Package leaflet: Information for the patient

AMICASIL 500 mg/2 ml injection solution

Amikacin sulfate
Please read all of this leaflet carefully before using this medicine because it contains important information for you.

Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor, pharmacist, or nurse.
This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, as it may be harmful.
If you experience any side effects, including those not listed in this leaflet, tell your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet

What AMICASIL is and what it is used for
What you need to know before using AMICASIL
How to use AMICASIL
Possible side effects
How to store AMICASIL
Contents of the pack and other information

1. What AMICASIL is and what it is used for

AMICASIL contains the active substance amikacin, which belongs to a group of medicines called antibiotics
(aminoglycoside antibiotics) used to treat infections caused by bacteria.
This medicine is used for the short-term treatment of serious infections caused by certain bacteria
(Gram-negative).
Specifically, AMICASIL is indicated for the treatment of:

blood infections (bacteraemia, septicaemia), neonatal sepsis (when sensitivity tests indicate that another aminoglycoside cannot be used);
severe and recurrent urinary and genital tract infections;
respiratory tract infections;
bone and/or joint infections (ostearticular infections);
central nervous system infections, including meningitis;
infections that may occur following burns;
intra-abdominal infections (endo-abdominal infections), including peritonitis (infection of the tissue lining the inside of the abdomen);
infections occurring after surgical procedures;
infections caused by staphylococci; it may be used as initial therapy in confirmed or suspected staphylococcal infections, when the patient is allergic to other antibiotics, or when a mixed infection caused by staphylococci and Gram-negative bacteria is present.

This medicine is effective against various types of bacteria (e.g. Proteus rettgeri, Providencia stuartii,
Serratia mercescens and Pseudomonas aeruginosa) that are resistant to other antibiotics such as gentamicin
or tobramycin.

2. What you need to know before using AMICASIL

Do not use AMICASIL

if you are allergic to amikacin, to other similar substances (other aminoglycosides), or to any of the other ingredients of this medicine (listed in section 6);
if you have previously experienced an allergic reaction or toxic reactions after using an antibiotic of the same class as AMICASIL (aminoglycoside antibiotics).

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before taking AMICASIL.
Before starting treatment with this medicine, an antibiogram is recommended.
Treatment may be initiated even when the results of the antibiogram are not yet available, particularly if an infection caused by a specific type of bacteria (Gram-negative) is suspected. Your doctor will determine whether continuing therapy is necessary.
Particular caution should be exercised when using AMICASIL if:

you have impaired kidney function,
you have impaired hearing,
you have neurological or muscular disorders, such as a specific type of muscle weakness called myasthenia gravis,
you have Parkinson's disease,
you have previously been treated with another antibiotic similar to amikacin. In all these cases, your doctor must exercise special caution.

If you or your family members have a genetic disorder causing mitochondrial mutation or antibiotic-induced hearing loss, 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 Amicasil.
If you suffer from any of the following conditions, you may be at higher risk of developing harmful effects on your hearing or nerves:

impaired kidney function
advanced age
dehydration
administration of high doses of this medicine
prolonged therapy beyond 5–7 days, even in healthy patients.

The first signs of harmful effects on hearing or nerves after taking this medicine may include:

difficulty hearing high-pitched sounds (high-frequency hearing loss)
dizziness
numbness, skin tingling, muscle spasms, seizures.

After administration of this medicine, respiratory paralysis (respiratory arrest) and impairment of neuromuscular function (neuromuscular blockade) may occur. Your doctor will take appropriate countermeasures.
During treatment with this medicine, your doctor will closely monitor you, paying particular attention to your hearing and kidney function.
Monitoring will include:

kidney function, especially if you have kidney failure or signs indicating the onset of kidney problems during treatment;
hearing and blood levels of amikacin, if necessary.

If signs of kidney damage appear or if kidney damage worsens, your doctor will reduce the daily doses and/or extend the intervals between doses.
If kidney damage becomes severe, amikacin will be discontinued.
Treatment with amikacin must also be stopped if tinnitus (ringing in the ears) or hearing loss occurs.
If you undergo surgical procedures involving wound irrigation with solutions containing amikacin or a similar antibiotic, this must be taken into account when determining the amikacin dosage.
As with other antibiotics, the use of this medicine may promote the development of other infections caused by bacteria or fungi to which AMICASIL is not effective (superinfections). If this occurs, it is advisable to discontinue treatment with this medicine and consult your doctor, who will recommend appropriate therapy.
Concomitant or sequential use of AMICASIL with other medicines (administered systemically, orally, or topically) that may increase the risk of kidney or nerve problems (nephrotoxicity, neurotoxicity) should be avoided (see section Other medicines and AMICASIL).

Elderly patients
If you are an elderly patient, your doctor will pay particular attention to your kidney function and may perform various tests to ensure your kidneys are not impaired, as elderly patients are more likely to have reduced kidney function.

Children
Caution is required when administering this medicine to newborns and premature infants due to immature kidney function.

Other medicines and AMICASIL
Tell your doctor or pharmacist if you are using, have recently used, or might use any other medicines.
Do not use this medicine if you are taking:

medicines that promote fluid elimination (diuretics), such as ethacrynic acid and furosemide, as they increase the ototoxic (ear-damaging) effects of AMICASIL.

Exercise particular caution and inform your doctor if you are taking or are scheduled to take any of the following medicines:

anaesthetics (medicines that reduce sensitivity to pain and induce sedation) and neuromuscular blocking agents (such as succinylcholine, decamethonium, atracurium, rocuronium, vecuronium) or citrate (used as an anticoagulant in blood transfusion bags); in these cases, muscle paralysis and/or respiratory arrest may occur;
medicines that may be toxic to the nervous system, ears, or kidneys (neurotoxic, ototoxic, and nephrotoxic medicines), such as kanamycin, tobramycin, bacitracin, cephaloridine, paromomycin, vancomycin, streptomycin, polymyxin B, colistin, neomycin, gentamicin, and viomycin or other aminoglycosides (antibiotics used to treat bacterial infections), amphotericin B (an antifungal used to treat fungal infections), cisplatin (a medicine used in cancer treatment), cyclosporine and tacrolimus (medicines used to treat autoimmune diseases or prevent transplant rejection). Avoid using these medicines concomitantly or sequentially with AMICASIL;
antibiotic medicines belonging to the cephalosporin group administered intravenously or intramuscularly (parenteral route), as they may increase kidney toxicity and may falsely elevate blood creatinine levels;
antibacterial medicines (aminoglycoside or penicillin antibiotics), as the effect of AMICASIL may be reduced;
bisphosphonates, medicines used to treat certain bone diseases; in this case, concomitant use may cause decreased calcium levels (hypocalcemia);
platinum-based medicines, as they may increase the risk of kidney and hearing toxicity;
vitamin B1 (thiamine), as it may lose its effect when administered together with AMICASIL;
indomethacin, used for the treatment of inflammation, as when administered to a newborn it may increase amikacin blood levels in the newborn.

Pregnancy, breastfeeding, and fertility
If you are pregnant, suspect you may be pregnant, planning to become pregnant, or breastfeeding, consult your doctor or pharmacist before taking this medicine.
If you are pregnant or planning to become pregnant, you will be given this medicine only if strictly necessary and under direct medical supervision, as AMICASIL crosses the placenta and may cause irreversible harm to the fetus (deafness).
If you are breastfeeding, consult your doctor, who will assess whether it is necessary to discontinue breastfeeding or treatment with this medicine.
Animal studies have not shown any effect on fertility.

Driving and using machines
The use of this medicine may cause adverse effects such as disturbances in balance, vision, and hearing, which may impair your ability to drive vehicles or operate machinery (see section Possible side effects). It is recommended to avoid driving and operating machinery.

AMICASIL contains sodium and sodium metabisulfite
This medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially 'sodium-free'.
This medicine contains sodium metabisulfite, which may rarely cause severe hypersensitivity reactions and bronchospasm.

3. How to use AMICASIL

This medicine will be administered to you by a doctor or a nurse.
Intramuscular and intravenous administration
Administration into a muscle (intramuscular administration) is preferred over direct administration into a vein (intravenous administration).
The same dosage may be used for both routes of administration.
Use in adults and children
The recommended dose for intramuscular or intravenous administration is 15 mg per kg of body weight per day, given in two equal doses of 7.5 mg per kg of body weight every 12 hours.
High-risk infections and/or those caused by Pseudomonas bacteria:
In adults, the initial dose may be increased to 500 mg every 8 hours, without exceeding a maximum daily dose of 1.5 g or extending treatment beyond 10 days.
The total maximum dose is 15 g.
Uncomplicated urinary tract infections (excluding Pseudomonas infections):
The recommended dose is 7.5 mg per kg of body weight, given as a single daily dose.
Use in newborns and/or premature infants
The recommended initial dose is 10 mg per kg of body weight, followed by doses of 7.5 mg per kg of body weight every 12 hours (see section "Children").
Use in patients with kidney problems
If you have kidney problems (renal dysfunction), your doctor will consider reducing the daily dose and/or increasing the interval between doses.
Duration of treatment
The duration of treatment is 3–7 days for intravenous administration and 7–10 days for intramuscular administration.
At the recommended doses, less severe infections caused by susceptible organisms respond to treatment within 24–48 hours.
Intravenous infusion administration
Amikacin must not be mixed with other substances for infusion, but must be administered alone, according to the established dosage regimen.
Use in adults
The contents of one vial should be diluted in 100–200 ml of a suitable solvent (sodium chloride solution, 5% glucose solution, or Ringer's lactate solution).
Intravenous administration should be carried out over a period of 30 to 60 minutes.
Use in children
In children, the volume of solvent (sodium chloride solution, 5% dextrose, Ringer's lactate) must be determined by the doctor according to the dose of AMICASIL to be administered.
Intravenous administration should be carried out over a period of 30 to 60 minutes; in younger children, a longer duration (1 to 2 hours) is recommended.
If you are given more AMICASIL than you should receive
This medicine will be administered to you by a doctor or nurse, so overdose is unlikely.
However, if you think you have been given too much of this medicine, inform your doctor immediately or go to the nearest hospital.
In case of overdose, damage to hearing, kidneys, and the nervous system (ototoxicity, nephrotoxicity, and neurotoxicity) may occur, as well as disturbances in muscle contraction (neuromuscular blockade) associated with respiratory paralysis.
In such cases, mechanical filtration of the blood may be considered to remove the medicine from the body (peritoneal dialysis, hemodialysis, or continuous arterio-venous hemofiltration).
In case of neuromuscular blockade with respiratory arrest, the doctor will administer necessary treatment, including administration of ionic calcium (e.g., as gluconate or lactobionate in a 10–20% solution).
In newborns, exchange transfusion may be considered.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
Amikacin and all other similar substances can cause toxic effects on hearing, kidneys, nerves, and muscles (neuromuscular blockade).
These effects are more frequently observed in patients:

who already have kidney problems,
who are treated with other medicines that may cause kidney and hearing toxicity (see section Warnings and precautions),
who receive prolonged treatment or doses higher than those recommended for this medicine.

The following side effects may occur:
Uncommon (may affect up to 1 in 100 people)

development of infections caused by resistant microorganisms (bacteria or yeasts against which AMICASIL is not effective);
nausea, vomiting;
rash.

Rare (may affect up to 1 in 1000 people)

changes in levels of red and white blood cells in blood (anaemia, eosinophilia);
decreased magnesium levels (hypomagnesaemia);
tremors, sensation of reduced sensitivity in arms and legs (paraesthesia);
headache (cephalalgia) and balance disorders;
perception of noises and/or ringing in the ear (tinnitus), reduced hearing (hypacusis);
decreased blood pressure (hypotension);
itching, skin irritation (urticaria);
joint pain (arthralgia);
repeated muscle contractions (spasms);
reduced urine production (oliguria);
increased creatinine levels in blood;
high concentration of albumin in urine (albuminuria);
increased blood nitrogen levels (azotemia);
presence of red and white blood cells in urine; presence of casts in urinary sediment;
changes in blood test results (increased serum creatinine, azotemia);
fever (pyrexia or iatrogenic fever);
vision loss and retinal problems (retinal infarction) if AMICASIL is administered by injection into the eye (intravitreal injection).

Not known (frequency cannot be estimated from available data)

severe allergic reactions (anaphylactic reaction, anaphylactic shock, and anaphylactoid reaction), hypersensitivity;
muscle block (paralysis);
deafness, even associated with nerve damage (sensorineural deafness);
temporary interruption of breathing (apnoea), breathing difficulties (bronchospasm);
kidney problems (acute renal failure);
toxic nephropathy, presence of cells in urine.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store AMICASIL

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton after "Expiry". The expiry date refers to the last day of that month.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What AMICASIL contains

The active substance is amikacin sulfate. Each vial contains 667.5 mg of amikacin sulfate equivalent to 500 mg of amikacin.
The other components are sodium citrate, sodium metabisulfite, sulfuric acid (as pH adjuster), sodium hydroxide (as pH adjuster), water for injections.

Description of the appearance of AMICASIL and contents of the pack
Pack of 10 vials of 2 ml.
Marketing Authorization Holder
Pharmatex Italia srl - Via San Paolo 1, - 20121 Milano
Manufacturer
Officina Farmaceutica Fisiopharma s.r.l. - Nucleo Industriale - 84020 Palomonte (SA)

The following information is intended exclusively for healthcare professionals:

Additional Warnings:
An antibiogram should be performed whenever possible before initiating therapy.
Amikacin may be used as initial therapy when a gram-negative etiology is suspected in an infection, even before antibiogram results are available. However, the decision to continue treatment with this antibiotic should be based on the results of sensitivity testing, the severity of the infection, the patient's clinical response, and the warnings outlined below.
Caution must be exercised in patients with pre-existing renal impairment or pre-existing hearing or vestibular dysfunction. Patients receiving parenteral aminoglycosides should be placed under close clinical observation due to the potential for ototoxicity and nephrotoxicity associated with their use. The safety of this medicinal product has not been established for treatment durations exceeding 14 days.

Neuro/ototoxicity
Neurotoxicity, manifesting as vestibular and/or bilateral auditory ototoxicity, may occur in patients treated with aminoglycosides. The risk of aminoglycoside-induced ototoxicity is higher in patients with impaired renal function or in those whose treatment duration exceeds 5–7 days, even in otherwise healthy individuals. High-frequency hearing loss usually occurs first and may only be detected by audiometric testing. Vertigo may occur and may be a sign of vestibular damage. Other manifestations of neurotoxicity may include numbness, skin tingling, muscle spasms, and seizures. Patients developing cochlear or vestibular damage may not exhibit symptoms during therapy to indicate eighth cranial nerve toxicity, and total or partial irreversible bilateral deafness or disabling vertigo may occur even after discontinuation of the drug. Aminoglycoside-induced ototoxicity is usually irreversible.
The risk of ototoxicity is increased in patients with mitochondrial DNA mutations (particularly at nucleotide 1555 with A-to-G substitution in the 12S rRNA gene), even when aminoglycoside serum levels remain within the recommended range during treatment. Alternative therapeutic options should be considered in these patients.
Alternative treatments or genetic testing should be considered before administration in patients with a family history of relevant mutations or aminoglycoside-induced hearing loss.

Neuromuscular toxicity
Neuromuscular blockade and respiratory paralysis have been reported following parenteral injection, topical use (e.g., in orthopedic surgery, abdominal irrigation, or local treatment of empyema), and after oral administration of aminoglycosides. The possibility of respiratory paralysis should be considered with all routes of aminoglycoside administration, especially in patients receiving anesthetics or muscle relaxants. If neuromuscular blockade occurs, calcium salts may reverse respiratory paralysis, but mechanical respiratory support 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 can exacerbate muscle weakness due to their potential curare-like effect at neuromuscular junctions.

Nephrotoxicity
Aminoglycosides are potentially nephrotoxic. Renal toxicity is independent of peak plasma concentrations (Cmax). The risk of nephrotoxicity is greater in patients with impaired renal function, those receiving high doses of the drug, or those undergoing prolonged treatment.
Patients should be well hydrated during treatment, and renal function should be assessed using standard methods before starting therapy and daily throughout treatment. It should be noted that when patients are well hydrated and have normal renal function, the risk of nephrotoxic reactions with amikacin is reduced, provided recommended doses are not exceeded. Dosage reduction is necessary if signs of renal dysfunction occur, such as the presence of urinary casts, white or red blood cells, albuminuria, decreased creatinine clearance, reduced urine specific gravity, increased blood urea nitrogen (BUN), elevated serum creatinine, or oliguria. If azotemia increases or progressive reduction in urine output occurs, treatment must be discontinued.
Elderly patients may have reduced renal function that may not be apparent in routine screening tests such as BUN or serum creatinine measurement. Determination of creatinine clearance may be more informative. Monitoring of renal function in elderly patients during aminoglycoside therapy is particularly important.
Renal function and eighth cranial nerve function must be closely monitored, especially in patients with known or suspected renal impairment at the start of therapy, as well as in those whose renal function is initially normal but who develop signs of renal dysfunction during treatment. Serum amikacin concentrations should be monitored whenever possible to ensure adequate levels and to avoid potentially toxic levels (sustained levels above 35 µg/mL). Urine should be examined for decreased specific gravity, increased protein excretion, and presence of cells or cellular casts. Blood urea nitrogen, serum creatinine, or creatinine clearance should be measured periodically. Serial audiograms should be performed whenever possible in patients old enough to be tested, particularly in high-risk patients. Any symptoms suggestive of ototoxicity (dizziness, vertigo, tinnitus, ringing in the ears, hearing loss) or nephrotoxicity require discontinuation or dosage adjustment of the drug.
Concomitant or sequential systemic, oral, or topical use of other neurotoxic or nephrotoxic agents 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 biological fluid samples collected for analysis, leading to inaccurate aminoglycoside assay results. Such samples must be handled appropriately (immediately frozen or treated with beta-lactamases).

Allergic reactions
Amikacin sulfate in injectable vials contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and asthma attacks, which can be life-threatening in susceptible individuals, or lead to milder reactions. The overall prevalence of sulfite sensitivity in the general population is uncommon and likely low. Sulfite sensitivity is more frequently observed in asthmatic individuals than in non-asthmatics. Cross-allergies with other aminoglycosides are possible.

Other
Aminoglycosides are rapidly and almost completely absorbed when applied locally, except in the urinary bladder, in association with surgical procedures. Following irrigation of both small and large surgical fields with aminoglycoside-containing solutions, cases of irreversible deafness, renal failure, and death due to neuromuscular blockade have been reported.
When amikacin is indicated in combination with other antibiotics, these agents should not be mixed in the same syringes or infusion bottles.
As with other antibiotics, the use of amikacin may lead to overgrowth of non-susceptible organisms. If this occurs, appropriate therapy should be initiated.
Aminoglycosides should be used with caution in neonates and premature infants due to the immature renal development in these patients, which leads to prolonged plasma half-life of these drugs.
The potential ototoxicity of amikacin in children is not fully known. Until more data are available, this antibiotic should be used in pediatric patients only when sensitivity tests indicate that other aminoglycosides cannot be used and when the child can be closely monitored for signs of toxicity.
Following intravitreal administration (injection into the eye), cases of macular infarction with subsequent vision loss have occasionally been reported.

Interference with laboratory tests

Dosage
Patients with impaired renal function
A recommended method for determining dosing intervals in patients with suspected or confirmed decreased renal function is to multiply the serum creatinine concentration (in mg/dL) by 9: the resulting number represents the dosing interval in hours.
Example: if the serum creatinine level is 2 mg/dL, the recommended dose should be administered every 18 hours.