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| نشرة الممارس الصحي | نشرة معلومات المريض بالعربية | نشرة معلومات المريض بالانجليزية | صور الدواء | بيانات الدواء |
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Nosocomial pneumonia
Community acquired pneumonia
Zillion is indicated in adults for the treatment of community acquired pneumonia and nosocomial pneumonia when known or suspected to be caused by susceptible Gram positive bacteria. In determining whether Zillion is an appropriate treatment, the results of microbiological tests or information on the prevalence of resistance to antibacterial agents among Gram positive bacteria should be taken into consideration (see section 5.1 for the appropriate organisms).
Zillion 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 (see section 4.4)
Zillion is indicated in adults 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.
Zillion is not active against infections caused by Gram negative pathogens. Zillion should only be used in patients with complicated skin and soft tissue infections with known or possible coinfection with Gram negative organisms if there are no alternative treatment options available (see section 4.4). In these circumstances treatment against Gram negative organisms must be initiated concomitantly.
Zillion 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
Zillion 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 Zillion 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 Zillion when administered for periods longer than 28 days have not been established (see section 4.4).
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 identical and are as follows:
Infections | Dosage | Duration of treatment |
Nosocomial pneumonia | 600 mg twice daily |
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Community acquired pneumonia |
| 10-14 Consecutive days |
Complicated skin and soft tissue infections | 600 mg twice daily |
Paediatric population:
The safety and efficacy of Zillion in children aged (< 18 years old) has not been established. Currently available data are described in section 4.8, 5.1, and 5.2 but no recommendation on a posology can be made.
Elderly:
No dose adjustment is required.
Renal impairment:
No dose adjustment is required (see sections 4.4 and 5.2). Severe renal impairment (i.e. CLCR < 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 Zillion in patients with severe renal insufficiency, Zillion 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 Zillion dose is removed during 3 hours of haemodialysis, Zillion should be given after dialysis in patients receiving such treatment. The primary metabolites of Zillion 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, Zillion 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 Zillion administration to patients undergoing continuous ambulatory peritoneal dialysis (CAPD) or alternative treatments for renal failure (other than haemodialysis). Hepatic impairment:
No dose adjustment is required. However, there are limited clinical data and it is recommended that Zillion should be used in such patients only when the anticipated benefit is considered to outweigh the theoretical risk (see sections 4.4 and 5.2).
Method of administration:
The recommended Zillion dosage should be administered orally twice daily.
Route of administration: Oral use.
The oral suspension may be taken with or without food.
A 600 mg dose is provided by 30 ml of reconstituted suspension (i.e. six 5 ml spoonfuls).
The appearance after reconstitution is a white to yellow-orange suspension.
For instructions on reconstitution of the medicinal product before administration, see section 6.6.
Myelosuppression
Myelosuppression (including anaemia, leucopenia, pancytopenia and thrombocytopenia) has been reported in patients receiving Zillion. In cases where the outcome is known, when Zillion 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 Zillion 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. Zillion 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 Zillion 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 Zillion regardless of baseline blood count.
In compassionate use studies, a higher incidence of serious anaemia was reported in patients receiving Zillion 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 Zillion 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 Zillion therapy for more than 28 days. Most patients fully or partially recovered following discontinuation of Zillion 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 Zillion, 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 Zillion 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 Zillion 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 Zillion should only be used in patients with known or possible co-infection with Gram negative organisms if there are no alternative treatment options available (see section 4.1). In these circumstances treatment against Gram negative organisms must be initiated concomitantly.
Antibiotic-associated diarrhoea and colitis
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 Zillion 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 Zillion. If antibiotic-associated diarrhoea or antibioticassociated colitis is suspected or confirmed, ongoing treatment with antibacterial agents, including Zillion, 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 Zillion. Patients who develop signs and symptoms of metabolic acidosis including recurrent nausea or vomiting, abdominal pain, a low bicarbonate level, or hyperventilation while receiving Zillion should receive immediate medical attention. If lactic acidosis occurs, the benefits of continued use of Zillion should be weighed against the potential risks.
Mitochondrial dysfunction
Zillion 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 Zillion and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) have been reported. Co-administration of Zillion and serotonergic agents is therefore contraindicated (see section 4.3) except where administration of Zillion 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 Zillion; 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 Zillion for longer than the recommended 28 days, their visual function should be regularly monitored.
If peripheral or optic neuropathy occurs, the continued use of Zillion should be weighed against the potential risks.
There may be an increased risk of neuropathies when Zillion 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 Zillion. 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
Zillion 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 Zillion when administered to patients with underlying conditions and/or on concomitant medications which might put them at risk from MAO inhibition. Therefore, Zillion is not recommended for use in these circumstances unless close observation and monitoring of the recipient is possible (see sections 4.3 and 4.5).
Use with tyramine-rich foods
Patients should be advised against consuming large amounts of tyramine-rich foods (see section 4.5).
Superinfection
The effects of Zillion 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 Zillion doses experienced drug-related candidiasis during clinical trials. Should superinfection occur during therapy, appropriate measures should be taken.
Special populations
Zillion 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 (see sections 4.2 and 5.2).
It is recommended that Zillion should be given to patients with severe hepatic insufficiency only when the perceived benefit outweighs the theoretical risk (see sections 4.2 and 5.2).
Impairment of fertility
Zillion 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 Zillion on the human male reproductive system are not known (see section 5.3).
Clinical trials
The safety and effectiveness of Zillion 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 Zillion in the treatment of these conditions is limited.
Excipients
The reconstituted oral suspension contains a source of phenylalanine (aspartame) equivalent to 20 mg/5 ml. Therefore, this formulation may be harmful for people with phenylketonuria. For patients with phenylketonuria, Zillion solution for infusion or tablets are recommended.
The suspension also contains sucrose, fructose, sorbitol, mannitol and sodium equivalent to 1.7 mg/ml.
Therefore, it should not be administered to patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency. Due to its mannitol and sorbitol content, the oral suspension may have a mild laxative effect. The product contains 8.5 mg sodium per 5 ml dose. The sodium content should be taken into account in patients on a controlled sodium diet. This medicinal product contains small amounts of ethanol (alcohol), less than 100 mg per 5 ml dose.
Monoamine oxidase inhibitors
Zillion is a reversible, non-selective inhibitor of monoamine oxidase (MAOI). There are very limited data from drug interaction studies and on the safety of Zillion when administered to patients on concomitant medications that might put them at risk from MAO inhibition. Therefore, Zillion is not recommended for use in these circumstances unless close observation and monitoring of the recipient is possible (see sections 4.3 and 4.4).
Potential interactions producing elevation of blood pressure
In normotensive healthy volunteers, Zillion enhanced the increases in blood pressure caused by pseudoephedrine and phenylpropanolamine hydrochloride. Co-administration of Zillion with either pseudoephedrine or phenylpropanolamine resulted in mean increases in systolic blood pressure of the order of 30-40 mmHg, compared with 11-15 mmHg increases with Zillion alone, 14-18 mmHg with either pseudoephedrine or phenylpropanolamine alone and 8-11 mmHg with placebo. Similar studies in hypertensive subjects have not been conducted. It is recommended that doses of drugs with a vasopressive action, including dopaminergic agents, should be carefully titrated to achieve the desired response when co-administered with Zillion.
Potential serotonergic interactions
The potential drug-drug interaction with dextromethorphan was studied in healthy volunteers. Subjects were administered dextromethorphan (two 20 mg doses given 4 hours apart) with or without Zillion. No serotonin syndrome effects (confusion, delirium, restlessness, tremors, blushing, diaphoresis and hyperpyrexia) have been observed in normal subjects receiving Zillion and dextromethorphan.
Post marketing experience: there has been one report of a patient experiencing serotonin syndrome-like effects while taking Zillion and dextromethorphan which resolved on discontinuation of both medications.
During clinical use of Zillion with serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), cases of serotonin syndrome have been reported. Therefore, while co-administration is contraindicated (see section 4.3), management of patients for whom treatment with Zillion and serotonergic agents is essential, is described in section 4.4.
Use with tyramine-rich foods
No significant pressor response was observed in subjects receiving both Zillion and less than 100 mg tyramine. This suggests that it is only necessary to avoid ingesting excessive amounts of food and beverages with a high tyramine content (e.g. mature cheese, yeast extracts, undistilled alcoholic beverages and fermented soya bean products such as soy sauce).
Drugs metabolised by cytochrome P450
Zillion is not detectably metabolised by the cytochrome P450 (CYP) enzyme system and it does not inhibit any of the clinically significant human CYP isoforms (1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Similarly, Zillion does not induce P450 isoenzymes in rats. Therefore, no CYP450induced drug interactions are expected with Zillion.
Rifampicin
The effect of rifampicin on the pharmacokinetics of Zillion was studied in sixteen healthy adult male volunteers administered Zillion 600 mg twice daily for 2.5 days with and without rifampicin 600 mg once daily for 8 days. Rifampicin decreased the Zillion Cmax and AUC by a mean 21% [90% CI, 15, 27] and a mean 32% [90% CI, 27, 37], respectively. The mechanism of this interaction and its clinical significance are unknown.
Warfarin
When warfarin was added to Zillion therapy at steady-state, there was a 10% reduction in mean maximum INR on co-administration with a 5% reduction in AUC INR. There are insufficient data from patients who have received warfarin and Zillion to assess the clinical significance, if any, of these findings.
Pregnancy
There are limited data from the use of Zillion in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). A potential risk for humans exists.
Zillion should not be used during pregnancy unless clearly necessary i.e. only if the potential benefit outweighs the theoretical risk.
Breast-feeding
Animal data suggest that Zillion and its metabolites may pass into breast milk and, accordingly, breast-feeding should be discontinued prior to and throughout administration.
Fertility
In animal studies, Zillion caused a reduction in fertility (see section 5.3).
Patients should be warned about the potential for dizziness or symptoms of visual impairment (as described in section 4.4 and 4.8) whilst receiving Zillion and should be advised not to drive or operate machinery if any of these symptoms occurs.
The table below provides a listing of adverse drug reactions with frequency based on allcausality data from clinical studies that enrolled more than 2,000 adult patients who received the recommended Zillion doses for up to 28 days.
Those most commonly reported were diarrhoea (8.4%), headache (6.5%), nausea (6.3%) and vomiting (4.0%).
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 Zillion 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)
System Organ Class | Common (≥1/100 to <1/10) | Uncommon (≥1/1,000 to <1/100) | Rare (≥1/10,000 to <1/1,000) | Very Rare (<1/10,00 0) | Frequency not known (cannot be estimated from available data) |
Infections and infestations | candidiasis, oral candidiasis, vaginal candidiasis, fungal infections | vaginitis | antibioticassociated colitis, including pseudomembrano us colitis* |
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Blood and the lymphatic system disorders | anaemia*† | leucopenia*, neutropenia, thrombocytopenia *, eosinophilia | pancytopenia* |
| myelosuppression *, sideroblastic anaemia* |
Immune system disorders |
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| anaphylaxis |
Metabolism |
| hyponatraemia |
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| lactic acidosis* |
and nutrition disorders |
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Psychiatric disorders | insomnia |
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Nervous system disorders | headache, taste perversion (metallic taste), dizziness | convulsions*, hypoaesthesia, paraesthesia |
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| serotonin syndrome**, peripheral neuropathy* |
Eye disorders |
| blurred vision* | changes in visual field defect* |
| optic neuropathy*, optic neuritis*, loss of vision*, changes in visual acuity*, changes in colour vision* |
Ear and labyrinth disorders |
| tinnitus |
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Cardiac disorders |
| arrhythmia (tachycardia) |
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Vascular disorders | hypertensio n | transient ischaemic attacks, phlebitis, thrombophlebitis |
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Gastrointestin al disorders | diarrhoea, nausea, vomiting, localised or general abdominal pain, constipation , dyspepsia | pancreatitis, gastritis, abdominal distention, dry mouth, glossitis, loose stools, stomatitis, tongue discolouration or disorder | superficial tooth discolouration |
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Hepato-biliary disorders | abnormal liver function test; increased AST, ALT or alkaline | increased total bilirubin |
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| phosphatase |
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Skin and subcutaneous tissue disorders | pruritus, rash | urticaria, dermatitis, diaphoresis |
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| bullous disorders such as those described as Stevens-Johnson syndrome and toxic epidermal necrolysis, angioedema, alopecia |
Renal and urinary disorders | increased BUN | renal failure, increased creatinine, polyuria |
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Reproductive system and breast disorders |
| vulvovaginal disorder |
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General disorders and administratio n site conditions | fever, localised pain | chills, fatigue, injection site pain, increased thirst |
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Investigations | Chemistry Increased LDH, creatine kinase, lipase, amylase or non fasting glucose. Decreased total protein, albumin, sodium or calcium. Increased or decreased potassium or bicarbonate. | Chemistry Increased sodium or calcium. Decreased non fasting glucose. Increased or decreased chloride.
Haematology Increased reticulocyte count. Decreased neutrophils. |
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| Haematolog y Increased neutrophils or eosinophils. Decreased haemoglobi n, haematocrit or red blood cell count. Increased or decreased platelet or white blood cell counts. |
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* See section 4.4.
** See sections 4.3 and 4.5
† See below
The following adverse reactions to Zillion were considered to be serious in rare cases: localised abdominal pain, transient ischaemic attacks and hypertension.
†
In controlled clinical trials where Zillion was administered for up to 28 days, 2.0% 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 Zillion 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.
Paediatric population
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 Zillion for paediatric patients differs from that for adult patients.
Reporting of suspected adverse reactions
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly (see details below). By reporting side affects; you can help provide more information on the safety of this medicine.
• Saudi Arabia:
The National Pharmacovigilance and Drug Safety Centre (NPC) |
o Other GCC States:
Please contact the relevant competent authority.
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 Zillion dose is removed during 3 hours of haemodialysis, but no data are available for the removal of Zillion by peritoneal dialysis or haemoperfusion. The two primary metabolites of Zillion are also removed to some extent by haemodialysis.
Signs of toxicity in rats following doses of 3000 mg/kg/day Zillion were decreased activity and ataxia whilst dogs treated with 2000 mg/kg/day experienced vomiting and tremors.
Pharmacotherapeutic group: Other antibacterials, ATC code: J 01 X 08.
General properties
Zillion 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. Zillion 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 Zillion 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 Zillion 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 ≤ 4 mg/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. Nonspecies 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.
Category |
Susceptible organisms Gram positive aerobes: Enterococcus faecalis Enterococcus faecium* Staphylococcus aureus* Coagulase negative staphylococci Streptococcus agalactiae* Streptococcus pneumoniae* Streptococcus pyogenes* Group C streptococci Group G streptococci Gram positive anaerobes: Clostridium perfringens Peptostreptococcus anaerobius Peptostreptococcus species |
Resistant organisms Haemophilus influenzae Moraxella catarrhalis Neisseria species Enterobacteriaceae Pseudomonas species |
*Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications Whereas Zillion shows some in vitro activity against Legionella, Chlamydia pneumoniae and Mycoplasma pneumoniae, there are insufficient data to demonstrate clinical efficacy.
Resistance
Cross resistance
Zillion'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 Zillion is usually active against organisms which are resistant to one or more other classes of antimicrobial agents.
Resistance to Zillion 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 Zillion. Resistance to Zillion 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 antibioticresistant 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 Zillion (10 mg/kg q8h) was compared to vancomycin (10- 15 mg/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 Zillion and vancomycin, respectively (95%CI: -4.9, 14.6).
Zillion primarily contains (s)-Zillion which is biologically active and is metabolised to form inactive derivatives.
Absorption
Zillion is rapidly and extensively absorbed following oral dosing. Maximum plasma concentrations are reached within 2 hours of dosing. Absolute oral bioavailability of Zillion (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 Zillion 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.
Zillion concentrations have been determined in various fluids from a limited number of subjects in volunteer studies following multiple dosing. The ratio of Zillion 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 Zillion in cerebrospinal fluid to plasma at Cmax was 0.7:1.0 after multiple Zillion dosing.
Biotransformation
Zillion 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, Zillion 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 Zillion averages at about 5-7 hours.
Non-renal clearance accounts for approximately 65% of the total clearance of Zillion. A small degree of non-linearity in clearance is observed with increasing doses of Zillion. This appears to be due to lower renal and non-renal clearance at higher Zillion concentrations. However, the difference in clearance is small and is not reflected in the apparent elimination half-life.
Special populations
Renal impairment: After single doses of 600 mg, there was a 7-8 fold increase in exposure to the two primary metabolites of Zillion 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 Zillion 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 Zillion were not affected.
The clinical significance of these observations has not been established as limited safety data are currently available (see sections 4.2 and 4.4).
Hepatic impairment: Limited data indicate that the pharmacokinetics of Zillion, 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 Zillion in patients with severe hepatic insufficiency (i.e. Child-Pugh class C) have not been evaluated. However, as Zillion is metabolised by a non-enzymatic process, impairment of hepatic function would not be expected to significantly alter its metabolism (see sections 4.2 and 4.4).
Paediatric population (< 18 years old): There are insufficient data on the safety and efficacy of
Zillion in children and adolescents (< 18 years old) and therefore, use of Zillion in this age group is not recommended (see section 4.2). 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), Zillion 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 Zillion (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), Zillion pharmacokinetics were similar to that in adults following a 600 mg 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 Zillion 10 mg/kg either 12 hourly or 8 hourly, variable cerebrospinal fluid (CSF) Zillion concentrations were observed following either single or multiple dosing of Zillion. Therapeutic concentrations were not consistently achieved or maintained in the CSF. Therefore, the use of Zillion for the empirical treatment of paediatric patients with central nervous system infections is not recommended.
Elderly: The pharmacokinetics of Zillion 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 Zillion 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.
Zillion decreased fertility and reproductive performance of male rats at exposure levels approximately equal to those in humans. In sexually mature animals these effects were reversible. However, these effects did not reverse in juvenile animals treated with Zillion 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. Zillion appeared to affect the maturation of rat spermatozoa. Supplementation of testosterone had no effect on Zillion-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 in humans. The same Zillion concentrations caused maternal toxicity in mice and were related to increased embryo death including total litter loss, decreased foetal 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 clinical exposures. Mild foetal toxicity, manifested as decreased foetal 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 foetal 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.
Zillion and its metabolites are excreted into the milk of lactating rats and the concentrations observed were higher than those in maternal plasma.
Zillion produced reversible myelosuppression in rats and dogs.
In rats administered Zillion 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.
Sucrose USP/NF (P.G. sugar #40/#80), Sucrose USP/NF (M.B sugar #80), Mannitol USP (Pearlitol SD 200), Microcrystalline cellulose USP/NF (Avicel-PH 101), Anhydrous Citric acid powder USP (Emprove), Trisodium citrate Dihydrate USP (powder 106446), Aspartame USP/NF (Powder, A1378), Sodium Benzoate USP/NF, Sodium chloride USP, Glycyrrhizinate
Ammonium USP/NF, Colloidal Silicon Dioxide USP/NF (Aerosil 200), Xanthan gum USP/NF
(Xantural 75), Microcrystallinecellulose / Carboxymethylcellulose Sodium USP/NF (Avicel
CL611), Hypromellose USP 2910 5cps (Methocel E5 LV premium), Vanilla flavor 501441 AP
2004, IH, N&A peppermint flavor FL SD #517, IH, Orange flavour 501071 AP0551, IH
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Keep the bottle in the outer carton in order to protect from light. Do not use this medicine after the expiry date which is stated on the carton after ‘EXP’. The expiry date refers to the last day of that month.
Any remaining, unused suspension should be discarded within 21 days of reconstitution. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment
Bottle
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