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AMIKIN injection 100 mg
AMIKIN injection 250 mg
AMIKIN injection 500 mg
AMIKIN injection 1g

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

AMIKIN injection 100 mg
AMIKIN injection 250 mg
AMIKIN injection 500 mg
AMIKIN injection 1g

COMPOSITION:
Vials containing amikacin sulphate equivalent to 100 mg, 250 mg and 500 mg amikacin base per 2 mL and 1g/4 mL sterile water respectively. Contains sodium bisulphite.

PHARMACOLOGICAL CLASSIFICATION:
A 20.1.1 - Broad spectrum antibiotics.

PHARMACOLOGICAL ACTION:
AMIKIN (amikacin sulphate) is a semi-synthetic aminoglycoside antibiotic which is active against a broad spectrum of Gram-negative organisms, including Pseudomonas and some Gram-positive organisms. Chemically, the medicine consists of 2 amino sugars glycosidically linked to deoxy-streptamine whose 1-amino group has been acylated by S-4-amino-2-hydroxy-butyric acid.
AMIKIN is rapidly absorbed after intramuscular administration. In normal adult volunteers, average peak serum concentrations of about 12 and 21 micrograms/mL are obtained 1 hour after intramuscular administration of 250 mg (3,7 mg/kg) and 500 mg (7,5 mg/kg), single doses, respectively. At 10 hours, serum levels are about 0,3 micrograms/mL and 2,1 micrograms/mL, respectively.
Mean urine concentrations for 6 hours are 563 micrograms/mL following a 250 mg dose and 832 micrograms/mL following a 500 mg dose.
Clinical Pharmacology: Intravenous administration
Single doses of 500 mg (7,5 mg/kg) administered to normal adults as an infusion over a period of 30 minutes produced a mean peak serum concentration of 38 micrograms/mL at the end of the infusion.
Repeat infusions of 7,5 mg/kg every 12 hours in normal adults were well tolerated and caused no drug accumulation.
Single doses of 15 mg/kg administered intravenously over 30 minutes to adult volunteers with normal renal function resulted in mean peak serum concentrations of 77 micrograms/mL and levels of 47 micrograms/mL and 1 micrograms/mL at 1 and 12 hours respectively following the infusions. A mean peak serum concentration of 55 micrograms/mL after a 30 minute infusion of 15 mg/kg is seen in elderly patients (mean creatinine clearance of 64 mL/min) with concentrations of 5,4 micrograms/mL at 12 hours and 1,3 micrograms/mL at 24 hours following the infusion.
In multiple dose studies, no accumulation was noted in patients with normal renal function receiving once daily doses of 15 to 20 mg/kg.
General:
Pharmacokinetics studies in normal adult subjects reveal mean serum half-life to be slightly over 2 hours with a mean total apparent volume of distribution of 24 litres, approximately 28% of the body weight. By the ultrafiltration technique, reports on serum protein binding range from 0 to 11%. The mean serum clearance rate is about 100 mL/min and the renal clearance rate is 94 mL/min in subjects with normal renal function.
Amikacin is excreted primarily by way of glomerular filtration.
Following administration at the recommended dose, therapeutic levels are found in significant concentrations in urine, bile, bronchial secretions, interstitial, pleural, and synovial fluids and peritoneal cavity.
Spinal fluid levels in normal infants are approximately 10 to 20% of the serum concentrations and may reach 50% when the meninges are inflamed. AMIKIN has been demonstrated to cross the placental barrier and yield significant concentrations in amniotic fluid.
Microbiology:
In vitro sensitivity does not necessarily imply in vivo efficacy.
Gram-negative: amikacin is active in vitro against Pseudomonas species, Escherichia coli, Proteus species (indole-positive and indole-negative), Providencia species, Klebsiella-Enterobacter-Serratia species, Acinetobacter (formerly Mima-Herellea) species and Citrobacter freundii.
Gram-positive: amikacin is active in vitro against penicillinase and non-penicillinase-producing Staphylococcus species including methicillin-resistant strains. Methicillin-resistant Staphylococcus aureus may not be completely sensitive to amikacin. Aminoglycosides in general have been shown to have a low order of activity against other Gram-positive organisms; viz, Streptococcus pyogenes, enterococci, and Streptococcus pneumoniae (formerly Diplococcus pneumoniae).
In-vitro studies have shown that AMIKIN combined with a beta-lactam antibiotic acts synergistically against many clinically significant Gram-negative organisms.
Amikacin resists degradation by most aminoglycoside inactivating enzymes.

INDICATIONS:
AMIKIN is indicated in the short-term treatment of serious infections due to susceptible strains of Gram-negative bacteria, including Pseudomonas species, Escherichia coli, species of indole-positive and indole-negative Proteus, Providencia species, Klebsiella-Enterobacter-Serratia species, and Acinetobacter (formerly Mima-Herellea) species and Citrobacter freundii.
NOTE:
AMIKIN injectable, is not indicated in uncomplicated initial episodes of urinary tract infections unless the causative organisms are not susceptible to antibiotics having less potential toxicity. When amikacin is indicated in the treatment of uncomplicated urinary tract infections, reduced dosage may be prescribed. (See DOSAGE AND DIRECTIONS FOR USE).
AMIKIN has also been shown to be effective in staphylococcal infections and may be considered as initial therapy under certain conditions in the treatment of known or suspected staphylococcal disease such as, severe infections where the causative organism may be either a Gram-negative bacterium or a staphylococcus, infections due to susceptible strains of staphylococci in patients allergic to other antibiotics, and in mixed staphylococcal/Gram-negative infections.
In certain severe infections, concomitant therapy with a beta-lactam antibiotic may be indicated.

CONTRA-INDICATIONS:

1.	A history of hypersensitivity to amikacin or any component of the formulation, and other aminoglycoside antibiotics.
2.	Pregnancy and lactation.
3.	Patients with myasthenia gravis

WARNINGS:
At times, AMIKIN injections may be indicated as concurrent therapy with other antibacterial agents in mixed or superinfections. In such instances, AMIKIN SHOULD NOT BE PHYSICALLY MIXED WITH OTHER ANTIBACTERIAL AGENTS IN SYRINGES, INFUSION BOTTLES OR ANY OTHER EQUIPMENT. EACH AGENT SHOULD BE ADMINISTERED SEPARATELY IN ACCORDANCE WITH ITS RECOMMENDED ROUTE OF ADMINISTRATION AND DOSAGE SCHEDULE.
AMIKIN contains sodium bisulphite, a sulphite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. Sulphite sensitivity is seen more frequently in asthmatic than in non-asthmatic subjects.

DOSAGE AND DIRECTIONS FOR USE:
Intramuscular or intravenous administration:
For adults and children with normal renal function:
The recommended dosage for adults, children, and older infants with normal renal function is 15 mg/kg/day divided into 2 or 3 equal doses administered at equally-divided intervals, i.e. 7,5 mg/kg every 12 hours or 5 mg/kg every 8 hours. Treatment of patients in the heavier weight classes shall not exceed 1,5g/day.
Treatment should preferably not continue for longer than 7 to 10 days, and the total dosage in adults should not exceed 15g.
In prematures, the recommended dose is 7,5 mg/kg every twelve hours. Newborns should receive 10 mg/kg as a loading dose and 7,5 mg/kg every 12 hours thereafter.
Alternatively, in patients with normal renal function reflected by creatinine clearance > 50 mL/min, a single daily intravenous dose of 15 mg/kg/day in adults, or 20 mg/kg/day in children (4 weeks or older) may be considered.
Amikacin should be infused over a 30 minute to one-hour period.
In paediatric patients, the amount of fluid used will depend on the amount tolerated by the patients. It should be a sufficient amount to infuse the amikacin over a 30 to 60 minute period. Infants should receive a 1 to 2 hour infusion.
Use of the 250 mg/2 mL and 100 mg/2 mL vials is recommended for children and infants for the accurate measurement of the appropriate dose.
When AMIKIN is indicated in uncomplicated urinary tract infections, a total daily dose of 500 mg daily may be administered either in a single dose or in two divided doses (250 mg twice daily).
As the activity of amikacin is enhanced by an increased pH, a urinary alkalinizing agent may be administered concurrently.
At the recommended dosage level, uncomplicated infections due to amikacin-sensitive organisms should respond in 24 to 48 hours. If definite clinical response does not occur within 3 to 5 days, therapy should be stopped and the antibiotic susceptibility pattern of the invading organism should be rechecked.
The status of renal function should be estimated by measurement of the endogenous creatinine clearance rate. Reassessment of renal function should be made periodically during therapy.
Whenever possible, amikacin concentrations in serum should be measured to assure adequate but not excessive levels. It is desirable to measure both peak and trough serum concentrations intermittently during therapy.
The peak and trough concentrations can vary depending on the frequency of administration.
For dosages administered 2-3 times a day, peak concentrations (30-90 minutes after injection) above 35 micrograms/mL and trough concentrations (just prior to the next dose) above 10 micrograms/mL should be avoided.
For once a day dosage in patients with normal renal function, excessive or prolonged peak concentrations should be avoided. However, the peak concentrations may in these cases exceed 35 micrograms/mL. Trough concentrations above 5 micrograms/mL should be avoided. Dosage should be adjusted as indicated.

For adult and children with impaired renal function:
Note: In patients with renal impairment reflected by creatinine clearance < 50 mL/min, administration of the recommended total daily dose of amikacin in single daily doses is not desirable since these patients will have protracted exposure to high concentrations. Patients with impaired renal function or diminished glomerular filteration excrete the drug much more slowly, prolonging the serum half-life. Renal function should be monitored carefully and dosage adjusted accordingly.
Whenever possible, serum amikacin concentrations should be monitored by appropriate assay procedures. Doses may be adjusted in patients with impaired renal function either by administering normal doses at prolonged intervals or by administering reduced doses at a fixed interval.
Both methods are based on the patient's creatinine clearance or serum creatinine values since these have been found to correlate with aminoglycoside half-lives in patients with diminished renal function. These dosage schedules must be used in conjunction with careful clinical and laboratory observations of the patient and should be modified as necessary. Neither method should be used when dialysis is being performed.
Normal dose at prolonged intervals between dosing:
If the creatinine clearance rate is not available and the patient's condition is stable, a dosage interval in hours for the single normal dose (i.e.: which would be given to patients with normal renal function on a twice a day schedule, i.e. 7,5 mg/kg) that can be calculated by multiplying the patient's serum creatinine by nine e.g., if the serum creatinine concentration is 2 mg/100 mL, (0,17 mmol/L) the recommended single dose (7,5 mg/kg) should be administered every 18 hours.
Reduced dose at fixed time intervals between dosing:
When renal function is impaired and it is desirable to administer AMIKIN at a fixed time interval, dose must be reduced. In these patients serum AMIKIN concentrations should be measured to assure accurate administration of AMIKIN and to avoid excessive serum concentrations. If serum assay determinations are not available and the patient's condition is stable, creatinine clearance values are the most readily available indicators of the degree of renal impairment to use as a guide for dosage.
First, initiate therapy by administering a normal dose, 7,5 mg/kg, as a loading dose. This dose is the same as the normally recommended dose which would be calculated for a patient with a normal renal function as described above.
To determine the size of maintenance doses administered every 12 hours, the loading dose should be reduced in proportion to the reduction in the patient's creatinine clearance rate:

Maintenance Dose Every 12 hours =

observed CC in mL/min X calculated loading dose in mg

normal CC in mL/min

(CC = creatinine clearance rate)

The above dosage schedules are not intended to be rigid recommendations but are provided as guides to dosage when the measurement of amikacin serum levels is not feasible.
Intravenous administration:
AMIKIN is stable for 24 hours at room temperature, at concentrations of 0,25 and 5,0 mg/mL in the following solutions:
5% Dextrose Injection
5% Dextrose and 0,2% Sodium Chloride Injection
5% Dextrose and 0,45% Sodium Chloride Injection
0,9% Sodium Chloride Injection
Lactated Ringer's Injection
Lactated Ringer's Injection with 5% Dextrose
AMIKIN should not be physically premixed with other drugs but should be administered separately according to the recommended dose and route.
Note:
For stability in parenteral solutions refer to "STORAGE INSTRUCTIONS".
IN VITRO MIXING OF AMINOGLYCOSIDES WITH BETA-LACTAM ANTIBIOTICS (PENICILLINS OR CEPHALOSPORINS) MAY RESULT IN SIGNIFICANT MUTUAL INACTIVATION.
A reduction in serum half-life or serum level may occur when an aminoglycoside or penicillin-type medicine is administered by separate routes. Inactivation of the aminoglycoside is clinically significant only in patients with severely impaired renal function. 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).

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Patients treated with parenteral amikacin should be under close clinical observation because of the potential ototoxicity and nephrotoxicity associated with its use. Safety for treatment periods which are longer than 14 days has not been established.
Neurotoxicity:
Neurotoxicity, manifested as vestibular and permanent bilateral auditory ototoxicity, can occur in patients with pre-existing renal damage and in patients with normal renal function treated at higher doses and/or for periods longer than those recommended. The risk of aminoglycoside-induced ototoxicity is greater in patients with renal damage.
High frequency deafness usually occurs first and can be detected only by audiometric testing. If therapy is expected to last seven days or more in patients with renal impairment, or ten days in other patients, a pre-treatment audiogram should be obtained, and repeated during therapy. Amikacin therapy should be stopped if tinnitus or subjective hearing loss develops, or if follow-up audiograms show significant loss of high frequency response. Vertigo may occur and may be evidence of vestibular injury. Other manifestations of neurotoxicity may include numbness, skin tingling, muscle twitching and convulsions. The risk of hearing loss due to aminoglycosides increases with the degree of exposure to either persistently high peak or high trough serum concentrations. Patients developing cochlear damage may not have symptoms during therapy to warn them of developing eighth nerve toxicity, and total or partial irreversible bilateral deafness may occur after the drug has been discontinued. Amikacin induced ototoxicity is usually irreversible.
Neuromuscular blockade and respiratory paralysis have been reported following parenteral injection, topical instillation (as in orthopedic and abdominal irrigation or in local treatment of empyema), and following oral use of aminoglycosides. The possibility of these phenomena should be considered if amikacin is administered by any route, especially in patients receiving anaesthetics, neuromuscular blocking agents such as tubocurarine, succinylcholine, decamethonium, or in patients receiving massive transfusions of citrate-anticoagulated blood. If blockage occurs, calcium salts may reverse these phenomena, but mechanical respiratory assistance may be necessary.
Amikacin should be used with caution in patients with muscular disorders or parkinsonism since amikacin may aggravate muscle weakness because of its potential curare-like effect on the neuromuscular junction.
Nephrotoxicity:
Aminoglycosides are potentially nephrotoxic. The risk of nephrotoxicity is greater in patients with impaired renal function, and in those who receive high doses, or in those whose therapy is prolonged.
Renal and eigth-cranial nerve function should be closely monitored especially in patients with known or suspected renal impairment 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.
Patients should be well hydrated during treatment and renal function should be assessed by the usual methods prior to starting therapy and daily during the course of treatment. A reduction of dosage (see DOSAGE AND DIRECTIONS FOR USE) is required 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 blood urea creatinine or oliguria. If azotemia increases, or if a progressive decrease in urinary output occurs, treatment should be stopped.
Adverse reactions which have been reported are skin rash, drug fever, headache, paraesthesia, tremor, nausea and vomiting, eosinophilia, arthralgia, anaemia, hypotension and hypomagnesemia.
Macular infarction sometimes leading to permanent loss of vision has been reported following intravitreous administration (injection into the eye) of amikacin.
Cross-allergenicity among aminoglycosides has been demonstrated.
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.
Note:
When patients are well hydrated and kidney function is normal, the risk of nephrotoxic reactions with amikacin is low if the dosage recommendations (see "DOSAGE AND DIRECTIONS FOR USE") are not exceeded.
Elderly patients may have reduced renal function which may not be evident in routine screening tests such as blood urea or serum creatinine. A creatinine clearance determination may be more useful. Monitoring of renal function during treatment with aminoglycosides is particularly important. Renal function changes are usually reversible when the drug is discontinued.
Concurrent and/or sequential systemic, oral, or topical use of other neurotoxic or nephrotoxic products, particularly bacitracin, cisplatin, amphotericin B, cephaloridine, 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.
The use of amikacin may result in overgrowth of nonsusceptible organisms. If this occurs, appropriate therapy should be instituted.
The concurrent use of AMIKIN with potent diuretics (ethacrynic acid, or furosemide) should be avoided since diuretics themselves may cause ototoxicity. Irreversible deafness may result. In addition, when administered intravenously, diuretics may enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue.
Paediatric use:
Amikacin 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 amikacin.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
See side-effects and special precautions.
In the event of overdosage or toxic reaction, peritoneal dialysis or haemodialysis will aid in the removal of amikacin from the blood. In the newborn infant, exchange transfusion may also be considered.

IDENTIFICATION:
Colourless solutions which may darken to pale yellow without loss of potency in clear glass vials with a green flip-off cap for the 100 mg strength, yellow for the 250 mg strength, blue for the 500 mg strength and white for the 1g strength.

PRESENTATION:
Each strength, 100 mg, 250 mg, 500 mg and 1g is available in cartons containing 5 vials.

STORAGE INSTRUCTIONS:
Keep out of reach of children.

Vials:

Store at temperatures not exceeding 25°C. At times the solution may darken from colourless to a pale yellow. This does not indicate a loss of potency. Any unused portion must be discarded if not used.

Stability in IV Fluids:
Amikacin at concentrations of 0,25 mg/mL and 5,0 mg/mL in 5% Dextrose in water, 5% Dextrose/0,2% Sodium Chloride Injection, 5% Dextrose/0,45% Sodium Chloride Injection, Normal Saline and Lactated Ringer's Injection, is stable for 24 hours at room temperature, 60 days at 4°C and 30 days at - 15°C.
Refrigerated and frozen solutions are stable for an additional 24 hours at room temperature.
Parenteral products should be inspected visually for particulate matter.

REGISTRATION NUMBERS:

AMIKIN injection 100 mg	: H/20.1.1/284
AMIKIN injection 250 mg	: H/20.1.1/285
AMIKIN injection 500 mg	: H/20.1.1/286
AMIKIN injection 1g	: 28/20.1.1/604

NAME AND BUSINESS ADDRESS OF APPLICANT:
Bristol-Myers Squibb (Pty) Ltd
47 Van Buuren Road
BEDFORDVIEW
2008

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
28 July 1999

Updated on this site: February 2001
Current: June 2005
Source: Pharmaceutical Industry
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