4.1. Therapeutic indications

Tobramycin Injection is indicated in the treatment of the following serious infections caused by susceptible micro-organisms:

• The treatment of central nervous system infections including meningitis, septicaemia and neonatal sepsis

• The treatment of gastro-intestinal infections including peritonitis

• The treatment of complicated and recurrent urinary tract infections such as pyelonephritis and cystitis

• The treatment of lower respiratory tract infections, including pneumonia, bronchopneumonia and acute bronchitis

• The treatment of skin, bone and soft tissue infections including burns.

Tobramycin may also be considered in serious staphylococcal infections for which penicillin or other less potentially toxic drugs are contraindicated and when bacterial susceptibility testing and clinical judgement indicate its use.

4.2. Posology and method of administration

Posology

Tobramycin Injection may be given intramuscularly or intravenously and the dosage is the same for either route of administration. To calculate the correct dosage, the patient's pre- treatment body weight should be obtained.

It is recommended that both peak and trough serum levels should be determined whenever possible to ensure the correct dosage is given.

Blood levels should always be determined in patients with chronic infections such as cystic fibrosis, or where longer duration of treatment may be necessary, or in patients with decreased renal function.

Duration of treatment

The usual length of treatment is seven to ten days. However, in difficult and complicated infections, a longer course of therapy may be necessary. In such cases monitoring of renal, auditory and vestibular functions is advised because neurotoxicity is more likely to occur when treatment is extended longer than ten days.

Patients with normal renal function

Adults

For adults with serious infections the usual recommended dosage is 3 mg/kg/day, administered in three equal doses every eight hours.

(see Table 1).

Patients with life-threatening infections, dosages up to 5 mg/kg/day may be administered in three or four equal dosages. The dosage should be reduced to 3 mg/kg/day as soon as clinically indicated. Dosage should not exceed 5 mg/kg/day, unless serum levels are monitored in order to prevent increased toxicity due to excessive blood levels. (see section 4.4).

It may be necessary to administer up to 8 to 10 mg/kg/day in equally divided doses, to achieve therapeutic serum levels for patients with cystic fibrosis. Serum levels should be monitored because serum concentrations of tobramycin vary from patient to patient.

In adults with normal renal function, mild to moderate infections of the urinary tract have responded to a dosage of 2-3 mg/kg/day administered as a single intramuscular injection. (see Table 1).

Table 1 Dosage schedule for adults with normal renal function (Dosage at 8-hour intervals)

Patient

Weight

Usual dose for

Serious Infections 1 mg/kg q 8 h.

(Total 3 mg/kg/day)

Maximum dose for

Life-threatening Infections (Reduce as soon as possible) 1.66 mg/kg q 8 h.

(Total 5 mg/kg/day - unless monitored)

Kg

mg/dose

ml/dose*

mg/dose

ml/dose*

120

120

3.0

200

5.0

100

100

2.5

166

4.0

80

80

2.0

133

3.0

60

60

1.5

100

2.5

40

40

1.0

66

1.6

* Applicable to 40 mg/ml product forms.

Following IM administration of a single dose of tobramycin of l mg/kg in adults with normal renal function, peak plasma tobramycin concentrations averaging 4-6 micrograms/ml are attained within 30-90 minutes; plasma concentrations of the drug are 1 microgram/ml or less at 8 hours. Following intravenous infusion of the same dose over 30-60 minutes, similar plasma concentrations of the drug are obtained.

Elderly

As for adults, but see recommendations for patients with impaired renal function.

Paediatric population

The recommended dosage is 6-7.5 mg/kg/day, administered in 3 or 4 equally divided doses. It may be necessary to administer higher doses in some patients.

Premature or full-term neonates

Dosages of up to 4 mg/kg/day may be administered in two equal doses every 12 hours, for children between 1.5 and 2.5 kg body weight.

In neonates, average peak plasma tobramycin concentrations of about 5 micrograms/ml are attained 30-60 minutes after a single IM dose of 2 mg/kg; plasma concentrations average 1-2 micrograms/ml at 12 hours.

Obese patients

The appropriate dose may be calculated using the patient's estimated lean body weight, plus 40% of the excess, as the weight on which to determine mg/kg.

Patients with impaired renal function

Following a loading dose of 1 mg/kg, subsequent dosage must be adjusted, either with lower doses administered at 8 hr intervals or with normal doses at prolonged intervals, (see Table 2). Both these regimens are suggested as guides to be used when serum levels of tobramycin cannot be measured directly. They are based on either the creatinine clearance or the serum creatinine of the patient, because these values correlate with the half-life of tobramycin. Neither regimen should be used when dialysis is being performed.

REGIMEN I - Reduced dosage at 8-hour intervals

An appropriate reduced dosage range can be found in the accompanying table, (see Table 2) for any patient for whom the creatinine clearance or serum creatinine values are known. The choice of dose within the indicated range should be based on the severity of the infection, the sensitivity of the pathogen, and individual patient considerations, especially renal function. Another rough guide for determining reduced dosage at 8-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 value (mg/100 ml).

REGIMEN II - Normal dosage at prolonged intervals

Table 2 illustrates the recommended intervals between doses. As a general rule, the dosage frequency in hours can be determined by multiplying the patient's serum creatinine level (expressed as mg/100 ml) by six.

The dosage schedules derived from either method should be used in conjunction with careful clinical and laboratory observations of the patient and should be modified as necessary. (see section 4.4).

Table 2 Two maintenance regimens based on renal function and body weight following a loading dose of 1 mg/kg*

Renal Function°

Regimen I

Regimen II

Adjusted doses at 8-hour intervals

Normal dosage at prolonged intervals

Serum Creatinine

Creatinine Clearance

Weight

Weight/Dose

50-60 kg : 60 mg

60-80 kg : 80 mg

mg/100 ml

μmol/litre

ml/min

50-60 kg

60-80 kg

< 1.3

<114.9

>70

60mg

80mg

q. 8h

1.4 - 1.9

123.8 - 168

69 – 40

30 - 60mg

50 - 80mg

q. 12h

2.0 - 3.3

176.8 - 291.7

39 – 20

20 - 25mg

30 - 45mg

q. 18h

3.4 - 5.3

300.6 - 468.5

19 – 10

10 - 18mg

15 - 24mg

q. 24h

5.4 - 7.5

477.4 - 663

9 – 5

5 - 9mg

7 - 12mg

q. 36h

> 7.6

> 671.8

<4

2.5 - 4.5mg

3.5 - 6mg

q.48h†

*

For life-threatening infections, dosages 50% above those normally recommended may be used. The dosages should be reduced as soon as possible when improvement is noted.

°

If used to estimate degree of renal impairment, serum creatinine concentrations

should reflect a steady state of renal uraemia

†

When dialysis is not being performed.

Method of administration

Precautions to be taken before handling or administering the medicinal product.

Intramuscular administration

Tobramycin Injection may be administered by withdrawing the appropriate dose directly from the vial.

Intravenous administration

Tobramycin Injection may be given by intravenous infusion or by direct intravenous injection. When given by infusion, Tobramycin Injection may be diluted (with 0.9% Sodium Chloride Intravenous Infusion or 5% Dextrose Intravenous Infusion) to volumes of 50-100 ml for adult doses. For children, the volume of diluent should be proportionately less than for adults. The diluted solution should be infused over a period of 20-60 minutes avoiding admixture with any other drug. Tobramycin Injection may be administered slowly by direct intravenous injection or into the tubing of a drip set. When given in this way, serum levels may exceed 12 mg/litre for a short time. (see section 4.4).

4.3. Contraindications

Intrathecal administration.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Because of the known cross-allergenicity of drugs in this class, hypersensitivity to any aminoglycoside is a contraindication to the use of tobramycin.

4.4. Special warnings and precautions for use

Evidence of impairment in renal, vestibular and/or auditory function requires discontinuation of the drug or dosage adjustment.

Ototoxicity

Both vestibular and auditory ototoxicity can occur. Eighth nerve impairment may develop in patients with pre-existing renal damage, and if tobramycin is administered for longer periods or in higher doses than those recommended. Other manifestations of neurotoxicity may include numbness, skin tingling, muscle twitching and convulsions.

The risk of aminoglycoside-induced hearing loss increases with the degree of exposure to either high peak or high trough serum concentrations.

Patients with mitochondrial DNA mutations, particularly the nucleotide 1555 A to G substitution in the 12S rRNA gene may be at higher risk for ototoxicity, even if the patient's aminoglycoside serum levels were within the recommended range. In case of family history of aminoglycoside-induced deafness or known mitochondrial DNA mutations in the 12S rRNA gene, alternative treatments other than aminoglycosides may need to be considered.

Patients who develop cochlear damage may not have symptoms during therapy to warn of eighth-nerve toxicity, and partial or total irreversible bilateral deafness may continue to develop after the drug has been discontinued.

Nephrotoxicity

Rarely, nephrotoxicity may not become manifest until the first few days after cessation of therapy. Aminoglycoside-induced nephrotoxicity is usually reversible. Therefore, renal and eighth cranial nerve function should be closely monitored in patients with known or suspected renal impairment and also in those whose renal function is initially normal but who develop signs of renal dysfunction during therapy.

Elderly

In elderly patients, it is particularly important to monitor renal function, when reduced renal function may not be evident in the results of routine screening tests, such as blood urea or serum creatinine. A creatinine clearance determination may be more useful. Serum concentrations should be monitored when possible, and prolonged concentrations above 12 mg/litre should be avoided. A useful guideline would be to perform serum level assays after 2 or 3 doses and also at 3 or 4 day intervals during therapy, so that the dosage could be adjusted if necessary. Rising trough levels (above 2 mg/L) may indicate tissue accumulation. Such accumulation and cumulative dose may contribute to ototoxicity and nephrotoxicity. In the event of changing renal function, more frequent serum levels should be obtained and the dosage or dosage intervals adjusted according to the guidelines provided (see section 4.2). In order to measure the peak level, a serum sample should be drawn about 30 minutes following intravenous infusion or at one hour after intramuscular injection. Trough levels are measured by obtaining serum samples at 8 hours or just prior to the next dose of tobramycin.

Renal impairment

In patients with normal renal function who do not receive tobramycin in higher doses or for longer periods of time than those recommended, the risk of toxic reactions is low. However, patients with reduced renal function are prone to the potential ototoxic and nephrotoxic effects of this drug, so dosage should be adjusted carefully on the basis of regular monitoring of serum drug concentrations and of renal function.

Neurotoxic and / or nephrotoxic drugs

Concurrent and sequential use of other nephrotic, neurotoxic or ototoxic drugs, particularly streptomycin, neomycin, kanamycin, gentamicin, cephaloridine, paromomycin, viomycin, polymyxin B, colistin, cisplatin, vancomycin and amikacin, should be avoided. Advanced age and dehydration may also increase patient risk.

Diuretics

Tobramycin should not be given concurrently with potent diuretics. Some diuretics themselves cause ototoxicity, and diuretics administered intravenously enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue.

General

It is desirable to measure both peak and trough serum concentrations as high doses of drug may be associated with a greater risk of toxicity.

Cross-allergenicity among aminoglycosides has been known to occur. Patients treated with aminoglycoside antibiotics such as tobramycin should be under close clinical observation because these drugs have an inherent potential for causing nephrotoxicity and ototoxicity.

Serum calcium, magnesium and sodium should be monitored. It is particularly important to monitor serum levels closely in patients with known renal impairment.

Urine should be examined for increased excretion of protein, cells and casts. Serum creatinine or creatinine clearance (preferred over blood urea) should be measured periodically. When possible, it is recommended that serial audiograms be obtained in patients old enough to be tested, particularly high-risk patients.

In patients with extensive burns or cystic fibrosis, altered pharmacokinetics may result in reduced serum drug levels. Dosage must be based on measured serum levels in these patients.

Administration

Aminoglycosides may be absorbed in significant quantities from body surfaces for local irrigation or application and may cause neurotoxicity and nephrotoxicity.

Although not indicated for intraocular and/or subconjunctival use, there have been reports of macular necrosis following this type of injection.

Effect on neuromuscular function

Aminoglycosides should be used with caution in patients with muscular disorders, such as myasthenia gravis or parkinsonism, since these drugs may aggravate muscle weakness because of their potential curare-like effect on neuromuscular function.

Neuromuscular blockade or respiratory paralysis may occur following rapid intravenous administration of many aminoglycosides and have been reported in cats receiving very high doses of tobramycin (40mg/kg). The possibility of prolonged secondary apnoea should be considered if tobramycin is administered to anaesthetised patients who are also receiving neuromuscular blocking agents such as succinylcholine, tubocurarine or decamethonium, or to patients receiving massive transfusions of citrated blood. If neuromuscular blockade occurs, it may be reversed by the administration of calcium salts.

Beta-lactam antibiotics

The inactivation of tobramycin by beta-lactam-type antibiotics (penicillins or cephalosporins) has been demonstrated in vitro and in patients with severe renal impairment. Such in activation has not been found in patients with normal renal function if the drugs are administered by separate routes.

Superinfection

If overgrowth of non-susceptible organisms occurs, appropriate therapy should be initiated.

Use in

Use in neonates

Tobramycin should be used with caution and in reduced dosage in premature and full term neonate infants younger than 6 weeks of age because of their renal immaturity and the resulting prolongation of serum half-life of the drug.

Excipient information

Tobramycin injection contains sodium metabisulphite which may rarely cause severe hypersensitivity reactions and bronchospasm. The overall prevalence of sulphite sensitivity in the general population is unknown and probably low, but it occurs more frequently in asthmatic patients.

This medicine contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Antibacterials: Tobramycin used in conjunction with other antibacterials such as cephalosporins notably cephalothin, there is an increased risk of nephrotoxicity.

Antifungals: Amphotericin B may produce synergistic renal toxicity.

Diuretics: Tobramycin should not be given in conjunction with ethacrynic acid, furosemide or other potent diuretics which may cause ototoxicity or enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue.

General anaesthetics and Neuromuscular Blocking Agents: Concurrent use of tobramycin with general anaesthetics (e.g. succinylcholine, tubocurarine) may potentiate neuromuscular blockade and cause respiratory paralysis.

Muscle Relaxants: Enhanced blockade of respiratory paralysis can occur with skeletal muscle relaxants.

Cytotoxics and Cyclosporins: There is increased risk of nephrotoxicity and possibly ototoxicity with Cisplatin as well as increased risk of nephrotoxicity with cyclosporins.

Tobramycin has been known to potentiate warfarin and phenindione.

Cholinergics: Antagonism of effect of neostigmine and pyridostigmine.

4.6. Fertility, pregnancy and lactation

Pregnancy

Aminoglycoside antibiotics cross the placenta and can cause foetal harm when administered to a pregnant woman. Serious side effects to mother, foetus or newborn have been reported in the treatment of pregnant women with aminoglycosides (e.g., several reports of total irreversible bilateral congenital deafness in children whose mothers received streptomycin during pregnancy). Tobramycin should not be administered to the pregnant patient unless the potential benefits clearly outweigh any potential risk. If tobramycin is used during pregnancy or if the patient becomes pregnant whilst taking tobramycin, she should be informed of the potential hazard to the foetus.

Breast-feeding

Tobramycin is excreted in the breast milk and should be avoided in nursing women.

4.7. Effects on ability to drive and use machines

The effect of tobramycin on the ability to drive or use machines has not been systematically evaluated.

4.8. Undesirable effects

The frequency grouping is defined using the following convention: Very common (≥1/10); Common (≥ 1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥ 1/10,000 to <1/1,000); Very Rare (< 1/10,000); and Not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Blood and lymphatic system disorders

Not known

Anaemia, granulocytopenia, thrombocytopenia, leucopenia, leucocytosis, eosinophilia

Immune system disorders

Not known

Hypersensitivity

Psychiatric disorders:

Not known

Mental confusion, disorientation

Nervous system disorders

Not known

Dizziness, headache, lethargy

Ear and labyrinth disorders1

Not known

Hearing loss, tinnitus, vertigo

Gastrointestinal disorders:

Not known

Nausea, vomiting, diarrhea

Skin and subcutaneous tissue disorders:

Not known

Dermatitis exfoliative, rash, itching, urticaria

Renal and urinary disorders2

Not known

Acute kidney injury, blood creatinine increased, blood urea increased, proteinuria, oliguria, cylindruria

General disorders and administration site conditions

Not known

Fever, pain at injection site

Investigations

Not known

Blood bilirubin increased, aspartate aminotransferase increased, alanine aminotransferase increased, blood calcium decreased, blood magnesium decreased, blood sodium decreased, blood potassium decreased

1 In patients receiving high doses or prolonged therapy, side effects on both vestibular and

auditory branches of the eighth cranial nerve have been reported. Similar effects have been noted in those given previous courses of therapy with an ototoxin, and in cases of dehydration. Symptoms include vertigo, tinnitus, roaring in the ears and hearing loss. Hearing loss is usually irreversible and is manifested initially by diminution of high tone acuity.

2 Renal function changes have been reported, especially in patients with a history of renal impairment who are treated for longer periods or with higher doses than these recommended. These changes can occur in patients with initially normal renal function.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Severity of the manifestations of a tobramycin overdose depend on the dose, the patient's renal function, state of hydration, age and whether concurrent medication with similar toxicities is being given. Toxicity may occur in patients treated for more than 10 days, given more than 5mg/kg/day, children given more than 7.5mg/kg/day, or patients with reduced renal function whose dose has not been appropriately adjusted.

Nephrotoxicity following the parenteral administration of an aminoglycoside is most closely related to the AUC of serum concentrations versus time. Nephrotoxicity is more likely if trough levels fail to fall below 2 micrograms/ml and is also proportional to the average blood concentration. Patients who are elderly, have renal impairment, are receiving other nephrotoxic or ototoxic drugs, or are volume depleted, are at greater risk for developing acute tubular necrosis or auditory and vestibular toxicity. These toxicities occur in patients treated longer than 10 days, in patients with abnormal renal function, in dehydrated patients, or in patients on other ototoxic drugs.

These patients may not have signs or symptoms or may experience dizziness, tinnitus, vertigo and a loss of high-tone acuity. Signs and symptoms may not occur until long after the drug has been discontinued.

Neuromuscular blockade or respiratory failure may occur following rapid intravenous administration of many aminoglycosides. These reactions and prolonged respiratory paralysis may occur more commonly in patients with myasthenia gravis or Parkinson's disease, or those receiving decamethonium, tubocurarine or succinylcholine.

Toxicity from ingested tobramycin is unlikely because aminoglycosides are poorly absorbed from an intact gastro-intestinal tract.

Treatment of overdose

Resuscitative measures should be initiated promptly if respiratory paralysis occurs. Haemodialysis or peritoneal dialysis will help remove tobramycin from the blood in the event of overdosage or toxic reactions. Depending on the duration and type of dialysis employed, approximately 25-70% of the administered dose may be removed. Haemodialysis is the more effective method. Fluid balance, creatinine clearance and tobramycin plasma levels should be carefully monitored until the tobramycin level falls below 2mg/l. Calcium salts given intravenously have been used to counter neuromuscular blockade, the effectiveness of neostigmine has been variable. Mechanical assistance may be necessary.