AMIFAR

                                      (PHARMATEX  İTALİYA)                                         

QUALI-QUANTITATIVE COMPOSITION

- One vial/ampoule of 2 ml contains : amikacin sulphate mg 667,5 equivalent to amikacin base  mg 500

- One vial/ampoule of 4 ml contains : amikacin sulphate mg 1335 equivalent to amikacin base   mg 1000

EXCIPIENTS : Sodium citrate, sodium metabisulphite, bidistilled water

PHARMACEUTICAL FORM

Antibacterial aminoglycoside

MARKETING AUTHORISATION HOLDER

PHARMATEX ITALIA SRL VIA APPIANI, 22 -  20121 – MILAN (ITALY)

MANUFACTURER

PHARMATEX ITALIA S.R.L. - Nucleo Industriale - 84020 PALOMONTE (SA) ITALY

THERAPEUTİC İNDİCATİON
Amifar is a semisynthetic aminoglycoside antibiotic derived from kanamycin and is used in a short treatment of severe Gram-negative infections, including Pseudomonas aeruginosa, E.Coli, Proteus indolo+ and indolo-, Providencia, Klebsiella enterobacter strains, Serratia, and Acinetobacter.
It is efficient in the treatment of :
-bacteremia, septicemia and neonatal sepsis;
-severe infections of respiratory tract, infections of bones and articulations, SNC infections (including meningitis), intra-abdominal infections (including peritonitis), burns and post-surgery infections (including vascular surgery infections);
-severe urinary tract recurring infections caused by Gram-negative germs 
On the other hand, likewise other aminoglycosides, amikacin is not indicated in the initial treatment of non complicated infective episodes of the urinary tract when the etiological agent is susceptible to the less toxic antibiotics;
-infections caused by staphylococcus; it may be adopted as attack therapy in case of ascertained or presumed staphylococcal infections, when the subject is allergic to other antibiotics or in case of infections caused by both staphylococcus and Gram-negative germs;
-neonatal sepsis when the antibiotic sensitivity test prohibits institution of any other aminoglycosides;
In such cases, other penicillin-antibiotic concomitant therapy may be indicated due to a possible Gram-positive superinfection (streptococcus and pneumococcus).
Amifar is active against some strains of Gram-negative bacteria which are resistant to gentamicin, tobramycin, and kanamycin, including Pseudomonas aeruginosa, Proteus rettgeri, Providencia stuartii, and Serratia marcescens.

CONTRAINDICATION

Amikacin is contra-indicated in patients with known history of hypersensibility to it.

SPECIAL WARNINGS AND PRECAUTIONS

- Amikacin may exhibit nephrotoxic, ototoxic and neurotoxic reactions
For this reason association of amikacin with other toxic drugs (see “Warnings”) should be avoided.

  • Since this antibiotic is concentrated in elevated quantities in the renal excretory system and to minimise renal tubules chemical irritation, the patients undergoing this treatment must be well hydrated.

  • Prior to initiation of the therapy and during the therapy, renal function must be controlled. In case of renal irritation signs (urinary casts, red blood cells, and leukocytes in the urinary sediment, albuminuria) the hydration must be increased.

  • If other signs of alteration appear including creatinine clearance reduction (CC), urine specific weight reduction, urea nitrogen increase and serum creatinine increase, oliguria, the doses must be reduced (see posology).

The treatment should be interrupted if the blood nitrogen is increased or if the urinary excretion is progressively reduced. 
However, if the patient is well hydrated, renal function normal, and if amikacin is given in recommended doses, the risk of nephrotoxic reactions with amikacin is reduced. 
-Since amikacin given in high doses has provoked the muscular paralysis in animals, possible neuromuscular blockade and respiratory paralysis must be considered when the drug is administered contemporarily with anesthetics or neuromuscular blocking agent. If nervous block has been observed the calcium salts neutralising this phenomena should be instituted.
-Cross-allergy with other aminoglycoside antibiotocs may occur
-Resistant germs superinfection may occur during the treatment with amikacin, as it may happen with other antibiotics, requiring instituting of adequate therapy.
Clinical studies on animals carried out by now have not demonstrated any negative influence of amikacin on gestation and on foetus. Such studies in humans are still missing. Since the risk has not yet been clearly defined, a possible foetal damage can not be excluded. For this reason amikacin should be given to a pregnant woman if only necessarily required.

WARNINGS

Amikacin may be used as initial therapy in treatment of Gram-negative infections when the results of antibiotic assay have not been completed. 
Continuation of therapy depends on the results of the antibiotic sensitivity test, severity of the infection, and on the patient response to the treatment considering the precautions reported in the further text.
Patients undergoing aminoglycoside-antibiotics treatment must be strictly controlled due to a potential ototoxicity and nephrotoxicity of these antibiotics.
The product contains sodium metabisulphite that may provoke allergic reactions and hard asthma attacks in sensitive subjects particularly in those affected by asthma.

Ototoxicity

In treatment with large amikacin doses for the period longer than recommended, the risk of ototoxicity, at the level of both auditory apparatus and vestibular system, is much more pronounced in patients with pre-existing renal impairment.
High frequency acoustic waves deafness that may be determined by audiometric tests only, is the first sign of deafness. Vertigo as the sign of vestibular damage may also appear.
Possible amikacin ototoxicity in children has not been observed. 
Until obtaining more information about safety of this antibiotic in pediatrics, children should be treated only if the antibiotic sensitivity test shows that other aminoglycosides can not be instituted, and under straight control of possible occurrence of toxicity.

Nephotoxicity
All aminoglycosides are potentially nephrotoxic.
Both renal function and the VIIIth cranial nerves pair function must be constantly controlled in patients with known or suspected renal insufficiency as well as in those with normal renal function in the beginning of the treatment that has been altered during the treatment itself. Renal function alteration is characterised by CC (creatinine clearance) reduction, cells or cylinders presence in the urinary sediment, oliguria, proteinuria, urine specific weight decrease, and nitrogen retention increase (creatinine urea nitrogen increase).
The therapy must be interrupted in case of renal, vestibular, and acoustic alterations.
Amikacin serum creatinine concentration should be controlled, and concentrations superior to 35gamma/ml should not be maintained. The urine test results should remain within parameters reported above

Interactions
Concomitant or successive administration of other antibiotics for topical or general use known to be neuro- or nephro-toxic, must be avoided, in particular:
Kanamycin, gentamicin, tobramycin, neomycin, streptomycin, cephaloridine, viomycine, polymyxin B, colistin, vancomycin.
Amikacin should not be given with strong diuretics (etacrinic acid, furosemide, mannitol). Some ototoxic diuretics given intravenously decrease toxicity of aminoglycosides, alterating the tissues serum concentrations.
THE PRODUCT SHOULD BE GIVEN TO A PREGNANT WOMAN AND IN EARLY INFANCY ONLY IF CLEARLY NEEDED AND UNDER STRAIGHT MEDICAL CONTROL.

USES AND ADMINISTRATION

A suggested dose for adults and children (with normal renal function) is the equivalent of 15mg of amikacin per kg of body-weight daily in equally divided doses every 8 hours or 12 hours by intramuscular injection, up to a maximum of 1.5 g daily in adults. (elevated body weight).
Neonates may be given a loading dose equivalent to amikacin 10 mg per kg followed by 15 mg per kg daily in two divided doses. 
Treatment should preferably not continue for longer than 7 to 10 days, the total dose given to adults should not exceed 15 g, and peak plasma concentrations greater than 10 mg per ml should be avoided. In patients with impaired renal function doses should be reduced or the intervals between them prolonged. In all patients, doses should be adjusted according to plasma-amikacin concentrations.
Recommended loading dose in neonates is 10 mg/kg followed by 7,5 mg/kg every 12 hours.
When posology is known, Amikacin is usually given to adults and children for 7 to 10 days. A favourable response should be reached in 48 hours if infections are not complicated by sensitive bacteria. If a desired clinical response fails to appear in 4 to 5 days, the treatment should be interrupted and the germs sensitivity test should be repeated. Lacking of response may be caused by the resistance of some bacteria or due to the presence of septic outlets requiring a surgical drainage.
If a treatment longer than 10 days is required, renal and acoustic function must be controlled daily.
In patients with impaired renal function the amikacin serum concentrations should be controlled as much as possible, and posology should be adjusted as follows:

  • Administration of doses recommended for subjects with normal renal functions, given at increased time intervals, or

  • Administration of doses which are lower than recommended ones, maintaining the time intervals fixed

In both cases, the CC and creatinine serum concentrations must be controlled in subjects with impaired renal function, since these data are correlated with the antibiotic half-life, particularly:

  • If CC concentrations are not available and the patient’s conditions are stable, the interval between doses is calculated multiplying the value of creatinine serum concentration by 9 (for example 2ml/100ml of creatinine x 9= 12 hour interval);

  • If amikacin given at fixed intervals is preferred, the antibiotic serum concentrations should be controlled that must not exceed 35 gamma/ml. If this is not possible and the patient’s conditions are stable and the CC and creatinemia values are available, amikacin could be given in loading dose of 7,5 mg/ml, stabilising a 12 hour interval. The successive dose given every 12 hours, is calculated applying the formula given below:

loading dose = 7,5 mg/kg                                                              cc observed (ml/min.)
maintaining dose =                                                                                             x 7,5
cc normal (ml/min.) (every 12 hours)                                   cc=  creatinine clearance

Alternatively, in case of known “steady state” value of creatinemia, the normal dose may be divided by this value such obtaining the reduced dose which is to be given every 12 hors. 
In case of intravenous administration, the loading and daily dose and total quantity of amikacin to be administered remain the same as those reported for intramuscular use. Mode of administration remains unchanged too (2-3 administrations at regular intervals). Antibiotic is given in adults dissolving a 500 mg ampoule/vial content in 200 ml of physiological solution or a 5% glucose solution or other compatible solution. The time of infusion is 30 to 60 minutes. Ampoule/vial containing 1 g is always diluted in 200 ml of compatible solution and given in a 60 minute infusion. 
The quantity of fluid in children is in direct proportion with the quantity of antibiotic to be administered. The infusion liquid must be administered over the period of 30 or 60 minutes. In small children the infusion should be done in 1 to 2 hours.
Amikacin should not be mixed with other substances and is given alone following the recommended posological scheme.

ADVERSE EFFECTS

The principal adverse effects that may appear with amikacin are:

  • the 8th nerve toxicity (particularly ototoxicity) and nephrotoxicity (albuminuria, presence of red blood cells, leukocytes, and cylinders in the urinary sediment, elevated blood nitrogen, and oliguria);

  • cutaneous rashes, iatrogenic fever, cephalea, paresthesia, tremors, nausea and vomiting, eosinophylia, anemia, and hypotension have rarely been observed.

In case of over-dosage or particularly severe adverse effects, hemodialysis or peritoneal dialysis should be introduced to accelerate the elimination of amikacin from the blood.
Adverse effects being not noted should immediately be reported to a physician or pharmacist.

OVER-DOSAGE

In case of over-dosage or particularly severe adverse effects, hemodialysis or peritoneal dialysis should be introduced to accelerate the elimination of amikacin.

SHELF- LIFE AND STORAGE

Shelf-life 36 months is indicated on the box and refers to the products packaged for dispensing and properly  stored.
Store at controlled  room temperature of 15°C – 30° C.
 
ATTENTION: DO NOT USE THE MEDICINE AFTER EXPIRY DATE INDICATED ON THE BOX

KEEP OUT OF THE REACH OF CHILDREN