Tobramycin

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 the table below). 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 the table below) 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:

The following 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.

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

* 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.

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

Enhanced blockade of respiratory paralysis can occur in co-administration of tobramycin with skeletal muscle relaxants.

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

Amphotericin B may produce synergistic renal toxicity in co-administration with tobramycin.

There is increased risk of nephrotoxicity and possibly ototoxicity with cisplatin as well as increased risk of nephrotoxicity with ciclosporin.

Tobramycin should not be given in conjunction with ethacrynic acid, furosemide or other potent diuretics which may cause ototoxicity or enhance aminoglycoside toxicity.

There is antagonism of effect of neostigmine and pyridostigmine in co-administration with tobramycin.

Tobramycin has been known to potentiate warfarin and phenindione.

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

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. 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. 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.

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 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.

IM / IV administration

Aminoglycosides can cause foetal harm when administered to a pregnant woman. Aminoglycosides such as tobramycin cross the placenta and there have been several reports of total irreversible bilateral congenital deafness in children whose mothers received streptomycin during pregnancy. Although serious side effects to mother, foetus, or newborn have not been reported in the treatment of pregnant women with other aminoglycosides, 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.

Inhalation

There are no adequate data on the use of tobramycin via inhalation in pregnant women. Animal studies with tobramycin do not indicate a teratogenic effect. However, aminoglycosides can cause foetal harm (e.g. congenital deafness) when high systemic concentrations are achieved in a pregnant woman. Systemic exposure following inhalation of tobramycin inhalation powder is very low, however tobramycin should not be used during pregnancy unless clearly necessary, i.e. when the benefits to the mother outweigh the risks to the foetus. Patients who use tobramycin inhalation powder during pregnancy, or become pregnant while taking tobramycin inhalation powder, should be informed of the potential hazard to the foetus.

Tobramycin is excreted in human breast milk after systemic administration. The amount of tobramycin excreted in human breast milk after administration by inhalation is not known, though it is estimated to be very low considering the low systemic exposure. Because of the potential for ototoxicity and nephrotoxicity in infants, a decision should be made whether to terminate breast-feeding or discontinue treatment with tobramycin inhalation powder, taking into account the importance of the treatment to the mother.

Fertility

No effect on male or female fertility was observed in animal studies after subcutaneous administration.

Tobramycin has no or negligible influence on the ability to drive and use machines.

IV / IM administration

Renal and urinary disorders

Renal function changes such as rising blood urea and serum creatinine and by oliguria, cylindruria and increased proteinuria, 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.

Ear and labyrinth disorders

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.

Nervous system disorders

Dizziness, headache, lethargy.

Investigations

Increased AST, ALT, and serum bilirubin; decreased serum calcium, magnesium, sodium, potassium.

Blood and lymphatic system disorders

Anaemia, granulocytopenia, thrombocytopenia, leucopenia, leucocytosis and eosinophilia.

Immune system disorders

Hypersensitivity.

General disorders and administration site conditions

Fever, pain at injection site.

Skin and subcutaneous tissue disorders

Rash, itching, urticaria, exfoliative dermatitis.

Gastrointestinal disorders

Nausea, vomiting, diarrhea.

Psychiatric disorders

Mental confusion and disorientation.

Respiratory administration

Summary of the safety profile

The most commonly reported adverse reactions in the main safety, active-controlled clinical study with tobramycin inhalation powder versus tobramycin nebuliser solution in cystic fibrosis patients with P. aeruginosa infection were cough, productive cough, pyrexia, dyspnoea, oropharyngeal pain, dysphonia and haemoptysis.

In the placebo-controlled study with tobramycin inhalation powder, the adverse reactions for which reported frequency was higher with inhalation powder than with placebo were pharyngolaryngeal pain, dysgeusia and dysphonia.

The vast majority of adverse reactions reported with tobramycin inhalation powder were mild or moderate, and severity did not appear to differ between cycles or between the entire study and on-treatment periods.

Summary of adverse reactions

Adverse drug reactions below are listed according to system organ classes in MedDRA. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category using the following convention (CIOMS III) is also provided for each adverse drug reaction: 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); not known: frequency cannot be estimated from the available data.

The frequencies in the following list are based on the reporting rates from the active-controlled study.

Ear and labyrinth disorders

Common: Hearing loss, Tinnitus

Vascular disorders

Very common: Haemoptysis

Common: Epistaxis

Respiratory, thoracic and mediastinal disorders

Very common: Dyspnoea, Dysphonia, Productive cough, Cough

Common: Wheezing, Rales, Chest discomfort, Nasal congestion, Bronchospasm, Aphonia

Not known: Sputum discoloured

Gastrointestinal disorders

Very common: Oropharnygeal pain

Common: Vomiting, Diarrhoea, Throat irritation, Nausea, Dysgeusia

Skin and subcutaneous tissue disorders

Common: Rash

Musculoskeletal, connective tissue and bone disorders

Common: Musculoskeletal chest pain

General disorders and administration site conditions

Very common: Pyrexia

Not known: Malaise

Description of selected adverse drug reactions

Cough was the most frequently reported adverse reaction in both clinical studies. However, no association was observed in either clinical study between the incidence of bronchospasm and cough events.

In the active-controlled study, audiology testing was performed in selected centres accounting for about a quarter of the study population. Four patients in the inhalation powder treatment group experienced significant decreases in hearing which were transient in three patients and persistent in one case.

In the active-controlled open-label study, patients aged 20 years and older tended to discontinue more frequently with inhalation powder than with the nebuliser solution; discontinuations due to adverse events accounted for about half of the discontinuations with each formulation. In children under 13 years of age, discontinuations were more frequent in the nebuliser solution arm whereas in patients aged 13 to 19, discontinuation rates with both formulations were similar.