LUKADIN 1 G/4 ML Injectable solution

Зміст інструкції

1. LUKADIN

LUKADIN

1 g/4 ml injectable solution
1 Vial of 4 ml
AMIKACIN SULFATE
COMPOSITION
One vial contains:
Active ingredient:
Amikacin sulfate g 1.335 (equivalent to Amikacin base g 1)
Excipients: Sodium citrate, Sodium bisulfite, Sulfuric acid q.s. pH 4.5, Water for injections.

PHARMACEUTICAL FORM
Injectable solution for intramuscular and intravenous use

PHARMACOTHERAPEUTIC CATEGORY
Aminoglycoside antibiotic

A.I.C. 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 in the short-term treatment of severe infections caused by sensitive strains of Gram-
negative germs, including species of Pseudomonas, E. coli, Proteus indole + and indole -, Providencia, Klebsiella-Enterobacter – Serratia group, and Acinetobacter.
This antibiotic proves effective:

• In the therapy of bacteremia, septicemia and neonatal sepsis;
• In the therapy of severe infections of the respiratory tract; bones and joints; the CNS (including meningitis); intra-abdominal infections (including peritonitis); burns and post-operative infections (including those of vascular surgery);
• In the therapy of severe, complicated and recurrent urinary tract infections, caused by Gram-negative germs. Conversely, like other aminoglycosides, Amikacin is not indicated in initial and uncomplicated urinary tract infections, when the etiological agent is sensitive to potentially less toxic antibiotics;
• In the therapy of staphylococcal infections; therefore it can be adopted as an attack therapy in case of ascertained or suspected staphylococcal infections, when the patient is allergic to other antibiotics, or there is a mixed infection with staphylococci and Gram-negatives;
• In the therapy of neonatal sepsis, when the sensitivity test indicates that other aminoglycosides cannot be used. In such cases, concomitant therapy with a penicillin-type antibiotic may also be indicated, due to the possibility of superinfection with Gram-positives (streptococci or pneumococci).

LUKADIN is able to combat infections from Gram-negative germs resistant to Gentamicin and
Tobramycin, particularly from Proteus rettgeri, Providencia stuarti, Serratia marcescens and Pseudomonas
aeruginosa.
Official guidelines on the appropriate use of antibacterial agents must be taken into account.

CONTRAINDICATIONS
Amikacin sulfate injectable is contraindicated in patients with known allergy 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 the known cross-sensitivity of patients to drugs belonging to this
class.

SPECIAL WARNINGS AND PRECAUTIONS FOR USE
It is advisable to perform an antibiogram before starting therapy.
Amikacin can still be adopted as initial therapy, when a Gram-negative etiology is suspected in an infection
and the results of the antibiogram are not yet available.
However, the decision to continue therapy with this antibiotic must be based on the results of sensitivity tests, on the severity of the infection, on the patient's response, and taking into account the warnings reported
above.
Caution must be exercised in patients with pre-existing renal insufficiency, or pre-existing hearing or vestibular
damage. Patients undergoing treatment with aminoglycosides parenterally must remain under strict clinical
control due to the potential ototoxicity and nephrotoxicity associated with their use.
Safety has not been established for treatment periods longer than 14 days.
This medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e. it is practically sodium-free.

Neuro/Ototoxicity
Neurotoxicity, manifested as auditory vestibular ototoxicity and/or bilateral, can occur in patients
undergoing treatment with aminoglycosides. The risk of aminoglycoside-induced ototoxicity is greater in
patients with impaired renal function, or in those whose therapy is prolonged beyond 5-7 days of treatment, even in healthy patients.
Generally, deafness begins towards high-frequency acoustic waves, so it can only be determined by
audiometric tests. Vertigo can also appear, which is an index of vestibular damage.
Other manifestations of neurotoxicity can include numbness, skin sensitivity, muscle spasms and convulsions.
Patients who develop cochlear or vestibular damage may not have symptoms during therapy that alert them to the development of eighth nerve toxicity, and total or partial bilateral irreversible deafness or disabling
vertigo may occur after treatment is discontinued.
Ototoxicity induced by Amikacin is usually irreversible.
The potential ototoxicity of Amikacin in children is not known. Until more data are available, this antibiotic
should be used in pediatrics only when sensitivity tests indicate that other aminoglycosides cannot be used and when the child can be closely monitored for the onset of toxicity at that level.
If you or your family members suffer from a genetic disease that causes mitochondrial mutation or hearing loss caused by taking antibiotics, we advise you to inform your doctor or pharmacist before taking an aminoglycoside as some mitochondrial mutations associated with this product may increase the risk of hearing loss. The doctor may recommend genetic testing before administering Lukadin.

Neuromuscular Toxicity
Following parenteral injection, topical instillation (as in orthopedics and abdominal lavage or in local
treatment of empyema) and after oral use of aminoglycosides, neuromuscular blockade and respiratory
paralysis have been reported. The possibility of respiratory paralysis must be considered if aminoglycosides are administered by any route, especially in patients undergoing anesthesia, neuromuscular blocking agents (see section Interactions). If neuromuscular blockade occurs, calcium salts may reverse respiratory paralysis, but mechanical respiratory assistance may be necessary.
Neuromuscular blockade and muscle paralysis have been demonstrated in laboratory animals treated with high doses of amikacin.
Aminoglycosides should be used with caution in patients with muscle disorders such as myasthenia gravis or parkinsonism as these drugs can worsen muscle weakness due to their curare-like effect at the neuromuscular junction.

Nephrotoxicity
Aminoglycosides are potentially nephrotoxic.
Nephrotoxicity is independent of the peak plasma concentration (Cmax). The risk of nephrotoxicity increases in patients with impaired renal function and in those who receive high doses, or prolonged therapy.
Patients must be well hydrated during treatment and renal function must be monitored using usual methods before starting therapy and every day during the course of treatment. A dose reduction is necessary if evidence of renal dysfunction occurs, such as the presence of urinary cylinders, white or red blood cells in the sediment, albuminuria, reduction of creatinine clearance, decrease in the specific gravity of urine, increased blood urea nitrogen, serum creatinine, or oliguria. If azotemia increases, or if a progressive decrease in urinary excretion occurs, treatment should be interrupted.
Elderly patients may have reduced renal function, which may not be evident in routine laboratory tests, such as blood urea nitrogen or serum creatinine. A creatinine clearance examination may be more useful. Monitoring of renal function is particularly important in elderly patients during treatment with aminoglycosides.
In particular, in patients with known or suspected renal insufficiency, and also in patients whose function initially normal but has altered during treatment, renal function and that of the eighth cranial nerve must be constantly monitored.
Serum concentrations of amikacin should be monitored when possible to ensure adequate levels and to avoid potentially toxic levels. Urine should be checked for a reduction in specific gravity, proteinuria, and the presence of cells or cylinders in the sediment.
Blood urea nitrogen, serum creatinine or creatinine clearance should be checked periodically.
Serial audiograms are recommended when possible in patients old enough to be tested, especially in high-risk patients. If ototoxicity (dizziness, vertigo, tinnitus, ringing in the ears or hearing loss) or nephrotoxicity occurs, the dosage should be modified or the drug discontinued.
The concomitant and/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 are advanced age and dehydration.
The inactivation of the aminoglycoside is clinically significant only in patients with severe renal impairment. Inactivation can continue in fluid samples collected for analysis, causing inaccurate aminoglycoside readings.
Such samples must be adequately treated (promptly analyzed, frozen, or treated with beta-lactamase).

Allergic Reactions
Amikacin sulfate injectable vials contain sodium bisulfite; this substance can cause allergic-type reactions in susceptible individuals, including anaphylactic shock symptoms and less severe or life-threatening asthma attacks.
The overall prevalence in the general population relating to sensitivity to this substance is uncommon and probably low. This sensitivity is more frequent in asthmatics than in non-asthmatics.

• Cross-allergy with other aminoglycosides is possible.
• It is possible, as with other antibiotics, that therapy with Amikacin induces the appearance of superinfection from resistant germs, in which case appropriate therapy must be instituted. In cases where Amikacin is indicated in association with other antibiotics, it is necessary to avoid mixing these agents both in syringes and in infusion bottles.

Other

• Aminoglycosides are rapidly and almost totally absorbed when applied topically in association with surgical procedures, with the exception of the urinary bladder,
• Following irrigation with an aminoglycoside preparation of small and large parts in the surgical field, irreversible deafness, renal failure and death due to neuromuscular blockade have been reported.
• As with other antibiotics, the use of amikacin may determine an excessive growth of non-sensitive organisms. If this occurs, appropriate therapy is required
• Following intravitreal administration (injection into the eye) of amikacin, retinal ischemia has been reported with sometimes resulting permanent loss of vision.

Paediatric Use
Aminoglycosides should be used with caution in premature infants and neonates due to the immaturity of the kidneys of these patients and the consequent prolongation of the serum half-life of these drugs.

PREGNANCY, BREASTFEEDING AND FERTILITY
Ask your doctor or pharmacist for advice before taking any medicine.

Pregnancy
The safety of use of Amikacin during pregnancy has not yet been established, therefore in pregnant women and in early infancy the product should be administered only in cases of actual need under the direct control of the doctor
Limited data are available on the use of aminoglycosides in pregnancy. Aminoglycosides can cause fetal harm. Aminoglycosides cross the placental barrier and cases of congenital bilateral total and irreversible deafness have been reported in children whose mothers were administered streptomycin during pregnancy. Although no adverse effects have been reported in fetuses or newborns of pregnant women treated with other aminoglycosides, the potential risk remains.
If amikacin is administered during pregnancy or if the patient becomes pregnant during treatment with this drug, she must be informed of the potential risks to the fetus.

Breastfeeding
It is not known whether amikacin is excreted in breast milk. Therefore, it is necessary to decide whether to interrupt breastfeeding or therapy.

Fertility
Reproductive toxicity studies in mice and rats have not shown effects on fertility or fetal toxicity.
The administration of amikacin in pregnant women and newborns should be carried out only in case of absolute need and under medical control (see section “Special Warnings and precautions for use”).

INTERACTIONS
Inform your doctor or pharmacist if you have recently taken any other medicines, even those without
a prescription .
Concomitant or subsequent use of other neurotoxic, ototoxic or nephrotoxic agents should be avoided, in par-
ticular bacitracin, cisplatin, amphotericin B, cyclosporine, tacrolimus, cephaloridine, paromomycin, viomi-
cin, polymyxin B, colistin, vancomycin, or other aminoglycosides Kanamycin, Gentamicin, Tobramycin,
Neomycin, Streptomycin, both systemically and topically due to the possibility of additive effects. Increased
nephrotoxicity has been reported following concomitant parenteral administration of
aminoglycoside antibiotics and cephalosporins. Concomitant use of cephalosporin may falsely elevate se-
rum creatinine levels.
Amikacin should not be administered with potent diuretics (e.g. ethacrynate, furosemide,
mannitol) as diuretics are themselves ototoxic. Furthermore, diuretics, when administered via i.v.
increase the toxicity of aminoglycosides, altering their concentration in serum and tissues.
A reduction in 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 hypocalcemia 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 B1) administered simultaneously may be destroyed by the reactive bisulfite component of the
amikacin sulfate formulation.
Indometacin may increase plasma concentration of amikacin in neonates.
There is a risk of respiratory paralysis in patients receiving anesthetics, neuromuscular blocking agents, co-
me succinylcholine, decamethonium, atracurium, rocuronium, vecuronium or in patients receiving massive
blood transfusions with citrate-based anticoagulant.

DOSAGE, ADMINISTRATION AND DURATION OF TREATMENT
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 to be 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 should not exceed 1.5 g. In patients with endocarditis and febrile neutropenia, the po-
sology should be two administrations per day, as there is insufficient data to support
single daily administration.

Children aged between 4 weeks and 12 years
The recommended intramuscular or intravenous (slow venous infusion) dosage for children with normal renal
function is 15-20 mg/kg/day administrable 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 and febrile neutropenia, the dosage should be two administrations per day, as there is insufficient data to support single daily administration.

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 dose in premature infants is 7.5mg/kg every 12 hours (see section “Special Warnings and
Precautions for Use”).
The average duration of treatment with Amikacin should be between 7 and 10 days, at the dosage established
in adults or children; with this regimen, infections, if uncomplicated and due to susceptible germs, should re-
spond favorably within 48 hours. If no desired clinical response is observed after 4-5 days, the
therapy should be discontinued and the sensitivity of the causative germ should be rechecked. Failure to respond
may be due to germ resistance or the presence of septic foci requiring surgical drainage.
When a treatment period longer than 10 days is necessary, renal and acoustic function should be checked daily.
In patients with impaired renal function, serum Amikacin concentration should always be checked, if possible, and the dosage adjusted;
a) administering the doses for a subject with normal function, at longer intervals;
or
b) administering dosages lower than normal, and maintaining fixed time intervals.
In both cases, CC and serum creatinine levels should be checked, as these data are correlated, in patients with reduced renal function, with the half-life of the antibiotic.
In particular:
a) if the CC (creatinine clearance) rate is not known and the patient's condition is stable,
the interval between administrations is calculated by multiplying the serum creatinine value by 9
(e.g.: 2 mg/100 ml of creatinine x 9 = 18 hours interval);
b) if it is preferable to administer Amikacin at fixed intervals, serum concentrations of the antibiotic should first be checked, to ensure that they do not exceed 35 gamma/ml. If this is not
possible, and the patient's condition is stable, having the CC and creatinine values available, you can start with a loading dose of 7.5 mg/Kg and establish the interval in 12 hours. The dose to
be administered subsequently, every 12 hours, will be calculated according to the following formula:
CC calculated in the patient
--------------------------------- X loading dose (= 7.5 mg x body weight)
Theoretical CC in normal
Alternatively, if the "steady-state" value of creatinine is known, the normal dose can be divided
by this value, and thus obtain the reduced dosage to be administered every 12 hours.

For intravenous administration, the initial dose, daily dosage and total amount of
Amikacin to be administered remain the same as those reported for intramuscular administration, as well as the
same method of administration (2-3 administrations 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 solution,
5% glucose solution, Ringer lactate solution; the infusion time should be between 30
and 60 minutes.

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

UNDESIRABLE EFFECTS
Like all medicines, Lukadin can cause side effects, although not everyone gets them.
All aminoglycosides are potentially capable of inducing ototoxicity, renal toxicity, and neuromuscular block.
These toxic effects occur more frequently in patients with renal insufficiency, in
patients treated with other ototoxic and nephrotoxic drugs, with doses higher or for longer periods of treatment than those recommended (see section Special Warnings and Precautions for Use)
The list presents the classification by systems and organs, according to MedDRA terminology, and the frequency
which uses the following 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 (the frequency cannot
be defined based on 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 (eye injection) administrations of amikacin
Changes in renal function are generally reversible when treatment is discontinued.
Toxic effects at the level of the eighth cranial nerve can cause hearing loss, loss of balance, or both. Amikacin primarily affects auditory function.
Cochlear damage includes high-frequency hearing loss and usually occurs before clinical hearing loss can be detected by audiometry (see section “Precautions for Use and Special Warnings”).
If any side effect occurs, including those not listed in this leaflet, contact your
doctor or pharmacist.
Adverse reactions can also be reported directly through the national reporting system
at www.agenziafarmaco.gov.it/it/responsabili”.
Reporting adverse reactions helps to provide more information on the safety of this
medicine

OVERDOSE
In case of accidental ingestion/intake of an excessive dose of Lukadin, immediately warn
your doctor or go to the nearest hospital.
In case of overdose, there is a general risk of nephro-oto and neurotoxic reactions (neuromuscular block). Neuromuscular block with respiratory arrest requires appropriate treatment including
the application of calcium ions (e.g. gluconate or lactobionate in 10-20% solution) (see para-
graph “Special Warnings and Precautions for Use”).
In case of overdose or toxic reaction, peritoneal dialysis or hemodialysis will be helpful in removing amikacin from the blood. Amikacin levels are also reduced during arteriovenous
continuous hemofiltration. In the neonate, exchange transfusion may also be considered.

Keep the medicine out of the sight and reach of children.