|
Update sections 4.1, 4.2, 4.4, 5.2 and 10 as noted below in bold to be in line with EU pediatric regulations.
4.1. Therapeutic indications
Genticin Injectable ampoules are indicated for the treatment of systemic infections due to susceptible bacteria such as, bacteraemia, septicaemia, urinary-tract infections and severe chest infections.
Consideration should be given to official local guidance on the appropriate use of antibacterial agents.
4.2. Posology and method of administration
Genticin is normally administered intramuscularly but may be given intravenously as a slow intravenous injection over at least 3 minutes or short infusion if required. Genticin should not be given as a slow infusion or mixed with other drugs before use (see Incompatibilities).
The daily recommended dose in children, adolescents and adults with normal renal function is 3-6 mg/kg body weight per day as one (preferred) up to two single doses.
The daily dose in infants after the first month of life is 4.5-7.5 mg/kg body weight per day as one (preferred) up to two single doses.
The daily dose in newborns is 4-7 mg/kg body weight per day. Due to the longer half-life, newborns are given the required daily dose in one single dose.
In cases of impaired renal function a reduction in dosage frequency is recommended. The following table is a guide to recommended dosage schedules:
|
Blood urea
(mg/100ml)
|
Creatinine clearance
(GFR) (ml/min)
|
Dose and frequency
of administration
|
|
< 40
40 – 100
100 – 200
> 200
Twice-weekly intermittent haemodialysis
|
> 70
30 - 70
10 - 30
5 - 10
< 5
|
80mg† 8-hourly
80mg† 12-hourly
80mg† daily
80mg† every 48 hours
80mg† after dialysis
|
|
† 60mg if body weight < 60kg.
|
|
|
In life-threatening infections the frequency of dosage may need to be increased to 6-hourly and the quantity of each dose may also be increased at the discretion of the clinician up to a total dosage of 5mg/kg in 24 hours. In such cases it is advisable to monitor gentamicin serum levels.
If renal function is not impaired, 160mg once daily may be used in some cases.
Monitoring advice:
Serum concentration monitoring of gentamicin is recommended, especially in elderly, in newborns and in patients with impaired renal function. Samples are taken at the end of a dosing interval (trough level). Trough levels should not exceed 2 μg/ml administering gentamicin twice daily and 1 μg/ml for a once daily dose.
Prolonged use should be avoided and whenever possible the treatment should not exceed 7 days.
Caution is advised in significant obesity as gentamicin is poorly distributed into fatty tissue. The dosage calculation should be based on an estimate of lean body weight. Serum levels should be monitored closely and the dose possibly adjusted (see 4.4).
4.4. Special warnings and precautions for use
Where renal function is impaired through disease or old age the frequency, but not the amount, of each dose should be reduced according to the degree of impairment. Gentamicin is excreted by simple glomerular filtration, and dosage frequency may be predicted by assessing serum creatinin, creatinine clearance rates or blood urea and reducing the frequency accordingly.
It is also advisable to check serum levels to confirm that peak (1 hour) levels do not exceed 10 micrograms/ml and that trough levels (before next injection) do not exceed 2 micrograms/ml when administering gentamicin twice daily and 1 microgram/ml for a once daily dose.
Caution is required in Parkinsonism and other conditions characterised by muscular weakness.
To avoid adverse events, continuous monitoring (before, during and after) of renal function (serum creatinin, creatinin clearance), control of function of vestibule and cochlea as well as hepatic and laboratory parameters is recommended. Regular assessment of auditory, vestibular, renal and hepatic function is particularly necessary in patients with additional risk factors. Impaired hepatic function or auditory function, bacteraemia and fever have been reported to increase the risk of ototoxicity. Volume depletion or hypotension and liver disease have been reported as additional risk factors for nephrotoxicity.
Caution is advised in significant obesity (see 4.2).
5.2. Pharmacokinetic properties
Gentamicin is rapidly absorbed following intramuscular injection, giving peak plasma concentrations after 30 minutes - 1 hour. Effective concentrations are still present 4 hours after injection. An injection of 1mg/kg body weight results in a peak plasma concentration of approximately 4 micrograms/ml.
> 90% gentamicin is excreted in the urine by glomerular filtration.
< 10% is bound to plasma protein.
T½ = 2 - 3 hours in individuals with normal kidney function, but can be increased in individuals with renal insufficiency.
Distribution
The distribution volume of gentamicin is about equivalent to the volume of extracellular water. In the newborn water makes up 70 to 75% of bodyweight, compared with 50 to 55% in adults. The extracellular water compartment is larger (40% of body weight compared with 25% of body weight in adults). Therefore, the volume of distribution of gentamicin per kg bodyweight is affected and decreases with increasing age from 0.5 to 0.7 L/kg for a premature newborn to 0.25 L/kg for an adolescent. The larger volume of distribution per kg bodyweight means that for adequate peak blood concentration a higher dose per kg bodyweight needs to be administered.
Elimination
Gentamicin is not metabolized in the body but is excreted unchanged in microbiologically active form predominantly via the kidneys. In patients with normal renal function the elimination half-life is about 2 to 3 hours. In neonates elimination rate is reduced due to immature renal function.
Elimination half-life averages approximately 8 hours in neonates at a gestational age of 26 to 34 weeks compared with about 6.7 hours in neonates at a gestational age of 35 to 37 weeks.
Correspondingly, clearance values increase from about 0.05 L/h in neonates at a gestational age of 27 to 0.2 L/h in neonates at a gestational age of 40 weeks.
10. DATE OF REVISION OF THE TEXT
December 2010
|
