AMIKACIN NORIDEM 250 mg/mL Injectable Solution and Perfusion Solution

2. What you need to know before you are given Amikacina Noridem

Amikacina Noridem must not be given if:

• you are allergic to amikacina or any of the other ingredients of this medicine (listed in section 6)
• you are allergic to other similar substances (other aminoglycosides)
• you are being treated with ataluren (a medicine used in Duchenne muscular dystrophy, a rare genetic neuromuscular disease)

Warnings and precautions

Talk to your doctor before you are given this medicine if:

• you have kidney problems
• you have had kidney or hearing problems after taking other antibiotics
• you have hearing difficulties or dizziness (tinnitus)
• you develop muscle disorders, such as severe myasthenia gravis (a disease that causes muscle weakness) or parkinsonism
• you are an elderly patient
• in case of fairly advanced liver cirrhosis (severe chronic liver disease)

If any of the above applies to you, talk to your doctor or nurse before using this medicine.

Other medicines and Amikacina Noridem

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including medicines administered without a prescription.

Some medicines may interact with others. Tell your doctor if you are taking:

• diuretics such as furosemide or etacrynic acid
• other medicines that may affect your kidneys or hearing, such as bacitracin, cisplatin, amphotericin B, cyclosporine, tacrolimus, cefaloridine, paromomycin, viomycin, polymyxin B, colistin, vancomycin, or other aminoglycosides
• penicillin-type medicines
• bisphosphonates (used to treat osteoporosis and similar diseases)
• vitamin B1
• platinum-based medicines
• muscle relaxants
• indomethacin, an anti-inflammatory medicine, may increase the amount of amikacina absorbed in newborns
• ataluren (used in Duchenne muscular dystrophy, a rare genetic neuromuscular disease)

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, think you may be pregnant, or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine.

Your doctor will use this medicine only if the expected benefits outweigh any potential risk to your baby.

Ask your doctor for advice before taking any medicine.

Driving and using machines

Do not drive or use machines if you experience side effects (such as dizziness) that may reduce your ability to react.

Amikacina Noridem contains metabisulfite sodium and sodium

This medicine contains metabisulfite sodium, which may rarely cause severe hypersensitivity reactions (severe allergy) and bronchospasm (difficulty breathing).

This medicine contains less than 1 mmol of sodium (23 mg) per ampoule, i.e., it is essentially ‘sodium-free’.

3. How Amikacina Noridem is given

This medicine is normally given by intramuscular injection. It may also be given by intravenous route (into a vein), either by injection or (after dilution) by infusion (drip).

Dose

Your doctor will decide the correct dose of amikacina for you and how often it is given.

The dose will depend on your weight, age, the infection you have, how well your kidneys are working, if you have hearing difficulties, and any other medicine you are taking.

It is usually given once or twice a day for up to 10 days.

During the course of treatment, you may have blood tests to monitor your kidney function and amikacina levels in your blood, and you may be asked to provide urine samples.

You may also have hearing tests before and during treatment to check for side effects. Your doctor may adjust your dose based on the results of these tests.

Use in children

Amikacina Noridem, like all aminoglycosides, should be used with caution in premature and newborn babies.

If you are given too much Amikacina Noridem

If you think you have been given too much of this medicine, talk to your doctor or nurse immediately.

An overdose may cause kidney damage, damage to the hearing nerves, or a blockage of muscle function (paralysis). In such cases, the amikacina infusion should be stopped.

In case of overdose or accidental ingestion, talk to your doctor or call the Toxicology Information Service, phone 91 562 04 20, indicating the medicine and the amount taken.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

If you notice any of the following serious side effects, contact your doctor immediately:

Very rare (may affect up to 1 in 10,000 people)

• respiratory paralysis

Frequency not known (cannot be estimated from the available data)

• swelling of the face, lips, or tongue, skin redness, difficulty breathing, as these may be symptoms of an allergic reaction

Other side effects include:

Uncommon (may affect up to 1 in 100 people)

• infections or growth of resistant bacteria
• nausea, vomiting
• dizziness, vertigo
• involuntary eye movements (nystagmus)
• kidney damage, kidney failure

Rare (may affect up to 1 in 1,000 people)

• abnormal blood cell and platelet count, such as anemia, eosinophilia, leukopenia, granulocytopenia, thrombocytopenia
• hypomagnesemia (low magnesium levels in the blood)
• tremors, hallucinations, headache, lack of balance
• blindness, retinal infarction
• tinnitus, hearing loss
• hypotension (low blood pressure)
• itching, rash, skin redness, exanthema
• arthralgia (joint pain), muscle contractions
• reduced urine production, elevated serum creatinine, albuminuria, azotemia, erythrocytes in urine, leukocytes in urine
• pyrexia (fever)
• migraine
• respiratory function depression
• increased aspartate aminotransferase, increased alanine aminotransferase, increased alkaline phosphatase (mild and transient)

Very rare (may affect up to 1 in 10,000 people)

• neuromuscular blockade
• respiratory paralysis (isolated cases), complete or severe weakness of the respiratory muscles

Frequency not known (cannot be estimated from the available data)

• anaphylactic reaction, anaphylactic shock, and anaphylactoid reaction, hypersensitivity
• paralysis
• deafness, sensorineural deafness
• apnea (a disorder that causes you to stop breathing while sleeping), bronchospasm
• acute kidney failure, toxic nephropathy (kidney damage due to toxic medicines or chemicals), epithelium in urine

If Amikacina Noridem is injected directly into the eye, serious vision problems may occur.

Reporting of side effects

If you experience any side effects, talk to your doctor, pharmacist, or nurse, even if they are not listed in this leaflet. You can also report side effects directly through the Spanish Pharmacovigilance System for Human Use Medicines, www.notificaRAM.es. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Amikacina Noridem

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

Do not use this medicine after the expiry date which is stated on the carton and on the label after EXP. The expiry date is the last day of the month shown.

Store below 25 °C

Do not use this medicine if you notice particles in the ampoule or if the solution is not colorless to pale yellow.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help protect the environment.

6. Container Content and Additional Information

Composition of Amikacina Noridem

• The active ingredient is amikacin sulfate.

Each ml of injectable solution and for perfusion contains 250 mg of amikacin (as sulfate).

Each 2 ml ampoule contains 500 mg of amikacin.

• The other ingredients are: sodium citrate dihydrate, sodium metabisulfite, sulfuric acid (for pH adjustment), water for injectable preparations.

Product Appearanceand Container Content

The amikacin solution is transparent, colorless to pale yellow, free of visible particles in transparent glass ampoules.

Package sizes: 1 and 10 ampoules

Only some package sizes may be marketed.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder

Noridem Enterprises Ltd.

Evagorou & Makariou

Mitsi Building 3, Office 115

1065 Nicosia, Cyprus

Manufacturer

DEMO S.A. PHARMACEUTICAL INDUSTRY

21st Km National Road Athens-Lamia.

14568 Greece

T:+30 210 8161802, F:+30 2108161587.

This medication is authorized in the Member States of the European Economic Area under the following names:

Date of last revision of this leaflet:05/2024

Detailed information on this medicinal product is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) (http://www.aemps.gob.es)

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This information is intended only for healthcare professionals or medical professionals:

Dosage and Administration

Amikacin is generally used in combination with other suitable antibiotics. The dose of amikacin depends on the infection, the patient's condition, and renal function. Local guidelines should be taken into account.

Dosage

The patient's body weight should be obtained prior to treatment for the calculation of the correct dosage.

The state of renal function should be estimated by measuring serum creatinine concentration or calculating endogenous creatinine clearance. Renal function should be reassessed periodically during treatment. Blood urea measurement is much less reliable for this purpose.

Whenever possible, amikacin serum concentrations should be measured to ensure adequate but not excessive concentrations. It is desirable to measure peak and trough concentrations intermittently during treatment. Peak concentrations (30-90 minutes after injection) above 35 mcg (micrograms)/ml and trough concentrations (just before the next dose) above 10 mcg (micrograms)/ml should be avoided. The dosage should be adjusted as indicated. In patients with normal renal function, a once-daily dosage may be used. Peak concentrations in these cases may exceed 35 mcg (micrograms)/ml (see below Administration once a day and Renal insufficiency).

Adults and children over 12 years:

The recommended intramuscular or intravenous dose for adults and adolescents with normal renal function (creatinine clearance ≥50 ml/min) is 15 mg/kg/day, which can be administered as a single daily dose or divided into 2 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 in febrile neutropenic patients, the dose should be administered twice a day, as there is insufficient data to support once-daily dosing.

Children aged 4 weeks to 12 years:

The recommended intramuscular or intravenous dose (slow intravenous infusion) in children with normal renal function is 15-20 mg/kg/day, which can be administered as 15-20 mg/kg once daily or as 7.5 mg/kg every 12 hours. In patients with endocarditis and in febrile neutropenic patients, the dose should be administered twice a day, as there is insufficient data to support once-daily dosing.

Neonates:

Initial loading dose of 10 mg/kg followed by 7.5 mg/kg every 12 hours (see sections 4.4 and 5.2).

Preterm infants:

The recommended dose in preterm infants is 7.5 mg/kg every 12 hours (see sections 4.4 and 5.2).

Data on once-daily administration to patients with other systemic infections are limited (see also above for control of amikacin peak and trough serum concentrations).

The usual duration of treatment is 7 to 10 days. In most cases, aminoglycosides are indicated only at the start of treatment when the inoculum is potentially high and when there is uncertainty about the effectiveness of treatment, and for a treatment duration of ≤ 5 days due to their benefit/safety ratio (bactericidal activity/toxicity correlated with treatment duration). The total daily dose with all modes of administration should not exceed 20 mg/kg/day. In difficult and complicated infections where treatment for more than 10 days is considered, the use of amikacin should be reassessed and, if continued, renal, auditory, and vestibular function as well as amikacin serum concentrations should be monitored.

At the recommended dose level, uncomplicated infections due to microorganisms sensitive to amikacin should respond to treatment within 24 or 48 hours. If no clear clinical response is observed after 3 to 5 days, treatment should be discontinued and susceptibility tests of the pathogen to the antibiotic should be repeated. Failure to respond to infection may be due to resistance of the microorganism or the presence of septic foci that require surgical drainage.

Renal Function Impairment

In patients with renal insufficiency reflected in a creatinine clearance of less than 50 ml/min, it is not recommended to administer the recommended total daily dose of amikacin in single daily doses, as these patients will be exposed to prolonged elevated trough concentrations. See below for dosage adjustments in patients with impaired renal function.

For patients with impaired renal function who receive the usual dosing of two or three times a day, amikacin serum concentrations should be monitored whenever possible using appropriate assay procedures. Doses should be adjusted in patients with impaired renal function by either administering normal doses at prolonged intervals or administering reduced doses at fixed intervals.

Both methods are based on creatinine clearance or serum creatinine values, as they have been observed to be correlated with the aminoglycoside half-life in patients with decreased renal function. These dosing regimens should be used in conjunction with careful clinical and laboratory observation of the patient and should be modified as necessary, including modification when dialysis is being performed.

Normal Dosage at Extended Intervals

If there are no data on creatinine clearance and the patient's condition is stable, a dosing interval in hours may be calculated for the normal single dose (i.e., that which would have been administered to patients with normal renal function on a twice-daily regimen, 7.5 mg/kg per day) by multiplying the patient's serum creatinine by nine. For example, if the serum creatinine concentration is 2 mg/100 ml, the recommended single dose (7.5 mg/kg) should be administered every 18 hours.

Reduced Dose at Fixed Time Intervals

When amikacin is to be administered at fixed time intervals in case of renal insufficiency, the dose should be reduced. In these patients, amikacin serum concentrations should be measured to ensure precise administration and avoid excessive serum concentrations. If serum concentration assays are not available and the patient's condition is stable, serum creatinine or creatinine clearance values are the most readily available indicators of the degree of renal insufficiency that can be used as a dosing guide.

First, treatment should be initiated by administering a normal dose, 7.5 mg/kg, as a loading dose. This dose is the same as that normally recommended for a patient with normal renal function, as described above.

To determine the size of the maintenance doses to be administered every 12 hours, the loading dose should be reduced in proportion to the reduction in the patient's creatinine clearance rate:

Maintenance dose every 12 hours =

Observed CrCL in ml/min X calculated loading dose in mg

Normal CrCL in ml/min

(CrCL = creatinine clearance)

An alternative guideline for determining a reduced dosage at 12-hour intervals (for patients whose steady-state serum creatinine values are known) is to divide the normally recommended dose by the patient's serum creatinine.

The above dosing regimens are not intended to be rigid recommendations but are given as dosing guidelines when serum concentration measurement is not feasible.

Obese Patients

Amikacin diffuses poorly into fatty tissue. The appropriate dose may be calculated using the patient's estimated ideal body weight plus 40% of the excess, as the weight on which to determine the mg/kg.

Dose adjustment should be made based on plasma monitoring. The maximum dose is 1.5 g per day and should not be exceeded. The duration of treatment should be limited to 7 to 10 days.

Patients with Ascites

Higher doses should be administered to achieve adequate serum concentrations, given the relatively greater distribution in the extracellular fluid compartment.

Administration

Amikacina Noridem can be administered by intramuscular or intravenous route. Local recommendations should be taken into account.

Intravenous Administration

In adults, it can be administered as is (2-3 minutes) or by slow infusion over 30 to 60 minutes. A suitable treatment may be considered a slow infusion over 30 minutes, in addition to measured amikacin serum concentrations 30 minutes after the end of the infusion, taking into account pharmacokinetic/pharmacodynamic objectives and monitored drug concentrations at appropriate times with a standardized approach.

Special recommendation for intravenous administration in the pediatric population

In pediatric patients, the amount of diluent used will depend on the amount of amikacin tolerated by the patient. The solution should be infused normally over a period of 30 to 60 minutes. Children should receive an infusion of 1 to 2 hours.

Amikacin should not be mixed with other medications, but it can be administered separately according to the recommended dose and route of administration.

For instructions on dilution of the medication before administration, see the section "Handling Instructions" below.

Incompatibilities

This medicinal product should not be mixed with any other medicinal product (except those mentioned in the "Handling Instructions" section).

Mixing aminoglycosides with beta-lactam antibiotics (penicillins or cephalosporins) in an infusion solution may lead to significant mutual inactivation. A decrease in activity in serum may also be observed when an aminoglycoside antibiotic or a penicillin-type antibiotic is administered in vivoby separate routes. Inactivation of the aminoglycoside is of clinical importance only in patients with severe renal insufficiency. Inactivation may persist in body fluid samples taken for assays, leading to inaccurate measurements of aminoglycosides. Samples should be handled properly (direct examination, freezing, or beta-lactamase effect).

Chemical incompatibilities are known for amphotericin, chlorothiazide, erythromycin, heparin, nitrofurantoin, novobiocin, phenytoin, sulfadiazine, thiopental, chlortetracycline, vitamin B, and vitamin C. Amikacin should not be pre-mixed with these medicinal products.

Overdose

In case of overdose, there is a general risk of nephrotoxic, ototoxic, and neurotoxic reactions (neuromuscular blockade). Neuromuscular blockade with respiratory arrest requires appropriate treatment, including the application of ionic calcium (e.g., as gluconate or lactobionate in a 10-20% solution). In case of overdose or toxic reaction, peritoneal dialysis or hemodialysis will help eliminate amikacin from the blood.

Amikacin concentrations are also reduced during continuous arteriovenous hemofiltration.

In newborns, an exchange transfusion may also be considered.

Handling Instructions

Intravenous Administration:Preparation of Solutions

The solution for intravenous use is prepared by adding the desired dose to 100 ml or 200 ml of sterile solvent such as sodium chloride solution or 5% dextrose in water or any other compatible solution.

Amikacin 125 mg/ml and amikacin 250 mg/ml are diluted under aseptic conditions with:

• 5% injectable dextrose
• 5% injectable dextrose and 0.2% sodium chloride
• 5% injectable dextrose and 0.45% sodium chloride
• 0.9% injectable sodium chloride
• Ringer-lactate injectable
• Ringer-lactate injectable with 5% dextrose

In pediatric patients, the amount of fluid to be used depends on the amount tolerated by the patient. It should be sufficient to inject amikacin over a period of 30 to 60 minutes.

After dilution:

Solutions diluted to final concentrations below 2.5 mg/ml should be used immediately.

Chemical and physical stability in use has been demonstrated for 24 hours at 23-27 °C under artificial light and at 2-8 °C with 0.9% injectable sodium chloride and Ringer-lactate injectable solution, at an amikacin concentration of 2.5 mg/ml, 5.0 mg/ml, 7.5 mg/ml, and 15.0 mg/ml.

Chemical and physical stability in use has been demonstrated for 3 hours at 23-27 °C under artificial light and for 12 hours at 2-8 °C with 5% injectable dextrose, 5% injectable dextrose and 0.2% sodium chloride, 5% injectable dextrose and 0.45% sodium chloride, and Ringer-lactate injectable solution with 5% dextrose, at an amikacin concentration of 2.5 mg/ml, 5.0 mg/ml, and 7.5 mg/ml.

Chemical and physical stability in use has been demonstrated for 6 hours at 23-27 °C under artificial light and for 24 hours at 2-8 °C with 5% injectable dextrose, 5% injectable dextrose and 0.2% sodium chloride, 5% injectable dextrose and 0.45% sodium chloride, and Ringer-lactate injectable solution with 5% dextrose, at an amikacin concentration of 15.0 mg/ml.

From a microbiological point of view, unless the opening method precludes the risk of microbiological contamination, the product should be used immediately. If not used immediately, the in-use storage times and conditions are the responsibility of the user.

The medicinal product should be visually inspected for the presence of particles and discoloration before administration.

Only clear solutions free of particles should be used.

For single use.

The unused solution should be discarded.

Disposal of the unused medicinal product and all materials that have come into contact with it should be carried out in accordance with local regulations immediately after use.