Gentamycin sulfate-em

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 Gentamycin Sulfate-EM.

No information provided.

Contraindications

Hypersensitivity to Gentamycin Sulfate-EM or any of the excipients; myasthenia gravis.

GARAMYCIN Sterile Ophthalmic Solution is contraindicated in patients with known hypersensitivity to any of the components.

Incompatibilities

In general, Gentamycin Sulfate-EM should not be mixed with other medicinal products. In particular the following are incompatible in mixed solution with Gentamycin Sulfate-EM 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 Gentamycin Sulfate-EM with diazepam, furosemide, flecainide acetate or heparin sodium. Dilution in the body will obviate the danger of physical and chemical incompatibility and enable Gentamycin Sulfate-EM 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:

Gentamycin Sulfate-EM is incompatible with amphotericin B, cephalothin sodium, nitrofurantoin sodium, sulfadiazine sodium and tetracyclines.

Addition of Gentamycin Sulfate-EM to solutions containing bicarbonate may lead to the release of carbon dioxide.

Undesirable effects

Under certain conditions Gentamycin Sulfate-EM shows ototoxic and/or nephrotoxic effects. Renal impairment is commonly observed in patients treated with Gentamycin Sulfate-EM 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.

Bacterial and fungal corneal ulcers have developed during treatment with gentamicin ophthalmic preparations.

The most frequently reported adverse reactions are ocular burning and irritation upon drug instillation, nonspecific conjunctivitis, conjunctival epithelial defects, and conjunctival hyperemia.

Other adverse reactions which have occurred rarely are allergic reactions, thrombocytopenic purpura, and hallucinations.

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

Gentamycin Sulfate-EM was not mutagenic in in vitro and in vivo tests. There are no long-term studies on animals on the carcinogenic potential of Gentamycin Sulfate-EM.

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 Gentamycin Sulfate-EM to the dams.

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterial for systemic use

ATC code: J01GB03

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

Mechanism of action:

Gentamycin Sulfate-EM 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.

Gentamycin Sulfate-EM 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 Gentamycin Sulfate-EM by microbial enzymes. The emergence of resistance during therapy is unusual.

Breakpoints

According to EUCAST, the following limit values apply for Gentamycin Sulfate-EM:

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 Gentamycin Sulfate-EM.

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 Gentamycin Sulfate-EM.

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, Gentamycin Sulfate-EM 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 Gentamycin Sulfate-EM is administered by intravenous short infusion of 30 minutes at 4 mg/kg body weight per day in three divided doses, peak and trough Gentamycin Sulfate-EM 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 Gentamycin Sulfate-EM 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 Gentamycin Sulfate-EM 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 Gentamycin Sulfate-EM 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.

Gentamycin Sulfate-EM crosses the placenta; the foetal concentrations can be 30% of the maternal plasma concentrations. Gentamycin Sulfate-EM 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 Gentamycin Sulfate-EM, approximately 50% of the concentrations reached in plasma is measured in the synovial, pleural, pericardial and peritoneal fluid. The penetration of Gentamycin Sulfate-EM 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

Gentamycin Sulfate-EM is not metabolised in the organism but is excreted unchanged in microbiologically active form.

Elimination

Gentamycin Sulfate-EM 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 Gentamycin Sulfate-EM more slowly than younger adults.

Special warnings and precautions for use

In patients with advanced renal impairment or with pre-existing inner ear deafness, Gentamycin Sulfate-EM 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 Gentamycin Sulfate-EM 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 Gentamycin Sulfate-EM 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 Gentamycin Sulfate-EM 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 Gentamycin Sulfate-EM. These diagnoses should be considered in any patient who develops diarrhoea during or shortly after treatment. Gentamycin Sulfate-EM 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

Gentamycin Sulfate-EM should be used in pregnancy and during lactation only after careful benefit risk assessment.

Once daily dosing of Gentamycin Sulfate-EM in elderly patients:

There is limited experience with once daily dosing of Gentamycin Sulfate-EM in elderly patients. Once daily dosing of Gentamycin Sulfate-EM 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 Gentamycin Sulfate-EM locally (inhalation, intratracheal, instillation), the amount of Gentamycin Sulfate-EM absorbed after local administration must also be taken into account for dose adjustment of systemic treatment.

- Monitoring of serum Gentamycin Sulfate-EM 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 Gentamycin Sulfate-EM 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.

NOT FOR INJECTION INTO THE EYE. Gentamicin Sulfate Ophthalmic Solution is not for injection. It should never be injected subconjunctivally, nor should it be directly introduced into the anterior chamber of the eye.

General

Prolonged use of topical antibiotics may give rise to overgrowth of nonsusceptible organisms including fungi. Bacterial resistance to gentamicin may also develop. If purulent discharge, inflammation, or pain becomes aggravated, the patient should discontinue use of the medication and consult a physician.

If irritation or hypersensitivity to any component of the drug develops, the patient should discontinue use of this preparation, and appropriate therapy should be instituted.

Information for Patients

To avoid contamination, do not touch tip of container to the eye, eyelid, or any surface.

Carcinogenesis, Mutagenesis, Impairment of Fertility

There are no published carcinogenicity or impairment of fertility studies on gentamicin. Aminoglycoside antibiotics have been found to be nonmutagenic.

Pregnancy

Pregnancy Category C: Gentamicin has been shown to depress body weights, kidney weights, and median glomerular counts in newborn rats when administered systemically to pregnant rats in daily doses approximately 500 times the maximum recommended ophthalmic human dose. There are no adequate and well-controlled studies in pregnant women. Gentamicin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pediatric Use

Safety and effectiveness in neonates have not been established.

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.

Special precautions for disposal and other handling

Gentamycin Sulfate-EM 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.