Gentamicin noridem

Package leaflet: Information for the user

Gentamicin Noridem, 20 mg/mL, solution for injection / infusion
Gentamicin Noridem, 40 mg/mL, solution for injection / infusion
Gentamicin Noridem, 80 mg/mL, solution for injection / infusion
Gentamicin
Please read carefully this leaflet 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 further questions, please ask your doctor, pharmacist, or nurse.
• If you experience any side effects, including any not listed in this leaflet, please tell your doctor, pharmacist, or nurse. See section 4.

Leaflet contents

1. What Gentamicin Noridem is and what it is used for
2. Important information before using Gentamicin Noridem
3. How Gentamicin Noridem is administered
4. Possible side effects
5. How to store Gentamicin Noridem
6. Contents of the pack and other information

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

Gentamicin Noridem contains the active substance gentamicin. It belongs to a group of antibiotics called aminoglycosides. This medicine is used to treat severe 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 infection of the inner lining of the heart (endocarditis);
• Intra-abdominal infections;
• Infections of the brain and spinal cord (bacterial meningitis);
• Bone and joint infections (osteomyelitis and bacterial arthritis);
• Treatment of patients with neutropenia and fever, when a bacterial infection is suspected;
• Systemic infection caused by Listeria monocytogenes in the blood;
• Severe infections in newborns;
• Bloodstream infections (bacteraemia) associated with any of the above-mentioned infections, or suspected to be associated with any of them.

Note:
Combination therapy is primarily 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 situations: life-threatening infections caused by unknown microorganisms, mixed infections involving anaerobic and/or aerobic bacteria, bacterial endocarditis, generalized Pseudomonas infections, and immunocompromised patients with absence of certain types of white blood cells (neutropenia).

2. Important information before using Gentamicin Noridem

When not to use Gentamicin Noridem

• if the patient is allergic to gentamicin or any of the other ingredients of this medicine (listed in section 6).
• subcutaneously (under the skin), because this medicine is not effective when administered by this route, and necrosis (tissue death) may occur at the injection site.

Warnings and precautions
Before receiving Gentamicin Noridem, discuss with your doctor, pharmacist or nurse:

• if the patient or family history (particularly maternal) includes a disease associated with mitochondrial mutation (a genetic disorder) or hearing loss caused by antibiotics; it is recommended to inform your doctor or pharmacist before taking an aminoglycoside. Certain mitochondrial mutations may increase the risk of hearing loss after administration of this medicine. Your doctor may recommend genetic testing before administering Gentamicin Noridem.
• if the patient has impaired kidney function;
• if the patient has impaired liver function;
• if the patient has diabetes;
• if the patient has deafness or hearing or balance disorders, history of ear infections, or if the patient has previously been treated with medicines affecting hearing;
• if the patient has severe diarrhoea.

In such cases, the patient will receive gentamicin only if the doctor considers treatment with this medicine absolutely necessary for treating the disease. The doctor will exercise special caution to carefully adjust the dose of gentamicin.
The doctor will be particularly cautious if the patient has neuromuscular disorders such as Parkinson's disease or myasthenia, or if the patient receives muscle relaxants during surgery, because gentamicin may have a blocking effect on nerve and muscle function.

Children and adolescents
According to available data, kidney and hearing organ toxicity occurs rarely in newborns and children.

Monitoring during treatment
To reduce the risk of kidney and inner ear nerve damage, the doctor will strictly follow the recommendations below:

• Monitoring of hearing, balance, and kidney function before, during, and after treatment.
• Selection of a dose adjusted to the patient's kidney function.
• Monitoring of gentamicin blood levels during treatment, if necessary for the individual patient.
• Avoidance of concomitant administration of other substances with gentamycin that may lead to damage of the inner ear nerves or kidneys. If this cannot be avoided, close monitoring of kidney function is required.
• If the patient develops severe diarrhoea, inform the doctor immediately.
• The patient must ensure adequate hydration and urine production.

Gentamicin Noridem and other medicines
Tell your doctor or pharmacist about all medicines the patient is currently taking or has recently taken, as well as any medicines the patient plans to take.
Medicines that may damage kidneys and hearing
Inform the doctor if the patient is receiving or is to receive treatment with medicines that may potentially damage the kidneys or hearing, as the risk of adverse effects is increased. These medicines include:

• amphotericin B (used to treat fungal infections);
• polymyxin B (antibiotic);
• cyclosporine (used in organ transplantation or severe skin disorders);
• cisplatin and other platinum-containing compounds (used in cancer treatment);
• other aminoglycoside antibiotics such as tobramycin, streptomycin;
• diuretics (water pills) in tablet or injectable form, such as furosemide;
• tacrolimus (used after organ transplantation);
• cephalothin (a cephalosporin antibiotic);
• methoxyflurane (anaesthetic gas);
• indomethacin (a non-steroidal anti-inflammatory drug used to treat pain and inflammation);
• anticoagulants (used to thin the blood), such as warfarin and phenindione;
• bisphosphonates (used to treat osteoporosis);
• iodine-containing contrast agents (used to improve radiological imaging), antiviral drugs (such as cyclivir drugs, 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 effects may be enhanced by gentamicin
Also inform the doctor if the patient is taking any of the following medicines, as their effects may be enhanced when used together with gentamicin:

• botulinum toxin (used to reduce activity of overactive muscles);
• curare-type drugs (muscle relaxants).

Pregnancy, breastfeeding and fertility

If the patient is pregnant or breastfeeding, suspects she may be pregnant, or is planning to have a child, she should consult her doctor or pharmacist before using this medicine.

Pregnancy
Gentamicin may be used during pregnancy only in life-threatening indications and when safer treatment options are not available, due to potential risk to the unborn child. This medicine is not recommended for use during pregnancy unless the doctor considers it appropriate for the patient.

Breastfeeding
Breastfeeding must not be performed during treatment with gentamicin. Small amounts of gentamicin pass into human milk, and low concentrations have been detected in the serum of breastfed infants. The doctor will decide whether to discontinue breastfeeding or to discontinue or withhold gentamicin administration.
Diarrhoea and oral thrush (fungal infection) may occur in breastfed infants during maternal treatment with this medicine.

Fertility
Men are advised not to father children while receiving treatment with this medicine and to use an effective method of contraception during treatment and for 3 months after its completion. Before starting treatment, discuss with the doctor about sperm preservation.

Gentamicin Noridem contains sodium and sodium metabisulfite
This medicine contains less than 1 mmol (23 mg) of sodium per vial, meaning the medicine is considered "sodium-free".
This medicine contains sodium metabisulfite, which may rarely cause severe hypersensitivity reactions and bronchospasm.

3. How is Gentamicin Noridem administered?

The medicine Gentamicin Noridem is always administered to the patient by a doctor or nurse.
The doctor will decide the appropriate dose for the patient based on the patient's body weight.
The correct dose also depends on the type of infection and any other medical conditions the patient may have.
The doctor or nurse will take blood samples to monitor whether the dose of the medicine is suitable for the patient.
Gentamicin levels in the patient's blood will be measured regularly to ensure that appropriate blood concentrations of the medicine are achieved.
Gentamicin treatment may cause hearing damage as well as kidney function impairment. The doctor will decide, depending on the patient's condition, how long the patient should receive gentamicin. In some cases, the doctor may perform blood tests to check the patient's kidney function before and during gentamicin treatment. Occasionally, the patient may also be asked to undergo a hearing test to check whether the medicine is affecting hearing.

Dosage

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

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

Use in patients with impaired kidney function
If the patient has impaired kidney function, the recommended daily dose should be reduced and adjusted according to kidney function.

Method of administration
This medicine is administered by intramuscular injection (into the muscle) or by intravenous injection (into the vein) after dilution.

Duration of treatment
The duration of treatment is determined by the doctor.
For common bacterial infections, the duration of treatment depends on the progression of the disease. Usually, a treatment period of 7 to 14 days is sufficient.
The duration of treatment should not exceed 10 to 14 days.
Avoid starting a course of Gentamicin Noridem immediately after a previous course of aminoglycosides. A waiting period of 7 to 14 days should be observed before starting gentamicin treatment.

If the patient feels that the effect of Gentamicin Noridem is too strong or too weak, they should speak with their doctor or nurse.

Overdose of Gentamicin Noridem
It is unlikely that a doctor or nurse would administer too high a dose of the medicine. The doctor and nurse will monitor the course of the disease and verify the medicine to be administered. In case of any doubts regarding the administered dose, always consult the doctor or nurse.

Missed dose of Gentamicin Noridem
The doctor or nurse follows instructions on when to administer the medicine to the patient. It is unlikely that the patient would miss a dose if the medicine has been prescribed. If the patient believes a dose has been missed, they should inform the doctor or nurse.

Interrupting treatment with Gentamicin Noridem
It is important that the treatment course prescribed by the doctor is completed. The patient may start to feel better, but it is essential to continue treatment until the doctor decides otherwise. Interrupting treatment may lead to worsening of the infection.

If there are any further questions regarding the use of this medicine, consult the doctor, pharmacist, or nurse.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone will experience them.
You must immediately inform the doctor if the patient notices any symptoms of an allergic reaction,
including anaphylactic shock (a life-threatening allergic reaction), such as:

• itching or skin rash;
• swelling of the face, lips, or throat;
• breathing difficulties or wheezing.

Other possible adverse reactions:
Common: may occur in up to 1 in 10 people

• kidney function disorders.

Uncommon: may occur in up to 1 in 100 people

• blood clotting disorders;
• mild to moderate skin redness without nodules or blisters.

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

• low levels of potassium, calcium, and magnesium in the blood;
• increased aldosterone levels in the blood;
• loss of appetite;
• weight loss;
• peripheral nerve damage;
• loss of sensation;
• nausea or vomiting;
• increased liver enzyme activity and blood urea (all reversible);
• increased salivation;
• inflammation of the mucous membrane lining the mouth;
• skin redness;
• muscle pain;
• elevated body temperature;
• increased serum bilirubin concentration.

Very rare: may occur in fewer than 1 in 10,000 people

• blood disorders affecting certain blood components, usually detectable in blood tests;
• decreased phosphate levels in the blood;
• confusion, hallucinations, depression;
• various brain disorders;
• seizures;
• neuromuscular blockade;
• central or peripheral vertigo, balance disorders, headache;
• visual disturbances;
• hearing loss;
• middle ear disorders, tinnitus;
• low blood pressure;
• high blood pressure;
• erythema multiforme;
• alopecia (hair loss);
• muscle atrophy (reduced muscle mass);
• acute kidney failure, increased phosphate excretion in urine and amino acids (known as Fanconi syndrome, associated with high doses administered over a long period);
• pain at the injection site.

Frequency not known: frequency cannot be estimated from available data

• infection with microorganisms resistant to gentamicin;
• irreversible hearing loss, deafness;
• symptoms of bruising, skin discoloration, small red spots; these may be symptoms of purpura;
• allergic reactions (including severe allergic reactions such as anaphylaxis), which may include:
• itchy, lumpy rash or hives
• swelling of hands, feet, ankles, face, lips, or throat, which may cause difficulty in swallowing or breathing
• fainting, dizziness, feeling faint (low blood pressure)
• diarrhea with or without blood and (or) stomach cramps;
• severe skin and mucous membrane allergic reactions with blister formation and skin redness (erythema multiforme), which in very severe cases may affect internal organs and be life-threatening (Stevens-Johnson syndrome, toxic epidermal necrolysis)

Reporting of adverse reactions
If any adverse reactions occur, including any not listed in this leaflet, inform your doctor, pharmacist, or nurse. Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products, Al. Jerozolimskie 181C, 02-222 Warsaw, Tel.: +48 22 49 21 301, Fax: +48 22 49 21 309, Website: https://smz.ezdrowie.gov.pl
Adverse reactions can also be reported to the responsible entity.
Reporting adverse reactions helps to gather more information on the safety of the medicine.

5. How to store Gentamicin 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 ampoules after: EXP. The expiry date refers to the last day of the stated month.
There are no special storage instructions for this medicine. Do not store in a refrigerator or
freeze.
The doctor or nurse will ensure appropriate storage of the medicine.
Gentamicin Noridem should be used immediately after opening the ampoule.
Gentamicin Noridem maintains chemical and physical stability for 24 hours at 25°C after dilution
in 0.9% (9 mg/mL) sodium chloride injection solution or 5% (50 mg/mL) glucose injection solution.
From a microbiological point of view, the medicine should be used immediately. If not used immediately,
the responsibility for storage conditions and duration prior to use lies with the user and typically
should not exceed 24 hours at 2–8°C, unless dilution was 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 inspected visually before use. Only clear solutions, practically free from
particulate matter, should be used.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose
of medicines no longer required. Such measures will help protect the environment.

6. Contents of the pack and other information

What Gentamicin Noridem contains

• The active substance is gentamicin.

Gentamicin Noridem 20 mg/mL: Each mL of solution contains 20 mg of gentamicin (as gentamicin sulfate).
Each 2 mL ampoule contains 40 mg of gentamicin.
Gentamicin Noridem 40 mg/mL: Each mL of solution contains 40 mg of gentamicin (as gentamicin sulfate).
Each 2 mL ampoule contains 80 mg of gentamicin.
Gentamicin Noridem 80 mg/mL: Each mL of solution contains 80 mg of gentamicin (as gentamicin sulfate).
Each 2 mL ampoule contains 160 mg of gentamicin.

• Other ingredients: disodium edetate, sodium metabisulphite (E 223), sodium hydroxide 1 N (for pH adjustment), sulfuric acid 0.5 M (for pH adjustment), water for injections.

What Gentamicin Noridem looks like and contents of the pack
Gentamicin Noridem solution for injection / for infusion is a clear, colourless solution for injection / for infusion.
Each glass ampoule contains 2 mL of solution. Packs containing 5, 10 or 20 ampoules are available.
Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder: Noridem Enterprises Ltd, Makariou & Evagorou 1, Mitsi Building 3, Office 115,
1065 Nicosia, Cyprus. Tel.: +302108161802
Manufacturer: DEMO S.A., PHARMACEUTICAL INDUSTRY, 21st km National Road Athens-Lamia, 14568
Krioneri, Attiki, Greece.

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

Information intended exclusively for healthcare professionals

For full information, see the Summary of Product Characteristics.

Dosage

The dose depends on the severity of the clinical condition, setting (hospital or outpatient), renal function, and type of infection. Several gentamicin pharmaceutical forms are available, some of which are more suitable for high-dose intravenous administration. The dose is calculated based on 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 divided into two doses.

In certain cases involving specific pathogens or infection sites, administration more than twice daily may be considered, in accordance with national and local guidelines.

Once-daily dosing is not recommended in endocarditis, depending on the causative pathogen. National and local guidelines for gentamicin therapy and serum concentration monitoring in patients with endocarditis should be followed.

The dose should be calculated based on ideal body weight.

Dosing recommendations

Dosing (adults and adolescents)

Recommended dose: 3–6 mg gentamicin/kg/day

Subsequent doses should be adjusted according to serum concentrations (see "Monitoring recommendations"), using local guidelines and nomograms.

Dosing in patients with impaired renal function

Gentamicin is primarily eliminated via glomerular filtration. Therefore, dosage must be appropriately adjusted in patients with impaired renal function.

Dose adjustment in patients with renal impairment should also be guided by therapeutic drug monitoring. In patients receiving once-daily dosing regimens, the dosing interval is generally prolonged. The initial dosing interval should be at least 24 hours and extended according to the degree of renal impairment and serum gentamicin concentration monitoring results.

Limited data are available for patients with severe renal impairment (creatinine clearance <30 mL/min) receiving once-daily dosing.

Dose calculation nomograms or dosing interval adjustments based on patient age, body weight, renal function, and plasma gentamicin concentrations are available. Local guidelines should be followed if available. In the absence of nomograms or local guidelines, the following principles may be applied:

There are two methods for dose adjustment:

A. Prolonging the dosing interval while maintaining the same dose (subsequent doses identical to the initial dose).

B. Reducing the dose while maintaining the same dosing interval (subsequent doses smaller than the initial dose).

For patients on once-daily dosing, prolongation of the dosing interval is preferred.

For patients receiving multiple daily doses, dose reduction is preferred.

The table below provides guidance for dose reduction while maintaining the same dosing interval (8-hour interval between doses):

| Serum creatinine | Creatinine clearance | Subsequent doses | |----------------------|--------------------------|-----------------------| | (mg/100 mL) | (mL/min/1.73 m²) | (% 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 be noted that renal function may change during treatment.

Creatinine clearance is the preferred parameter, especially in patients with variable serum creatinine concentrations, such as those observed in severe infections (e.g., sepsis).

If only serum creatinine concentration is known, creatinine clearance can be estimated using the following formulas:

Men:

Body weight (kg) × (140 – age)
Clcr = _________________________________________
72 × serum creatinine (mg/100 mL)

or

Body weight (kg) × (140 – age)
Clcr = _________________________________________
0.814 × serum creatinine (µmol/L)

Women: 0.85 × value calculated for men

When serum creatinine levels are used to assess renal function, repeated measurements are necessary, as correlation with creatinine clearance values exists only when the degree of renal impairment remains stable.

Children and adolescents

The recommended daily dose in children aged 1 year and older with normal renal function is 3–6 mg/kg body weight/day, preferably as a single dose 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, preferably as a single dose or divided into two doses. The recommended daily dose in neonates is 4–7 mg/kg body weight/day. Due to a longer half-life, neonates should receive the recommended dose as a single dose.

Special attention must be paid to preparation (dilution) and administered volume. Any error, even minor, may significantly affect serum concentrations achieved.

Elderly patients

Evidence suggests that elderly patients may be more susceptible to the toxic effects of aminoglycosides, secondary to pre-existing hearing and/or vestibular organ impairment or borderline renal function. Therefore, treatment should be carefully monitored through frequent serum gentamicin concentration measurements, assessment of renal function, and evaluation of ototoxicity symptoms.

In cases of renal impairment, the recommended daily dose should be reduced and adjusted according to renal function.

Hepatic impairment

Gentamicin may be prescribed in hepatic impairment, and dose adjustment is not required.

Dosing in hemodialysis patients

Gentamicin is dialyzable. During hemodialysis lasting 4–5 hours or 8–12 hours, a reduction in concentration of 50–60% and 70–80%, respectively, can be expected. After each dialysis session, supplemental single doses should be administered, depending on the current serum gentamicin concentration. The usual post-dialysis dose is 1–1.7 mg/kg body weight.

Since hemodialysis patients are usually on anticoagulant therapy, intramuscular injections should not be administered due to the risk of hematoma formation.

Obese patients

The dose should be calculated based on ideal body weight. In cases of marked obesity, serum gentamicin concentrations should be carefully monitored.

Monitoring recommendations

Serum gentamicin concentration monitoring is recommended in all patients, particularly in elderly patients, neonates, obese patients, patients with renal impairment, and patients with cystic fibrosis. Gentamicin should not be prescribed if serum concentration monitoring is not possible.

There are no universally accepted recommendations for gentamicin therapeutic monitoring. Local guidelines for monitoring and dose adjustment should be followed if available. The following approach is generally recommended:

Monitoring before drug administration ("trough concentration") is recommended to ensure appropriate dosing intervals. Trough concentration is measured at the end of the dosing interval and should not exceed 1 mg/L with once-daily dosing or 2 mg/L with multiple daily dosing. Elevated trough concentrations indicate the need to prolong the dosing interval rather than reduce the dose.

Monitoring after drug administration ("peak concentration") is recommended to verify appropriate dosing or ensure it is not excessive and potentially toxic. Peak concentration should be measured 1 hour after intravenous bolus injection or intramuscular bolus injection, or 30 minutes after completion of infusion. A plasma concentration <4 mg/L suggests the dose may be inadequate and dose increase should be considered; a plasma concentration >10 mg/L indicates an increased risk of toxicity, particularly ototoxicity, and dose reduction should be considered.

Any dose adjustment should be re-evaluated by measuring both pre-dose and post-dose concentrations to confirm the appropriateness of the new dose and dosing interval.

Method of administration

For single use only.

For intramuscular, intravenous bolus, or intravenous infusion after dilution. The same dosing regimen is recommended for both intramuscular and intravenous administration. Intramuscular administration should be considered if intravenous administration is not feasible or less suitable for the patient.

If clinically indicated, gentamicin may be administered directly into the vein in undiluted form, with the injection given slowly over 2–3 minutes. Rapid, direct intravenous administration may initially lead to potentially neurotoxic concentrations; therefore, the prescribed dose must be administered over the recommended time period. Alternatively, the prescribed dose may be diluted in up to 100 mL of 9 mg/mL (0.9%) sodium chloride injection solution or 50 mg/mL (5%) glucose injection solution and administered as an infusion lasting no longer than 20 minutes. The product is intended for use in a single patient and contains no antimicrobial preservatives. The injection/infusion must not be administered together with other medicinal substances.

Overdose

Gentamicin has a narrow therapeutic index. Accumulation (e.g., due to impaired renal function) may lead to nephrotoxicity and vestibulocochlear nerve damage. Nephrotoxicity is correlated with trough concentrations above 4 mg/L.

Management of overdose:

Discontinue the drug. There is no specific antidote. In cases of overdose or toxic reactions, serum gentamicin concentration can be reduced by peritoneal dialysis or hemodialysis.

In the event of neuromuscular blockade (usually due to interactions, see details), calcium chloride administration is indicated; artificial ventilation should be applied if necessary.

Pharmaceutical incompatibilities

Gentamicin preparations should generally not be mixed. Pharmaceutical incompatibilities in prepared solutions have been observed particularly with: penicillins, cephalosporins, erythromycin, heparins, sodium bicarbonate. *Dilution in the body will eliminate the risk of physical and chemical incompatibilities and allows simultaneous administration of gentamicin with the medicinal products listed above via bolus injection into an infusion line, with appropriate flushing, or at separate sites.

In the case of carbenicillin, administration must occur at a separate site.

*Combining these two solutions may lead to carbon dioxide release. It usually dissolves in the solution, but under certain conditions small bubbles may form.

This also applies to combinations of gentamicin with diazepam, furosemide, or flecainide acetate.