Syntostigmin Injection


1. NAME OF THE MEDICINAL PRODUCT

                                                            SYNTOSTIGMIN

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
Active substance: Neostigmine methylsulphate 0.5 mg in 1 ml. 
For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM 
Solution for injection 
Description of the preparation: clear, colourless solution.

4. CLINICAL PARTICULARS 
4.1 Therapeutic indications 
Inhibition of intestinal peristalsis up to paralytic ileus, postoperative atonia of urinary bladder, myasthenia gravis, bulbar syndroms of different ethiology, urinary retention after thymoleptics, as an antidote to myorelaxant effect of tubocurarine.
4.2 Posology and method of administration 
Dosage for children 
The dose for children is 0.02 mg/kg of body mass, i.e. less than 1 year of age 0.15-0.20 mg, from 1 to 6 years 0.25-0.30 mg, from 6 to 15 years 0.30- 0.50 mg daily. 

Dosage for adults 
Atonia of the intestines: 1 ampoule subcutaneously, intramuscularly or slowly intravenously. The dose can be repeated after 3-6 hours. For intravenous injection it is recommended to apply the preparation diluted in infusion solutions (isotonic sodium chloride solution, 5% glucose solution). The preparation may also be applied preventively immediately after the operation. A half dose (0.5 ampoule) can be used and administration can be repeated after 4-6 hours. 

In myasthenia gravis: 1-2 ampoules are administered subcutaneously or intramuscularly. 
In bulbar syndrome: it is recommended to administer 0,5 - 1 ampoule , once or twice per day, subcutaneously or intramusculary
In anaesthesiology as an antidote of myorelaxant effect of tubocurarine: 1-2 mg of neostigmine combined with 0.5-1 mg of atropine. In some cases, for elimination of adverse reactions of neostigmine, the simultaneous application of atropine in a dose of 0.1-0.5 mg 3 times daily is suitable.
Recommended daily dose in subcutaneous or intramuscular application is  0,25-0,5 mg.
The maximal single dose is 1 mg, the maximal daily dose 3 mg. 

4.3 Contraindications 
Occlusive ileus, hypersensitivity to active substance or any of excipients, retention of urine due to mechanical obstruction, peritonitis. 

4.4 Special warning and precautions for use
Cautious use is recommended in patients with bronchial asthma, heart arrhythmia, bradycardia, coronary occlusion, hyperthyreoidism, peptic ulcer of stomach and epilepsy. The preparation may sometimes give rise to paradoxic adverse reactions, tachycardia and hypertension. This may be explained by the interaction of nicotinic and muscarinic effects. 

4.5 Interaction with other medicinal products and other forms of interaction
Neostigmine intensifies the analgesic effect of analgesics and aminophenazone. In patients treated with blockers of beta-adrenergic receptors, neostigmine may cause severe bradycardia and also intensifies the effect of hypotensives and vasodilators, antidysrhythmic agents, cardiotonics, beta-sympatholytics. Neostigmine antagonises the obstipative effects of morphine and retention of urine after application of cholinolytic substances. In dampening of neuromuscular blockade, caused by pachycurare myorelaxants, the repeated application of neostigmine may cause a neuromuscular block, induced by acetylcholin, which may be dangerous in general anaesthesia. The effect of neostigmine is potentiated by cholinergic substances and pantothenic acid in high doses; the effect is reduced beside the common cholinolytics also by synthetic spasmolytics.
 
4.6 Pregnancy and lactation 
 Use of the product during pregnancy is risky. Neostigmine crosses the placental barrier and might cause womb contractions with the risk of abortion. The information concerning crossing in breast milk are not avilable
.
4.7 Effects on ability to drive and use machines
Neostigmine has no dampening effect on the central nervous system, but it causes miosis and blurred distant vision and in the final effect may influence concentration when driving car or operating machinery. 

4.8 Undesirable effects 
Profuse secretion - salivation, lacrimation, bronchial secretion with cough and risk of provocation of asthmatic attack, accommodation disorders, miosis, increased peristalsis up to spasms of GIT, colic pains, nausea up to vomiting, pollakiuria, myoclonia up to tonic spasms.

4.9 Overdose 
Neostigmine, considering its properties, belongs to strongly toxic substances. The toxicity of neostigmine is close to that of physostigmine and neostigmine is a signifficantly toxic substance even in chronic administration. 
LD50 in intravenous administration to mices is 0,3 mg/kg, in intramuscular administration 0,395 mg/kg, in subcutaneous administration 0,54 mg/kg.
LD50 in intravenous administration to laboratory rat is 0,315 mg/kg, in intramuscular administration 0,423 mg/kg, in subcutaneous administration 0,445 mg/kg.
Despite the opinion that short-term application of acetylcholinesterase inhibitors in pregnant women does not cause fetal malformations, the application of neostigmine in perinatal period with caution is required.
 Information on the mutagenicity and carcinogenicity are not available. 
Overdosage may arise in the event of a quick intravenous injection. The symptoms are manifested by muscarinic and nicotinic central and peripheral effects (cholinergic crisis). In patients with myasthenia gravis the symptoms of overdosage are less evident and can be noticed only through weakness of the muscles. It is important to distinguish this fact from a myasthenic crisis and if it can not be reliably distinguished, it is possible to apply edrophonium carefully. 
Treatment: Preference must be given to respiratory functions. Muscarinic symptoms can be suppressed by injections of atropine. Atropine is applied intravenously in an initial dose of 1-2 mg which, if necessary, can be repeated, Nicotinic effects, including weakness of the muscles and paralysis, can not be influenced by atropine. 

5. PHARMACOLOGICAL PROPERTIES 
5. 1 Pharmacodynamic properties
Pharmacotherapeutic group: Parasympathomimetic 
ATC code: N 07 AA 01
Mechanism of action 
Neostigmine is a synthetic derivative of alkaloid physostigmine, from the group of acetylcholinesterase inhibitors. One of the most significant effects is the cholinomimetic action of muscarine type on all organs innervated by parasympathetic nervi. Central effects of neostigmine are not too evident, because only a small part of the substance penetrates through the blood-¬brain barrier. Along with the inhibitory effect on acetylcholinesterase, it may directly act on acetylcholin receptors, according to the constitution of its molecule. The muscarinic effect affects especially the intestinal tract and eye, while the effect on haemodynamics is relatively weak. Neostigmine is a less effective miotic than physostigmine, but it acts approximately equally on the motility of the intestinal tract. After administration, the blood pressure does not change or falls quite slightly. Neostigmine induces moderate bronchostenosis, contraction of urinary and gall bladders and spleen capsule. After therapeutic doses, nonsignificant changes in heart activity and in values of blood pressure sometimes occur in humans. 
Neostigmine inhibits reversibly the activity of acetylcholinesterase and prolongs and strengthens the muscarinic and nicotinic effects of acetylcholin. It is very plausible, that neostigmine also has direct agonistic effects on nicotinic receptors of skeletal muscles. It is used, first of all, due to its effect on striated muscles, less often for raising the action of smooth muscles. Adverse reactions arise as a consequence of muscarinic effect can be removed by previous oral or parenteral application of atropine. 

5.2 Pharmacokinetic properties
Neostigmine is quickly resorbed from subcutaneous and muscular tissues. It is partly biotransformed, probably by hydrolysis of esteric binding. In parenteral administration, 60% to 70% of unchanged neostigmine is excreted in the urine. Neostigmine is quickly eliminated from the plasma of patients to whom it was administered intravenously. The plasma concentration of neostigmine decreases within 5 minutes to 8% of the initial value, while the distribution half-life is shorter than 1 minute. The elimination half-life is in the range of 15 to 30 minutes. One hour after intravenous application, only trace amounts can be found in plasma. It is assumed that biotransformation processes and biliar excretion may play a significant role in the elimination of neostigmine. 
5.3 Preclinical safety data
LD50 in intravenous application in mice has been estimated at 0.3 mg/kg, in intramuscular administration 0.395 mg/kg, in subcutaneous administration 0.54 mg/kg. 
LD50 in rats in intravenous administration has been estimated at 0.315 mg/kg, in intramuscular administration 0.423 mg/kg, in subcutaneous administration 0.445 mg/kg. 
In spite of the opinion, that the application of short-acting inhibitors of acetylcholinesterase do not induce malformation in human, carefulness is requested in the administration of neostigmine during the perinatal period. Information about mutageneity and cancerogenic activity of neostigmine are not known.

6. Pharmaceutical particulars 

6.1 List of excipients 
Sodium chloride, water for injection. 
Sodium content in the preparation: 3,542 mg/ml, what corresponds to 0.154 mmol/ml 

6.2 Incompatibilities 
Not applicable. 

6.3 Shelf life
4 years 

6.4 Special precautions for storage 
Do not store above 25°C. Do not refrigerate or freeze.

6.5 Nature and contents of container  
Colourless glass ampoule, PVC mould, paper folder. 
Size of the package: 10 ampoules of 1 ml 

6.6 Special precautions for disposal
No special requirements.

7. MARKETING AUTHORIZATION HOLDER
BB Pharma Ltd., Pod Višňovkou 1662/21, 1400 00 Praha 4, Czech Republic 

8. MARKETING AUTHORIZATION NUMBER(S) 
67/771/92-S/C

9. DATE OF FIRST AUTHORIZATION/RENEWAL OF THE AUTHORIZATION
December 31st, 1992/ September 8th, 1999

10. DATE OF REVISION OF THE TEXT
December 28th, 2005