Bramicil

Package leaflet: Information for the user

BRAMICIL 100 mg/2 ml injectable solution, 150 mg/2 ml injectable solution

Tobramycin
Generic medicine
Read this entire 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 or nurse.
• If you experience any side effects, including those not listed in this leaflet, consult your doctor or nurse. See section 4.

Contents of this leaflet:

1. What BRAMICIL is and what it is used for
2. What you need to know before using BRAMICIL
3. How to use BRAMICIL
4. Possible side effects
5. How to store BRAMICIL
6. Contents of the pack and other information

1. What BRAMICIL is and what it is used for

BRAMICIL contains the active substance tobramycin, which belongs to the class of antibiotics known as aminoglycosides.
This medicine is used to treat severe bacterial infections, such as:

• severe blood infections (septicaemia);
• lung infections;
• severe infections of the nervous system (meningitis);
• abdominal infections (including peritonitis);
• bone, skin and skin appendage infections (nails, sebaceous glands);
• complicated or recurrent urinary tract infections;
• infections caused by E. coli and Staphylococcus, as a second-choice treatment.

2. What you should know before using BRAMICIL

Do not use BRAMICIL

• if you are allergic to tobramycin, to other similar medicines (aminoglycoside antibiotics) or to any of the other ingredients of this medicine (listed in section 6);
• if you are pregnant or breastfeeding.

Warnings and precautions
Talk to your doctor or nurse before using this medicine.
Pay special attention to the use of this medicine and avoid high doses for prolonged periods, especially if you have serious kidney problems (renal failure), as the use of BRAMICIL is associated with kidney and hearing toxicity. If these conditions occur, stop treatment immediately. Additionally, decreased reflexes (numbness), tingling sensations, muscle twitching and seizures may occur.
During treatment, kidney function should be monitored, and blood and urine tests should be performed periodically. In particular, the parameters to monitor include blood levels of nitrogen and creatinine (azotemia and creatininemia), presence of protein in the urine (proteinuria), and creatinine clearance rate.
Avoid concomitant use with other medicines that may be harmful to the kidneys or hearing.
During treatment, regularly monitor blood levels of the medicine to prevent accumulation. Blood levels above 12 micrograms/ml for prolonged periods should be avoided. Baseline serum levels that tend to rise above 2 micrograms/ml may indicate tissue accumulation.
In patients with extensive burns, monitoring blood levels of BRAMICIL is advisable to calculate the required dosage.
The use of BRAMICIL in patients undergoing anesthesia with neuromuscular blocking agents such as succinylcholine, tubocurarine, decamethonium, or massive transfusions of citrated blood, may cause serious respiratory problems (apnea).
- If you or your family members have a mitochondrial mutation disease (a disorder caused by variants in mitochondrial genome, the parts of cells that help produce energy) or hearing loss due to antibiotic use, certain mitochondrial mutations may increase the risk of hearing loss with this product.

Children
BRAMICIL should be administered with caution in premature infants and newborns due to its kidney toxicity.

Other medicines and BRAMICIL
Inform your doctor or nurse if you are taking, have recently taken, or might take any other medicines.
Avoid using BRAMICIL together with the following medicines:

• medicines used for infections, such as cephalosporins, amikacin, streptomycin, neomycin, kanamycin, gentamicin and paromomycin, cephaloridine, viomycin, polymyxin B, colistin and vancomycin;
• a medicine called cisplatin, used in cancer therapy;
• medicines used to promote fluid elimination (diuretics) such as furosemide and ethacrynic acid.

Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, planning a pregnancy, or breastfeeding, consult your doctor or nurse before using this medicine.
Do not use this medicine if you are pregnant, as it may cause serious harm to the fetus (e.g. deafness). Serious adverse effects in mother, fetus and newborns have occurred following treatment with other aminoglycosides.

Driving and using machines
BRAMICIL does not affect the ability to drive vehicles or use machinery.

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

3. How to use BRAMICIL

Use this medicine exactly as instructed by your doctor or
nurse. If you have any doubts, consult your doctor or nurse.
This medicine can be administered into the muscle (intramuscular route) or directly
into a vein (intravenous route).
The dosage will be appropriately adjusted by the doctor according to the severity of the infection, body
weight, and blood levels of the medicine. The usual duration of treatment is
7–10 days.

Intramuscular administration
The recommended dose is 1 mg per kilogram (kg) of body weight every 8 hours, for 7–10
days.
Higher doses (up to 5 mg/kg per day) may be required in cases of very
severe infections. This dosage should be reduced to 3 mg per kg of body weight per day as soon
as possible.

Intravenous administration
This medicine will be administered directly into a vein (intravenous route), only
when intramuscular administration is not possible.
The recommended dose is the same as that used for intramuscular administration, without
exceeding the limit of 1 mg of BRAMICIL per ml.
The intravenous infusion should last 1–2 hours.
Whenever possible, this medicine should not be administered concomitantly with other
medicines.

Use in children
The recommended dose ranges from 6 to 7.5 mg per kilogram (kg) of body weight per day, divided
into 3–4 doses given at regular intervals.
The maximum recommended dose in newborns and premature infants is 4 mg per kilogram of
body weight (kg) per day, divided into 2 doses every 12 hours.

Use in patients with kidney problems (renal impairment)
The recommended initial dose is 1 mg per kilogram (kg) of body weight. The doctor
will subsequently decide how to adjust the dose based on specific blood test results (creatinine clearance, serum creatinine).

If you use more BRAMICIL than you should
This medicine will be administered by specialized medical personnel, so overdose is unlikely.
However, prolonged treatment with a dosage higher than recommended, or use in patients with
impaired kidney function, dehydrated patients, elderly patients, or patients receiving other medicines toxic to hearing, may result in the following symptoms:

• ototoxicity, which may present as dizziness, vertigo, development of persistent ringing or noise in the ears (tinnitus), or hearing loss;
• problems affecting the nervous system and muscles (neuromuscular blockade), respiratory paralysis or difficulty breathing (respiratory paralysis, respiratory failure), especially if you suffer from a serious neurological disease such as Parkinson’s disease or a condition causing muscle weakness (myasthenia gravis).

Please note that if you accidentally ingest BRAMICIL, poisoning is unlikely because this class of medicines (aminoglycosides) is poorly
absorbed from the intestine.
However, if you think you have been given too high a dose of BRAMICIL, inform your doctor or
another healthcare professional immediately.
If you have any doubts about how to use this medicine, contact your doctor or nurse immediately.

4. Possible side effects

Like all medicines, this medicine may cause side effects, although not everybody gets them.
The following side effects may occur, particularly in people treated for long periods and with high doses:

• dizziness;
• unpleasant noises in the ear (tinnitus, acouphene), irreversible hearing loss;
• increased nitrogen (total and urea azotemia) and creatinine in the blood;
• decreased amount of urine produced (oliguria);
• presence of proteins in the urine (proteinuria, cylindruria);
• severe respiratory problems (secondary or prolonged apnea) in anaesthetized patients;
• reduction in red blood cells, white blood cells, and platelets (anaemia, granulocytopenia, thrombocytopenia);
• fever;
• skin rash, itching, urticaria;
• nausea, vomiting, diarrhoea;
• headache, drowsiness (lethargy), confusion and disorientation;
• pain at the injection site;
• increased serum transaminases (SGOT, SGPT) and lactate dehydrogenase;
• decreased levels of calcium, magnesium, sodium, and potassium in the blood;
• reduction in white blood cells (leucopenia, leucocytosis, and eosinophilia).

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system at the following 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 BRAMICIL

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the packaging after "Exp. date:".
The expiry date refers to the last day of that month and applies to the product in its original, unopened packaging, properly stored.
Do not store above 25°C.
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 BRAMICIL contains
BRAMICIL 100 mg/2 ml
Each vial contains:

• Active substance: sulfate of tobramycin, equivalent to Tobramycin 100 mg
• Other components: phenol, sodium metabisulfite, disodium edetate, water for injection

BRAMICIL 150 mg/2 ml
Each vial contains:

• Active substance: sulfate of tobramycin, equivalent to Tobramycin 150 mg
• Other components: phenol, sodium metabisulfite, disodium edetate, water for injection

Description of BRAMICIL's appearance and package contents
Each package of BRAMICIL 100 mg/2 ml contains 10 vials of 2 ml injectable solution.
Each package of BRAMICIL 150 mg/2 ml contains 10 vials of 2 ml injectable solution.

Marketing Authorization Holder and Manufacturer
FISIOPHARMA s.r.l.
Industrial Area
84020 PALOMONTE (SA)
Italy

The following information is intended exclusively for physicians or healthcare professionals

BRAMICIL 100 mg/2 ml injectable solution
BRAMICIL 150 mg/2 ml injectable solution
Tobramycin
Equivalent medicine
Dosage and method of administration
Administration in patients with renal impairment
Serum levels of BRAMICIL should be carefully monitored. When monitoring is not feasible, it is advisable to administer a precautionary loading dose of 1 mg/kg and adjust subsequent doses based on creatinine clearance or serum creatinine levels, as BRAMICIL's half-life correlates with these values. It is recommended to use one of the following two methods:

1. Reduction of the dose to be administered every 8 hours

If creatinine clearance (CrCl) or serum creatinine values are known, the amount of
BRAMICIL to be administered can be determined according to the following
table:
MAINTENANCE DOSING IN PATIENTS WITH IMPAIRED RENAL FUNCTION (*)

(*) For infections that threaten the patient's life, doses up to 50% higher than those recommended may be administered, subsequently reduced as soon as initial improvement is observed.
(**) If serum creatinine concentrations are used to assess the degree of renal insufficiency, they should reflect a stable level of azotemia.
(***) When dialysis is not performed.
Alternatively, the dose may be more approximately calculated by dividing the weight-based dose by the serum creatinine values.

1. 2. Normal dose administered at extended intervals. If creatinine clearance values are unknown and the patient's condition is stable, the dosage is determined based on the patient's body weight, while the dosing frequency in hours is calculated by multiplying the serum creatinine value by 6.

Overdose
Signs and Symptoms
The severity of signs and symptoms following Tobramycin overdose depends on the administered dose, the patient's renal function, hydration status, age, and whether other drugs with similar toxicity are concomitantly administered. Toxicity may occur in patients treated for more than 10 days with doses exceeding 5 mg/kg per day, or 7.5 mg/kg per day in children or patients with impaired renal function when dosage adjustments have not been appropriately made, in dehydrated patients, or in patients receiving concomitant ototoxic drugs.
Elderly patients with impaired renal function, concomitantly treated with other nephrotoxic drugs or with reduced blood volume, are at increased risk of developing renal damage (acute tubular necrosis).
Auditory and vestibular toxicity have been associated with aminoglycoside overdose. These patients may experience feelings of faintness, tinnitus (perception of ringing sounds), vertigo, and progressive high-frequency hearing loss as manifestations of ototoxicity. Signs and symptoms of ototoxicity may not appear until long after the drug has been discontinued.
Neuromuscular blockade, respiratory paralysis, and respiratory failure may occur following administration of aminoglycosides, most commonly in patients with myasthenia gravis or Parkinson’s disease. Respiratory paralysis may also occur in patients anesthetized with agents causing neuromuscular blockade.
Toxicity is unlikely following oral ingestion of Tobramycin, as aminoglycosides are poorly absorbed from an intact gastrointestinal tract.

Treatment
In managing Tobramycin overdose, multiple overdoses, interactions with other drugs, and unusual pharmacokinetics in the individual patient must be considered.
In cases of Tobramycin overdose, initial intervention should focus on the respiratory system to ensure adequate ventilation and oxygenation.
If neuromuscular blockade occurs, it can be treated by administration of calcium salts; mechanical ventilatory support may also be required.
If respiratory paralysis occurs, prompt resuscitative measures must be initiated.
Patients with normal renal function who have received an overdose of Tobramycin should be adequately hydrated to maintain a urinary creatinine clearance of 3–5 ml/kg/h. Fluid balance, creatinine clearance, and plasma Tobramycin levels should be closely monitored until serum Tobramycin levels fall below 2 mcg/ml. Patients whose elimination half-life exceeds 2 hours or who have impaired renal function may require more aggressive treatment. Hemodialysis may be beneficial in such patients.

Incompatibilities
Tobramycin is compatible with most commonly used intravenous fluids, but is incompatible with heparin solutions and may undergo chemical interaction with β-lactam compounds, depending on the concentration and pH of both Tobramycin and the β-lactam compounds. Aminoglycosides are in fact inactivated in vitro by various penicillins and cephalosporins through interaction with the β-lactam ring; inactivation depends on temperature, concentration, and duration of contact. Tobramycin has been shown to be the most sensitive to such inactivation.
Due to their potential incompatibility, aminoglycosides should not be mixed with other agents in the same syringe or infusion solution, nor should they be administered through the same intravenous line. When aminoglycosides are administered concomitantly with a β-lactam antibiotic, administration should occur at different sites.
Tobramycin is incompatible with infusion solutions containing alcohol, with sargramostim, and with clindamycin phosphate when diluted with glucose injectable solution. Tobramycin is physically incompatible with carbenicillin.

Instructions for use.
Administration method
For intravenous administration in adults, the dose of BRAMICIL should be diluted in 50–100 ml of physiological saline or 5% glucose solution and infused over a period of 60 minutes.
In children, proportionally smaller volumes of diluent should be used.
BRAMICIL must not be mixed with other drugs, but administered separately.
Please refer to the Summary of Product Characteristics for further prescribing information.