Consumer medicine information

DBL Amikacin Injection

Amikacin

BRAND INFORMATION

Brand name

DBL Amikacin Injection

Active ingredient

Amikacin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using DBL Amikacin Injection.

What is in this leaflet

This leaflet answers some common questions about DBL Amikacin Injection.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you being given Amikacin Injection against the benefits they expect it will have for you.

If you have any concerns about being given this medicine, ask your doctor or pharmacist.

Keep this leaflet in a safe place.

You may need to read it again.

What DBL Amikacin Injection is used for

Amikacin is an antibiotic that belongs to a group of medicines called aminoglycosides (pronounced a-my-noe-GLY-koe-sides). It is used to treat serious bacterial infections.

Amikacin works by killing bacteria or preventing their growth.

Your doctor may have prescribed amikacin for another reason.

Ask your doctor if you have any questions about why amikacin has been prescribed for you.

This medicine is available only with a doctor’s prescription.

Before you are given DBL Amikacin Injection

When you must not be given it

You must not be given DBL Amikacin Injection if you have an allergy to amikacin or any of the ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction may include:

  • shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

You must not be given DBL Amikacin Injection if you have experienced serious reactions (such as hearing loss or kidney problems) to amikacin, streptomycin, gentamicin, tobramycin, kanamycin, polymyxin B, colistin, cefaloradine, viomycin, or neomycin in the past.

You must not be given DBL Amikacin Injection if you have myasthenia gravis, a condition in which the muscles become weak and tire easily.

You must not be given amikacin if you are pregnant or planning to become pregnant. Amikacin may affect your developing baby if you are given it during pregnancy.

You must not be given amikacin if you are breast-feeding. Amikacin passes into breast milk.

If you are not sure whether you should be given amikacin, talk to your doctor or pharmacist.

Before you are given it

Tell your doctor or pharmacist if you have allergies to:

  • any other medicines, in particular any other antibiotics
  • sulfites / sulfates
  • any other substances, such as foods, preservatives or dyes.

Tell your doctor or pharmacist if you have or have had any medical conditions, especially the following:

  • kidney disease
  • hearing impairment, or if you or your family have a mitochondrial mutation disease (a genetic condition), or loss of hearing due to antibiotic medicines; certain mitochondrial mutations may increase your risk of hearing loss with this product. Your doctor may recommend genetic testing before you are given DBL Amikacin.
  • muscular disorders (e.g. myasthenia gravis, Parkinson’s disease).

If you have not told your doctor or pharmacist about any of the above, tell them before you are given amikacin.

Taking other medicines

Tell your doctor or pharmacist if you are taking/using any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and amikacin may interfere with each other. These include:

  • fluid tablets (e.g. furosemide (frusemide), etacrynic acid)
  • platinum compounds used to treat cancer, such as cisplatin
  • some other antibiotics (e.g. vancomycin, clindamycin, colistin, bacitracin, paromomycin, polymyxin B, cephalosporins, penicillins, viomycin)
  • amphotericin, a medicine used to treat some fungal infections
  • some medicines used to help prevent organ transplant rejection or to treat certain problems with the immune system, e.g. ciclosporin, tacrolimus
  • suxamethonium, a medicine used during surgery to relax muscles
  • some general anaesthetic agents
  • opioid analgesics (e.g. codeine, morphine, pethidine, fentanyl)
  • thiamine (vitamin B1)
  • bisphosphonates, medicines used to treat loss of bone mass
  • indometacin, an anti-inflammatory medicine.

These medicines may be affected by amikacin, or may affect how well it works. You may need different amounts of your medicine, or you may need to take/use different medicines. Your doctor or pharmacist will advise you.

Your doctor and pharmacist may have more information on medicines to be careful with or avoid while receiving amikacin.

How DBL Amikacin Injection is given

How much is given

Your doctor will decide what dose you will receive. This depends on your condition and other factors, such as your weight and kidney function.

How it is given

DBL Amikacin Injection is usually given as an injection into a muscle. DBL Amikacin Injection can also be given as a slow injection into a vein (intravenously).

DBL Amikacin Injection must only be given by a doctor or nurse.

How long it is given for

Your doctor will decide what dose and how long you will receive DBL Amikacin Injection. This depends on your infection and other factors, such as your weight. For most infections, DBL Amikacin Injection is usually given in divided doses throughout the day.

If you are given too much (overdose)

As DBL Amikacin Injection is most likely to be given to you in hospital under the supervision of your doctor, it is very unlikely that you will receive an overdose. However, if you experience severe side effects, tell your doctor immediately or go to Emergency at the nearest hospital.

In case of overdose, immediately contact the Poisons Information Centre for advice (telephone 13 11 26).

Symptoms of an amikacin overdose may include ringing in the ears, hearing difficulties, dizziness, fever, headache, pins and needles in the hands and feet, problems with passing urine, and paralysis.

While you are being given DBL Amikacin Injection

Things you must do

Tell any other doctors, dentists, and pharmacists who are treating you that you are being given DBL Amikacin Injection.

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are being given DBL Amikacin Injection.

If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are being given amikacin.

If you become pregnant while being treated with DBL Amikacin Injection, tell your doctor immediately.

Things to be careful of

Be careful driving or operating machinery until you know how DBL Amikacin Injection affects you.

As with other aminoglycoside medicines, amikacin may drowsiness, tiredness or dizziness in some people.

Make sure you know how you react to amikacin before you drive a car, operate machinery, or do anything else that could be dangerous if you are drowsy, tired or dizzy. If this occurs do not drive.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are being given DBL Amikacin Injection. Amikacin helps most people with infections, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects. If you are over 65 years of age you may have an increased chance of getting side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or nurse if you notice any of the following and they worry you:

  • pain at the injection site
  • feeling sick
  • decreased appetite
  • headache
  • nausea and vomiting
  • fever.

These side effects are usually mild.

Tell your doctor or nurse immediately if you notice any of the following:

  • dizziness, spinning sensation (vertigo)
  • hearing problems, ringing or unusual sounds in the ears (tinnitus)
  • loss of vision
  • passing less urine than is normal, blood in the urine
  • numbness, skin tingling, muscle twitching and convulsions, paralysis
  • signs of an allergic reaction, such as rash, itching or hives on the skin; swelling of the face, lips, tongue or other parts of the body; shortness of breath, wheezing or difficulty breathing.

Other side effects not listed above may occur in some patients.

Your doctor may request blood or urine test to monitor your progress and determine possible side effects.

Tell your doctor, nurse or pharmacist if you notice anything that is making you feel unwell.

Do not be alarmed by this list of possible side effects.

You may not experience any of them.

After being given DBL Amikacin Injection

Storage

DBL Amikacin Injection will usually be stored in the pharmacy or on the ward. The injection is kept in a cool dry place, protected from light, where the temperature stays below 25°C.

Product description

What it looks like

DBL Amikacin Injection comes in a glass vial containing a clear, colourless to pale yellow solution free from visible particulate matter.

Ingredients

Active ingredients:

  • Each 2 mL of DBL Amikacin Injection contains amikacin sulfate equivalent to 500 mg (500,000 international units) of amikacin activity.

Other ingredients

  • sodium citrate dihydrate
  • sodium metabisulfite
  • water for injection.

DBL Amikacin Injection does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Sponsor

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free Number: 1800 675 229
www.pfizermedicalinformation.com.au

DBL Amikacin Injection is available in the following strengths and pack size:

  • 500 mg/2 mL x 5 vials

AUST R 49945

Date of leaflet preparation: December 2023

™ = Trademark

Published by MIMS February 2024

BRAND INFORMATION

Brand name

DBL Amikacin Injection

Active ingredient

Amikacin

Schedule

S4

 

1 Name of Medicine

Amikacin.

2 Qualitative and Quantitative Composition

DBL Amikacin Injection is available in 500 mg/2 mL strength. Each 2 mL contains amikacin sulfate equivalent to amikacin activity 500 mg (500,000 IU).

Excipient with known effect.

Sulfites.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection.
DBL Amikacin Injection is a sterile clear, colourless to pale yellow solution free from visible particulate matter.

4 Clinical Particulars

4.1 Therapeutic Indications

DBL Amikacin Injection is indicated in the short-term treatment of serious infections caused by susceptible strains of Gram negative bacteria (see Section 5.1 Pharmacodynamic Properties).
Staphylococcus aureus, including methicillin resistant strains, is the principal Gram-positive organism sensitive to amikacin.
The use of amikacin in the treatment of staphylococcal infections should be restricted to second line therapy, and should be confined to patients suffering from severe infections caused by susceptible strains of Staphylococcus who have failed to respond or are allergic to other available antibiotics.
DBL Amikacin Injection is indicated in the treatment of neonatal sepsis when sensitivity testing indicates that other aminoglycosides cannot be used.
In certain severe infections such as neonatal sepsis, concomitant therapy with a penicillin type drug may be indicated because of the possibility of infections due to Gram-positive organisms such as Streptococci or Pneumococci. If concomitant treatment with a penicillin type drug is indicated, then the drugs should be administered separately because in vitro mixing of the two drugs causes inactivation of amikacin.
Clinical studies have shown amikacin to be effective in treating bacteraemia, septicaemia including neonatal sepsis and serious infections of the respiratory tract, bones and joints, central nervous system, skin and skin structures (including those resulting from burns), intra-abdominal organs, post-operative infections and complicated and recurrent urinary tract infections, when caused by susceptible organisms.

4.2 Dose and Method of Administration

Dosage.

Dosage of amikacin sulfate is expressed in terms of amikacin and calculated on a body weight basis. Dosage is identical for both routes of administration.

Adults and children.

The usual recommended dose of amikacin is 15 mg/kg daily given in two or three equally divided doses.

Neonates and premature infants.

Dosage given for patients with normal renal function. Initiate treatment with a loading dose of 10 mg/kg followed by 7.5 mg/kg every 12 hours. The maximum total daily dose should not exceed 15 mg/kg. Solution infusions via the IV route should be given over a 1 to 2 hour period.
Insufficient clinical use has not enabled firm dosage guidelines to be established for the use of amikacin in premature infants.

Elderly.

Amikacin is excreted by the renal route. Since renal function could be failing in the elderly, it should be assessed whenever possible and the dosage adjusted accordingly, if necessary. See Dosage adjustment, Renal impairment.

Urinary tract infections (other than pseudomonal infections).

500 mg/day in two equally divided doses is recommended.

Method of administration.

DBL Amikacin Injection is for use in one patient on one occasion only. Discard any residue.
Uncomplicated infections due to sensitive organisms should respond to treatment within 24 to 48 hours at the recommended dosage. If no improvement occurs within three to five days, the use of amikacin sulfate should be re-evaluated and consideration be given to alternative therapy. Failure of the infection to respond may be due to resistance of the organism or to the presence of septic foci requiring surgical drainage.
Whenever possible, and especially in patients with impaired renal function, peak and trough amikacin serum concentrations should be determined and dosage adjusted where necessary to maintain desired serum concentrations. In general, desired peak concentrations are between 15 to 30 microgram/mL, and trough concentrations should not exceed 5 to 10 microgram/mL. An increased risk of toxicity may be associated with prolonged peak amikacin serum concentrations greater than 30 to 35 microgram/mL.

Intramuscular or intravenous administration.

The intramuscular route is preferred for most infections, but in life-threatening infections or when an intramuscular injection is not feasible, an intravenous infusion (0.25% over 30 to 60 minutes) may be used.
The compatible diluents for intravenous use if required are as follows: 5% Glucose Intravenous Infusion BP in Water for Injections BP and Sodium Chloride Intravenous Infusion BP (0.9%). To reduce microbiological hazard, use as soon as practicable after dilution. If storage is necessary, hold at 2 to 8°C for not more than 12 hours.
No antimicrobial preservative is added to the formulation. This product is for single use in one patient only. Discard any residue.

Dosage adjustment.

Renal impairment.

In patients with impaired renal function, either the dose or the dosage interval needs to be adjusted to avoid accumulation. The dosage interval may be calculated using the following formula (see Equation 1):
This formula should not be used to calculate the dosage interval for elderly patients. Instead, it is advisable to base dosage on creatinine clearance. (See Table 1.)
As renal function may alter appreciably during therapy, the serum creatinine should be checked frequently and the dosage regimen modified accordingly.
If it is desired to administer amikacin at a fixed time interval, the dosage must be reduced. It is recommended that the drug be given every 12 hours. Serum concentrations of the drug should be measured in these patients to ensure accurate administration and to avoid toxic serum levels.
If serum assay determinations are not available and the patient's condition is stable, serum creatinine and creatinine clearance values are the most readily available indicators of the degree of renal impairment to use in determining the dosage.
First, begin therapy by administering 7.5 mg/kg, which is half the normal daily dose.
To determine the size of maintenance doses administered every 12 hours, the initial dose should be reduced in proportion to the reduction in the patient's creatinine clearance rate (cc) (see Equation 2):
An alternate rough guide for determining 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 dosage schedules are provided as guides to dosage when the measurement of amikacin serum levels is not feasible and are not intended to be rigid recommendations.

4.3 Contraindications

Aminoglycosides may impair neuromuscular transmission, and should not be given to patients with myasthenia gravis.
DBL Amikacin Injection is contraindicated in patients with a known history of hypersensitivity to amikacin, any constituents of the injection (see Section 6.1 List of Excipients) or in patients who may have subclinical renal or eighth nerve damage induced by prior administration of nephrotoxic and/or ototoxic agents, as the toxicity may possibly be additive. A history of hypersensitivity or serious toxic reactions to aminoglycosides may contraindicate the use of any aminoglycoside because of the known cross-sensitivities of patients to drugs in this class.
Pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).
Lactation (see Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation).

4.4 Special Warnings and Precautions for Use

Patients should be well hydrated during amikacin therapy.
Caution should be applied to patients with pre-existing renal insufficiency, pre-existing hearing or vestibular damage and diminished glomerular filtration. Treatment with amikacin for more than 14 days has not been established as being safe. Patients undergoing treatment with parenteral aminoglycosides should be under close clinical observation and evaluation because of the potential ototoxicity and nephrotoxicity associated with their use.

Allergic reactions.

Cross allergenicity among aminoglycosides has been demonstrated. Therefore, caution should be exercised in patients who have shown hypersensitivity to this class of drugs.
The use of amikacin in patients with a history of allergy to aminoglycosides or in patients who may have subclinical renal or eighth nerve damage induced by prior administration of nephrotoxic and/or ototoxic agents such as streptomycin, dihydrostreptomycin, gentamicin, tobramycin, kanamycin, neomycin, polymyxin B, colistin, cefaloridine or viomycin should be considered with caution, as toxicity may be additive. In these patients amikacin should be used only if, in the opinion of the physician, therapeutic advantages outweigh the potential risks.
Large doses of amikacin administered during surgery have been responsible for a transient myasthenic syndrome.

Sulfite-sensitivity.

DBL Amikacin Injection contains sodium metabisulfite, which may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in susceptible people. The overall prevalence of sulfite sensitivity in the general population is uncommon and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic subjects.

Neurotoxicity.

Neurotoxicity, manifested as vestibular and/or bilateral ototoxicity, can occur in patients treated with aminoglycosides. Other manifestations of neurotoxicity may include numbness, skin tingling, muscle twitching and convulsions.

Ototoxicity.

In patients treated at higher doses or those whose therapy is prolonged over 5-7 days of treatment, even in healthy patients, ototoxicity, both auditory and vestibular can occur. Patients with impaired renal function have the highest risk of developing amikacin induced ototoxicity. The risk of ototoxicity due to aminoglycosides increases with the degree of exposure to either persistently high peak or high trough serum concentrations. As with other aminoglycosides, on rare occasions changes in renal and eighth cranial nerve function may not become manifest until soon after completion of therapy. Aminoglycoside induced ototoxicity is usually irreversible.
A pre-treatment audiogram should be obtained and repeated during therapy in patients with renal impairment undergoing treatment for 7 days or more as well as in other patients being treated for 10 days. High frequency deafness usually occurs first and can be detected only by audiometric testing. If tinnitus, dizziness, vertigo, roaring in the ears or subjective hearing loss develops; or if follow-up audiograms show significant loss of high frequency response, the use of amikacin sulfate therapy should be discontinued immediately. Lost function may not be fully restored.
There is an increased risk of ototoxicity in patients with mitochondrial DNA mutations (particularly the nucleotide 1555 A to G substitution in the 12S rRNA gene), even if aminoglycoside serum levels are within the recommended range during treatment. Alternative treatment options should be considered in such patients.
In patients with a family history of relevant mutations or aminoglycoside induced deafness, alternative treatments should be considered.

Neuromuscular toxicity.

Neuromuscular blockade and respiratory paralysis have been reported following parenteral injection, topical instillation (as in orthopaedic and abdominal irrigation or in local treatment of empyema), and following oral use of aminoglycosides. The possibility of respiratory paralysis and neuromuscular blockade should be considered if aminoglycosides are administered by any route, especially in patients receiving anaesthetics, neuromuscular blocking agents such as tubocurarine, succinylcholine, decamethonium, atracurium, rocuronium, vecuronium or in patients receiving massive transfusions of citrate-anticoagulated blood. If neuromuscular blockade occurs, calcium salts may reverse respiratory paralysis, but mechanical respiratory assistance may be necessary. Neuromuscular blockade and muscular paralysis have been demonstrated in laboratory animals given high doses of amikacin (e.g. in cats with high doses of amikacin [188 mg/kg]).

Patients with muscular disorders.

Amikacin must not be used in patients with myasthenia gravis. Aminoglycosides, including amikacin, should be used with caution in patients with muscular disorders such as Parkinsonism, since these drugs may aggravate muscle weakness because of their potential curare-like effect on neuromuscular junction.

Vision.

Macular infarction sometimes leading to permanent loss of vision has been reported following intravitreous administration (injection into the eye) of amikacin.

Monitoring of serum levels.

Whenever possible, and especially in patients with renal impairment, peak and trough serum concentrations of amikacin should be determined periodically, and dosage should be adjusted, to maintain desired serum concentrations. In general, desirable peak concentrations of amikacin are 15-30 microgram/mL, and trough concentrations of the drug should not exceed 5-10 microgram/mL. An increased risk of toxicity may be associated with prolonged peak amikacin serum concentrations greater than 30-35 microgram/mL.

Concurrent use with other antibiotics or potent diuretics.

Since the risk of ototoxicity, irreversible deafness and nephrotoxicity is increased when amikacin is used in conjunction with the systemic or topical use of other potentially neurotoxic and/or nephrotoxic drugs (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions), such therapy should be avoided. This includes concurrent use with potent diuretics and other aminoglycosides. Other factors which may increase the risk of toxicity are dehydration and advancing age.

Superinfection.

If overgrowth of nonsusceptible organisms occurs, appropriate therapy should be initiated.

Topical use.

Aminoglycosides are quickly and almost totally absorbed when they are applied topically, except to the urinary bladder, in association with surgical procedures. Irreversible deafness, renal failure and death due to neuromuscular blockade have been reported following irrigation of both small and large surgical fields with an aminoglycoside preparation.

Use in renal impairment.

As with other aminoglycosides, amikacin sulfate is potentially nephrotoxic and neurotoxic; therefore, precautions on dosage and adequate hydration should be observed. The risk of nephrotoxicity is greater in patients with impaired renal function, and in those who receive higher doses, or in those whose therapy is prolonged.
Amikacin is present in high concentrations in the renal excretory system; therefore, patients should be well hydrated to minimize chemical irritation/damage of the renal tubules. Prior to initiating therapy, kidney function should be assessed by the usual methods and monitored periodically during the course of treatment.
A reduction in dosage is required (see Section 4.2 Dose and Method of Administration, Renal impairment) if evidence of renal dysfunction occurs such as presence of urinary casts, white or red cells, albuminuria, decreased creatinine clearance, decreased urine specific gravity, increased BUN, increased serum creatinine or oliguria. If azotaemia increases or a progressive decrease in urinary output occurs, treatment should be stopped.
Renal and eighth-cranial nerve function should be closely monitored especially in patients with known or suspected renal impairment (e.g. diminished glomerular filtration) at the onset of therapy, and also in those whose renal function is initially normal but who develop signs of renal dysfunction during therapy. Serum concentrations of amikacin should be monitored when feasible to assure adequate levels and to avoid potentially toxic levels. Urine should be examined for decreased specific gravity, increased excretion of proteins, and the presence of cells or casts. Blood urea nitrogen, serum creatinine, or creatinine clearance should be measured periodically. Serial audiograms should be obtained where feasible in patients old enough to be tested, particularly high risk patients. Evidence of ototoxicity (dizziness, vertigo, tinnitus, roaring in the ears, and hearing loss) or nephrotoxicity requires discontinuation of the drug or dosage adjustment.
Concurrent and/or sequential, oral, or topical use of other neurotoxic or nephrotoxic products, particularly bacitracin, cisplatin, amphotericin B, cefaloridine, paromomycin, viomycin, polymyxin B, colistin, vancomycin, or other aminoglycosides, should be avoided. Other factors that may increase risk of toxicity are advanced age and dehydration.
Patients suffering from pre-existing renal insufficiency should be assessed by the usual methods prior to therapy and periodically during therapy. Daily doses should be reduced and/or the interval between doses lengthened in accordance with serum creatinine concentrations to avoid accumulation of abnormally high blood levels and to minimise the risk of ototoxicity. Regular monitoring of serum drug concentration and of renal function is particularly important in elderly patients, who may have reduced renal function that may not be evident in the results of routine screening tests i.e. blood urea and serum creatinine.

Use in the elderly.

Because of its toxicity, amikacin should be used with caution in elderly patients only after less toxic alternatives have been considered and/or found ineffective. Elderly patients are more likely to have an age-related decrease in renal function. This may not be evident in the results of routine screening tests such as BUN or serum creatinine.
A creatinine clearance determination may be more useful. Recommended doses should not be exceeded, and monitoring of renal function in elderly patients during treatment with aminoglycosides is particularly important. Elderly patients may require smaller daily doses of amikacin in accordance with their increased age, decreased renal function, and possibly, decreased weight. In addition, loss of hearing may result even in patients with normal renal function.

Paediatric use.

Aminoglycosides should be used with caution in premature and neonatal infants because of the renal immaturity of these patients and the resulting prolongation of serum half-life of these drugs (see Section 4.6 Fertility, Pregnancy and Lactation).

Effects on laboratory tests.

Laboratory abnormalities possibly related to aminoglycosides include: increased levels of serum transaminase (ALT, AST) serum LDH and bilirubin; decreased serum calcium, magnesium, sodium and potassium; anaemia, leukopenia, granulocytopenia, transient agranulocytosis, eosinophilia, increased and decreased reticulocyte counts, and thrombocytopenia. While clinical laboratory test abnormalities may be isolated findings, they may also be associated with clinically related signs and symptoms. For example, tetany and muscle weakness may be associated with hypomagnesemia, hypocalcemia and hypokalemia.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Potent diuretics.

If possible, do not give amikacin in conjunction with etacrynic acid, furosemide or other potent diuretics which may themselves cause ototoxicity or enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue.

Other neurotoxic and/or nephrotoxic agents.

The concurrent or sequential use of other ototoxic, neurotoxic and/or nephrotoxic agents, particularly polymyxin B, colistin, cisplatin, vancomycin, amphotericin B, clindamycin, bacitracin, ciclosporin, tacrolimus, cefaloridine, paromomycin, viomycin and cephalosporins, or other aminoglycosides, should be avoided either systemically or topically because of the potential for additive effects. Where this is not possible, monitor carefully.
Increased nephrotoxicity has been reported following concomitant parenteral administration of aminoglycoside antibiotics and cephalosporins. Concomitant cephalosporin use may spuriously elevate creatinine serum level determinations.
There is an increased risk of nephrotoxicity and possibly of ototoxicity when aminoglycosides are administered with platinum compounds.

Anaesthetics/ neuromuscular blocking agents or medications with neuromuscular blocking activity.

Concurrent use of amikacin with agents with neuromuscular blocking activity, e.g. succinylcholine, tubocurarine, decamethonium, halogenated hydrocarbon inhalation anaesthetics (including halothane, ether), opioid analgesics and massive transfusions with citrated anticoagulated blood, should be carefully monitored; neuromuscular blockade may be enhanced, resulting in skeletal muscle weakness and respiratory depression or paralysis (apnoea); caution is recommended when these medications and amikacin are used concurrently during surgery or in the postoperative period, especially if there is a possibility of incomplete reversal of neuromuscular blockade postoperatively; treatment with anticholinesterase agents or calcium salts may help to reverse the blockade.

Beta-lactam antibiotics.

In vitro admixture of aminoglycosides with beta-lactam antibiotics (penicillins or cephalosporins) may result in significant mutual inactivation. A reduction in serum activity may also occur when an aminoglycoside or penicillin-type drug is administered in vivo by separate routes. Inactivation of the aminoglycoside is clinically significant only in patients with severely impaired renal function who maintain a higher level of the penicillin for a longer period of time compared to patients with normal renal function. Therefore, when amikacin and penicillins are used together in patients with renal failure, the time of administration of each drug should be staggered so that several hours separate each infusion. Inactivation may continue in specimens of body fluids collected for assay, resulting in inaccurate aminoglycoside readings. Such specimens should be properly handled (assayed promptly, frozen, or treated with beta-lactamase).

Other.

There is an increased risk of hypocalcaemia when aminoglycosides are administered with bisphosphonates.
Concomitantly administered thiamine (vitamin B1) may be destroyed by the reactive sodium bisulfite component of the amikacin sulfate formulation.
Indometacin may increase the plasma concentration of amikacin in neonates.

Compatibilities.

Amikacin sulfate is stable for 24 hours at room temperature in the presence of light at 5 mg/mL and 0.25 mg/mL in 0.9% Sodium Chloride Intravenous Infusion BP and 5% Glucose Intravenous Infusion BP solutions.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In reproduction toxicity studies in mice and rats, no effects on fertility or fetal toxicity were reported.
(Category D)
The safety of amikacin in pregnancy has not yet been established.
There are limited data on use of aminoglycosides in pregnancy. Aminoglycosides can cause fetal harm. Gentamicin and other aminoglycosides cross the placenta and there have been reports of total, irreversible, bilateral congenital deafness in children whose mothers received streptomycin during pregnancy. Adverse effects on the fetus or newborns have been reported in pregnant women treated with other aminoglycosides, therefore, the potential for harm exists. There is evidence of selective uptake of gentamicin by the fetal kidney resulting in damage (probably reversible) to immature nephrons. Eighth cranial nerve damage has also been reported following in utero exposure to some of the aminoglycosides. Because of the chemical similarity, all aminoglycosides must be considered potentially nephrotoxic and ototoxic to the fetus. It should also be noted that therapeutic blood levels in the mother do not equate with safety for the fetus. If amikacin is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Amikacin should be administered to pregnant women and neonatal infants only when clearly needed and under medical supervision (see Section 4.4 Special Warnings and Precautions for Use).
 Amikacin is excreted in breast milk. A decision should be made whether to discontinue breast-feeding or to discontinue therapy.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed. Due to the occurrence of some adverse reactions (see Section 4.8 Adverse Effects (Undesirable Effects)) the ability to drive and use machines may be impaired.

4.8 Adverse Effects (Undesirable Effects)

Amikacin induced hepatotoxicity is not a common side effect, however it may occur. Increased serum transaminases (ALT, AST), increased serum bilirubin, hepatomegaly, and hepatic necrosis have been reported.
The percentages below refer to incidence in clinical trials.

More common reactions.

Auditory and vestibular.

Hearing loss (4%) (permanent in some cases). Hearing loss is usually manifested initially by diminution of high-tone acuity.

Biochemical abnormalities.

Increased serum urea, decreased creatinine clearance, elevated serum creatininea, azotaemiaa.

Genitourinary.

Reduced renal function, oliguriaa.

Injection site reactions.

Pain at site of intramuscular injection (6%).

Less common reactions.

Auditory and vestibular.

Tinnitusa, vertigo, dizziness, nystagmus, changes in caloric testing or electronystagmograms.

Biochemical abnormalities.

Casts, cellsa or protein in the urine, eosinophilia, increase in AST.

Dermatological.

Pruritus, rash.

Gastrointestinal.

Nausea, vomiting.

General.

Drug fever.

Genitourinary.

Renal failure.

Haematological.

Anaemia.

Musculoskeletal.

Arthralgia.

Nervous system.

Paraesthesiaa, tremora.
a See Section 4.4 Special Warnings and Precautions for Use.
This following list is presented by system organ class, MedDRA preferred term, and frequency using the following frequency categories: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000) and not known (cannot be estimated from the available data).

Uncommon.

Infections and infestations.

Superinfections or colonisation with resistant bacteria or yeasta.

Gastrointestinal disorders.

Nausea, vomiting.

Skin and subcutaneous tissue disorders.

Rash.

Rare.

Metabolism and nutrition disorders.

Hypomagnesaemia.

Nervous system disorders.

Tremor, paraesthesiaa, headache, balance disordera.

Eye disorders.

Blindnessb, retinal infarctionb.

Ear and labyrinth disorders.

Tinnitusa, Hypoacusisa.

Vascular disorders.

Hypotension.

Skin and subcutaneous tissue disorders.

Pruritus, urticaria.

Musculoskeletal, connective tissue and bone disorder.

Arthralgia, muscle twitchinga.

Renal and urinary disorders.

Oliguriaa, blood creatinine increaseda, albuminuriaa, azotemiaa, red blood cells urinea, white blood cells urinea.

General disorders and administration site conditions.

Pyrexia.

Not known.

Immune system disorders.

Anaphylactic response (anaphylactic reaction, anaphylactic shock and anaphylactoid reaction), hypersensitivity.

Nervous system disorders.

Paralysisa.

Ear and labyrinth disorders.

Deafnessa, deafness neurosensorya.

Respiratory, thoracic and mediastinal disorders.

Apnoea, bronchospasm.

Renal and urinary disorders.

Renal failure acute, nephropathy toxic, cells in urine.
a See Section 4.4 Special Warnings and Precautions for Use.
b Amikacin is not formulated for intravitreal use. Blindness and retinal infarction have been reported following intravitreous administrations (injection into the eye) of amikacin.

Serious or life-threatening reactions.

All aminoglycosides have the potential to induce ototoxicity, renal toxicity, and neuromuscular blockade. Serious adverse effects on both vestibular and auditory branches of the eighth cranial nerve have been reported, primarily in patients with renal impairment (especially if dialysis is required), and in patients on high doses and/or prolonged therapy. Other factors which may increase the risk of toxicity include excessive dosage, dehydration and previous exposure to ototoxic or nephrotoxic drugs.
Toxic effects on the eighth cranial nerve can result in hearing loss, loss of balance, or both. Amikacin primarily affects auditory function. Cochlear damage includes high frequency deafness and usually occurs before clinical hearing loss can be detected by audiometric testing (see Section 4.4 Special Warnings and Precautions for Use).
Macular infarction sometimes leading to permanent loss of vision has been reported following intravitreous administration (injection into the eye) of amikacin.

Other reactions.

Other adverse effects reported with the use of aminoglycosides include: respiratory depression, lethargy, confusion, depression, visual disturbances, decreased appetite, weight loss, anorexia, hypertension, generalised burning, laryngeal edema, increased salivation, stomatitis, purpura, pseudotumor cerebri, acute organic brain syndrome, pulmonary fibrosis, alopecia, joint pain, transient hepatomegaly, splenomegaly, convulsions and a myasthenia gravis-like syndrome.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms and signs.

In case of overdosage there is a general risk for nephro-, oto- and neurotoxic (neuromuscular blockage) reactions.
Likely signs and symptoms include tinnitus, vertigo, reversible or irreversible deafness, skin rash, drug fever, headache, paraesthesia, reduced renal function or renal failure.

Recommended treatment.

Neuromuscular blockage with respiratory arrest needs appropriate treatment including application of ionic calcium (e.g. as gluconate or lactobionate in 10-20% solution) (see Section 4.4 Special Warnings and Precautions for Use).
In the event of overdosage or toxic reactions peritoneal dialysis or haemodialysis will aid in the removal of amikacin from the blood. Amikacin levels are also reduced during continuous arteriovenous hemofiltration. These procedures are of particular importance in patients with impaired renal function. In the newborn infant, exchange transfusion may also be considered.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Amikacin is a semisynthetic aminoglycoside antibiotic derived from kanamycin.

Microbiology.

Amikacin is active, in vitro, against the following organisms listed in Table 2:
Amikacin's structure has been altered to reduce the possible route of enzymatic deactivation, thus reducing bacterial resistance. Many strains of Gram-negative organisms resistant to gentamicin and tobramycin have shown to be sensitive to amikacin in vitro.

Susceptibility testing.

The Kirby-Bauer test can determine the sensitivity of an organism to amikacin. This test operates on the principle that antibiotics will diffuse from a paper disc into an agar medium containing test organisms. Inhibition is observed as a failure of the organism to grow in the region of the antibiotic.
When the Kirby-Bauer method of disc susceptibility is used, a 30 microgram amikacin disc should give a zone of 17 mm or greater when tested against an amikacin susceptible bacterial strain. Such a result indicates that the infecting organism is likely to respond to therapy. A zone size of 14 mm or less indicates resistance, or that the infecting organism is unlikely to respond to therapy. Zone sizes of 15 to 16 mm indicate intermediate susceptibility, in other words the organism will probably be susceptible if the infection is confined to tissues and fluids (e.g. urine) in which high antibiotic levels are obtained.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Following IM administration of a single dose of amikacin of 7.5 mg/kg in adults with normal renal function, peak plasma amikacin concentrations of 17 to 25 microgram/mL are attained within 45 minutes to 2 hours.
Following IV infusion of the same dose given over 1 hour, peak plasma concentrations of the drug average 38 microgram/mL immediately following the infusion, 5.5 microgram/mL at 4 hours, and 1.3 microgram/mL at 8 hours.

Distribution.

Following administration of usual dosages of amikacin, amikacin has been found in bone, heart, gallbladder and lung tissue. Amikacin is also distributed into bile, sputum, bronchial secretions, and interstitial, pleural, and synovial fluids.

Excretion.

The plasma elimination half-life of amikacin is usually 2 to 3 hours in adults with normal renal function and is reported to range from 30 to 86 hours in adults with severe renal impairment.
In adults with normal renal function, 94 to 98% of a single IM or IV dose of amikacin is excreted unchanged by glomerular filtration within 24 hours. The drug may be completely recovered within approximately 10 to 20 days in patients with normal renal function. Terminal elimination half-lives of greater than 100 hours have been reported in adults with normal renal function following repeated IM or IV administration of the drug.
In patients with impaired renal function, the clearance of amikacin is decreased; the more severe the impairment, the slower the clearance. Therefore, the interval between doses should be adjusted according to the degree of renal impairment. Endogenous creatinine clearance rate and serum creatinine which have high correlation with serum half-life of amikacin may be used as a guide for this purpose (see Section 4.2 Dose and Method of Administration, Renal impairment).

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

No data available.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium citrate dihydrate, sodium metabisulfite, water for injections.

6.2 Incompatibilities

DBL Amikacin Injection may be prescribed as concurrent therapy with other antibacterial agents in mixed or superinfections. In such situations, DBL Amikacin Injection should never be physically mixed with other antibacterial agents in infusion bags, syringes or any other container equipment. Each agent should be administered separately following the manufacturer's recommended route.
Amikacin is incompatible with some penicillins and cephalosporins, amphotericin chlorothiazide sodium, erythromycin gluceptate, heparin, nitrofurantoin sodium, phenytoin sodium, thiopentone sodium and warfarin sodium, and depending on the composition and strength of the vehicle, tetracyclines, vitamins of the B group with vitamin C, and potassium chloride.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Strength: 500 mg (500,000 IU)/2 mL.
Pack Size: 5 x 2 mL Type I clear glass vials with a bromobutyl closure and aluminum seal with plastic flip-off top.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.


Chemical name: as 6-O-(3-amino-3- deoxy-α-d-glucopyranosyl)- 4-O-(6-amino-6- deoxy-α-d-glucopyranosyl)-N1-[(2S)-4-amino-2- hydroxybutyryl]-2-deoxystreptamine sulfate.
Molecular formula: C22H43N5O13.2H2SO4.
Molecular weight: 781.8.
Amikacin sulfate is a white crystalline powder. It is freely soluble in water and practically insoluble in alcohol and acetone.

CAS number.

39831-55-5.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes