Netromycin (Netilmicin Sulfate)

NETROMYCIN®

Schering

Netilmicin Sulfate

Antibiotic

Action And Clinical Pharmacology: Netilmicin is a semisynthetic, aminocyclitol, aminoglycoside antibiotic prepared from a dehydrogenated analog of gentamicin Cla.

Netilmicin is a bactericidal antibiotic which acts by inhibiting normal protein synthesis in susceptible bacteria. It is thought to prevent amino acid polymerization by binding to the 30S ribosomal subunit.

Netilmicin is rapidly and completely absorbed after i.m. administration. In adult subjects with normal renal function, mean peak serum levels of 5.5 and 8.8 mL were obtained 30 to 60 minutes after a single i.m. administration of 2 and 3 mg/kg, respectively.

When 2 mg/kg or 3 mg/kg was given as a 30 minute infusion in normal saline, the average maximum serum concentrations, occurring at the end of infusion, were 11.8 and 15.6 g/mL, respectively. An infusion of 2 mg/kg over 60 minutes resulted in a peak concentration of 10.8 g/mL.

Netilmicin can also be administered by bolus injection over a 2 to 5 minute interval. A single dose of 2 mg/kg given in this manner resulted in a peak serum concentration of 17 to 20 g/mL at 5 minutes post injection.

Netilmicin is not metabolized and is excreted in the urine by glomerular filtration. In adult patients with normal renal function, 60 to 70% of a 2 mg/kg dose was recovered in the urine during the first 6 hours and 80 to 90% in the first 24 hours. Renal clearance was about 80 mL/minute per 1.73m i.e. 60% of the creatinine clearance.

For infants receiving 3 mg/kg doses, the average concentrations of netilmicin in urine were 46 g/mL (range 11 to 98 g/mL) during the first 3 hours post injection and 29 g/mL (range 10 to 66 g/mL) during the subsequent 3 hour collection period. On the average, 18% of a 2.5 mg/kg i.m. dose was excreted in the urine during the first 8 hours.

Renal insufficiency: In patients with chronic renal insufficiency, plasma levels increased with greater renal impairment. The increase in the elimination half life was particularly pronounced when the creatinine clearance fell below 30 mL/min per 1.73 m Renal insufficiency did not significantly modify the apparent volume of distribution. Urinary elimination was inversely related to the degree of renal impairment as only 7.1 to 15.7% of an injected dose was recovered in the urine of severely uremic patients during the first 24 hours.

In patients with renal failure undergoing hemodialysis, the amount of netilmicin removed from the blood will depend upon several factors such as plasma flow rate, length of procedure and dialysis equipment used. A 7 to 8 hour dialysis session showed a mean serum concentration decrease to 63.3±9% of the initial concentration and a mean half life of 5.49±0.72 hours.

Indications And Clinical Uses: The treatment of infections caused by susceptible strains of E. coli, Proteus species, (indole negative and some indole positive), Klebsiella, Enterobacter, Citrobacter and Staphylococcus species.

Clinical studies have shown netilmicin to be effective in some serious infections caused by P. aeruginosa and Serratia species.

Netilmicin may be indicated in the treatment of the following when caused by susceptible organisms: septicemia, lower respiratory tract infections, urinary tract infections, peritonitis, endometritis.

Limited clinical studies have shown netilmicin may also be effective in the treatment of serious bone and soft tissue infections.

Appropriate sensitivity studies should be performed to determine the susceptibility of the causative organism to netilmicin. On the basis of clinical judgment and anticipated bacteriological findings, therapy may be instituted before results of these tests are obtained. If susceptibility tests show that the causative organism is resistant to netilmicin, treatment should be replaced by other appropriate therapy.

Although netilmicin may be indicated for the treatment of serious staphylococcal infections, its use should be reserved for those staphylococcal infections also involving susceptible strains of gram-negative bacteria and then only when penicillin or other potentially less nephrotoxic drugs are inappropriate, (e.g. patients allergic to penicillin).

Contra-Indications: History of hypersensitivity to aminoglycosides.

Manufacturers’ Warnings In Clinical States: Netilmicin has the potential to cause disturbances in balance and a hearing loss. At greater risk are those patients with compromised renal function, those who have been treated previously with ototoxic drugs, or those who are receiving higher doses of netilmicin than recommended. Reversal of developing ototoxicity is contingent on early recognition of the signs and symptoms such as tinnitus, dizziness or hearing loss.

In patients with impaired renal function, the dose and/or frequency of administration of netilmicin must be reduced (see Administration and Dosage) and renal, vestibular and auditory function, as well as serum levels of netilmicin should be monitored frequently.

Netilmicin should not be administered concomitantly with potent loop diuretics such as furosemide and ethacrynic acid as the potential for ototoxicity is enhanced by the combination. Diuretics may enhance aminoglycoside toxicity either by altering the antibiotic concentration in serum and tissues or by a direct action on the auditory apparatus.

The administration of other potentially nephrotoxic drugs prior to or in conjunction with netilmicin is likely to increase the risk of nephrotoxicity.

Nephrotoxicity manifested by an increase in the level of blood urea nitrogen or serum creatinine, a decrease in creatinine clearance, or the presence of casts, cells or protein in the urine has been observed in patients administered netilmicin. These have been observed more frequently in the elderly, in patients with a history of decreased renal function and in patients treated with larger doses of netilmicin than those recommended. In most cases, these changes have been mild and were reversible on discontinuing the administration of netilmicin. Other risk factors include duration of therapy and concomitant administration of anticoagulants or furosemide. Patients with diabetes mellitus appeared to have a slightly higher incidence of renal reactions.

Pregnancy: The safety of netilmicin for use during pregnancy has not been established. Aminoglycoside antibiotics cross the placenta and may cause harm when administered to pregnant women. Irreversible bilateral congenital deafness in children whose mothers received streptomycin during pregnancy has been reported. Serious side effects to mother, fetus, or newborn have not been reported following treatment of pregnant women with other aminoglycosides, however, the potential for fetal toxicity exists. It is not known whether netilmicin can cause fetal harm when administered to pregnant women or can affect reproductive capacity. Netilmicin should be used during pregnancy only in life threatening situations or severe infections, bearing in mind the possible adverse effects on the fetus.

Lactation: Studies in nursing mothers indicate that small amounts of the drug are excreted in breast milk. Because of the potential for serious adverse reactions from aminoglycosides in nursing infants, a decision should be made whether to discontinue nursing, or to discontinue netilmicin therapy, taking into account the importance of the drug to the mother.

Precautions: Treatment with netilmicin may result in the overgrowth of nonsusceptible organisms. If superinfection occurs, appropriate therapeutic measures should be instituted.

Netilmicin, at doses considerably above those clinically recommended (i.e. greater than 10 times), has been shown to cause neuromuscular blockade and respiratory arrest in rats and mice. The injection of calcium chloride elicited a complete and rapid antagonistic effect whereas neostigmine was ineffective.

The possibility of neuromuscular blockade and respiratory arrest occurring in man should be considered, particularly if netilmicin is administered to patients receiving anesthetics, neuromuscular blocking agents (e.g. succinylcholine or tubocurarine) or massive transfusions of citrate anticoagulated blood. Thiazide diuretics have been reported to aggravate tubocurarine induced neuromuscular block.

Patients with neuromuscular disorders, such as myasthenia gravis, Parkinson’s disease or infant botulism, are at particular risk, since netilmicin could aggravate muscular weakness.

Netilmicin should be used with caution in premature and neonatal infants because of renal immaturity and the resulting prolongation of serum half life of the drug.

In patients with renal or pre-existing 8th nerve dysfunction, pre-treatment audiograms should be performed and repeated during the course of therapy. If tinnitus or subjective hearing loss should occur, the administration of netilmicin should be discontinued.

It is recommended that peak serum concentrations of netilmicin be monitored where feasible. Peak concentrations in excess of 16 g/mL for prolonged periods as well as trough concentrations greater than 4 g/mL should be avoided.

The possibility of development of resistance during prolonged therapy with netilmicin should be kept in mind.

Concurrent and/or sequential systemic or topical use of other potentially neurotoxic and/or nephrotoxic drugs, such as cisplatin, bacitracin, polymyxin B, colistin, cephaloridine, amphotericin B, kanamycin, acyclovir, gentamicin, amikacin, sisomicin, tobramycin, neomycin, streptomycin, paromomycin, viomycin and vancomycin should be avoided. Advanced age and dehydration may increase patient risk of toxicity.

A Fanconi-like syndrome, with aminoaciduria and metabolic acidosis, has been reported in some adults and infants treated with netilmicin.

In vitro mixing of an aminoglycoside with beta-lactam type antibiotics (penicillins or cephalosporins) may result in a significant mutual inactivation. Even when an aminoglycoside and a penicillin-type drug are administered separately by different routes, a reduction in aminoglycoside serum half-life or serum levels has been reported in patients with normal renal function. Usually such inactivation of the aminoglycoside is clinically significant only in patients with severely impaired renal function.

Netromycin contains sodium metabisulfite and sodium sulfite; these may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. Sulfite sensitivity is observed more frequently in asthmatic than in non-asthmatic people.

Netromycin ranges in color from water white to pale yellow. Dark yellow solutions should not be used.

Adverse Reactions: In addition to the ototoxicity and nephrotoxicity, other rarely reported adverse reactions possibly related to netilmicin include: headache, malaise, visual disturbances, disorientation, tachycardia, hypotension, palpitations, thrombocytosis, paresthesia, rash, chills, fever, fluid retention, vomiting and diarrhea. Very rarely, anaphylaxis has been reported.

Laboratory abnormalities possibly related to netilmicin include: increased blood sugar; increased alkaline phosphatase; increased AST or ALT, bilirubin; increased potassium; other abnormal liver function tests; decreased hemoglobin, WBCs and platelets; eosinophilia, anemia and increase in prothrombin time.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: In the event of overdose or toxic reaction, hemodialysis will aid in the removal of netilmicin from the blood. Appropriate supportive therapy should be instituted to maintain respiratory and kidney function.

Dosage And Administration: Netilmicin deep i.m. injection or i.v. The recommended dose for i.m. and i.v. administration is identical. Dosage should be calculated on the basis of body weight but in obese patients or emaciated patients with low volumes of distribution, dosage should be based on an estimate of lean body mass.

It is desirable to measure peak and trough netilmicin serum concentrations to assure adequate but not excessive levels. With the administration of netilmicin in 2 or 3 daily doses, the peak concentration, measured 30 minutes to 1 hour after administration, is expected to be in the range of 4 to 12 g/mL; the dosage should be adjusted to avoid prolonged peak serum concentrations above 16 g/mL. Trough concentrations above 4 g/mL, measured just before the next dose is given, should be avoided. Generally, desirable peak and trough concentrations should be in the range of 6 to 10 and 0.5 to 2 g/mL, respectively.

The usual duration of treatment is 7 to 14 days. In complicated infections, a longer course of therapy may be necessary. Patients treated beyond the usual period should be carefully monitored for changes in renal, auditory and vestibular function.

Patients with normal renal function: Adults: Patients with uncomplicated urinary tract infections: 4.0 mg/kg/day divided into 2 equal doses and administered every 12 hours for 7 to 10 days. For the average adult (50 to 80 kg) 150 mg may be given every 12 hours.

Patients with systemic infections: 4.0 to 6.0 mg/kg/day divided into 2 or 3 equal doses and administered every 12 or 8 hours, respectively. For the average adult (50 to 80 kg), depending on the severity of infection, the usual dose is 100 mg to 150 mg administered every 8 hours or 150 mg to 200 mg every 12 hours for 7 to 14 days.

Patients with serious systemic infections (life threatening), i.v. dosages up to 7.5 mg/kg/day divided into 3 equal doses. This dosage should be reduced to 6.0 mg/kg/day as soon as clinically indicated, usually within 48 hours.

Concomitant administration of a penicillin type antibiotic with netilmicin should be considered as initial therapy in certain cases of sepsis, particularly in immunosuppressed patients, while awaiting culture and susceptibility results. Treatment should be adjusted when these results become available.

Children: 6.0 to 7.5 mg/kg/day divided into 3 equal doses and administered every 8 hours. This should be reduced to 6.0 mg/kg/day as soon as clinically indicated.

Infants and Neonates: (Greater than 1 week of age): 7.5 to 9.0 mg/kg/day divided into 3 equal doses and administered every 8 hours.

Premature and Full Term Neonates: (Less than 1 week of age): 6 mg/kg/day divided into 2 equal doses and administered every 12 hours (see Precautions).

Patients with impaired renal function: Adults: The initial dose is the same as that recommended for patients with normal renal function. Dosage must be adjusted in patients with impaired renal function and when possible, serum concentrations of netilmicin should be monitored. If serum concentrations cannot be monitored, serum creatinine or preferably, creatinine clearance values can be used as a guide for dosage adjustments. Adjustments in dosage can be made by either lengthening the interval between doses or by a reduction in dose administered at 8 hour intervals as follows. In the elderly or debilitated patients, it is suggested that creatinine clearance values be used:

Adjusted Intervals: Normal Dosage: If the patient’s serum creatinine is known, the interval between the usual single dose given at 8 hourly intervals can be calculated by multiplying the patient’s serum creatinine by a factor of 8. Thus, a patient with a serum creatinine of 3 mg/100 mL would be given 2 mg/kg every 24 hours (i.e. 3 x 8=24) rather than the usual dose of 2 mg/kg every 8 hours.

For patients requiring dialysis, as approximately 50% of the initial dose may be removed during standardized hemodialysis, at least 50% of the initial loading dose would be required after dialysis. In these patients serum concentrations of netilmicin should be monitored.

Children: At present there is insufficient data to recommend a specific dosage for children with impaired renal function.

Administration: I.M.: Netilmicin should be given by deep i.m. injection.

I.V.: I.V. administration of netilmicin is recommended when the i.m. route is not advisable, e.g. patients in shock or with severe burns, hematological bleeding disorders or a reduced muscle mass.

Adults: A single dose of netilmicin may be diluted in 50 to 200 mL of one of the compatible sterile solutions listed below and administered over a 30 to 60 minute period. A single 2.0 mg/kg dose may also be given directly into a vein or side-arm of an i.v. tubing, provided that it is administered over a 3 to 5 minute period.

Infants and Children: The volume of diluent should be proportionally less, according to the fluid requirements of the patient.

I.V. Solution: Netilmicin has been shown to be compatible with the following solutions: sterile water for injection, normal saline, 5% dextrose in water, 10% dextrose in water, Ringer’s solution and lactated Ringer’s solution. When diluted to a concentration of 3 mg/mL the prepared solutions should not be stored for longer than 24 hours at room temperature or 48 hours under refrigeration.

Netromycin should not be physically premixed with other drugs but should be administered separately in accordance with the recommended dosage schedule.

Availability And Storage: 100 mg/mL: Each mL of clear, sterile aqueous solution contains: netilmicin (as sulfate USP) 100 mg. Nonmedicinal ingredients: benzyl alcohol, edetate disodium, sodium metabisulfite and sodium sulfite. Vials of 2 mL and pharmacy bulk vials of 20 mL.

50 mg/mL: Each mL of clear, sterile aqueous solution contains: netilmicin (as sulfate USP) 50 mg. Nonmedicinal ingredients: edetate disodium, methylparaben, propylparaben, sodium metabisulfite, sodium sulfate and sodium sulfite. Vials of 2 mL.

Store at 2 to 30°C. Protect from freezing.

NETROMYCIN® Schering Netilmicin Sulfate Antibiotic

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