Gentamicin sulfate solution for injections 4%

Overdose

Haemodialysis and peritoneal dialysis will aid removal from the blood but the former is probably more efficient.

Calcium salts given intravenously have been used to counter the neuromuscular blockade caused by Gentamicin sulfate solution for injections 4%.

Contraindications

Hypersensitivity to Gentamicin sulfate solution for injections 4% or any of the excipients; myasthenia gravis.

Incompatibilities

In general, Gentamicin sulfate solution for injections 4% should not be mixed with other medicinal products. In particular the following are incompatible in mixed solution with Gentamicin sulfate solution for injections 4% injection: beta-lactam antibiotics (e.g. penicillins, cephalosporins), erythromycin, or lipiphysan (a special oil-in-water-emulsion for parenteral nutrition) as this may cause physico-chemical inactivation. This also applies to a combination of Gentamicin sulfate solution for injections 4% with diazepam, furosemide, flecainide acetate or heparin sodium. Dilution in the body will obviate the danger of physical and chemical incompatibility and enable Gentamicin sulfate solution for injections 4% to be given concurrently with the drugs listed above either as a bolus injection into the drip tubing, with adequate flushing, or at separate sites. In the case of carbenicillin, administration should only be at a separate site.

The following active substances or solution for reconstitution/dilution should not be administered simultaneously:

Gentamicin sulfate solution for injections 4% is incompatible with amphotericin B, cephalothin sodium, nitrofurantoin sodium, sulfadiazine sodium and tetracyclines.

Addition of Gentamicin sulfate solution for injections 4% to solutions containing bicarbonate may lead to the release of carbon dioxide.

Pharmaceutical form

Undesirable effects

Under certain conditions Gentamicin sulfate solution for injections 4% shows ototoxic and/or nephrotoxic effects. Renal impairment is commonly observed in patients treated with Gentamicin sulfate solution for injections 4% and is usually reversible upon withdrawal of the drug. In most cases nephrotoxicity is associated with an excessively high dosage or prolonged treatment, pre-existing renal abnormalities or associated with other substances reported to be nephrotoxic.

The adverse reactions considered at least possibly related to treatment are listed below by body system organ class and absolute frequency. Frequencies are defined as:

very common (>1/10);

common (>1/100 to <1/10);

uncommon (>1/1000 to <1/100);

rare (>1/10 000 to <1/1000);

very rare (<1/10 000),

not known (frequency cannot be estimated from the available data).

1 Usually in these cases other antibiotics are also involved.

2 May occur as hypersensitivity reactions

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system, by the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Preclinical safety data

Chronic toxicity

In studies on chronic toxicity (i.m. application) carried out on various animal species, nephrotoxic and ototoxic effects were observed at high dosages.

Mutagenic and carcinogenic potential

Gentamicin sulfate solution for injections 4% was not mutagenic in in vitro and in vivo tests. There are no long-term studies on animals on the carcinogenic potential of Gentamicin sulfate solution for injections 4%.

Reproductive toxicity

There is a potential risk of inner ear and renal damage to the fetus as was observed for the class of aminoglycoside antibiotics. Fetal renal abnormalities have been documented in rats and guinea pigs after administration of Gentamicin sulfate solution for injections 4% to the dams.

Therapeutic indications

Indications : Gentamicin sulfate solution for injections 4% is indicated in bacteraemia, urinary tract infections, chest infections, severe neonatal infections and other serious systemic infections due to susceptible organisms, in adults and children including neonates.

Consideration should be given to official local guidance on the appropriate use of antibacterial agents.

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterial for systemic use

ATC code: J01GB03

Gentamicin sulfate solution for injections 4% is an aminoglycoside antibiotic extracted from Micromonospora purpurea. It represents a mixture of the structurally very similar homologues Gentamicin sulfate solution for injections 4% C1, C1a and C2. The Gentamicin sulfate solution for injections 4% homologue C2 is classified as the component with the highest toxicity. The antibacterial activity of Gentamicin sulfate solution for injections 4% sulphate is determined both on the basis of units and also on the basis of mass (weight).

Mechanism of action:

Gentamicin sulfate solution for injections 4% has bactericidal efficacy both in the proliferation and in the resting stage of bacteria. It forms a bond with the proteins of the 30S subunits of the bacterial ribosomes, which causes “misreading” of the mRNA.

PK/PD relationship

The aminoglycosides show a concentration dependent anti-bacterial effect.

Gentamicin sulfate solution for injections 4% and other aminoglycosides show a clear post-antibiotic effect in vitro and in vivo in most experimental models of infection. Provided sufficiently high doses are administered, these drugs are therefore efficacious against infections with many susceptible micro-organisms even if the concentration in plasma and tissues remains below the MIC during part of the dosage interval. The post-antibiotic effect permits the dosage interval to be extended without loss of efficacy against most Gram-negative bacilli.

Mechanism of resistance

Resistance may be due to a failure of permeation, low affinity for the bacterial ribosome or inactivation of Gentamicin sulfate solution for injections 4% by microbial enzymes. The emergence of resistance during therapy is unusual.

Breakpoints

According to EUCAST, the following limit values apply for Gentamicin sulfate solution for injections 4%:

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable. Especially in such circumstances, samples should be obtained in order to identify the causal micro- organism and to measure its sensitivity to Gentamicin sulfate solution for injections 4%.

Abbreviations:

MSSA = Methicillin-sensitive Staphylococcus aureus,

MRSA = Methicillin-resistant Staphylococcus aureus

Infections caused by Streptococci or Enterococci:

Aminoglycosides are suitable combination partners for other antibiotics against Gram-positive cocci. For some indications (endocarditis), synergistic effects with beta-lactams have been described. This synergy is abolished when Streptococci or Enterococci present a high level acquired resistance to Gentamicin sulfate solution for injections 4%.

Other notes:

Synergistic effects have been described with acylamino penicillins (e.g. piperacillin) on Pseudomonas aeruginosa and with cephalosporins on Klebsiella pneumoniae.

Pharmacokinetic properties

Absorption

Like all aminoglycoside antibiotics, Gentamicin sulfate solution for injections 4% is barely absorbed by healthy intestinal mucosa after oral administration. Therefore therapeutic application is parenteral.

Higher peak and lower trough levels are found when the total daily dose is given as a single daily infusion. When Gentamicin sulfate solution for injections 4% is administered by intravenous short infusion of 30 minutes at 4 mg/kg body weight per day in three divided doses, peak and trough Gentamicin sulfate solution for injections 4% concentrations measured in adult patients were 4.7 µg/ml and 1.0 µg/ml, respectively. With the same daily dose administered once daily, peak and trough concentrations of 9.5 µg/ml and 0.4 µg/ml were measured.

Therapeutic serum concentrations generally lie between 2 and 8 µg/ml. Therapeutic peak serum concentrations are in the range of 5 - 10 µg/ml for multiple daily dosing and 20 - 30 µg/ml for once daily dosing. Maximum serum concentrations of 10 - 12 µg/ml should not be exceeded when administered conventionally, in several doses per day. Before another dose is administered, the serum concentration when administered conventionally, in several doses per day, should have fallen below 2 µg/ml.

Distribution

The distribution volume of Gentamicin sulfate solution for injections 4% 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 sulfate solution for injections 4% 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.

The distribution of Gentamicin sulfate solution for injections 4% to the individual organs results in varying tissue concentrations; the highest concentrations appear in the renal tissue. Smaller concentrations are found in the liver and gall bladder, the lung and spleen.

Gentamicin sulfate solution for injections 4% crosses the placenta; the foetal concentrations can be 30% of the maternal plasma concentrations. Gentamicin sulfate solution for injections 4% is excreted in small quantities in breast milk (1/3 of the concentration is found here, as in the case of the maternal plasma).

After repeated injection of Gentamicin sulfate solution for injections 4%, approximately 50% of the concentrations reached in plasma is measured in the synovial, pleural, pericardial and peritoneal fluid. The penetration of Gentamicin sulfate solution for injections 4% into the cerebrospinal fluid is poor in un-inflamed meninges. In inflamed meninges, concentrations reach up to 30% of the concentrations measured in plasma.

Plasma protein binding: less than 10%.

Biotransformation

Gentamicin sulfate solution for injections 4% is not metabolised in the organism but is excreted unchanged in microbiologically active form.

Elimination

Gentamicin sulfate solution for injections 4% is eliminated unchanged in microbiologically active form principally in the urine by glomerular filtration. The dominant elimination half-life in patients with normal renal function is around 2 - 3 hours. Elderly patients eliminate Gentamicin sulfate solution for injections 4% more slowly than younger adults.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

In patients with advanced renal impairment or with pre-existing inner ear deafness, Gentamicin sulfate solution for injections 4% should be used only if its use is considered essential by the physician. The frequency or dose of administration should be reduced in patients with impaired renal function.

Renal impairment

Renal impairment such as restriction of glomerular filtration is observed in approximately 10% of patients treated with Gentamicin sulfate solution for injections 4% and is usually reversible. The most important risk factors are high total dose, long duration of therapy, raised serum level (high trough level); in addition, other potential risk factors are age, hypovolaemia and shock.

Clinical signs of renal damage are: proteinuria, cylindruria, haematuria, oliguria, raised creatinine and urea concentrations in serum.)

Neuromuscular disorders

Since Gentamicin sulfate solution for injections 4% has neuromuscular blocking properties, particular caution should be exercised in patients with pre- existing neuromuscular diseases (e.g.)

Neuromuscular blockade and respiratory paralysis have been reported from administration of aminoglycosides to patients who have received curare-type muscle relaxants during anaesthesia.)

Effect on vestibulocochlear nerve

Damage to the vestibulocochlear nerve (eighth cranial nerve), whereby both balance and hearing may be affected, is possible. Vestibular damage is the most common ototoxic reaction. Hearing loss is manifested initially by diminution of high-tone acuity and is usually irreversible. Important risk factors are pre-existing renal impairment or a history of damage to the eighth cranial nerve; in addition, the risk increases in proportion to the level of the total and daily dose or by association with potentially ototoxic substances. Symptoms of ototoxic effects are: dizziness, ringing/roaring in the ears (tinnitus), vertigo and less common hearing loss.

With Gentamicin sulfate solution for injections 4% the vestibular mechanism may be affected if trough levels of 2 µg/ml are exceeded.)

Antibiotic-associated diarrhoea, pseudomembranous colitis Antibiotic-associated diarrhoea and pseudomembranous colitis have been reported with the use of Gentamicin sulfate solution for injections 4%. These diagnoses should be considered in any patient who develops diarrhoea during or shortly after treatment. Gentamicin sulfate solution for injections 4% should be discontinued if severe and/or bloody diarrhoea occurs during treatment and appropriate therapy instituted. Drugs that inhibit peristalsis must not be given.

Pregnancy and lactation

Gentamicin sulfate solution for injections 4% should be used in pregnancy and during lactation only after careful benefit risk assessment.

Once daily dosing of Gentamicin sulfate solution for injections 4% in elderly patients:

There is limited experience with once daily dosing of Gentamicin sulfate solution for injections 4% in elderly patients. Once daily dosing of Gentamicin sulfate solution for injections 4% may not be suitable and therefore, close monitoring is warranted in these patients.

Excipients

This medicine contains 0,78 mg of sodium per ampoule (less than 23 mg per ampoule), i.e. it is essentially sodium free.

Sodium metabisulphite, one of the excipients of this medicinal product, may rarely cause severe hypersensitivity reactions and bronchospasm.

Cross-allergenicity/-resistance

Cross resistance and hypersensitivity to aminoglycosides may occur.

Monitoring

To avoid adverse events, continuous monitoring (before, during and after treatment) of renal function (serum creatinin, creatinin clearance), control of function of vestibule and cochlea as well as hepatic and laboratory parameters is recommended.

In order to reduce the risk of nephrotoxicity and ototoxicity, the following instructions should be considered:

- Regular assessment of auditory, vestibular and renal 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.

- Monitoring of renal function before, during and after treatment.

- Dosage strictly according to creatinine clearance (or serum creatinine concentration). In patients with impaired renal function, the dosage must be adjusted according to renal performance.

- In patients with impaired renal function additionally receiving Gentamicin sulfate solution for injections 4% locally (inhalation, intratracheal, instillation), the amount of Gentamicin sulfate solution for injections 4% absorbed after local administration must also be taken into account for dose adjustment of systemic treatment.

- Monitoring of serum Gentamicin sulfate solution for injections 4% concentrations during therapy in order to avoid that peak levels exceed 10 µg/ml (toxic threshold for the cochleo-vestibular system) with conventional multiple daily dosing or trough levels exceed 2 µg/ml when administrating Gentamicin sulfate solution for injections 4% twice daily and 1 mg/l for a once daily dosing.

- In patients with pre-existing inner ear damage (hearing impairment or balance function impairment), or where treatment is long-term, additional monitoring of the balance function and hearing is required.

- Prolonged treatment should be avoided. If possible, the duration of therapy should be limited to 7 - 10 days.

- Avoid therapy with aminoglycosides immediately subsequent to previous aminoglycoside treatment; if possible, there should be an interval of 7 - 14 days between treatments.

- If possible, avoid concurrent administration of other potentially ototoxic and nephrotoxic substances. If this is unavoidable, particular careful monitoring of renal function is indicated.

- Ensure adequate hydration and urine production.

Effects on ability to drive and use machines

Caution is advised when driving and using machines in view of the possible undesired effects such as dizziness and vertigo.

Dosage (Posology) and method of administration

Adults:

Systemic infections: if renal function is not impaired, 3-5 mg/kg/day in divided doses according to severity of infection, adjusting according to clinical response and body weight.

Serious infections: if renal function is not impaired, 5mg/kg daily in divided doses at six or eight hourly intervals. The total daily dose may be subsequently increased or decreased as clinically indicated.

Urinary tract infections: as 'systemic infections'. Or, if renal function is not impaired, 160mg once daily may be used.

Paediatric Patients:

The daily dose recommended in children (aged 1 year and above) and adolescents with normal renal function, is 3-6 mg/kg body weight per day as 1 single dose (preferred) or up to 2 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 1 single dose (preferred) or up to 2 single doses.

The daily dose in neonates is 4-7 mg/kg body weight per day. Due to the longer half-life, neonates are given the required daily dose in 1 single dose.

Elderly:

There is some evidence that elderly patients may be more susceptible to aminoglycoside toxicity whether secondary to previous eighth nerve impairment or borderline renal dysfunction.

Accordingly, therapy should be closely monitored by frequent determination of Gentamicin sulfate solution for injections 4% serum levels, assessment of renal function and signs of toxicity.

Renal impairment:

Gentamicin sulfate solution for injections 4% is excreted by simple glomerular filtration. In impaired renal function, the recommended daily dose has to be decreased and adjusted to the renal function.

Nomograms are available for the calculation of the dose, which depends on the patient's age, weight, and renal function

The following table may be useful when treating adults.

*60mg if body weight <60kg. Frequency of dosage in hours may also be approximated as serum creatine (mg%) x eight or in SI units, as serum creatine (μmol/l) divided by 11. If these dosage guides are used peak serum levels must be measured. Peak levels of Gentamicin sulfate solution for injections 4% occur approximately one hour after intramuscular injectable and intravenous injectable. Trough levels are measured just prior to the next injectable. Assay of peak serum levels gives confirmation of adequacy of dosage and also serves to detect levels above 10mg/l, at which the possibility of ototoxicity should be considered. One hour concentrations of Gentamicin sulfate solution for injections 4% should not exceed 10mg/l (but should reach 4mg/l), while the pre-dose trough concentration should be less than 2mg/l

The recommended dose and precautions for intramuscular and intravenous administration are identical. Gentamicin sulfate solution for injections 4% when given intravenously should be injected directly into a vein or into the drip set tubing over no less than three minutes. If administered by infusion, this should be over no longer than 20 minutes and in no greater volume of fluid than 100ml.

Monitoring advice:

Serum concentration monitoring of Gentamicin sulfate solution for injections 4% is recommended, especially in elderly, in newborns and in patients with impaired renal function.

Special precautions for disposal and other handling

Gentamicin sulfate solution for injections 4% can be diluted with 0.9% sodium chloride or 5% glucose solution.

For single use only

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