4.1. Therapeutic indications

Gentamicin is indicated for the treatment of the following infections in adults and children from birth when less toxic antimicrobial agents are not effective (see sections 4.4 and 5.1)

Under these conditions, Gentamicin is indicated in the treatment of the following infections:

– Complicated urinary tract infection (cUTI), including acute pyelonephritis

– Complicated intra-abdominal infection (cIAI)

– Hospital-acquired pneumonia (HAP) including ventilator-associated pneumonia (VAP)

– Broncho-pulmonary infections in patients with cystic fibrosis

– Infective endocarditis

– Burn wound infections

– Treatment of patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above.

Gentamicin should for all indications, except complicated urinary tract infections, only be used in combination with other relevant antibiotics (predominantly together with a beta-lactam antibiotic or with an antibiotic effective against anaerobic bacteria).

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

4.2. Posology and method of administration

CAUTION: In the absence of data, administration of Gentamicin solution for injection/infusion via inhalation is not recommended (see section 4.4)

Posology

The dose depends on the severity of the clinical picture, the setting, the patient's renal function and the bacterium identified.

Dosage and dosage interval should be adjusted individually in accordance with the patient's renal function, the bacterium identified and must be controlled by regular determination of the serum concentration.

The dose is expressed in terms of the patient's body weight.

Dosing regimens are identical for intravenous and intramuscular use. During treatment the patient should be sufficiently hydrated.

Adults

Gentamicin is generally used at the start of combined antibiotic treatment and for a maximum duration of 7 days, with discontinuation usually after 48 to 72 hours of treatment (i.e. when results from antimicrobial susceptibility tests become available).

The preferred dosing regimen is the single daily dose (SDD), i.e. the entire daily dose administered as a single daily injection (see section 4.4).

In certain situations the daily dose may be divided into 2 daily injections.The dose ranges from 3 to 6 mg/kg/day according to official recommendations, with the maximum dose of 6 mg/kg/day particularly recommended at the start of treatment, in severe infections and/or in cases where there is a risk of infection due to a bacterial strain with reduced sensitivity and with an increased minimum inhibitory concentration (MIC) for gentamicin.

Paediatric population

The daily recommended dose in children and adolescents with normal renal function is 3-6mg/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 1 (preferred) up to 2 single doses.

The daily dose in neonates and pre-term infants (aged 0-4 weeks old) is 4-7 mg/kg body weight per day. Due to the longer half-life, new-borns are given the required daily dose in 1 single dose.

Particular attention must be paid to the preparation (dilution) and amount administered. Any error, however slight, can have a major impact on the serum concentrations obtained.

There is no dose recommendation for children with impaired renal function.

Elderly Patients

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 serum levels, assessment of renal function and signs of ototoxicity.

Patients with Renal impairment

Since gentamicin is chiefly eliminated via the kidneys by glomerular filtration, the elimination rate depends on the patient's renal function, and the recommended daily dose must therefore be adjusted to the renal function.

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

>70

80mg† 8-hourly

40 - 100

30 - 70

80mg† 12-hourly

100 - 200

10 - 30

80mg† daily

>200

5 - 10

80mg† every 48 hours

Twice-weekly intermittent haemodialysis

<5

80mg† after dialysis

† 60mg if body weight <60kg

If the dose is not reduced, and/or the dosage interval not lengthened, abnormally high and possibly toxic concentrations can be reached in the blood and tissues due to accumulation.

The SDD regimen and short treatment periods must be preferred (generally: 1 or 2 injections), other risk factors promoting aminoglycoside nephrotoxicity must be taken into account and monitoring of renal and auditory functions must be performed (see sections 4.4 and 4.8).

For the first injection, the dosage is identical to that of patients with normal renal function, regardless of the degree of renal impairment (including all situations involving renal replacement therapy).

Further injections at the same dose as the first injection should be performed, unless the single dose needs to be adjusted according to the peak assay.

Continuous renal replacement therapy in patients on dialysis, injections should be given 2 to 4 hours before the dialysis session to reduce the potential for toxicity.

Adjustment of treatment should be considered by performing repeated assays to determine residual levels; gentamicin may be reinjected only when levels are below the toxicity threshold.

Patients with renal impairment not receiving renal replacement therapy: no further injections should be performed while residual levels are above the toxicity threshold (see sections 4.2 and 4.4).

If the residual assay (generally performed 24 hours post-dose) is higher than the toxicity threshold, the assay must be repeated 24 hours later.

Patients with Hepatic impairment

In patients with impaired hepatic function no dose adjustment is necessary.

Obese Patients

The dose in mg/kg must be calculated according to adjusted body weight:

Adjusted body weight = ideal weight1 + 0.43 x excess weight (Excess weight = total weight - ideal weight)

1 Lorentz formula (ideal weight expressed in kg):

Women = height (cm) – 100 – [height (cm) - 150] / 2

Men = height (cm) – 100 – [height (cm) – 150] / 4

Conditions for use of this formula:

• age over 18 years;

• height between 140 and 220 cm.

Method of administration

The recommended dose and precautions for intramuscular and intravenous administration are identical. Gentamicin 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 20 – 30 minutes and in no greater volume of fluid than 100 ml. Longer infusion times of up to 60 minutes may be used, in particular for a once daily dosing regimen. Once daily dosing should only be administered through the intravenous route.

Special clinical circumstances

Therapeutic monitoring

Regular serum concentration monitoring of gentamicin is recommended for all patients, and especially the elderly, newborns, obese patients, patients with impaired renal function and patients with cystic fibrosis. Gentamicin should not be prescribed if serum concentrations cannot be monitored.

There are no universally accepted guidelines for therapeutic drug monitoring of gentamicin. Local monitoring and dose adjustment guidelines should be followed where available.

Pre-dose (“trough level”) monitoring is recommended to ensure that the interval between doses is correct. Trough levels are measured at the end of a dosing interval and should not exceed 1 mg/l for once daily dosing or 2 mg/l for multiple daily dosing. Levels in excess of these indicate the need to extend the interval between doses, not reduction of the dose.

Post-dose (“peak level”) monitoring is recommended to check the adequacy of a dose or to ensure that it is not excessive and likely to cause toxicity. Peak levels should be measured one hour after an intravenous bolus or intramuscular bolus dose, or 30 minutes after the end of an infusion. A plasma concentration < 4 mg/l indicates that the dose is likely to be inadequate and a dose increase should be considered.

Any change in dose should be re-assessed with pre- and post-dose levels to confirm the adequacy of the new dose and the appropriateness of the dose interval.

4.3. Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

- Myasthenia gravis.

4.4. Special warnings and precautions for use

General information

In the absence of data, Gentamicin solution for injection/infusion is not recommended for use via inhalation. Aminoglycosides must be used within a strict prescribing framework (indications restricted to severe infections or due to resistant bacteria, administration regimens must be observed) and accompanied by appropriate surveillance. Prescription of gentamicin must meet this objective.

Risks for the development of renal and auditory toxicities increase with treatment periods of more than 5-7 days, even in healthy subjects; the risk is greater in patients with renal impairment. Nevertheless, early toxicity can even appear with the very first doses.

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.

Concurrent use with Neurotoxic or nephrotoxic antibiotics

Simultaneous and/or sequential systemic or topical treatment with other potentially neuro- and/or nephrotoxic agents should be avoided.

Neuromuscular blockade and respiratory paralysis have been reported following administration of aminoglycosides in patients receiving non-depolarising muscle relaxants during anaesthesia. These patients must also be very closely monitored (see section 4.8).

Ototoxicity

Damage to the vestibulocochlear nerves (eighth cranial nerve), where balance and hearing are affected, is possible. Vestibular damage is the most common ototoxic reaction. Hearing loss is initially manifested by reduced high-frequency acuity and is usually irreversible.

Symptoms of ototoxicity are: dizziness, ringing/whistling noises (tinnitus), vertigo and less commonly, loss of hearing (see section 4.8).

There is an increased risk of ototoxicity in patients with mitochondrial DNA mutations (particularly the nucleotide 1555 A to G substitution in the 12S rRNA gene), even if aminoglycoside serum levels are within the recommended range during treatment. Alternative treatment options should be considered in such patients.

In patients with a maternal history of relevant mutations or aminoglycoside induced deafness, alternative treatments or genetic testing prior to administration should be considered.

In patients with end-stage renal disease, on intermittent haemodialysis or chronic peritoneal dialysis, toxicity is mainly auditory, as the kidneys are no longer functional.

Muscular weakness

Since gentamicin has neuromuscular blocking properties, particular attention must be paid to patients with pre-existing neuromuscular disease (e.g. Parkinson's disease). Close monitoring must always be instituted in such patients (see section 4.8).

Singe Daily Dose

SDD optimises pharmacokinetic-pharmacodynamic parameters (see section 5.1), promotes tissue diffusion has a clinical efficacy at least identical to that obtained following administration divided into several daily injections is responsible for renal and auditory toxicities comparable to or even less than those observed with other methods of administration, decreases the risk for the emergence of resistant mutant strains.

Impaired renal function

In the presence of acute or chronic pre-existing renal impairment, aminoglycosides should be used only when absolutely necessary. All possible non-nephrotoxic alternatives should be looked into. Dosage adjustments are required in patients with renal impairment (see section 4.2).

Clinical signs of kidney damage are: proteinuria, cylindruria, haematuria, oliguria, increased blood concentrations of creatinine and urea. In isolated cases, acute kidney failure may occur (see section 4.8).

Paediatric population

According to the data available, renal and auditory toxicities remain rare in newborns and children.

Elderly Patients

Elderly patients can have impaired renal function that does not show up in routine analyses like BUN and serum creatinine. Creatinine clearance determination is more practicable. Checking the function is particularly important in these patients.

Patients with severe burns injuries

Patients with severe burn injuries must be monitored extra carefully due to the altered pharmacokinetics.

Treatment with gentamicin may produce an excessive growth of drug-resistant microorganisms. If this happens, an appropriate treatment should be initiated.

Diarrhoea and pseudomembranous colitis have been observed when gentamicin is combined with other antibiotics. These diagnoses should be considered in every patient that develops diarrhoea during or immediately after treatment. Gentamicin should be discontinued if the patient suffers severe diarrhoea and/or bloody diarrhoea during treatment and an appropriate treatment should be initiated. Drugs that inhibit peristalsis should not be administered (see section 4.8).

Gentamicin contains sodium

This medicine contains 4.90 mg of sodium per 2 ml vial.

4.5. Interaction with other medicinal products and other forms of interaction

• Other aminoglycosides in concomitant administration. Increased risk of nephrotoxicity and ototoxicity.

• Loop diuretics

Increased nephrotoxic and ototoxic risks due to the aminoglycoside (functional renal impairment associated with diuretic-induced dehydration). Combination is possible together with monitoring of hydration status, renal and vestibulocochlear functions, aminoglycoside plasma concentrations.

• Ototoxic agents

Concomitant use of medicinal products with intrinsic ototoxicity increases the risk of vestibulocochlear damage. If such a combination is necessary, monitoring of auditory function must be increased. In particular, such medicines include antibiotics of the glycopeptide group, such as vancomycin and teicoplanin, aminoglycosides, cytotoxic agents such as organoplatinum compounds and loop diuretics.

• Nephrotoxic agents

Concomitant use of medicinal products with intrinsic renal toxicity increases the risk of nephrotoxicity. If such a combination is necessary, monitoring of kidney function tests must be increased. In particular, such medicines include iodinated contrast media, aminoglycosides, organoplatinum compounds, high-dose methotrexate, certain antiviral agents (e.g. the “–ciclovir” group, foscarnet), amphotericin B, pentamidine, ciclosporin or tacrolimus.

Gentamicin is usually contraindicated in patients treated with cisplatine and platinum compounds, as the nephrotoxicity of gentamicin may be increased for several weeks after the administration of cisplatine or platinum therapy.

• Polymyxin B

Additive nephrotoxic effects. If the combination cannot be avoided, the bacteriological justification for its use should be irrefutable and strict surveillance is required.

• Curare-type muscle relaxants during anaesthesia

Potentiation of non-depolarising muscle relaxants when the antibiotic is administered parenterally and/or peritoneally before, during or after the neuromuscular blocking agent. Monitor the degree of muscle relaxation at the end of anaesthesia

• Contraceptives

In rare cases, some antibiotics for systemic use are supposedly capable of diminishing the effect of contraceptive pills. This unusual interaction is said to occur in women with high biliary excretion of steroid conjugates.

• Botulinum toxin

Risk of potentiation of the effects of botulinum toxin with aminoglycosides (extrapolated from effects observed with botulism). Use another antibiotic.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of gentamicin in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Gentamicin crosses the placenta. Because of the potential risk of inner ear and renal damage to the fetus, gentamicin should not be used in pregnancy unless in case of a life-threatening indication and if no other treatment options are available.

In case of exposition to gentamicin during pregnancy, monitoring of hearing and renal function of the newborn is recommended.

Breast-feeding

Gentamicin is excreted in human breast milk and was detected in low concentrations in serum of breast-fed children. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from gentamicin therapy. Diarrhoea and fungus infection of the mucous membranes could occur in the breast-fed infant, so that nursing might have to be discontinued. The possibility of sensitisation should be borne in mind.

4.7. Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

As this treatment is likely to induce impairment of balance, drivers and operators of machinery should be warned of this potential risk.

4.8. Undesirable effects

Those adverse reactions deemed most likely to be treatment-related are listed below by organ and by frequency. Frequencies are defined as:

Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000); Not known (cannot be estimated from the available data).

System organ class

Common

(≥1/100 to <1/10)

Uncommon

(≥1/1,000 to <1/100)

Rare

(≥1/10,000 to <1/1,000)

Very rare

(<1/10,000)

Not known (cannot be estimated from the available data)

Infections and infestations

Superinfection (caused by gentamicin-resistant bacteria), pseudo-membranous colitis (see section 4.4)1

Blood and lymphatic system disorders

Dyscrasia

Thrombocytopenia, reticulocytopenia, leukopenia, eosinophilia, granulocytopenia, anaemia

Immune system disorders

Hypersensitivity reactions of varying degrees of severity ranging from rash and pruritus, drug-induced fever to severe acute hypersensitivity reactions (anaphylaxis), up to anaphylactic reactions (including anaphylactic shock)

Metabolism and nutrition disorders

Hypokalaemia, hypocalcaemia, hypomagnesaemia, pseudo-Bartter's syndrome in patients treated with high doses over a long period (more than 4 weeks), loss of appetite, weight loss

Hypophosphataemia

Psychiatric disorders

Confusion, hallucinations, depression

Nervous system disorders

Polyneuropathies, peripheral paraesthesia

Encephalopathy, seizures, neuromuscular block, dizziness, impaired balance, headache (see section 4.4)

Eye disorders

Visual disorders

Ear and labyrinth disorders

Vestibular damage, loss of hearing, Meniere's disease, tinnitus, vertigo (see section 4.4)

Irreversible hearing loss, deafness

Vascular disorders

Hypotension, hypertension

Gastrointestinal disorders

Vomiting, nausea, increased salivation, stomatitis

Hepatobiliary disorders

Increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), increased alkaline phosphatase (ALP), reversible increase of serum bilirubin (all reversible)

Skin and subcutaneous tissue disorders

Allergic skin exanthema

Skin reddening

Toxic epidermal necrolysis2, Lyell's syndrome2, Stevens- Johnson syndrom, Erythema multiforme2, Alopecia

Musculoskeletal and connective tissue disorders

Muscle pain (myalgia)

Amyostasia

Renal and urinary disorders

Renal function impairment2

Blood urea nitrogen increased (reversible)

Acute renal failure, hyperphosphaturia, aminoaciduria, Fanconi-like syndrome in patients treated with a prolonged course of, high-dose treatment (see section 4.4)

General disorders and administration site conditions

Increased body temperature

Pain at the injection site

1 Generally, 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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for 'MHRA Yellow Card' in the Google Play or Apple App Store. By reporting side effects you can help provide more information on the safety of this medicine.

4.9. Overdose

Gentamicin has a narrow therapeutic margin.

Symptoms

In the event of accumulation, renal damage and damage to the vestibulocochlear nerves may occur.

Treatment

Stop treatment. Provide good, preferably somewhat increased diuresis. Can be also removed from the blood by dialysis.

Monitor the serum concentration

In the event of neuromuscular blockade, administration of calcium chloride is recommended, as well as the use of artificial ventilation, if necessary.