1. Name Of The Medicinal Product
AMIKIN INJECTION 100MG/2ML
2. Qualitative And Quantitative Composition
Each vial contains in 2 ml amikacin sulphate equivalent to amikacin activity 100mg (100,000 international units).
3. Pharmaceutical Form
Solution for administration to human beings by injection.
4. Clinical Particulars
4.1 Therapeutic Indications
Amikacin sulphate is an aminoglycoside antibiotic which is active against a broad spectrum of Gram-negative organisms, including Pseudomonas spp., Escherichia coli, indole-positive and indole-negative Proteus spp. Klebsiella-Enterobacter-Serratia spp, Salmonella, Shigella, Minea-Herellae, Citrobacter freundii and Providencia spp.
Many strains of these gram-negative organisms resistant to gentamicin and tobramycin may show sensitivity to amikacin in vitro. The principal Gram-positive organism sensitive to amikacin is Staphylococcus aureus, including methicillin-resistant strains. Amikacin has some activity against other Gram-positive organisms including certain strains of Streptococcus pyogenes, Enterococci and Diplococcus pneumoniae.
Amikin is indicated in the short-term treatment of serious infections due to susceptible strains of Gram-negative bacteria. It may also be indicated for the treatment of known or suspected staphylococcal disease.
Consideration should be given to official guidance on the appropriate use of antibacterial agents
4.2 Posology And Method Of Administration
For most infections the intramsucular route is preferred, but in life-threatening infections, or in patients in whom intramuscular injection is not feasible the intravenous route, either slow bolus (2 to 3 minutes) or infusion (0.25% over 30 minutes) may be used.
Intramuscular and intravenous administration
At the recommended dosage level, uncomplicated infections due to sensitive organisms should respond to therapy within 24 to 48 hours.
If clinical response does not occur within three to five days consideration should be given to alternative therapy.
Adults and children over 12 years:
The recommended intramuscular or intravenous dosage for adults and adolescents with normal renal function (creatinine clearance
Children 4 weeks to 12 years:
The recommended intramuscular or intravenous (slow intravenous infusion) dose in children with normal renal function is 15-20 mg/kg/day which may be administered as 15-20 mg/kg, once a day; or as 7,5 mg/kg q 12 h. In endocarditis and in febrile neutropenic patients dosing should be twice daily, as there is not enough data to support once daily dosing.
Neonates:
An initial loading dose of 10 mg/kg followed by 7.5 mg/kg q 12 h (see sections 4.4 and 5.2).
Premature infants:
The recommended dose in prematures is 7.5 mg/kg in every 12 hours (see sections 4.4 and 5.2).
Specific recommendation for intravenous administration
In paediatric patients the amount of diluents used will depend on the amount of amikacin tolerated by the patient. The solution should normally be infused over a 30 to 60 minute period. Infants should receive a 1 to 2 hour infusion.
Elderly
Amikacin is excreted by the renal route. Renal function should be assessed whenever possible and dosage adjusted as described under impaired renal function.
Life-threatening infections and/or those caused by Pseudomonas
The adult dose may be increased to 500mg every eight hours but should neither exceed 1.5g/day nor be administered for a period longer than 10 days. A maximum total adult dose of 15g should not be exceeded.
Urinary tract infections: (other than pseudomonal infections)
7.5mg/kg/day in two equally divided doses (equivalent to 250mg b.i.d. in adults). As the activity of amikacin is enhanced by increasing the pH, a urinary alkalising agent may be administered concurrently.
Impaired renal function
In patients with impaired renal function, the daily dose should be reduced and/or the intervals between doses increased to avoid accumulation of the drug. A suggested method for estimating dosage in patients with known or suspected diminished renal function is to multiply the serum creatinine concentration (in mg/100ml) by 9 and use the resulting figure as the interval in hours between doses.
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As renal function may alter appreciably during therapy, the serum creatinine should be checked frequently and the dosage regimen modified as necessary.
Intraperitoneal use
Following exploration for established peritonitis, or after peritoneal contamination due to faecal spill during surgery, Amikin may be used as an irrigant after recovery from anaesthesia in concentrations of 0.25% (2.5mg/ml). If instillation is desired in adults, a single dose of 500mg is diluted in 20ml of sterile distilled water and may be instilled through a polyethylene catheter sutured into the wound at closure. If possible, instillation should be postponed until the patient has fully recovered from the effects of anaesthesia and muscle-relaxing drugs.
Other routes of administration
Amikin in concentrations of 0.25% may be used satisfactorily as an irrigating solution in abscess cavities, the pleural space, the peritoneum and the cerebral ventricles.
4.3 Contraindications
Hypersensitivity to any of the components of the product.
Myasthenia gravis.
4.4 Special Warnings And Precautions For Use
Patients should be well hydrated during amikacin therapy.
In patients with impaired renal function or diminished glomerular filtration, amikacin should be used cautiously. In such patients, renal function should be assessed by the usual methods prior to therapy and periodically during therapy. Daily doses should be reduced and/or the interval between doses lengthened in accordance with serum creatinine concentrations to avoid accumulation of abnormally high blood levels and to minimise the risk of ototoxicity.
As with other aminoglycosides, ototoxicity and/or nephrotoxicity can result from the use of amikacin; precautions on dosage and adequate hydration should be observed.
If signs of renal irritation appear (such as albumin, casts, red or white blood cells), hydration should be increased and a reduction in dosage may be desirable. These findings usually disappear when treatment is completed. However, if azotaemia or a progressive decrease in urine output occurs, treatment should be stopped.
The use of amikacin in patients with a history of allergy to aminoglycosides or in patients who may have subclinical renal or eighth nerve damage induced by prior administration of nephrotoxic and/or ototoxic agents such as streptomycin, dihydrostreptomycin, gentamicin, tobramycin, kanamycin, bekanamycin, neomycin, polymyxin B, colistin, cephaloridine, or viomycin should be considered with caution, as toxicity may be additive.
In these patients amikacin should be used only if, in the opinion of the physician, therapeutic advantages outweigh the potential risks.
Aminoglycosides may impair neuromuscular transmission and should be used with caution in patients with muscular disorders such as parkinsonism. Large doses given during surgery have been responsible for a transient myasthenic syndrome.
Paediatric use
Aminoglycosides should be used with caution in premature and neonatal infants because of the renal immaturity of these patients and the resulting prolongation of serum half-life of these drugs.
The intraperitoneal use of amikacin is not recommended in young children.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Concurrent use with other potentially nephrotoxic or ototoxic drug substances should be avoided. Where this is not possible, monitor carefully.The risk of ototoxicity is increased when amikacin is used in conjunction with rapidly acting diuretic drugs, particularly when the diuretic is administered intravenously. Such agents include frusemide and ethacrynic acid which is itself an ototoxic agent. Irreversible deafness may result.
The intraperitoneal use of amikacin is not recommended in patients under the influence of anaesthetics or muscle-relaxing drugs (including ether, halothane, d
Indomethacin may increase the plasma concentration of amikacin in neonates.
In patients with severely impaired renal function, a reduction in activity of aminoglycosides may occur with concomitant use of penicillin-type drugs.
4.6 Pregnancy And Lactation
There are limited data on use of aminoglycosides in pregnancy. Aminoglycosides can cause foetal harm. Aminoglycosides cross the placenta and there have been reports of total, irreversible, bilateral congenital deafness in children whose mothers received streptomycin during pregnancy. Although adverse effects on the foetus or newborns have not been reported in pregnant women treated with other aminoglycosides, the potential for harm exists. In reproduction toxicity studies in mice and rats no effects on fertility or foetal toxicity were reported. If amikacin is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the foetus.
It is not known whether amikacin is excreted in human milk. A decision should be made whether to discontinue breast-feeding or to discontinue therapy.
Amikacin should be administered to pregnant women and neonatal infants only when clearly needed and under medical supervision (see section 4.4).
4.7 Effects On Ability To Drive And Use Machines
None stated.
4.8 Undesirable Effects
When the recommended precautions and dosages are followed the incidence of toxic reactions, such as tinnitus, vertigo, partial reversible or irreversible deafness, skin rash, drug fever, headache, paraesthesia, nausea and vomiting is low. Urinary signs of renal irritation (albumin, casts and red or white blood cells), azotaemia and oliguria have been reported. There have been reports of retinal toxicity following intravitreal injection of amikacin.
4.9 Overdose
In the event of overdosage or toxic reaction, peritoneal dialysis or haemodialysis will aid in the removal of amikacin from the blood.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Amikacin sulphate is an aminoglycoside antibiotic which is active against a broad spectrum of Gram-negative organisms, including Pseudomonas spp, Escherichia coli, indole-positive and indole-negative Proteus spp. Klebsiella-Enterobacter-Serratia spp, Salmonella, Shigella, Minea-Herellae, Citrobacter Freundii and Providencia spp.
Many strains of these Gram-negative organisms resistant to gentamicin and tobramycin may show sensitivity to amikacin in vitro. The principal Gram-positive organism sensitive to amikacin is Staphylococcus aureus, including methicillin-resistant strains. Amikacin has some activity against other Gram-positive organisms including certain strains of Streptococcus pyogenes, Enterococci and Diplococcus pneumoniae.
5.2 Pharmacokinetic Properties
Amikin is rapidly absorbed after intramuscular injection. Peak serum levels of approximately 11mg/l and 23mg/l are reached one hour after i.m. doses of 250mg and 500mg respectively. Levels 10 hours after injection are of the order of 0.3mg/l and 2.1mg/l respectively.
Twenty per cent or less is bound to serum protein and serum concentrations remain in the bactericidal range for sensitive organisms for 10 to 12 hours.
Amikin diffuses readily through extracellular fluids and is excreted in the urine unchanged, primarily by glomerular filtration. Half-life in individuals with normal renal functions is two to three hours.
Following intramuscular administration of a 250mg dose, about 65% is excreted in six hours and 91% within 24 hours. The urinary concentrations average 563 mg/l in the first 6 hours and 163 mg/l over 6 to 12 hours. Mean urine concentrations after a 500mg i.m. dose average 832 mg/l in the first six hours.
Single doses of 500mg administered to normal adults as an intravenous infusion over a period of 30 minutes produce a mean peak serum concentration of 38mg/l at the end of the infusion. Repeated infusions do not produce drug accumulation.
Amikin has been found in cerebrospinal fluid, pleural fluid, amniotic fluid and in the peritoneal cavity following parenteral administration.
Data from multiple daily dose trials show that spinal fluid levels in normal infants are approximately 10 to 20% of the serum concentrations and may reach 50% in meningitis.
Intramuscular and intravenous administration
In neonates and particularly in premature babies, the renal elimination of amikacin is reduced.
In a single study in newborns (1-6 days of post natal age) grouped according to birthweights (<2000, 2000-3000 and>3000g). Amikacin was administered intramuscularly and/or intravenously at a dose of 7.5 mg/kg. Clearance in neonates>3000 g was 0.84 ml/min/kg and terminal half-life was about 7 hours. In this group, the initial volume of distribution and volume of distribution at steady state was 0.3 ml/kg and 0.5 mg/kg, respectively. In the groups with lower birth weight clearance/kg was lower and half-life longer. Repeated dosing every 12 hours in all the above groups did not demonstrate accumulation after 5 days.
5.3 Preclinical Safety Data
No further relevant information.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Sodium bisulphite, sodium citrate, sulphuric acid, water for injection.
6.2 Incompatibilities
None.
6.3 Shelf Life
36 months.
6.4 Special Precautions For Storage
Store below 25°C.
6.5 Nature And Contents Of Container
Five 2 ml flint glass Type 1 vial with butyl rubber stopper and aluminium seal in a cardboard carton.
6.6 Special Precautions For Disposal And Other Handling
None stated.
7. Marketing Authorisation Holder
Bristol-Myers Squibb Holdings Ltd
Uxbridge Business Park
Sanderson Road
Uxbridge
Middlesex UB8 1DH
8. Marketing Authorisation Number(S)
0125/0090R
9. Date Of First Authorisation/Renewal Of The Authorisation
30th January 1991
10. Date Of Revision Of The Text
February 2010
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