200 mg/ml, 400 mg/2 ml
1 gm/5 ml, 2 gm/10 ml
For the use of a Registered Medical Practitioner or a Hospital or a Institution only.
MUCOTYLE (Acetylcysteine) is the N-Acetyl derivative of the naturally occurring amino acid, L-cysteine. Chemically, Acetylcysteine is designated as N-acetyl-L-cysteine. Its molecular formula is C5H9NO3S and its molecular weight is 163.20.
STRUCTURAL FORMULA :
Its structural formula is :
MUCOTYLE is a clear, colourless to light purple sterile aqueous solution filled in ampoule of suitable size.
Each ml contains :
Acetylcysteine USP............... 200 mg
Water for Injections I.P........... q.s.
Contains no preservatives.
The viscosity of pulmonary mucous secretions depends on the concentrations of mucoprotein and to a lesser extent, deoxyribonucleic acid (DNA). The latter increases with increasing purulence owing to the presence of cellular debris. The mucolytic action of acetylcysteine is related to the sulfhydryl group in the molecule. This group probably “opens” disulfide linkages in mucus thereby lowering the viscosity. The mucolytic activity of acetylcysteine is unaltered by the presence of DNA and increases with increasing pH. Significant mucolysis occurs between pH 7 and 9.
Acetylcysteine undergoes rapid deacetylation in vivo to yield cysteine or oxidation to yield diacetylcystine. Occasionally, patients exposed to the inhalation of an acetylcysteine aerosol respond with thedevelopment of increased airways obstruction of varying and unpredictable severity. Those patients who are reactors cannot be identified a priori from a random patient population. Even when patients are known to have reacted previously to the inhalation of an acetylcysteine aerosol, they may not react during a subsequent treatment. The converse is also true; patients who have had inhalation treatments of acetylcysteine without incident may still react to a subsequent inhalation with increased airways obstruction. Most patients with bronchospasm are quickly relieved by the use of a bronchodilator given by nebulization. If bronchospasm progresses, the medication should be discontinued immediately.
ACETAMINOPHEN POISONING :
Paracetamol is metabolised in the liver, mainly by conjugation with glucuronide and sulphate. It is also metabolised by cytochrome P450 to form a reactive, potentially toxic, metabolite. This metabolite is normally detoxified by conjugation with hepatic glutathione, to form non-toxic derivatives. In paracetamol overdosage, the glucuronide and sulphate conjugation pathways are saturated, so that more of the toxic metabolite is formed. As hepatic glutathione stores are depleted, this toxic metabolite may bind to hepatocyte proteins, leading to liver cell damage and necrosis. Acetylcysteine is a sulphydryl (SH) group donor and may protect the liver from damage by restoring depleted hepatic-reduced glutathione levels, or by acting as an alternative substrate for conjugation with and thus detoxification of the toxic paracetamol metabolite.
Acetylcysteine is the N-acetyl derivative of the naturally occurring amino acid, L-cysteine and is deacetylated in the liver to cysteine or oxidised to other metabolites such as N-acetylcystine or N, N diacetylcystine. The parent compound and metabolites may be present in
the plasma either free or protein bound. Renal clearance accounts for about 30 % of total body clearance. Following intravenous administration, mean terminal half lives have been calculated to be 1.95 and 5.58 hours respectively for reduced and total acetylcysteine.
1. (i) As a mucolytic in respiratory disorder associated with the production of viscous mucus such as acute and chronic bronchitis.
(ii) In alveolar proteinosis to remove proteinaceous material by repeated lavage with heparin which may prolong survival upto 5 years.
(iii) During mechanical ventilation in premature infants to relieve severe recurrent atelectasis.
(iv) In adult respiratory distress syndrome Acetylcysteine Solution is given intravenously.
(v) In routine to clean blocked tracheal tubes in patients on ventilator in ICU few drops of Acetylcysteine Solution are sufficient (5 - 6 drops).
2. As adjuvant therapy for patients with abnormal,viscid or inspissated mucous secretions in such conditions as :
(i) Chronic bronchopulmonary disease (chronic emphysema, emphysema with bronchitis, chronic asthmatic bronchitis, tuberculosis,bronchiectasis and primary amyloidosis of the lung).
(ii) Acute bronchopulmonary disease (pneumonia, bronchitis, tracheobronchitis).
(iii) Pulmonary complications of cystic fibrosis.
(iv) Post-tracheostomy care.
(v) Pulmonary complications associated with surgery.
(vi) Use during anaesthesia; post-traumatic chest conditions.
(vii) Atelectasis due to mucous obstruction.
(viii) Diagnostic bronchial studies (bronchograms, bronchospirometry and bronchial wedge catheterization).
3. (i)Antidote to paracetamol poisoning.
(ii) Ratol poisoning (Yellow Phosphorus Poisoning).
(iii) Carbon tetrachloride poisoning :
Prompt intravenous therapy with MUCOTYLE may help to minimise hepatorenal damage in acute poisoning with carbon tetrachloride.
4. Combined use of nitroglycerine and N-acetylcysteine in the management of unstable angina pectoris :
(i) MUCOTYLE when administered with nitroglycerine augments the clinical efficacy of NTG, particularly by preventing acute myocardial infarction.
(ii) Interaction of NTG and NAC may lead to the formation of S-nitroso- NAC, which strongly inhibits platelet aggregation.
(iii) MUCOTYLE appears to be able to potentiate the peripheral and coronary effects of glyceryl trinitrate.
(iv) Thus used as an adjunct to nitrate therapy in the treatment of cardiovascular disorders, especially in the management of unstable angina pectoris.
5.In Colposcopy : To clean the cervix and to remove cervical mucus prior to colposcopy.
6.As a therapeutic agent in AIDS, MUCOTYLE inhibits the stimulation of viral production during latency by restoring Glutathione concentrations.
7.To prevent Radiographic-Contrast-Agent-Induced Reductions in renal function.
Administration of Aerosol - Materials : MUCOTYLE may be administered using conventional nebulizers made of plastic or glass. Certain materials used in nebulization equipment react with acetylcysteine. The most reactive of these are certain metals (notably iron and copper) and rubber. Where materials may come into contact with acetylcysteine solution, parts made of the following acceptable materials should be used : glass, plastic, aluminium, anodized aluminium, chromed metal, tantalum, sterling silver or stainless steel. Silver may become tarnished after exposure, but this is not harmful to the drug action or the patient.
Nebulizing Gases :
Compressed tank gas (air) or an air compressor should be used to provide pressure for nebulizing the solution. Oxygen may also be used but should be used with usual caution in patients with severe respiratory disease and CO2 retention.
Acetylcysteine is usually administered as fine nebulae and the nebulizer used should be capable of providing optimal quantities of a suitable range of particle sizes. Commercially available nebulizers will produce nebulae of acetylcysteine satisfactory for retention in
the respiratory tract. Most of the nebulizers tested will supply a high proportion of the drug solution as particles of less than 10 microns in diameter. Clinical studies have shown that particles less than 10 microns should be retained in the respiratory tract satisfactorily. The nebulized solution may be inhaled directly from the nebulizer. Nebulizers may also be attached to plastic face masks or plastic mouthpieces.
Suitable nebulizers may also be fitted for use with the various intermittent positive pressure breathing (IPPB) machines. The nebulizing equipment should be cleaned immediately after use because the residues may clog the smaller orifices or corrode metal parts. Hand bulbs are not recommended for routine use for nebulizing acetylcysteine because their output is generally too small. Also, some hand operated nebulizers deliver particles that are larger than optimum for inhalation therapy. Acetylcysteine should not be placed directly into the chamber of a heated (hot pot) nebulizer. A heated nebulizer may be part of the nebulization assembly to provide a warm saturated atmosphere if the acetylcysteine aerosol is introduced by means of a separate unheated nebulizer. Usual precautions for administration of warm saturated nebulae should be observed.
The nebulized solution may be breathed directly from the nebulizer. Nebulizers may also be attached to plastic face masks, plastic face tents, plastic mouth pieces, conventional plastic oxygen tents or head tents. Suitable nebulizers may also be fitted for use with the various intermittent positive pressure breathing (IPPB) machines. The nebulizing equipment should be cleaned immediately after use, otherwise the residues may occlude the fine orifices or corrode metal parts. Prolonged Nebulization : When three fourths of the initial volume of Acetylcysteine Solution have been nebulized, a quantity of Sterile Water for Injections I.P. (approximately equal to the volume of solution remaining) should be added to the nebulizer. This obviates any concentration of the agent in the residual solvent remaining after prolonged nebulization.
INSTRUCTION FOR USE OF AMPOULE :
The ampoule used in this product is equipped with O.P.C (One Point Cut) opening system. No ampoule file is needed to open the ampoule. The neck of the ampoule is prescored at the point of constriction. A coloured dot on the ampoule head helps to orientate the ampoule. Take the ampoule and face the coloured dot. Let the solution at the head of the ampoule to flow down by shaking or a gentle stroke. The ampoule opens easily by placing the thumb on the coloured dot and gently pressing downwards as shown.
As a Mucolytic Agent :
The 20 % solution may be diluted to a lesser concentration with either sterile normal saline or Sterile Water for Injections I.P. Any unused portion of a solution should be discarded. Nebulization-face mask, mouth piece, tracheostomy : When nebulized into a face mask, mouth piece or tracheostomy, 1 to 10 ml of the 20 % solution may be given every 2 to 6 hours; the recommended dose for most patients is 3 to 5 ml of the 20 % solution 3 to 4 times daily.
Nebulization-tent, croupette :
In special circumstances it may be necessary to nebulize into a tent or croupette and this method of use must be individualized to take into account the available equipment and the patient’s particular needs. This form of administration requires very large volumes of the solution, occasionally as much as 300 ml during a single treatment period. If a tent or croupette must be used, the recommended dose is the volume of solution that will maintain a very heavy mist in the tent or croupette for the desired period. Administration for ermittent or continuous prolonged periods, including overnight, may be desirable.
Direct Instillation : When used by direct instillation, 1 to 2 ml of a 10 to 20 % solution may be given as often as every hour. When used for the routine nursing care of patients with tracheostomy, 1 to 2 ml of a 10 to 20 % solution may be given every 1 to 4 hours by instillation into the tracheostomy. MUCOTYLE may be introduced directly into a particular segment of the bronchopulmonary tree by inserting (under local anaesthesia and direct vision) a small plastic catheter into the trachea. 2 to 5 ml of the 20 % solution may then be instilled by means of a syringe connected to the catheter. MUCOTYLE may also be given through a percutaneous intratracheal catheter. 1 to 2 ml of the 20 % solution may be given every 1 to 4 hours by a syringe attached to the catheter.
Diagnostic Bronchograms :
For diagnostic bronchial studies, 2 or 3 administrations of 1 to 2 ml of the 20 % solution should be given by nebulization or by instillation intratracheally, prior to the procedure. MUCOTYLE may also be given by mouth in doses of 200 mg three times daily along with cola drinks. Children aged upto 2 years may be given 200 mg once daily and those aged 2 to 6 years 200 mg twice daily.
As an Antidote for Acetaminophen Poisoning :
In the case of an overdosage of acetaminophen, MUCOTYLE should be administered immediately if 24 hours or less have elapsed from the reported time of ingestion. To be effective in protecting against severe liver damage, therapy with MUCOTYLE must be started within 10 hours of acetaminophen ingestion. There is some evidence of progressively diminished efficacy thereafter, possibly lasting up to 24 hours. It should be borne in mind that after a fatal dose of acetaminophen, the patient may appear relatively well initially and may even continue normal activities for a day or two before the onset of hepatic failure.
PREPARATION OF SOLUTION FOR ORAL ADMINISTRATION :
Oral administration requires dilution of the 20 % solution with cola drinks, or other soft drinks, to a final concentration of 5 % (see Table I). If administered via gastric tube or Miller-Abbott tube, water may be used as the diluent. The dilutions should be freshly prepared and utilized within 1 hour. Remaining undiluted solutions must be discarded.
PREPARATION OF SOLUTION FOR I.V.
Acetylcysteine may be used for I.V. administration following acetaminophen overdose according to Dosage Guidelines in Table II. Dilutions recommended should be prepared with 5 % Dextrose and Water, as appropriate. Acetylcysteine for I.V. use should be considered as a single-dose container. Solutions recommended under each column in Table II should be freshly prepared and used only over times stated.
SUPPORTIVE TREATMENT OF ACETAMINOPHEN OVERDOSE :
Maintain fluid and electrolyte balance based on clinical evaluation of state of hydration and serum electrolytes. Treat as necessary for hypoglycaemia. Administer vitamin K1 if prothrombin time ratio exceeds 1.5 or fresh frozen plasma if the prothrombin time ratio exceeds 3.0. Diuretics and forced diuresis should be avoided. Haemodialysis or peritoneal dialysis have not been found helpful.
Carbon tetrachloride poisoning :
MUCOTYLE could be used in addition to supportive therapy of Carbon tetrachloride poisoning where the initial dosage regimen should be the same as that are used for paracetamol poisoning. Since carbon tetrachloride has a much longer half-life than paracetamol, the duration of treatment may need to be increased (longer than the 20 hours recommended for paracetamol poisoning).
Combined use of NTG and NAC in the management of unstable angina pectoris :
MUCOTYLE (5 gm in 200 ml 5 % Dextrose) should be administered by slow intravenous infusion 15 to 30 minutes after initiation of nitroglycerine infusion. Acetylcysteine Solution has to be infused by slow intravenous infusion over 15 minutes (Acetylcysteine Solution if administered by rapid intravenous infusion, the risk of the development of hypotension with the combined use of NAC / NTG is increased.) Supplement infusion of MUCOTYLE has to be repeated every 6 hr for 24 hr.
In Colposcopy :
2 ml of MUCOTYLE along with 2 ml of normal saline & 2 to 3 % (upto 5 %) solution of Acetic acid is used. To prevent Radiographic-Contrast-Agent-Induced Reductions in renal function : MUCOTYLE should be given orally at a dose of 600 mg twice daily, on the day before and on the day of administration of contrast agent, for a total of 2 days.
The physical and chemical compatibility of acetylcysteine solutions with certain other drugs that might be concomitantly administered by nebulization, direct instillation, or topical application has been studied. Acetylcysteine should not be mixed with certain antibiotics. For example, the antibiotics tetracycline hydrochloride, oxytetracycline hydrochloride and erythromycin lactobionate were found to be incompatible when mixed in the same solution. These agents may be administered from separate solutions if administration of these agents is desirable.
MUCOTYLE is contraindicated in patients with hypersensitivity or previous anaphylactic reaction to acetylcysteine or any component of the preparation. There are no contraindications to oral or I.V. administration of acetycysteine in the treatment of acetaminophen overdose.
After proper administration of acetylcysteine, an increased volume of liquified bronchial secretions may occur. When cough is inadequate, the airway must be maintained open by mechanical suction if necessary. When there is a mechanical block due to foreign body or
local accumulation, the airway should be cleared by endotracheal aspiration, with or without bronchoscopy. Asthmatics under treatment with acetylcysteine should be watched carefully. Most patients with bronchospasm are quickly relieved by the use of a bronchodilator given by nebulization. If bronchospasm progresses, the medication should be discontinued immediately. Generalized urticaria has been observed rarely in patients receiving oral acetylcysteine for acetaminophen overdose. If this occurs and other allergic symptoms appear, treatment with acetylcysteine should be discontinued unless it is deemed essential and the allergic symptoms cannot be otherwise controlled. If encephalopathy due to hepatic failure is evident, acetylcysteine treatment should be discontinued to avoid further administration of nitrogenous substances. There are no data indicating acetylcysteine adversely influences hepatic failure; however, this remains a theoretical possibility.
With the administration of acetylcysteine as a mucolytic agent, the patient may initially notice a slight disagreeable odour which soon is not noticeable. With a face mask, there may be a stickiness on the face after nebulization which is easily removed by washing with water. Under certain conditions, a colour change may take place in the solution of acetylcysteine in the open vial. The light purple colour is the result of a chemical reaction which does not significantly impair the safety or mucolytic efficacy of acetylcysteine. Continued nebulization of an acetylcysteine solution with a dry gas will result in an increased concentration of the drug in the nebulizer because of evaporation of the solvent. Extreme concentration may impede nebulization and efficient delivery of the drug. Dilution of the nebulizing solution with Sterile Water for Injections I.P., as concentration occurs, will obviate this problem.
Occasionally severe and persistent vomiting occurs as a symptom of acute acetaminophen overdose.Treatment with oral acetylcysteine may aggravate the vomiting. Patients at risk of gastric haemorrhage (e.g., oesophageal varices, peptic ulcers, etc.) should be evaluated concerning the risk of upper gastrointestinal haemorrhage versus the risk of developing hepatic toxicity and treatment with acetylcysteine given accordingly. Dilution of the acetylcysteine with cola drinks minimizes the propensity of oral acetylcysteine to aggravate vomiting.
SPECIAL PRECAUTIONS :
MUCOTYLE should be used with caution in asthma or where there is a history of bronchospasm. It should also be used with caution with patients with a past history of oesophageal varices and peptic ulceration (acetylcysteine-induced vomiting may increase the risk of haemorrhage).
Pregnancy : Category B
Reproduction studies of MUCOTYLE with isoproternol have been performed in rats and of N-Acetylcysteine alone in rabbits at doses upto 2.6 times the human dose. These have revealed no evidence of impaired fertility or harm to the foetus due to N-Acetylcysteine. There are however no adequate and well-controlled studies in pregnant women.Because animal reproduction studies may not always be predictive of human responses, this drug should be used during pregnancy only if clearly needed.
Nursing mothers :
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when acetylcysteine is administered to a nursing woman.
Drug/Laboratory Interaction :
Acetylcysteine may cause a false-positive reaction with reagent dipstick tests for urinary ketones.
Paediatric Use :
The safety and effectiveness of MUCOTYLE in children has not been established. No paediatric-specific adverse reactions have been documented.
Elderly Use :
There are no adequate or well controlled studies in elderly patients. For this reason, the safety and effectiveness of MUCOTYLE in the elderly has not been established.
Renal/Hepatic Impaired Patients :
Caution should be taken when administering acetylcysteine in patients with hepatic or renal failure, since there is little data relating to the effects of acetylcysteine in impaired renal and/or hepatic function. The decision to administer should be passed on a risk/benefit assessment for the individual subject. In the presence of hepatic failure due to paracetamol overdose the degree of existing liver damage and the possible risk associated with the administration of acetylcysteine should be considered.
SIDE EFFECTS :
Adverse effects have included stomatitis, nausea, vomiting, fever, rhinorrhea, drowsiness, clamminess, chest tightness and bronchoconstriction. Clinically overt acetylcysteine induced bronchospasm occurs infrequently and unpredictably even in patients with asthmatic bronchitis or bronchitis complicating bronchial asthma. Acquired sensitization to acetylcysteine has been reported rarely. Reports of sensitization in patients have not been confirmed by patch testing. Sensitization has been confirmed in several inhalation therapists who reported a history of dermal eruptions after frequent and extended exposure to acetylcysteine.
Reports of irritation to the tracheal and bronchial tracts have been received and although haemoptysis has occurred in patients receiving acetylcysteine such findings are not uncommon in patients with bronchopulmonary disease and a causal relationship has not been established. Oral or I.V. administration of acetylcysteine, especially in the large doses needed to treat acetaminophen overdose, in order of frequency may result in nausea, vomiting and other gastrointestinal symptoms. Hypersensitivity reactions following the I.V.
administration of acetylcysteine have been reported. Symptoms include rashes, facial oedema, urticaria, hypotension and bronchospasm. Bronchospasm may occur in conjunction with a generalised anaphylactoid reaction. The symptoms of the anaphylactic-like reaction to acetylcysteine include airway obstruction (bronchospasm), angioedema, dyspnoea, hypotension, shock, tachycardia, urticaria, and injection site reaction (including rash). These reactions occur most commonly either during, or at the end of the period of the loading dose infusion and may in fact be dose- related. Since these anaphylactic-like reactions usually occur following the loading dose, careful monitoring is recommended.
Symptoms following overdosage with acetylcysteine have been similar to those of anaphylactoid reactions noted under “Side Effects”, but they may be more severe. Hypotension appears to be especially prominent. There is also a theoretical risk of hepatic encephalopathy.
TREATMENT OF OVERDOSAGES :
There is no specific treatment. General supportive measures should be carried out. It has been suggested that generalised reactions to acetylcysteine can be treated with intravenous injection of an antihistamine and infusion of acetylcysteine should be temporarily stopped but can be restarted at a slower rate without further reaction.
PHARMACEUTICAL PRECAUTIONS :
Acetylcysteine does not contain an antimicrobial agent and care must be taken to minimize contamination of the sterile solution. Dilutions of acetylcysteine should be used freshly prepared and utilized within 1 hour. Unused solution must be discarded after the dose has been withdrawn.
Store below 30°C (86°F), protected from light.
Do not refrigerate.
SHELF LIFE :
24 months from the date of manufacture.
MUCOTYLE is supplied as per below table.
Disclaimer : For the use of a Registered Medical Practitioner or a Hospital or a Institution only. Also it is not intended to be used by healthcare professionals or patients for the purpose of prescribing or administering these products. Questions regarding the complete and current content of product labeling / specification / presentation should be directed to SGPharma.