La-Mika Injection

Amikacin injection

La-Mika® 100 Injection

Each vial (2ml) contains:

Amikacin Sulphate IP

equivalent to Amikacin 100 mg,

Methylparaben IP (as preservatives) 0.08 % w/v

Propylparaben IP (as preservatives) 0.02 % w/v

Water for Injection IP q.s.

LaMika® 250 Injection

Each vial (2ml) contains:

Amikacin Sulphate IP

equivalent to Amikacin 250 mg,

Methylparaben IP (as preservatives) 0.08 % w/v

Propylparaben IP (as preservatives) 0.02 % w/v

Water for Injection IP q.s.

LaMika® 500 Injection

Each vial (2ml) contains:

Amikacin Sulphate IP equivalent to Amikacin 500 mg,

Methylparaben IP (as preservatives) 0.08 % w/v

Propylparaben IP (as preservatives) 0.02 % w/v

Water for Injection IP q.s.

Injection 125 mg/250 mg/500 mg

4.1 Therapeutic indications

Treatment of serious infections due to amikacin sensitive organisms.

4.2 Posology and method of administration

Adults and adolescents over 12 years

The recommended intramuscular or intravenous dose for adults and adolescents with normal renal function (creatinine clearance ≥50 mg/min) is 15 mg/kg/day given either as a single daily dose or as several equal doses (e.g. 7.5 mg/kg all 12 hours, or 5 mg/kg every 8 hours). The total daily dose should not exceed 1.5 g. For endocarditis and febrile neutropenic patients, dosing should be done twice a day, as there is insufficient data for once-daily dosing.

Children from 4 weeks to 12 years

The recommended intramuscular or intravenous (slow intravenous infusion) dosage for children with normal renal function is 15-20 mg/kg/day, given either as a single daily dose of 15-20 mg/kg or divided into two doses of 7.5 mg/kg every 12 hours.

For endocarditis and febrile neutropenic patients, dosing should be done twice a day, as there is insufficient data for once-daily dosing.

Neonates

An initial dose of 10 mg/kg, then 7.5 mg/kg every 12 hours.

Preterm infants

The recommended dose for preterm infants is 7.5 mg/kg every 12 hours.

Dosage in elderly patients (≥ 65 years)

Renal function should be taken into account in elderly patients.

Life-threatening infections and/or those caused by Pseudomonas

The adult dose may be increased to 500 mg every eight hours but should neither exceed 1.5 g/day nor be administered for a period longer than 10 days. A maximum total adult dose of 1.5 g should not be exceeded.

Urinary tract infections (other than pseudomonal infections)

7.5 mg/kg/day in two equally divided doses (equivalent to 250 mg twice daily in adults). As the activity of amikacin is enhanced by increasing the pH, a urinary alkalizing agent may be administered concurrently.

Other routes of administration

Amikacin in concentrations of 0.25 % (2.5 mg/ml) may be used satisfactorily as an irrigating solution in abscess cavities, the pleural space, the peritoneum and the cerebral ventricles.

Intraperitoneal use

Following exploration for established peritonitis, or after peritoneal contamination due to faecal spill during surgery, Amikacin may be used as an irrigant after recovery from anaesthesia in concentrations of 0.25 % (2.5 mg/ml). If instillation is desired in adults, a single dose of 500 mg is diluted in 20 ml of sterile distilled water and may be instilled through a polyethylene catheter sutured into the wound at closure. If possible, instillation should be postponed until the patient has fully recovered from the effects of anaesthesia and muscle-relaxing drugs.

Monitoring

The renal function status should be evaluated by measuring the serum creatinine concentration or preferably by estimation of creatinine clearance. Blood urea nitrogen (BUN) is far less reliable for this purpose. Assessment of renal function should be performed at the start of therapy and should be re-evaluated at regular intervals during treatment.

Amikacin concentrations in serum should be measured in all patients receiving parenteral amikacin and must be measured in obesity, if high doses are being given, the elderly and in cystic fibrosis. Both peak and trough serum concentrations should be measured intermittently during therapy to ensure adequate but not excessive serum levels. In patients receiving multiple daily dosing peak concentrations (30-90 minutes after injection) of above 35 μg/ml and trough concentrations (just before the next dose) of above 10 μg/ml should be avoided.

In patients receiving once daily (or extended interval) dosing pre-dose ('trough') concentration should be less than 5 mcg/ml. Peak concentrations (approximately 60 minutes after administration) may exceed 35 mcg/ml.

If the pre-dose ('trough') concentration is high, the interval between doses must be increased. If the post-dose ('peak') concentration is high, the dose must be decreased.

Auditory and vestibular function should also be monitored during treatment, in particular if longer treatment duration (>7-10 days) is considered.

Dosage in renal impairment

In patients with impaired renal function (creatinine clearance <50 ml/min) the recommended dose has to be decreased and adjusted to the renal function. This can be achieved by increasing the dose interval and/or reducing the dose.

In all patients with renal impairment, serum amikacin peak and trough concentration and renal function must be monitored regularly and the dose regimen altered as necessary.

Once daily/extended interval dosing

Patients with renal impairment in whom once daily dosing would be considered appropriate if their renal function were normal may receive extended interval dosing.

The initial dose may be the same as in normal renal function. The dose interval should be at least 24 hours and extended according to the degree of renal impairment and the results of serum amikacin level measurements.

In severe renal impairment, the initial dose may have to be reduced in addition.

Once daily or extended interval dosing should be avoided in patients with a creatinine clearance less than 20 ml/minute.

A once daily/extended interval dose regimen should be avoided in children over 1 month of age with a creatinine clearance less than 20 ml/minute/1.73 m2.

Reduced dose at fixed intervals

If patients with renal impairment are given amikacin at fixed time intervals, the dose must be reduced. In these patients, the serum amikacin concentration should be measured to ensure accurate administration and to avoid excessive serum concentrations. If a determination of serum concentration is not possible and the patient's condition is stable, serum creatinine and creatinine clearance rates are the most readily available indicators of the extent of renal dysfunction and the consequent reduction in dose.

As renal function may alter appreciably during therapy, the serum creatinine should be checked frequently and the dosage regimen modified as necessary.

Multiple daily dosing

In patients with renal impairment in whom multiple daily dosing at fixed intervals would be considered appropriate if their renal function were normal, the dose must be reduced while the dose interval is maintained. Serum amikacin concentrations should be measured and creatinine clearance should be estimated regularly.

Treatment duration

At recommended dosages, infections caused by susceptible pathogens should respond to therapy within 24-48 hours. If clinical response does not occur within 3-5 days, therapy should be discontinued and the antibiotic susceptibility pattern of the invading organism should be rechecked. If necessary, alternative therapy should be considered. Failure of therapy may be due to the resistance of the organism or to septic locus requiring surgical drainage.

The average duration of treatment is 7-10 days. For all routes of administration, the maximum daily dose should not exceed 15-20 mg/kg/day. If prolonged treatment is required, it should be carried out after reviewing the necessity of using amikacin, determination of serum amikacin concentrations and additionally monitoring of renal, auditory and vestibular functions as closely as possible daily.

Method of administration

IM use or IV use after dilution.

4.3 Contraindications

• Hypersensitivity to the active substance or other aminoglycoside antibiotics.
• Due to the known cross sensitivities in this class of drugs, a history of hypersensitivity or serious toxic reactions to aminoglycosides may be a contraindication to all aminoglycosides.
• Because of its sulphate content, Amikacin must not be used in asthmatics with sulphate hypersensitivity.

4.4 Special warnings and precautions

Neuromuscular toxicity

Neuromuscular blockade and respiratory paresis have been reported following parenteral injection, topical lavage (such as orthopaedic and abdominal irrigation, or with local empyema treatment) or after oral administration of aminoglycosides. The risk of respiratory paresis when administering aminoglycosides irrespective of the route of administration should be considered, especially in patients receiving anaesthetics or neuromuscular blockers. Antidote in neuromuscular blockade: supply of calcium in ionized form (to relieve respiratory paralysis) and neostigmine. Mechanical ventilation may be necessary. In animal studies, neuromuscular blocks and myoparesis were found after administration of high doses of amikacin.

Aminoglycosides should be used with extreme caution in patients with myasthenia gravis as the curare-like effect on the neuromuscular junction may increase myasthenia with the potential for respiratory failure.

Aminoglycosides 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 the neuromuscular junction.

Nephrotoxicity and Ototoxicity

Amikacin is potentially nephrotoxic and ototoxic; therefore, patients must be carefully monitored clinically. Particular caution should be applied to patients with pre-existing renal insufficiency, or pre-existing hearing or vestibular damage. Safety for treatment periods which are longer than 14 days has not been established.

Precautions regarding the dose should be observed and adequate hydration maintained. Neurotoxicity occurring in patients treated with aminoglycosides is manifested as vestibular and/or bilateral ototoxicity.

Ototoxicity:

The risk of aminoglycoside-induced ototoxicity is greater in patients with impaired renal function, and in those who receive high doses, or in those whose therapy is prolonged over 5-7 days. High frequency deafness usually occurs first and can be detected only by audiometric testing. Vertigo or dizziness may occur and may be evidence of vestibular injury.

Other manifestations of neurotoxicity include numbness, tingling of the skin, muscle twitching and muscle spasms. At the first sign of hearing and/or balance disorders, therapy with amikacin should be discontinued.

The risk of ototoxicity due to aminoglycosides increases with the level of exposure either through consistently high peak serum concentrations or high serum trough concentrations. Patients who develop auditory or vestibular damage may not have any symptoms during therapy that may alert them to eighth nerve damage, and total or partial irreversible bilateral deafness or disabling vertigo may occur after the drug has been discontinued.

Aminoglycoside-induced ototoxicity is usually irreversible.

Evidence of ototoxicity (dizziness, vertigo, tinnitus, roaring in the ears and hearing loss) or nephrotoxicity requires discontinuation of the drug or dosage adjustment.

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, bekanamycin, neomycin, polymyxin B, colistin, cephaloridine, 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.

Nephrotoxicity

Aminoglycosides are potentially nephrotoxic. Renal toxicity appears independent of plasma obtained at the peak (Cmax). The risk of nephrotoxicity is increased in patients with impaired renal function and in patients receiving high doses or prolonged drug therapy.

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 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 BUN, serum creatinine, or oliguria. If azotemia increases, or if a progressive decrease in urinary output occurs, treatment should be stopped.

Aminoglycosides may be inactivated by betalactams. Inactivation may continue in samples (serum, cerebrospinal fluid, etc.) taken for laboratory testing and then interfere with aminoglycoside level assays. The samples should therefore be adequately treated after collection (immediate determination, storage in the freezer or addition of beta-lactamase).

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.

Other

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.

Prolonged antibiotic use may occasionally lead to overgrowth of resistant pathogens. The patient should be constantly monitored in this regard. Should a superinfection occur during therapy, appropriate measures must be taken.

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

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.

4.5 Interaction with other medicinal products and other forms of interaction

Concurrent or serial use with other neurotoxic, ototoxic or nephrotoxic agents, particularly bacitracin, cisplatin, amphotericin B, cyclosporine, tacrolimus, cephaloridine, paromomycin, viomycin, colistimethate/colistin, vancomycin, or other aminoglycosides should be avoided both systemically and topically because of the potential for additive effects. Increased nephrotoxicity has been reported following concomitant parenteral administration of aminoglycoside antibiotics and cephalosporins. Concomitant cephalosporin use may spuriously elevate creatinine serum level determinations.

The risk of ototoxicity is increased when amikacin is used in conjunction with rapidly acting diuretic drugs, particularly when the diuretic is administered intravenously.

Diuretics may enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. Such agents include furosemide and ethacrynic acid which is itself an ototoxic agent. Irreversible deafness may result.

There is an increased risk of nephrotoxicity and possible ototoxicity when aminoglycosides are co-administered with platinum compounds.

The use of amikacin is not recommended in patients receiving anaesthetics or musclerelaxing drugs (such as volatile anaesthetics, d-tubocurarine, succinylcholine, decamethonium, atracurium, rocuronium, vecuronium) or in patients receiving massive transfusions of citrate-anticoagulated blood) as neuromuscular blockade and consequent respiratory depression may occur. If blockade occurs, calcium salts may reverse this phenomenon.

Indomethacin may increase the plasma concentration of amikacin in neonates.

In patients with severely impaired renal function, a reduction in activity of aminoglycosides may occur with concomitant use of penicillin-type drugs.

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.

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).

There is an increased risk of hypocalcaemia when aminoglycosides are administered with bisphosphonates.

There is an increased risk of nephrotoxicity and possibly of ototoxicity when aminoglycosides are administered with platinum compounds.

Concomitantly administered thiamine (vitamin B1) may be destroyed by the reactive sodium metabisulfite component of the amikacin sulphate formulation.

Sulphate is a very reactive compound. Therefore, mixtures with other medicinal products should be avoided.

4.6 Use in special populations

Pregnancy

Amikacin should be used in pregnant women and newborns only if clearly indicated and under medical supervision.

There is limited data on the use of aminoglycosides in pregnancy. Aminoglycosides can affect the development of the embryo/foetus in the womb. Aminoglycosides cross the placental barrier and there have been many reports of total, irreversible, bilateral congenital deafness in children whose mothers were treated with streptomycin during pregnancy.

Although adverse reactions to the unborn or neonate in pregnant women who have been treated with other aminoglycosides have not been reported, there is potential for harm.

If a pregnant patient is to be treated or becomes pregnant during treatment, medical advice should be provided on the risk of the potential hazard to the fetus.

Breast-feeding

It is not known if amikacin passes into the breast milk. The decision should be made to either stop breastfeeding or stop the therapy.

Fertility

In reproduction toxicity studies in mice and rats, no effects on fertility or foetal toxicity were reported.

4.7 Effects on ability to drive and use machines

No studies on the ability to drive and the use of machines have been performed. However, the occurrence of some side effects may affect the ability to drive vehicles and operate machinery.

4.8 Undesirable effects

All aminoglycosides have oto-, nephro- and neurotoxic potential.

The risk of these side effects is greater in patients with already impaired renal function, in patients receiving more than the recommended doses, prolonged therapy and in patients treated with other ototoxic or nephrotoxic drugs.

* Changes in renal function are usually reversible at the end of therapy. ** Amikacin is not intended for administration to the vitreous body. When amikacin was injected directly into the eye, maculopathies were observed, occasionally leading to complete loss of vision.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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 via email to: medico@zuventus.com

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

Significant risk of overdose is a potential nephro, oto and neurotoxic (neuromuscular blockade) effect. Respiratory neuromuscular blockade should be appropriately treated, including the administration of calcium in ionised form (for example as gluconate or lactobionate in 10-20 % solution). In case of overdose or toxic reactions, amikacin can be removed by peritoneal or hemodialysis. Continuous arteriovenous hemofiltration also leads to a reduction of amikacin. In neonates an exchange transfusion may be considered.

5.1 Mechanism of action / Pharmacodynamic properties

The mechanism of action of amikacin is due to a disruption of protein biosynthesis on the bacterial ribosome by interaction with the rRNA and subsequent inhibition of translation. This results in a bactericidal effect.

5.2 Pharmacokinetic Properties

After IM injection, amikacin is well tolerated locally and rapidly absorbed. After administration of 250 mg amikacin IM average serum peak concentrations of 11 μg/ml are achieved within one hour when amikacin 21 μg/ml is administered. I.V. short infusion of 500 mg amikacin results in an average serum concentration of 38 μg/ml (end of infusion). After 1 hour, 18 μg/ml were still detectable. In elderly patients (with mean creatinine clearance of 64 ml/min) the blood levels are 55 μg/ml after a 30-minute infusion of 15 mg/kg, 5.4 μg/ml after 12 hours and 1.3 μg/ml after 24 hours.

Serum half-life in patients with normal renal function is 2.4 hours, with an average volume of distribution of 24 litres and about 28 % of body weight. Plasma protein binding ranges from 0-11 %. The average serum clearance rate is 100 ml/min; The renal clearance rate in normal renal function is 94 ml/min. Amikacin is not metabolized and excreted almost exclusively by glomerular filtration. In normal renal function, approximately 91 % of the IM administered dose is excreted within the first 8 hours via urine in active form and 98 % within 24 hours.

Amikacin is removable by both peritoneal dialysis and hemodialysis. By peritoneal dialysis (patients without infection) about 20 % of the administered amikacin dose could be removed within 8-12 hours. Hemodialysis is much more effective. Depending on the dialysis method, either 50 % (range 29-81 %) of the administered dose was removed within 4 hours or 40-80 % was removed within 8 hours.

6.1 Animal toxicology or pharmacology

No long-term studies have been performed to evaluate the carcinogenic or mutagenic potential. Studies in rats have shown that daily doses up to 10 times recommended dose for humans did not cause any adverse effects on male and female fertility.

Amikacin, (as the sulphate) is a semi-synthetic aminoglycoside antibiotic derived from kanamycin.

D-Streptamine,O-3-amino-3-deoxy-α-D-glucopyranosyl-(1→6)-O-[6-amino-6-deoxy-α-D-glucopyranosyl-(1→4)]-N1-(4-amino-2-hydroxy-1-oxobutyl)-2-deoxy-, (S)-, sulphate (1:2) (salt).

Chemical Structure: C₂₂H₄₃N₅O₁₃ • 2H2SO4

Molecular weight: 781.75

8.1 Incompatibilities

Aminoglycosides such as amikacin should not be combined with other medicines, but must be administered separately.

8.2 Shelf-life

Refer on package

8.3 Packaging information

2ml Injection vial containing amikacin

125 mg/250 mg/500 mg

8.4 Storage and handing instructions

Store below 300C. Protect from light and moisture. Don’t freeze. Keep out of reach of children. Do not use if solution is not clear or has particulate matter in vial.

Patients should be counselled that antibacterial drugs including amikacin sulphate injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When amikacin sulphate injection is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by amikacin sulphate injection or other antibacterial drugs in the future.

Patients should be counselled that diarrhoea is a common problem caused by antibiotics, and it usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after having taken their last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.