Gentamicin Noridem

Package leaflet: Information for the user

Gentamicina Noridem 20 mg/ml solution for injection or infusion, 40 mg/ml solution for injection or infusion, 40 mg/ml solution for injection or infusion

Gentamicin
Generic medicine
Please read all of this leaflet carefully before you are given 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.
• If you get any side effects, including those not listed in this leaflet, talk to your doctor, pharmacist or nurse. See section 4.

Contents of this leaflet

1. What Gentamicina Noridem is and what it is used for
2. What you need to know before you are given Gentamicina Noridem
3. How Gentamicina Noridem is administered
4. Possible side effects
5. How to store Gentamicina Noridem
6. Contents of the pack and other information

1. What Gentamicina Noridem is and what it is used for

Gentamicina Noridem contains the active substance gentamicin. It belongs to a group of antibiotics called aminoglycosides. This medicine is used to treat serious bacterial infections, including:

• urinary tract infections (including kidneys or bladder)
• chest infections (including lungs), such as hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP)
• bacterial inflammation of the inner lining of the heart (endocarditis)
• abdominal infections
• infections of the brain and spinal cord (bacterial meningitis)
• bone and joint infections (osteomyelitis and bacterial arthritis)
• management of febrile neutropenic patients with suspected bacterial infection
• systemic infections due to the presence of Listeria monocytogenes in the blood
• serious infections in newborns
• bloodstream infections (bacteraemia occurring in association with, or suspected to be associated with, any of the infections listed above)

Note:
Concomitant treatment is mainly indicated with a beta-lactam antibiotic (such as penicillin) or with an antibiotic effective against anaerobic bacteria (bacteria that do not live or grow in the presence of oxygen) in the following cases: potentially life-threatening infections due to unknown bacteria or mixed anaerobic/aerobic infections, bacterial infection of the inner lining of the heart (endocarditis), generalized Pseudomonas infections, and in patients with impaired immune systems who have a deficiency in certain types of white blood cells (neutropenia).

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

Do not be given Gentamicina Noridem

• if you are allergic to gentamicin or to any of the other ingredients of this medicine (listed in section 6).
• by subcutaneous route (under the skin), as it is ineffective via this route and necrosis (tissue death) may occur at the injection site.

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before you are given Gentamicina Noridem:

• if you have, or have a maternal family history of mitochondrial mutation disease (a genetic disorder) or hearing loss due to antibiotics, you must inform your doctor or pharmacist before taking an aminoglycoside; certain mitochondrial mutations may increase the risk of hearing loss with this medicine. Your doctor may recommend genetic testing before administration of Gentamicina Noridem.
• if you have kidney problems
• if you have liver problems
• if you have diabetes
• if you suffer from deafness or have a hearing or balance disorder, a history of ear infections, or have previously been treated with medicines that affect hearing.
• if you experience severe diarrhoea.

In these cases, gentamicin will only be administered if your doctor considers this treatment to be absolutely necessary for your condition. Your doctor will carefully adjust your dose of gentamicin.
Your doctor will pay particular attention if you suffer from a disease affecting nerve and muscle function, such as Parkinson's disease or myasthenia gravis, or if you are receiving a muscle relaxant during surgery, since gentamicin can cause blockade of nerve and muscle function.

Children and adolescents
Based on available data, renal and auditory toxicity remain rare in neonates and children.

Monitoring during treatment
To reduce the risk of kidney or auditory nerve damage, your doctor will carefully follow these recommendations:

• Monitoring of hearing, balance, and kidney function before, during, and after treatment.
• Selection of a dose adjusted according to your kidney function.
• Monitoring of gentamicin blood concentrations during therapy, if necessary in your case.
• Avoidance of administering other substances with potential harmful effects on the auditory nerves or kidneys together with gentamicin. If this is unavoidable, particularly careful monitoring of kidney function will be required.
• You must inform your doctor immediately if you develop severe diarrhoea.
• In addition, adequate hydration and urine output must be maintained.

Other medicines and Gentamicina Noridem
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicine.
Medicines that may damage the kidneys and hearing
Inform your doctor if you are receiving or are about to receive treatment with medicines that may potentially damage the kidneys or hearing, as there is an increased risk of adverse effects. These medicines include:

• Amphotericin B (used to treat fungal infections)
• Polymyxin B (antibiotic)
• Cyclosporine (used in organ transplants or for severe skin conditions)
• Cisplatin or other platinum-containing compounds (used to treat cancer)
• Other aminoglycoside antibiotics, such as tobramycin, streptomycin
• Diuretic tablets or injections such as furosemide
• Tacrolimus (used after organ transplants)
• Cephalothin (an antibiotic belonging to the cephalosporin group)
• Methoxyflurane (an anaesthetic gas)
• Indomethacin (belongs to a group of medicines called non-steroidal anti-inflammatory drugs, used to treat pain and inflammation)
• Anticoagulants (used to thin the blood) such as warfarin and phenindione
• Bisphosphonates (used to treat osteoporosis)
• Iodinated contrast agents (agents used to enhance radiographic imaging), antivirals (such as acyclovir group, foscarnet), methotrexate, pentamidine
• Glycopeptide antibiotics, such as vancomycin and teicoplanin
• Neostigmine or pyridostigmine (used to treat muscle weakness)
• Digoxin (used to treat various heart conditions)

Medicines whose effect may be increased by gentamicin
Inform your doctor also if you are taking the following medicines, as their effect may be increased when used together with gentamicin:

• Botulinum toxin (used to reduce activity of overactive muscles)
• Curare-based medicines (muscle relaxants).

Pregnancy, breastfeeding, and fertility
If you are pregnant, suspect you may be pregnant, plan to become pregnant, or are breastfeeding, consult your doctor or pharmacist before you are given this medicine.
Pregnancy
Gentamicin should be used during pregnancy only for potentially life-threatening indications and when safer alternative treatments are not available, due to the potential risk to the unborn child.
This medicine is not recommended for use during pregnancy unless considered appropriate by your doctor.
Breastfeeding
Do not breastfeed during treatment with gentamicin. Small amounts of gentamicin are excreted in human breast milk, and low concentrations have been detected in the serum of breastfed infants.
A decision must be made whether to discontinue breastfeeding or to discontinue or withhold gentamicin therapy.
Infants breastfed by mothers receiving this medicine may develop diarrhoea and oral thrush (fungal infection) during treatment.
Fertility
Men are advised not to father a child while receiving treatment with this medicine and to use an effective contraceptive method during treatment and for up to 3 months after the end of treatment. Consult your doctor before starting treatment for information on sperm preservation.

Gentamicina Noridem contains sodium and sodium metabisulfite
This medicine contains less than 1 mmol of sodium (23 mg) per vial, i.e. it is practically sodium-free.
This medicine contains sodium metabisulfite, which may rarely cause severe hypersensitivity reactions and bronchospasm.

3. How Gentamicina Noridem is administered

Gentamicina Noridem is always administered by a doctor or nurse.
The doctor will determine the dose based on your weight. The correct dose also depends on the type of infection and any other medical conditions you may have. The doctor or nurse will take blood samples to ensure the dose is appropriate for you.
Your blood levels of gentamicin will be monitored regularly to ensure that the correct blood concentrations have been achieved. Treatment with gentamicin may cause damage to hearing and kidney function. Based on your condition, the doctor will decide how long you should receive gentamicin. In some cases, the doctor may perform blood tests to monitor kidney function before and during treatment with gentamicin. Occasionally, you may also be asked to have a hearing test to ensure the medicine is not causing hearing damage.

Dosage
The recommended daily dose for children, adolescents, and adults with normal kidney function is 3–6 mg/kg body weight per day, preferably administered as a single dose, or otherwise divided into two separate doses.

Use in children
The recommended daily dose for children aged 1 year and older with normal kidney function is 3–6 mg/kg/day as a single dose (preferred) or divided into two doses. The recommended daily dose for children after the first month of life is 4.5–7.5 mg/kg body weight per day, preferably administered as a single dose, or otherwise divided into two separate doses. The recommended daily dose for newborns is 4–7 mg/kg body weight per day. Due to the longer half-life, newborns receive the required dose as a single dose.

Patients with kidney problems
If you have kidney problems, your recommended daily dose must be reduced and adjusted according to kidney function.

Method of administration
After dilution, this medicine is injected into a muscle (intramuscular route) or into a vein (intravenous route).

Duration of treatment
The duration of treatment is determined by the doctor.
For common bacterial infections, the treatment duration depends on the course of the disease. Generally, a treatment period of 7–14 days is sufficient.
The duration of therapy should preferably not exceed 10–14 days.
Repeated courses of treatment with Gentamicina Noridem should be avoided immediately after a previous course with an aminoglycoside. A waiting period of 7–14 days should be observed before starting treatment with gentamicin.

Inform your doctor or nurse if you feel that the effect of Gentamicina Noridem is too strong or too weak.

If you are given more Gentamicina Noridem than you should
It is unlikely that the doctor or nurse will give you too much medicine. Your doctor and nurse will monitor your progress and check the medicine you have been given. Always ask your doctor or nurse if you are unsure why you are receiving a particular dose.

If you miss a dose of Gentamicina Noridem
The doctor or nurse have instructions on when to administer the medicine. It is very unlikely that the medicine will not be given as prescribed. If you think you have missed a dose, speak to your doctor or nurse.

If you stop taking Gentamicina Noridem
It is important to complete the full course of treatment prescribed by your doctor. You may start to feel better, but it is essential to continue treatment as long as your doctor recommends. If you stop treatment prematurely, the infection may worsen again.

If you have any doubts about the use of this medicine, consult your doctor, nurse, or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
Immediately inform your doctor if you notice signs of an allergic reaction, including anaphylactic shock
(a potentially fatal allergic reaction), such as:

• itching and skin rash
• swelling of the face, lips, or throat
• difficulty breathing or wheezing

Other possible side effects:
Common: may affect up to 1 in 10 people

• kidney function problems

Uncommon: may affect up to 1 in 100 people

• blood clotting problems
• skin redness, with varying intensity, without papules or blisters

Rare: may affect up to 1 in 1,000 people

• low levels of potassium, calcium, and magnesium in the blood
• increased levels of aldosterone in the blood
• loss of appetite
• weight loss
• damage to peripheral nerves
• loss of sensation
• nausea or vomiting
• increased liver enzymes and urea (nitrogen) in the blood (all reversible)
• increased saliva production
• inflammation of the inside of the mouth
• skin redness
• muscle pain
• increased body temperature
• increased level of serum bilirubin in the blood

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

• blood disorders affecting certain blood components, usually detected by blood tests
• reduced levels of phosphates in the blood
• confusion, hallucinations, depression
• a range of brain-related problems
• seizures
• neuromuscular blockade
• dizziness, vertigo, balance disorders, headache
• visual disturbances
• hearing loss
• inner ear problems, tinnitus
• low blood pressure
• high blood pressure
• erythema multiforme
• hair loss
• muscle wasting (reduction in muscle mass)
• acute kidney failure, increased levels of phosphate and amino acids in urine (known as Fanconi syndrome, associated with high doses administered over a prolonged period)
• pain at the injection site

Not known: frequency cannot be estimated from the available data

• infection with other microorganisms resistant to gentamicin
• irreversible hearing loss, deafness
• lethargy (lack of energy and enthusiasm)
• symptoms of bruising, skin discoloration, formation of red spots. These may be signs of purpura.
• allergic reactions (including severe allergic reactions such as anaphylaxis), which may include:
  • raised, itchy skin rash (urticaria)
  • swelling of hands, feet, ankles, face, lips, or throat, which may cause difficulty swallowing or breathing
  • fainting, dizziness, feeling of vertigo (low blood pressure)
  • diarrhoea, with or without blood and/or muscle cramps
• severe allergic skin reaction and mucous membranes, accompanied by blistering and skin redness, which in very severe cases may affect internal organs and may be potentially fatal (Stevens-Johnson syndrome, toxic epidermal necrolysis).

Reporting of side effects
If you get any side effects, including any not listed in this leaflet, talk to your doctor, pharmacist, or nurse.
You can also report side effects directly via the website: 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 Gentamicina Noridem

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the outer packaging and on the vials after
"Exp". The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions. Do not refrigerate or freeze.
The doctor or nurse will ensure that the medicine is stored correctly.
Gentamicina Noridem must be used immediately after opening the vial.
Gentamicina Noridem is chemically and physically stable for 24 hours at 25 °C after dilution in a 0.9%
sodium chloride injectable solution (9 mg/ml) or a 5% glucose injectable solution (50 mg/ml). From a
microbiological standpoint, the product should be used immediately. If not used immediately, the storage
times during use and the conditions prior to use are the responsibility of the user and should generally not
exceed 24 hours at a temperature between 2 °C and 8 °C, unless the dilution has been carried out under
controlled and validated aseptic conditions.
After opening, any unused portion must not be stored and should be immediately discarded.
This medicine should be visually inspected before use. Only clear solutions practically free from visible
particles should be used.
Do not dispose of any medicine via wastewater or household waste. Ask the nurse or pharmacist how to
dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Gentamicina Noridem contains

• The active substance is gentamicin.

Gentamicina Noridem 20 mg/ml: Each ml of solution contains 20 mg of gentamicin (as
gentamicin sulfate).
Each 2 ml vial of solution contains 40 mg of gentamicin.
Gentamicina Noridem 40 mg/ml: Each ml of solution contains 40 mg of gentamicin (as
gentamicin sulfate).
Each 2 ml vial of solution contains 80 mg of gentamicin.
Gentamicina Noridem 80 mg/ml: Each ml of solution contains 80 mg of gentamicin (as
gentamicin sulfate).
Each 2 ml vial of solution contains 160 mg of gentamicin.

• The other ingredients are disodium edetate, sodium metabisulphite (E 223), sodium hydroxide 1 N (for pH adjustment), sulfuric acid 0.5 M (for pH adjustment), water for injectable preparations.

Description of the appearance of Gentamicina Noridem and contents of the pack
Gentamicina Noridem solution for injection/infusion is a clear, colourless solution for injection/infusion.
Each glass vial contains 2 ml of solution. Packs containing 5, 10 or 20 vials are available.
Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder
Noridem Enterprises Limited
Evagorou & Makariou
Mitsi Building 3, Office 115
1065 Nicosia, Cyprus

Manufacturer:
DEMO S.A. PHARMACEUTICAL INDUSTRY
21st Km National Road Athens–Lamia,
14568 Krioneri, Attiki, Greece
T: +30 210 8161802, F: +30 2108161587

This medicinal product is authorised in the European Economic Area and the United Kingdom (Northern Ireland) under the following names:

The following information is intended exclusively for physicians or healthcare professionals:
Please refer to the Summary of Product Characteristics for complete prescribing information.

Dosage
The dose depends on the severity of the clinical condition, the patient's status, renal function, and the type of infection. Various formulations of gentamicin are available, some of which are more suitable for high-dose intravenous administration. The dose is expressed according to the patient's body weight.
The recommended daily dose in adolescents and adults with normal renal function should preferably be administered as a single dose, or otherwise divided into two separate doses.
A dosing frequency of more than twice daily may be adopted for certain specific pathogens or infection sites, as recommended in national and local guidelines.
Once-daily dosing is not recommended in cases of endocarditis, depending on the causative pathogens. In cases of endocarditis, national and local treatment guidelines for gentamicin must be followed, and serum level monitoring must be performed.
Dose calculations should be based on ideal body weight.

Dosing Recommendations
Dosage (adults and adolescents)
Recommended dose: 3–6 mg gentamicin/kg/day
Subsequent doses should be adjusted according to serum concentration levels (see "Monitoring Recommendations") using local guidelines or nomograms.

Dosage in Renal Impairment
Gentamicin is primarily excreted by glomerular filtration. Therefore, dosing in patients with renal impairment must be adjusted accordingly.
Dose adjustments in patients with renal impairment should also be based on therapeutic drug monitoring. For patients on once-daily dosing, prolongation of the dosing interval is generally recommended. The initial dosing interval should be at least 24 hours and extended according to the degree of renal impairment and serum gentamicin monitoring results. Limited data are available in patients with severe renal impairment (creatinine clearance <30 ml/min) for once-daily dosing.

Dose Adjustment
Nomograms are available to calculate dose or dosing interval based on patient age, weight, renal function, and plasma concentrations. Where available, local guidelines should be followed. If nomograms or local guidelines are not available, the following may be used:
Two options are available for dose adjustment:
A. Prolongation of the dosing interval while maintaining the same dose (subsequent doses identical to the initial dose).
B. Reduction of the dose while maintaining the same dosing intervals (subsequent doses lower than the initial dose).
For patients receiving once-daily dosing, prolongation of the dosing interval is preferred. For patients receiving multiple daily doses, dose reduction is preferred.
The following table provides a guideline for dose reduction while maintaining the same dosing interval (8-hour dosing interval):

| Serum Creatinine (mg/100 ml) | Creatinine Clearance (ml/min/1.73m²) | Subsequent Doses (% of initial dose) | |----------------------------------|------------------------------------------|------------------------------------------| | <1.0 | >100 | 100 | | 1.1–1.3 | 71–100 | 80 | | 1.4–1.6 | 56–70 | 65 | | 1.7–1.9 | 46–55 | 55 | | 2.0–2.2 | 41–45 | 50 | | 2.3–2.5 | 36–40 | 40 | | 2.6–3.0 | 31–35 | 35 | | 3.1–3.5 | 26–30 | 30 | | 3.6–4.0 | 21–25 | 25 | | 4.1–5.1 | 16–20 | 20 | | 5.2–6.6 | 11–15 | 15 | | 6.7–8.0 | <10 | 10 |

It should also be remembered that renal function may change during treatment.
Creatinine clearance is the preferred parameter, especially in patients with variable plasma creatinine concentrations, such as those observed in severe infections (e.g., sepsis).
If only serum creatinine values are known, creatinine clearance can be estimated using the following formulas:

Men:
Body weight (kg) × (140 – age in years)
Cl = _________________________________________
72 × serum creatinine (mg/100 ml)

or

Men:
Body weight (kg) × (140 – age in years)
Cl = ________________________________________
0.814 × serum creatinine (µmol/l)

Women: 0.85 × the value calculated for men

If serum creatinine values are used to assess renal function, they should be measured several times, as the correlation with creatinine clearance exists only when renal impairment remains stable.

Paediatric Population
The recommended daily dose in children aged 1 year and older with normal renal function is 3–6 mg/kg/day as a single dose (preferred) or divided into two doses. The recommended daily dose in children after the first month of life is 4.5–7.5 mg/kg/day and should preferably be administered as a single dose, or otherwise divided into two separate doses. The recommended daily dose in neonates is 4–7 mg/kg body weight per day. Due to the longer half-life, neonates receive the required dose as a single dose.
Particular attention must be paid to preparation (dilution) and the amount administered. Any error, even minor, may significantly affect the resulting serum concentrations.

Elderly
There is evidence that elderly patients may be more sensitive to aminoglycoside toxicity, which may be secondary to pre-existing hearing/vestibular impairment or borderline renal dysfunction. Therefore, therapy must be carefully monitored through frequent measurement of serum gentamicin levels, assessment of renal function, and signs of ototoxicity. If renal function is impaired, the recommended daily dose must be reduced and adjusted according to renal function.

Hepatic Impairment
Gentamicin may be prescribed in cases of hepatic impairment, and no dose adjustment is necessary.

Dosage in Patients Undergoing Haemodialysis
Gentamicin is dialyzable. With a haemodialysis session lasting 4–5 hours or 8–12 hours, a reduction in concentration of approximately 50–60% and 70–80%, respectively, is expected. After each dialysis session, supplemental doses should be administered based on the current serum gentamicin concentration. Generally, the recommended dose after dialysis is 1–1.7 mg/kg body weight.
Since patients undergoing haemodialysis generally receive anticoagulant therapy, intramuscular injections should not be administered in these cases due to the risk of hematoma formation.

Obese Patients
Dose calculations should be based on ideal body weight. In cases of significant obesity, serum gentamicin concentrations should be closely monitored.

Monitoring Recommendations
Regular monitoring of serum gentamicin concentration is recommended for all patients, and especially in the elderly, neonates, 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 monitoring of gentamicin. When available, local guidelines for monitoring and dose adjustment should be followed.
Generally, the following is recommended: pre-dose monitoring ("trough level") is recommended to ensure the dosing interval 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 exceeding these values indicate the need to extend the dosing interval, not to reduce the dose.
Post-dose monitoring ("peak level") is recommended to assess dose adequacy or to ensure it is not excessive and potentially toxic. Peak levels should be measured one hour after an intravenous or intramuscular bolus dose, or 30 minutes after the end of an infusion. A plasma concentration <4 mg/l indicates the dose is likely inadequate and dose increase should be considered; plasma concentrations >10 mg/l indicate an increased risk of toxicity, particularly ototoxicity, and dose reduction should be considered.
Any dose modification should be re-evaluated with pre- and post-dose levels to confirm the adequacy of the new dose and the appropriateness of the dosing interval.

Method of Administration
For single use only.
For intramuscular injection, intravenous injection, or intravenous infusion after dilution. The same dosing regimen is recommended for intramuscular and intravenous administration. Intramuscular administration should be considered when the intravenous route is not feasible or less appropriate for the patient.
Gentamicin may, if clinically indicated, be injected directly into the vein in undiluted form; the injection must be administered slowly over 2–3 minutes. Rapid and direct intravenous administration may initially cause potentially neurotoxic concentrations; therefore, it is essential that the prescribed dose be administered over the recommended time. Alternatively, the prescribed dose must be dissolved in a volume up to 100 ml of sodium chloride 9 mg/ml (0.9%) injection solution or glucose 50 mg/ml (5%) injection solution, and the solution must be infused over no more than 20 minutes. The medicinal product is intended for a single patient and contains no antimicrobial agent.
The injection/infusion must not be administered together with other medicinal products.

Overdose
Gentamicin has a narrow therapeutic window. In case of accumulation (e.g., as a consequence of impaired renal function), damage to the kidneys and the vestibulocochlear nerve may occur. Renal damage is associated with trough levels exceeding 4 mg/l.
Treatment in case of overdose:
Discontinue the drug. There is no specific antidote. In case of overdose or toxic reaction, peritoneal dialysis or haemodialysis will reduce serum gentamicin levels.
In case of neuromuscular blockade (mainly caused by interactions; see details), administration of calcium chloride is advisable and, if necessary, artificial ventilation should be used.

Incompatibilities
In general, gentamicin-containing preparations must not be mixed. In particular, the following substances are incompatible in solutions mixed with gentamicin preparations: penicillins, cephalosporins, erythromycin, heparins, sodium bicarbonate. *Dilution in the body will avoid the risk of physical and chemical incompatibility and allows gentamicin to be administered together with the listed medicinal products as a bolus injection into the infusion line after adequate flushing, or at separate sites. In the case of carbenicillin, administration must be performed only at a separate site.
*Combining the two solutions may lead to the release of carbon dioxide. This generally dissolves in solution, but in some circumstances small bubbles may form.
This also applies to a combination of gentamicin with diazepam, furosemide, or flecainide acetate.