Bactolin

Nosocomial pneumonia

Community acquired pneumonia

Bactolin is indicated for the treatment of community acquired pneumonia and nosocomial pneumonia when known or suspected to be caused by susceptible Gram positive bacteria.).

Bactolin is not active against infections caused by Gram negative pathogens. Specific therapy against Gram negative organisms must be initiated concomitantly if a Gram negative pathogen is documented or suspected.

Complicated skin and soft tissue infections

Bactolin is indicated for the treatment of complicated skin and soft tissue infections only when microbiological testing has established that the infection is known to be caused by susceptible Gram positive bacteria.

Bactolin is not active against infections caused by Gram negative pathogens. Bactolin should only be used in patients with complicated skin and soft tissue infections with known or possible co-infection with Gram negative organisms if there are no alternative treatment options available. In these circumstances treatment against Gram negative organisms must be initiated concomitantly.

Bactolin should only be initiated in a hospital environment and after consultation with a relevant specialist such as a microbiologist or infectious diseases specialist.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Posology

Bactolin solution for infusion, film-coated tablets or oral suspension may be used as initial therapy. Patients who commence treatment on the parenteral formulation may be switched to either oral presentation when clinically indicated. In such circumstances, no dose adjustment is required as Bactolin has an oral bioavailability of approximately 100%.

Recommended dosage and duration of treatment for adults: The duration of treatment is dependent on the pathogen, the site of infection and its severity, and on the patient's clinical response.

The following recommendations for duration of therapy reflect those used in the clinical trials. Shorter treatment regimens may be suitable for some types of infection but have not been evaluated in clinical trials.

The maximum treatment duration is 28 days. The safety and effectiveness of Bactolin when administered for periods longer than 28 days have not been established..

No increase in the recommended dosage or duration of treatment is required for infections associated with concurrent bacteraemia.

The dose recommendation for the solution for infusion and the tablets/granules for oral suspension are identicalare as follows:

Paediatric population: There are insufficient data on the safety and efficacy of Bactolin in children and adolescents (< 18 years old) to establish dosage recommendations. Therefore, until further data are available, use of Bactolin in this age group is not recommended.

Elderly patients: No dose adjustment is required.

Patients with renal insufficiency: No dose adjustment is required.

Patients with severe renal insufficiency (i.e. CL_CR < 30 ml/min): No dose adjustment is required. Due to the unknown clinical significance of higher exposure (up to 10 fold) to the two primary metabolites of Bactolin in patients with severe renal insufficiency, Bactolin should be used with special caution in these patients and only when the anticipated benefit is considered to outweigh the theoretical risk.

As approximately 30% of a Bactolin dose is removed during 3 hours of haemodialysis, Bactolin should be given after dialysis in patients receiving such treatment. The primary metabolites of Bactolin are removed to some extent by haemodialysis, but the concentrations of these metabolites are still very considerably higher following dialysis than those observed in patients with normal renal function or mild to moderate renal insufficiency.

Therefore, Bactolin should be used with special caution in patients with severe renal insufficiency who are undergoing dialysis and only when the anticipated benefit is considered to outweigh the theoretical risk.

To date, there is no experience of Bactolin administration to patients undergoing continuous ambulatory peritoneal dialysis (CAPD) or alternative treatments for renal failure (other than haemodialysis).

Patients with hepatic insufficiency: No dose adjustment is required. However, there are limited clinical data and it is recommended that Bactolin should be used in such patients only when the anticipated benefit is considered to outweigh the theoretical risk.

Method of administration:

The recommended Bactolin dosage should be administered intravenously or orally twice daily.

Route of administration: Oral use.

The film-coated tablets may be taken with or without food.

Bactolin should not be used in patients taking any medicinal product which inhibits monoamine oxidases A or B (e.g. phenelzine, isocarboxazid, selegiline, moclobemide) or within two weeks of taking any such medicinal product.

Unless there are facilities available for close observation and monitoring of blood pressure, Bactolin should not be administered to patients with the following underlying clinical conditions or on the following types of concomitant medications:

- Patients with uncontrolled hypertension, phaeochromocytoma, carcinoid, thyrotoxicosis, bipolar depression, schizoaffective disorder, acute confusional states.

- Patients taking any of the following medications: serotonin re-uptake inhibitors , tricyclic antidepressants, serotonin 5-HT₁ receptor agonists (triptans), directly and indirectly acting sympathomimetic agents (including the adrenergic bronchodilators, pseudoephedrine and phenylpropanolamine), vasopressive agents (e.g. epinephrine, norepinephrine), dopaminergic agents (e.g. dopamine, dobutamine), pethidine or buspirone.

Animal data suggest that Bactolin and its metabolites may pass into breast milk and, accordingly, breastfeeding should be discontinued prior to and throughout administration.

Myelosuppression

Myelosuppression (including anaemia, leucopenia, pancytopenia and thrombocytopenia) has been reported in patients receiving Bactolin. In cases where the outcome is known, when Bactolin was discontinued, the affected haematologic parameters have risen toward pretreatment levels. The risk of these effects appears to be related to the duration of treatment. Elderly patients treated with Bactolin may be at greater risk of experiencing blood dyscrasias than younger patients. Thrombocytopenia may occur more commonly in patients with severe renal insufficiency, whether or not on dialysis. Therefore, close monitoring of blood counts is recommended in patients who: have pre-existing anaemia, granulocytopenia or thrombocytopenia; are receiving concomitant medications that may decrease haemoglobin levels, depress blood counts or adversely affect platelet count or function; have severe renal insufficiency; receive more than 10-14 days of therapy. Bactolin should be administered to such patients only when close monitoring of haemoglobin levels, blood counts and platelet counts is possible.

If significant myelosuppression occurs during Bactolin therapy, treatment should be stopped unless it is considered absolutely necessary to continue therapy, in which case intensive monitoring of blood counts and appropriate management strategies should be implemented.

In addition, it is recommended that complete blood counts (including haemoglobin levels, platelets, and total and differentiated leucocyte counts) should be monitored weekly in patients who receive Bactolin regardless of baseline blood count.

In compassionate use studies, a higher incidence of serious anaemia was reported in patients receiving Bactolin for more than the maximum recommended duration of 28 days. These patients more often required blood transfusion. Cases of anaemia requiring blood transfusion have also been reported post marketing, with more cases occurring in patients who received Bactolin therapy for more than 28 days.

Cases of sideroblastic anaemia have been reported post-marketing. Where time of onset was known, most patients had received Bactolin therapy for more than 28 days. Most patients fully or partially recovered following discontinuation of Bactolin with or without treatment for their anaemia.

Mortality imbalance in a clinical trial in patients with catheter-related Gram positive bloodstream infections

Excess mortality was seen in patients treated with Bactolin, relative to vancomycin/dicloxacillin/oxacillin, in an open-label study in seriously ill patients with intravascular catheter-related infections [78/363 (21.5%) vs 58/363 (16.0%)]. The main factor influencing the mortality rate was the Gram positive infection status at baseline. Mortality rates were similar in patients with infections caused purely by Gram positive organisms (odds ratio 0.96; 95% confidence interval: 0.58-1.59) but were significantly higher (p=0.0162) in the Bactolin arm in patients with any other pathogen or no pathogen at baseline (odds ratio 2.48; 95% confidence interval: 1.38-4.46). The greatest imbalance occurred during treatment and within 7 days following discontinuation of study drug. More patients in the Bactolin arm acquired Gram negative pathogens during the study and died from infection caused by Gram negative pathogens and polymicrobial infections. Therefore, in complicated skin and soft tissue infections Bactolin should only be used in patients with known or possible co-infection with Gram negative organisms if there are no alternative treatment options available. In these circumstances treatment against Gram negative organisms must be initiated concomitantly.

Antibiotic-associated diarrhoea and colitis

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including Bactolin. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of any antibacterial agent. In cases of suspected or verified antibiotic-associated colitis, discontinuation of Bactolin may be warranted. Appropriate management measures should be instituted.

Antibiotic-associated diarrhoea and antibiotic-associated colitis, including pseudomembranous colitis and Clostridium difficile-associated diarrhoea, has been reported in association with the use of nearly all antibiotics including Bactolin and may range in severity from mild diarrhoea to fatal colitis. Therefore, it is important to consider this diagnosis in patients who develop serious diarrhoea during or after the use of Bactolin. If antibiotic-associated diarrhoea or antibiotic-associated colitis is suspected or confirmed, ongoing treatment with antibacterial agents, including Bactolin, should be discontinued and adequate therapeutic measures should be initiated immediately. Drugs inhibiting peristalsis are contraindicated in this situation.

Lactic acidosis

Lactic acidosis has been reported with the use of Bactolin. Patients who develop signs and symptoms of metabolic acidosis including recurrent nausea or vomiting, abdominal pain, a low bicarbonate level, or hyperventilation while receiving Bactolin should receive immediate medical attention. If lactic acidosis occurs, the benefits of continued use of Bactolin should be weighed against the potential risks.

Mitochondrial dysfunction

Bactolin inhibits mitochondrial protein synthesis. Adverse events, such as lactic acidosis, anaemia and neuropathy (optic and peripheral), may occur as a result of this inhibition; these events are more common when the drug is used longer than 28 days.

Serotonin syndrome

Spontaneous reports of serotonin syndrome associated with the co-administration of Bactolin and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) have been reported. Co-administration of Bactolin and serotonergic agents is therefore contraindicated except where administration of Bactolin and concomitant serotonergic agents is essential. In those cases patients should be closely observed for signs and symptoms of serotonin syndrome such as cognitive dysfunction, hyperpyrexia, hyperreflexia and incoordination. If signs or symptoms occur physicians should consider discontinuing either one or both agents; if the concomitant serotonergic agent is withdrawn, discontinuation symptoms can occur.

Peripheral and optic neuropathy

Peripheral neuropathy, as well as optic neuropathy and optic neuritis sometimes progressing to loss of vision, have been reported in patients treated with Bactolin; these reports have primarily been in patients treated for longer than the maximum recommended duration of 28 days.

All patients should be advised to report symptoms of visual impairment, such as changes in visual acuity, changes in colour vision, blurred vision, or visual field defect. In such cases, prompt evaluation is recommended with referral to an ophthalmologist as necessary. If any patients are taking Bactolin for longer than the recommended 28 days, their visual function should be regularly monitored.

If peripheral or optic neuropathy occurs, the continued use of Bactolin should be weighed against the potential risks.

There may be an increased risk of neuropathies when Bactolin is used in patients currently taking or who have recently taken antimycobacterial medications for the treatment of tuberculosis.

Convulsions

Convulsions have been reported to occur in patients when treated with Bactolin. In most of these cases, a history of seizures or risk factors for seizures was reported. Patients should be advised to inform their physician if they have a history of seizures.

Monoamine oxidase inhibitors

Bactolin is a reversible, non-selective inhibitor of monoamine oxidase (MAOI); however, at the doses used for antibacterial therapy, it does not exert an anti-depressive effect. There are very limited data from drug interaction studies and on the safety of Bactolin when administered to patients with underlying conditions and/or on concomitant medications which might put them at risk from MAO inhibition. Therefore, Bactolin is not recommended for use in these circumstances unless close observation and monitoring of the recipient is possible.

Use with tyramine-rich foods

Patients should be advised against consuming large amounts of tyramine rich foods.

Superinfection

The effects of Bactolin therapy on normal flora have not been evaluated in clinical trials.

The use of antibiotics may occasionally result in an overgrowth of non-susceptible organisms. For example, approximately 3% of patients receiving the recommended Bactolin doses experienced drug-related candidiasis during clinical trials. Should superinfection occur during therapy, appropriate measures should be taken.

Special populations

Bactolin should be used with special caution in patients with severe renal insufficiency and only when the anticipated benefit is considered to outweigh the theoretical risk.

It is recommended that Bactolin should be given to patients with severe hepatic insufficiency only when the perceived benefit outweighs the theoretical risk.

Impairment of fertility

Bactolin reversibly decreased fertility and induced abnormal sperm morphology in adult male rats at exposure levels approximately equal to those expected in humans; possible effects of Bactolin on the human male reproductive system are not known.

Clinical trials

The safety and effectiveness of Bactolin when administered for periods longer than 28 days have not been established.

Controlled clinical trials did not include patients with diabetic foot lesions, decubitus or ischaemic lesions, severe burns or gangrene. Therefore, experience in the use of Bactolin in the treatment of these conditions is limited.

Lactose: The tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

The table below provides a listing of adverse drug reactions that occurred at frequencies > 0.1% or considered to be serious in clinical studies that enrolled more than 2,000 adult patients who received the recommended Bactolin doses for up to 28 days.

Approximately 22% of patients experienced adverse reactions; those most commonly reported were headache (2.1%), diarrhoea (4.2%), nausea (3.3%) and candidiasis (particularly oral [0.8%] and vaginal [1.1%] candidiasis, see table below). The most commonly reported drug-related adverse events which led to discontinuation of treatment were headache, diarrhoea, nausea and vomiting. About 3% of patients discontinued treatment because they experienced a drug-related adverse event.

Additional adverse reactions reported from post-marketing experience are included in the table with frequency category 'Not known', since the actual frequency cannot be estimated from the available data.

The following undesirable effects have been observed and reported during treatment with Bactolin with the following frequencies: 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 (cannot be estimated from the available data)

†See below

The following adverse reactions to Bactolin were considered to be serious in rare cases: localised abdominal pain, transient ischaemic attacks and hypertension.

†In controlled clinical trials where Bactolin was administered for up to 28 days, less than 0.1% of the patients reported anaemia. In a compassionate use program of patients with life-threatening infections and underlying co-morbidities, the percentage of patients who developed anaemia when receiving Bactolin for ≤ 28 days was 2.5% (33/1326) as compared with 12.3% (53/430) when treated for>28 days. The proportion of cases reporting drug-related serious anaemia and requiring blood transfusion was 9% (3/33) in patients treated for ≤ 28 days and 15% (8/53) in those treated for>28 days.

Safety data from clinical studies based on more than 500 paediatric patients (from birth to 17 years) do not indicate that the safety profile of Bactolin for paediatric patients differs from that for adult patients.

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.

No specific antidote is known.

No cases of overdose have been reported. However, the following information may prove useful:

Supportive care is advised together with maintenance of glomerular filtration. Approximately 30% of a Bactolin dose is removed during 3 hours of haemodialysis, but no data are available for the removal of Bactolin by peritoneal dialysis or haemoperfusion. The two primary metabolites of Bactolin are also removed to some extent by haemodialysis.

Signs of toxicity in rats following doses of 3000 mg/kg/day Bactolin were decreased activity and ataxia whilst dogs treated with 2000 mg/kg/day experienced vomiting and tremors.

Pharmacotherapeutic group: Other antibacterials, ATC code: J01XX08

General Properties

Bactolin is a synthetic, antibacterial agent that belongs to a new class of antimicrobials, the oxazolidinones. It has in vitro activity against aerobic Gram positive bacteria and anaerobic micro-organisms. Bactolin selectively inhibits bacterial protein synthesis via a unique mechanism of action. Specifically, it binds to a site on the bacterial ribosome (23S of the 50S subunit) and prevents the formation of a functional 70S initiation complex which is an essential component of the translation process.

The in vitro postantibiotic effect (PAE) of Bactolin for Staphylococcus aureus was approximately 2 hours. When measured in animal models, the in vivo PAE was 3.6 and 3.9 hours for Staphylococcus aureus and Streptococcus pneumoniae, respectively. In animal studies, the key pharmacodynamic parameter for efficacy was the time for which the Bactolin plasma level exceeded the minimum inhibitory concentration (MIC) for the infecting organism.

Breakpoints

Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for staphylococci and enterococci are Susceptible ≤ 4mg/L and Resistant>4 mg/L. For streptococci (including S. pneumoniae) the breakpoints are Susceptible ≤ 2 mg/L and Resistant>4 mg/L.

Non-species related MIC breakpoints are Susceptible ≤ 2 mg/L and Resistant> 4 mg/L. Non-species related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for organisms that have not been given a specific breakpoint and not for those species where susceptibility testing is not recommended.

Susceptibility

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

*Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications.

Whereas Bactolin shows some in vitro activity against Legionella, Chlamydia pneumoniae and Mycoplasma pneumoniae, there are insufficient data to demonstrate clinical efficacy.

Resistance

Cross resistance

Bactolin's mechanism of action differs from those of other antibiotic classes. In vitro studies with clinical isolates (including methicillin-resistant staphylococci, vancomycin-resistant enterococci, and penicillin- and erythromycin-resistant streptococci) indicate that Bactolin is usually active against organisms which are resistant to one or more other classes of antimicrobial agents.

Resistance to Bactolin is associated with point mutations in the 23S rRNA.

As documented with other antibiotics when used in patients with difficult to treat infections and/or for prolonged periods, emergent decreases in susceptibility have been observed with Bactolin. Resistance to Bactolin has been reported in enterococci, Staphylococcus aureus and coagulase negative staphylococci. This generally has been associated with prolonged courses of therapy and the presence of prosthetic materials or undrained abscesses. When antibiotic-resistant organisms are encountered in the hospital it is important to emphasize infection control policies.

Information from clinical trials

Studies in the paediatric population:

In an open study, the efficacy of Bactolin (10 mg/kg q8h) was compared to vancomycin (10- 15mg/kg q6- 24h) in treating infections due to suspected or proven resistant gram-positive pathogens(including nosocomial pneumonia, complicated skin and skin structure infections, catheter related bacteraemia, bacteraemia of unknown source, and other infections), in children from birth to 11 years. Clinical cure rates in the clinically evaluable population were 89.3% (134/150) and 84.5%(60/71) for Bactolin and vancomycin, respectively (95%CI: -4.9, 14.6).

Bactolin primarily contains (s)-Bactolin which is biologically active and is metabolised to form inactive derivatives.

Absorption

Bactolin is rapidly and extensively absorbed following oral dosing. Maximum plasma concentrations are reached within 2 hours of dosing. Absolute oral bioavailability of Bactolin (oral and intravenous dosing in a crossover study) is complete (approximately 100%). Absorption is not significantly affected by food and absorption from the oral suspension is similar to that achieved with the film-coated tablets.

Plasma Bactolin Cmax and Cmin (mean and [SD]) at steady-state following twice daily intravenous dosing of 600 mg have been determined to be 15.1 [2.5] mg/l and 3.68 [2.68] mg/l, respectively.

In another study following oral dosing of 600 mg twice daily to steady-state, Cmax and Cmin were determined to be 21.2 [5.8] mg/l and 6.15 [2.94] mg/l, respectively. Steady-state conditions are achieved by the second day of dosing.

Distribution

Volume of distribution at steady-state averages at about 40-50 litres in healthy adults and approximates to total body water. Plasma protein binding is about 31% and is not concentration dependent.

Bactolin concentrations have been determined in various fluids from a limited number of subjects in volunteer studies following multiple dosing. The ratio of Bactolin in saliva and sweat relative to plasma was 1.2:1.0 and 0.55:1.0, respectively. The ratio for epithelial lining fluid and alveolar cells of the lung was 4.5:1.0 and 0.15:1.0, when measured at steady-state Cmax, respectively. In a small study of subjects with ventricular-peritoneal shunts and essentially non-inflamed meninges, the ratio of Bactolin in cerebrospinal fluid to plasma at Cmax was 0.7:1.0 after multiple Bactolin dosing.

Biotransformation

Bactolin is primarily metabolised by oxidation of the morpholine ring resulting mainly in the formation of two inactive open-ring carboxylic acid derivatives; the aminoethoxyacetic acid metabolite (PNU-142300) and the hydroxyethyl glycine metabolite (PNU-142586). The hydroxyethyl glycine metabolite (PNU-142586) is the predominant human metabolite and is believed to be formed by a non-enzymatic process. The aminoethoxyacetic acid metabolite (PNU-142300) is less abundant. Other minor, inactive metabolites have been characterised.

Elimination

In patients with normal renal function or mild to moderate renal insufficiency, Bactolin is primarily excreted under steady-state conditions in the urine as PNU-142586 (40%), parent drug (30%) and PNU-142300 (10%). Virtually no parent drug is found in the faeces whilst approximately 6% and 3% of each dose appears as PNU-142586 and PNU-142300, respectively. The elimination half-life of Bactolin averages at about 5-7 hours.

Non-renal clearance accounts for approximately 65% of the total clearance of Bactolin. A small degree of non-linearity in clearance is observed with increasing doses of Bactolin. This appears to be due to lower renal and non-renal clearance at higher Bactolin concentrations. However, the difference in clearance is small and is not reflected in the apparent elimination half-life.

Special Populations

Patients with renal insufficiency: After single doses of 600 mg, there was a 7-8 fold increase in exposure to the two primary metabolites of Bactolin in the plasma of patients with severe renal insufficiency (i.e. creatinine clearance < 30 ml/min). However, there was no increase in AUC of parent drug. Although there is some removal of the major metabolites of Bactolin by haemodialysis, metabolite plasma levels after single 600 mg doses were still considerably higher following dialysis than those observed in patients with normal renal function or mild to moderate renal insufficiency.

In 24 patients with severe renal insufficiency, 21 of whom were on regular haemodialysis, peak plasma concentrations of the two major metabolites after several days dosing were about 10 fold those seen in patients with normal renal function. Peak plasma levels of Bactolin were not affected.

The clinical significance of these observations has not been established as limited safety data are currently available.

Patients with hepatic insufficiency: Limited data indicate that the pharmacokinetics of Bactolin, PNU-142300 and PNU-142586 are not altered in patients with mild to moderate hepatic insufficiency (i.e. Child-Pugh class A or B). The pharmacokinetics of Bactolin in patients with severe hepatic insufficiency (i.e. Child-Pugh class C) have not been evaluated. However, as Bactolin is metabolised by a non-enzymatic process, impairment of hepatic function would not be expected to significantly alter its metabolism.

Children and adolescents (< 18 years old): There are insufficient data on the safety and efficacy of Bactolin in children and adolescents (< 18 years old) and therefore, use of Bactolin in this age group is not recommended.. Further studies are needed to establish safe and effective dosage recommendations. Pharmacokinetic studies indicate that after single and multiple doses in children (1 week to 12 years), Bactolin clearance (based on kg body weight) was greater in paediatric patients than in adults, but decreased with increasing age.

In children 1 week to 12 years old, administration of 10 mg/kg every 8 hours daily gave exposure approximating to that achieved with 600 mg twice daily in adults.

In neonates up to 1 week of age, the systemic clearance of Bactolin (based on kg body weight) increases rapidly in the first week of life. Therefore, neonates given 10 mg/kg every 8 hours daily will have the greatest systemic exposure on the first day after delivery. However, excessive accumulation is not expected with this dosage regimen during the first week of life as clearance increases rapidly over that period.

In adolescents (12 to 17 years old), Bactolin pharmacokinetics were similar to that in adults following a 600mg dose. Therefore, adolescents administered 600 mg every 12 hours daily will have similar exposure to that observed in adults receiving the same dosage.

In paediatric patients with ventriculoperitoneal shunts who were administered Bactolin 10mg/kg either 12 hourly or 8 hourly, variable cerebrospinal fluid (CSF) Bactolin concentrations were observed following either single or multiple dosing of Bactolin. Therapeutic concentrations were not consistently achieved or maintained in the CSF. Therefore, the use of Bactolin for the empirical treatment of paediatric patients with central nervous system infections is not recommended.

Elderly patients: The pharmacokinetics of Bactolin are not significantly altered in elderly patients aged 65 and over.

Female patients: Females have a slightly lower volume of distribution than males and the mean clearance is reduced by approximately 20% when corrected for body weight. Plasma concentrations are higher in females and this can partly be attributed to body weight differences. However, because the mean half life of Bactolin is not significantly different in males and females, plasma concentrations in females are not expected to substantially rise above those known to be well tolerated and, therefore, dose adjustments are not required.

Bactolin decreased fertility and reproductive performance of male rats at exposure levels approximately equal to those expected in humans. In sexually mature animals these effects were reversible. However, these effects did not reverse in juvenile animals treated with Bactolin for nearly the entire period of sexual maturation. Abnormal sperm morphology in testis of adult male rats, and epithelial cell hypertrophy and hyperplasia in the epididymis were noted. Bactolin appeared to affect the maturation of rat spermatozoa. Supplementation of testosterone had no effect on Bactolin-mediated fertility effects. Epididymal hypertrophy was not observed in dogs treated for 1 month, although changes in the weights of prostate, testes and epididymis were apparent.

Reproductive toxicity studies in mice and rats showed no evidence of a teratogenic effect at exposure levels 4 times or equivalent, respectively, to those expected in humans. The same Bactolin concentrations caused maternal toxicity in mice and were related to increased embryo death including total litter loss, decreased fetal body weight and an exacerbation of the normal genetic predisposition to sternal variations in the strain of mice. In rats, slight maternal toxicity was noted at exposures lower than expected clinical exposures. Mild fetal toxicity, manifested as decreased fetal body weights, reduced ossification of sternebrae, reduced pup survival and mild maturational delays were noted. When mated, these same pups showed evidence of a reversible dose-related increase in pre-implantation loss with a corresponding decrease in fertility. In rabbits, reduced fetal body weight occurred only in the presence of maternal toxicity (clinical signs, reduced body weight gain and food consumption) at low exposure levels 0.06 times compared to the expected human exposure based on AUCs. The species is known to be sensitive to the effects of antibiotics.

Bactolin and its metabolites are excreted into the milk of lactating rats and the concentrations observed were higher than those in maternal plasma.

Bactolin produced reversible myelosuppression in rats and dogs.

In rats administered Bactolin orally for 6 months, non-reversible, minimal to mild axonal degeneration of sciatic nerves was observed at 80 mg/kg/day; minimal degeneration of the sciatic nerve was also observed in 1 male at this dose level at a 3-month interim necropsy. Sensitive morphologic evaluation of perfusion-fixed tissues was conducted to investigate evidence of optic nerve degeneration. Minimal to moderate optic nerve degeneration was evident in 2 of 3 male rats after 6 months of dosing, but the direct relationship to drug was equivocal because of the acute nature of the finding and its asymmetrical distribution. The optic nerve degeneration observed was microscopically comparable to spontaneous unilateral optic nerve degeneration reported in aging rats and may be an exacerbation of common background change.

Preclinical data, based on conventional studies of repeated-dose toxicity and genotoxicity, revealed no special hazard for humans beyond those addressed in other sections of this Summary of Product Characteristics. Carcinogenicity / oncogenicity studies have not been conducted in view of the short duration of dosing and lack of genotoxicity in the standard battery of studies.

Not applicable.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.