimination

Glycopyrollate is excreted through bile and urine as unchanged drug.

Neostigmine is rapidly eliminated and is excreted in the urine both as unchanged drug and metabolites.

5.3 Preclinical safety data

Although reproduction studies in rats and rabbits revealed no teratogenic effects from glycopyrrolate, safety in human pregnancy and lactation has not been established.

Diminished rates of conception and of survival at weaning were observed in rats, in a dose related manner. Studies in dogs suggest that this may be due to diminished seminal secretion which is evident at high doses of glycopyrrolate. The significance of this for man is not clear.

  1. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Disodium Hydrogen Phosphate, Dodecahydrate.

Citric Acid Monohydrate, Sodium Hydroxide, Water for Injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

18 Months

6.4 Special precautions for storage

Store below 25°C. Keep the ampoule in the outer carton in order to protect from light.

6.5 Nature and contents of container

Glycopyrrolate Neostigmine Injection is presented in clear glass ampoules packed in cardboard cartons to contain 5 or 10 ampoules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Keep this medicine out of the sight and reach of children.If only part of an ampoule is used, discard the remaining solution.

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

7.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

Glycopyrrolate and Neostigmine Methylsulphate Injection 0.5mg+2.5mg/5ml

Package leaflet: Information for the user

(Glycopyrronium Bromide and Neostigmine Metilsulfate)

Read all of 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 or nurse.

If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

This product is known by the above name but will be referred to as Glycopyrronium-Neostigmine Injection throughout the rest of this leaflet.

What is in this leaflet

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

  1. WHAT GLYCOPYRRONIUM-NEOSTIGMINE INJECTION IS AND WHAT IT IS USED FOR

Glycopyrronium-Neostigmine Injection contains two active ingredients:

  • Neostigmine which belongs to a group of medicines called cholinesterase inhibitors. It has the effect of reversing the action of certain muscle-relaxing drugs.
  • Glycopyrronium Bromide which belongs to a group of medicines called anticholinergic drugs. Its purpose is to block some of the unwanted effects that may occur with Neostigmine such as slowing the heart rate or excess production of saliva.

Glycopyrronium-Neostigmine Injection is used at the end of an operation to reverse the effects of some of the drugs used during surgery such as anaesthetics and muscle relaxants.

  1. WHAT YOU NEED TO KNOW BEFORE YOU ARE GIVEN GLYCOPYRRONIUM-NEOSTIGMINE INJECTION

Do not use Glycopyrronium-Neostigmine Injection:

  • if you are allergic to Glycopyrronium Bromide or Neostigmine or any of the other ingredients of this medicine (listed in section 6)
  • if you are also receiving Suxamethonium, a muscle relaxant usually given during operations
  • if you think you may have a blockage in your intestine or urinary passage
  • Anticholinesterase-antimuscarinic combinations such as neostigmine plus glycopyrronium should be avoided in patients with a prolonged QT interval (irregular heart rhythm).

Warnings and precautions

Talk to your doctor or nurse before you are given Glycopyrronium-Neostigmine Injection

  • if you suffer from asthma attacks, wheezing or difficulty in breathing
  • if you suffer from glaucoma (Increased pressure in the eye)
  • if you have had a recent operation on the intestines (Gut)
  • if you suffer from stomach ulcers
  • if you have a high temperature (fever)
  • if you have low or high blood pressure
  • if you suffer from cardiac arrhythmia (irregular heart beats) or slow heart rate (less than 60 beats per minute) or you are suffering from coronary artery disease
  • if you suffer from coronary artery disease, a heart attack, heart failure or heart disease
  • if you are under influence of anaesthetics like Cyclopropane or Halothane.
  • if you have an overactive thyroid gland
  • if you are suffering from epilepsy or Parkinsonism (A disorder in the brain causing muscle stiffness and shaking)
  • if you suffer from myasthenia gravis (a disease resulting in severe muscle weakness and fatigue)
  • if you have an enlarged prostrate gland
  • if you suffer from obstruction of the stomach (pyloric stenosis) or bowel causing vomiting, abdominal pain and swelling (paralytic ileus)
  • if you suffer from kidney problems
  • if you have disorder resulting from overstimulation of the vagus nerve, causing a slowing of the heart rate, fainting, constipation and sweating
  • if you suffer from stomach ulcer
  • if you are pregnant or breast feeding.

Glycopyrronium bromide should be used with caution in children and elderly people.

Other medicines and Glycopyrronium-Neostigmine Injection

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

This is especially important with the following medicines as they may interact with Glycopyrronium-Neostigmine Injection:

  • medicines to treat depression (e.g. Tricyclic Antidepressant for example amitriptyline or imipramine, MAOI’s for example phenelzine, tranylcypramine)
  • medicine used to treat mental illness (e.g. Clozapine)
  • medicine used to relieve the pain (e.g. Nefopam)
  • Amantadine which is used to treat Parkinson’s disease or viral infection
  • Suxamethonium, a muscle relaxant usually given during operations
  • 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.

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 using this medicine.

Driving and using machines

This medicine may cause your eyesight to become weak and this could interfere with your ability to drive or operate machinery safely.

Ask your doctor for advice before you drive or operate machinery.

Glycopyrronium-Neostigmine Injection contains sodium

This injection contains less than 1mmol (23mg) of sodium per 2ml (essentially ‘sodium-free’).

  1. HOW GLYCOPYRRONIUM-NEOSTIGMINE INJECTION IS GIVEN TO YOU

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

Glycopyrronium-Neostigmine Injection is administered by injection into a vein.

The recommended dose is

Adults and elderly: 1-2 ml injected into a vein over a period of 10 to 30 seconds. Alternatively, a dose of 0.02 ml per kg body weight may be injected into a vein over a period of 10 to 30 seconds.

Use in Children: 0.02ml per kg body weight may be injected into a vein over a period of 10 to 30 seconds.

Your doctor will decide the correct dose for you depending on your circumstances.

Your dose may be calculated according to your weight.

The injection is usually given over a period of 10-30 seconds, and may need to be repeated depending on your response.

If you have been given more Glycopyrronium-Neostigmine Injection than you should

This is unlikely because the dose will be administered by a health professional. An overdose may cause changes in the speed of heart rate, increased production of saliva and difficulty in breathing.

If you have any further questions on the use of 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. All medicines can cause allergic reactions although serious allergic reactions are very rare. Any sudden wheeziness, difficulty in breathing, swelling of the eyelids, face or lips, rash or itching (especially affecting your whole body) should be reported to a doctor immediately.

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

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

The following side effects have also been reported but their frequency is not known:

  • dry mouth
  • difficulty in passing stools (Constipation)
  • a very slow heart rate (Bradycardia)
  • an awareness of strong, thumping heart beats (Palpitation) or irregular heart beats (could be related to either glycopyrrolate or neostigmine)
  • reduced secretion in lungs
  • difficulty in passing urine
  • inability to completely empty the bladder (urinary retention)
  • uncontrollable urge to pass urine
  • difficulty in passing stools
  • visual disturbances
  • increased sensitivity of the skin to light (Photophobia)
  • enlargement of pupil
  • glaucoma (increased pressure in the eye)
  • absence of sweating
  • dryness of the skin
  • reddening of the skin and other areas of the skin (Flushing)
  • confusion
  • nausea (feeling sick)
  • vomiting (being sick), dizziness
  • increased secretions of stomach
  • increase in mucus secretion
  • too much saliva
  • tummy cramps
  • diarrhea

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.

By reporting side effects you can help provide more information on the safety of this medicine.

  1. HOW TO STORE GLYCOPYRRONIUM-NEOSTIGMINE INJECTION

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and ampoule label after ‘Exp date’. The expiry date refers to the last day of that month.

Do not store above 25°C.

Keep the ampoules in the outer carton in order to protect from light.

Once opened, use immediately.

If only part used, discard the remaining solution.

Do not dilute.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

  1. CONTENTS OF THE PACK AND OTHER INFORMATION

What Glycopyrronium-Neostigmine Injection contains

The active substances are Glycopyrronium bromide and Neostigmine metilsulfate.

Each glass ampoule contains 1 ml of solution, which contains the two active ingredients glycopyrronium bromide 0.5mg and neostigmine metilsulfate 2.5mg.

The other ingredients are disodium phosphate dodecahydrate, citric acid monohydrate, citric acid solution or sodium hydroxide (for pH adjustment) in water for injections.

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

Glycopyrronium-Neostigmine Injection is a clear, colourless, sterile solution for injection.

Each carton contains ten 1ml ampoules of Glycopyrronium-Neostigmine Injection.

Glycopyrronium-Neostigmine Injection is supplied in packs containing 1, 4 or 5 vials.

Not all pack sizes may be marketed.

 

7.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