Lukadin

LUKADIN
1 g/4 ml injectable solution
1 Vial of 4 ml
AMIKACIN SULFATE

COMPOSITION
One vial contains:
Active substance:
Amikacin sulfate g 1.335 (equivalent to amikacin base g 1)
Excipients: Sodium citrate, sodium bisulfite, sulfuric acid q.s. to pH 4.5, water for injectable preparations.

PHARMACEUTICAL FORM
Injectable solution for intramuscular and intravenous use

THERAPEUTIC CATEGORY
Aminoglycoside antibacterial agent

MARKETING AUTHORISATION HOLDER
LANOVA FARMACEUTICI S.R.L. – Via Conca D’Oro n. 212 – 00141 Rome
MANUFACTURER AND FINAL CONTROLLER
Esseti Farmaceutici Srl – Via Campobello, 15 – 00071 Pomezia (Rome)

THERAPEUTIC INDICATIONS
LUKADIN is indicated for short-term treatment of severe infections caused by susceptible Gram-negative strains, including Pseudomonas, E. coli, indole-positive and indole-negative Proteus, Providencia, the Klebsiella-Enterobacter-Serratia group, and Acinetobacter.

This antibiotic has proven effective:

• In the treatment of bacteraemia, septicaemia, and neonatal sepsis;
• In the treatment of severe respiratory tract infections; bone and joint infections; central nervous system (CNS) infections (including meningitis); intra-abdominal infections (including peritonitis); infections in burns; and postoperative infections (including those following vascular surgery);
• In the treatment of severe, complicated, and recurrent urinary tract infections caused by Gram-negative bacteria. However, like other aminoglycosides, amikacin is not indicated for initial, uncomplicated urinary tract infections when the causative agent is susceptible to potentially less toxic antibiotics;
• In the treatment of staphylococcal infections; thus, it may be used as initial therapy in confirmed or suspected staphylococcal infections, particularly when the patient is allergic to other antibiotics or when a mixed infection involving staphylococci and Gram-negative bacteria is present;
• In the treatment of neonatal sepsis, when sensitivity testing indicates that other aminoglycosides cannot be used. In such cases, concomitant therapy with a penicillin-type antibiotic may be indicated due to the risk of superinfection with Gram-positive organisms (streptococci or pneumococci).

LUKADIN is effective against Gram-negative organisms resistant to gentamicin and tobramycin, particularly Proteus rettgeri, Providencia stuartii, Serratia marcescens, and Pseudomonas aeruginosa.
Official guidelines on the appropriate use of antibacterial agents should be taken into account.

CONTRAINDICATIONS
Injectable amikacin sulfate is contraindicated in patients with known hypersensitivity to amikacin or to any of the excipients.
Following a history of hypersensitivity or severe toxic reactions to aminoglycosides, the use of any aminoglycoside is contraindicated due to known cross-sensitivity among patients to drugs in this class.

SPECIAL WARNINGS AND PRECAUTIONS FOR USE
An antibiogram should be performed before initiating therapy.
Amikacin may still be used as initial therapy when Gram-negative infection is suspected and antibiogram results are not yet available.
However, the decision to continue therapy with this antibiotic must be based on sensitivity test results, infection severity, patient response, and the precautions outlined below.
Caution is required in patients with pre-existing renal impairment or pre-existing hearing or vestibular damage. Patients receiving parenteral aminoglycosides must remain under close clinical monitoring due to the potential ototoxicity and nephrotoxicity associated with their use.
Safety has not been established for treatment periods exceeding 14 days.
This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e. it is practically sodium-free.

Neuro/Ototoxicity
Neurotoxicity, manifesting as auditory and/or vestibular ototoxicity, may occur in patients receiving aminoglycosides. The risk of aminoglycoside-induced ototoxicity is higher in patients with impaired renal function or when treatment exceeds 5–7 days, even in otherwise healthy individuals.
Typically, hearing loss begins at high-frequency sound waves and may only be detectable via audiometric testing. Vertigo, indicating vestibular damage, may also occur.
Other manifestations of neurotoxicity may include numbness, skin hypersensitivity, muscle spasms, and seizures.
Patients developing cochlear or vestibular damage may not experience symptoms during treatment warning of eighth nerve toxicity, and irreversible bilateral total or partial deafness or disabling vertigo may occur after treatment has been discontinued.
Amikacin-induced ototoxicity is usually irreversible.
The potential ototoxicity of amikacin in children is not known. Until more data are available, this antibiotic should be used in paediatrics only when sensitivity tests indicate that other aminoglycosides cannot be used and when the child can be closely monitored for signs of toxicity.
If you or your family members have a genetic disorder causing mitochondrial mutation or hearing loss induced by antibiotic use, you are advised to inform your doctor or pharmacist before taking an aminoglycoside, as certain mitochondrial mutations associated with this product may increase the risk of hearing loss. Your doctor may recommend genetic testing before administering Lukadin.

Neuromuscular Toxicity
Neuromuscular blockade and respiratory paralysis have been reported following parenteral injection, topical instillation (e.g. in orthopaedics, abdominal lavage, or local empyema treatment), and oral use of aminoglycosides. The possibility of respiratory paralysis should be considered when aminoglycosides are administered by any route, particularly in patients receiving anaesthetics or neuromuscular blocking agents (see section Interactions). If neuromuscular blockade occurs, calcium salts may reverse respiratory paralysis, but mechanical ventilation may be required.
Neuromuscular blockade and muscular paralysis have been demonstrated in laboratory animals treated with high doses of amikacin.
Aminoglycosides should be used with caution in patients with neuromuscular disorders such as myasthenia gravis or parkinsonism, as these drugs may exacerbate muscle weakness due to their curare-like effect at the neuromuscular junction.

Nephrotoxicity
Aminoglycosides are potentially nephrotoxic.
Nephrotoxicity is independent of the achieved plasma peak (Cmax). The risk of nephrotoxicity increases in patients with impaired renal function, those receiving high doses, or those undergoing prolonged therapy.
Patients should be well hydrated during treatment, and renal function should be monitored using standard methods before starting therapy and daily throughout treatment. Dosage reduction is necessary if signs of renal dysfunction occur, such as presence of urinary casts, white or red blood cells in sediment, albuminuria, reduced creatinine clearance, decreased urine specific gravity, increased blood urea nitrogen (BUN), increased serum creatinine, or oliguria. Treatment must be discontinued if BUN increases or if progressive reduction in urinary excretion occurs.
Elderly patients may have reduced renal function that may not be evident in routine laboratory tests such as BUN or serum creatinine. Measurement of creatinine clearance may be more useful. Monitoring of renal function is particularly important in elderly patients during aminoglycoside therapy.
In particular, patients with known or suspected renal insufficiency, and those with initially normal renal function that deteriorates during treatment, require constant monitoring of renal function and of the eighth cranial nerve.
Serum amikacin concentrations should be monitored whenever possible to ensure adequate levels and to avoid potentially toxic levels. Urine should be checked for reduced specific gravity, proteinuria, and presence of cells or casts in sediment.
BUN, serum creatinine, or creatinine clearance should be monitored periodically.
Serial audiograms are recommended whenever possible in patients old enough to be tested, especially high-risk patients. If ototoxicity (dizziness, vertigo, tinnitus, ringing in the ears, or hearing loss) or nephrotoxicity occurs, dosage should be adjusted or the drug discontinued.
Concomitant or sequential systemic, oral, or topical use of other neurotoxic or nephrotoxic drugs should be avoided. Other factors that may increase the risk of toxicity include advanced age and dehydration.
Inactivation of aminoglycosides is clinically significant only in patients with severe renal impairment. Inactivation may continue in body fluid samples collected for analysis, leading to inaccurate aminoglycoside measurements.
Such samples must be appropriately handled (promptly analysed, frozen, or treated with beta-lactamase).

Allergic Reactions
Injectable amikacin sulfate vials contain sodium bisulfite; this substance may cause allergic-type reactions in sensitive individuals, including anaphylactic shock symptoms and less severe or life-threatening asthma attacks.
The overall prevalence in the general population for sensitivity to this substance is uncommon and likely low. This sensitivity is more frequent in asthmatics than in non-asthmatic individuals.

• Cross-allergy with other aminoglycosides is possible.
• As with other antibiotics, amikacin therapy may lead to superinfection with resistant organisms; appropriate therapy should be initiated if this occurs. When amikacin is indicated in combination with other antibiotics, these agents should not be mixed in syringes or infusion bottles.

Other

• Aminoglycosides are rapidly and almost completely absorbed when applied topically in association with surgical procedures, except in the urinary bladder.
• Irrigation with aminoglycoside preparations in small and large surgical fields has been associated with irreversible deafness, renal failure, and death due to neuromuscular blockade.
• As with other antibiotics, amikacin use may lead to overgrowth of non-susceptible organisms. If this occurs, appropriate therapy is required.
• Following intravitreal administration (injection into the eye), amikacin has been associated with retinal ischaemia, sometimes resulting in permanent vision loss.

Paediatric Use
Aminoglycosides should be used with caution in premature infants and neonates due to their immature renal function, which leads to prolonged serum half-life of these drugs.

PREGNANCY, BREASTFEEDING AND FERTILITY
Consult your doctor or pharmacist before taking any medicine.

Pregnancy
The safety of amikacin use during pregnancy has not yet been established. Therefore, in pregnant women and in early infancy, the product should be administered only when strictly necessary and under direct medical supervision.
Limited data are available on the use of aminoglycosides during pregnancy. Aminoglycosides may cause fetal harm. They cross the placental barrier, and cases of total, bilateral, irreversible congenital deafness have been reported in children whose mothers received streptomycin during pregnancy. Although adverse effects have not been reported in fetuses or neonates of women treated with other aminoglycosides during pregnancy, the potential risk remains.
If amikacin is administered during pregnancy or if a patient becomes pregnant while being treated with this drug, she should be informed of the potential risks to the fetus.

Breastfeeding
It is not known whether amikacin is excreted in human milk. A decision must therefore be made whether to discontinue breastfeeding or the therapy.

Fertility
Reproductive toxicity studies in mice and rats have not shown effects on fertility or fetal toxicity.
Administration of amikacin to pregnant women and neonates should be carried out only when absolutely necessary and under medical supervision (see section “Special Warnings and Precautions for Use”).

INTERACTIONS
Inform your doctor or pharmacist if you have recently taken any other medicines, including those without a prescription.
Concomitant or sequential use of other neurotoxic, ototoxic, or nephrotoxic agents should be avoided, particularly bacitracin, cisplatin, amphotericin B, cyclosporine, tacrolimus, cephaloridine, paromomycin, viomycin, polymyxin B, colistin, vancomycin, or other aminoglycosides (kanamycin, gentamicin, tobramycin, neomycin, streptomycin), whether administered systemically or topically, due to the possibility of additive effects. Increased nephrotoxicity has been reported with concomitant parenteral administration of aminoglycoside antibiotics and cephalosporins. Concomitant use of cephalosporins may falsely elevate serum creatinine measurements.
Amikacin should not be administered with potent diuretics (e.g. ethacrynic acid, furosemide, mannitol), as diuretics are themselves ototoxic. Moreover, diuretics, when administered intravenously, increase aminoglycoside toxicity by altering their serum and tissue concentrations.
Reduced serum activity may also occur when an aminoglycoside or penicillin-like drug is administered in vivo via separate routes.
There is an increased risk of hypocalcaemia when aminoglycosides are administered with bisphosphonates.
There is an increased risk of nephrotoxicity and possibly ototoxicity when aminoglycosides are administered with platinum compounds.
Thiamine (vitamin B) administered concomitantly may be destroyed by the reactive sodium bisulfite component in the amikacin sulfate formulation.
Indomethacin may increase amikacin plasma concentrations in neonates.
There is a risk of respiratory paralysis in patients receiving anaesthetics, neuromuscular blocking agents (e.g. succinylcholine, decamethonium, atracurium, rocuronium, vecuronium), or in patients receiving massive blood transfusions with citrate-based anticoagulant.

DOSAGE, METHOD AND DURATION OF ADMINISTRATION

Adults and children over 12 years
The recommended intramuscular or intravenous dosage for adults and adolescents with normal renal function (creatinine clearance ≥ 50 ml/min) is 15 mg/kg/day, administered as a single daily dose or divided into two equal doses (i.e. 7.5 mg/kg every 12 hours).
The total daily dose must not exceed 1.5 g. In patients with endocarditis or febrile neutropenia, the dosage regimen should consist of two daily administrations, as sufficient data supporting once-daily dosing are lacking.

Children aged between 4 weeks and 12 years
The recommended intramuscular or intravenous (slow intravenous infusion) dosage for children with normal renal function is 15–20 mg/kg/day, administered as a single dose of 15–20 mg/kg or divided into two doses of 7.5 mg/kg every 12 hours.
In patients with endocarditis or febrile neutropenia, the dosage regimen should consist of two daily administrations, as sufficient data supporting once-daily dosing are lacking.

Neonates
An initial loading dose of 10 mg/kg followed by 7.5 mg/kg every 12 hours (see section “Special Warnings and Precautions for Use”).

Premature Infants
The recommended dosage in premature infants is 7.5 mg/kg every 12 hours (see section “Special Warnings and Precautions for Use”).

The average duration of amikacin treatment should be 7 to 10 days, at the dosage established for adults or children. With this regimen, infections—provided they are uncomplicated and caused by susceptible organisms—should respond favourably within 48 hours. If no clinical response is observed after 4–5 days, therapy should be discontinued and microbial sensitivity re-evaluated. Lack of response may be due to microbial resistance or the presence of septic foci requiring surgical drainage.
When treatment longer than 10 days is required, renal and auditory function must be monitored daily.
In patients with impaired renal function, serum amikacin concentrations should be monitored whenever possible, and dosage adjusted accordingly:
a) administering standard doses for patients with normal renal function at longer intervals;
or
b) administering reduced doses at fixed intervals.
In both cases, creatinine clearance (CC) and serum creatinine levels should be monitored, as these parameters correlate with the antibiotic’s half-life in patients with reduced renal function.
Specifically:
a) if the CC rate is unknown and the patient’s condition is stable, the dosing interval can be calculated by multiplying the serum creatinine value by 9 (e.g., 2 mg/100 ml creatinine × 9 = 18-hour interval);
b) if amikacin is to be administered at fixed intervals, serum antibiotic concentrations should first be checked to ensure they do not exceed 35 gamma/ml. If this is not possible, and the patient’s condition is stable, with known CC and serum creatinine values, an initial dose of 7.5 mg/kg may be given, with a 12-hour interval. Subsequent doses every 12 hours can be calculated using the following formula:
CC measured in the patient
--------------------------------- × loading dose (= 7.5 mg × body weight)
CC theoretical in normal
Alternatively, if the “steady-state” serum creatinine value is known, the normal dose divided by this value yields the reduced dose to be administered every 12 hours.

Intravenous administration
The initial dose, daily dosage, and total amount of amikacin administered intravenously remain the same as for intramuscular administration, as does the mode of administration (2–3 doses per day at regular intervals).
In adults, the antibiotic should be administered by diluting the contents of the 1 g vial in 200 ml of physiological saline, 5% glucose solution, or Ringer’s lactate solution; the infusion time should be 30 to 60 minutes.

Specific recommendation for intravenous administration
In paediatric patients, the volume of diluent used depends on the amount of amikacin tolerated by the patient. Normally, the solution should be infused over 30 to 60 minutes.
Infants should receive the infusion over 1 to 2 hours.
Compatible diluents for infusion include: physiological saline, 5% dextrose, Ringer’s lactate.
Amikacin must not be mixed with other substances for infusion but must be administered alone, according to the established dosage regimen.

UNDESIRABLE EFFECTS
Like all medicines, Lukadin can cause adverse effects, although not everyone experiences them.
All aminoglycosides are potentially capable of inducing ototoxicity, nephrotoxicity, and neuromuscular blockade. These toxic effects occur more frequently in patients with renal impairment, those receiving other ototoxic or nephrotoxic drugs, those receiving higher-than-recommended doses, or those undergoing longer-than-recommended treatment durations (see section Special Warnings and Precautions for Use).
The following list presents adverse effects classified by system organ class according to MedDRA terminology, and frequency categories: Very common (≥ 1/10), common (≥ 1/100, <1/10), uncommon (≥ 1/1,000, <1/100), rare (≥ 1/10,000, <1/1,000), very rare (<1/10,000), not known (frequency cannot be estimated from available data).

a See section “Precautions for Use and Special Warnings”
b Amikacin is not formulated for intravitreal use. Blindness and retinal ischemia have been reported
following intravitreal administration (injection into the eye) of amikacin.
Changes in renal function are generally reversible when treatment is discontinued.
Toxic effects on the eighth cranial nerve may cause hearing loss, loss of balance, or both.
Amikacin primarily affects auditory function.
Cochlear damage includes high-frequency deafness and usually occurs before clinical hearing loss can be detected by audiometric testing (see section “Precautions for Use and Special Warnings”).
If any adverse reaction occurs, including those not listed in this leaflet, consult your doctor or pharmacist.
Adverse reactions may also be reported directly via the national reporting system at www.agenziafarmaco.gov.it/it/responsabili.
Reporting of adverse reactions helps provide more information on the safety of this medicine.
OVERDOSE
In case of accidental ingestion/overdose of Lukadin, contact your doctor immediately or go to the nearest hospital.
In case of overdose, there is a general risk of nephro-, oto-, and neurotoxic reactions (neuromuscular blockade). Neuromuscular blockade with respiratory arrest requires appropriate treatment, including administration of ionic calcium (e.g., gluconate or lactobionate in a 10–20% solution) (see section “Special Warnings and Precautions for Use”).
In case of overdose or toxic reaction, peritoneal dialysis or hemodialysis may assist in removing amikacin from the blood. Amikacin levels are also reduced during continuous arteriovenous hemofiltration. In the newborn, exchange transfusion may also be considered.
WARNING: Do not use this medicine after the expiry date stated on the packaging. The expiry date refers to the last day of that month.
Keep the medicine out of the sight and reach of children.