Omacip

Omacip 2 mg/ml solution for infusion is indicated for the treatment of the following infections. Special attention should be paid to available information on resistance to Omacip before commencing therapy.

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

Adults

- Lower respiratory tract infections due to Gram-negative bacteria

- exacerbations of chronic obstructive pulmonary disease

- broncho-pulmonary infections in cystic fibrosis or in bronchiectasis

- pneumonia

- Chronic suppurative otitis media

- Acute exacerbation of chronic sinusitis especially if these are caused by Gram-negative bacteria

- Urinary tract infections

- Genital tract infections

- epididymo-orchitis including cases due to susceptible Neisseria gonorrhoeae

- pelvic inflammatory disease including cases due to susceptible Neisseria gonorrhoeae

- Infections of the gastro-intestinal tract (e.g. travellers` diarrhoea)

- Intra-abdominal infections

- Infections of the skin and soft tissue caused by Gram-negative bacteria

- Malignant external otitis

- Infections of the bones and joints

- Inhalation anthrax (post-exposure prophylaxis and curative treatment)

Omacip may be used in the management of neutropenic patients with fever that is suspected to be due to a bacterial infection.

Children and adolescents

- Broncho-pulmonary infections in cystic fibrosis caused by Pseudomonas aeruginosa

- Complicated urinary tract infections and pyelonephritis

- Inhalation anthrax (post-exposure prophylaxis and curative treatment)

Omacip may also be used to treat severe infections in children and adolescents when this is considered to be necessary.

Treatment should be initiated only by physicians who are experienced in the treatment of cystic fibrosis and/or severe infections in children and adolescents.

Posology

The dosage is determined by the indication, the severity and the site of the infection, the susceptibility to Omacip of the causative organism(s), the renal function of the patient and, in children and adolescents the body weight.

The duration of treatment depends on the severity of the illness and on the clinical and bacteriological course.

After intravenous initiation of treatment, the treatment can be switched to oral treatment with tablet or suspension if clinically indicated at the discretion of the physician. IV treatment should be followed by oral route as soon as possible.

In severe cases or if the patient is unable to take tablets (e.g. patients on enteral nutrition), it is recommended to commence therapy with intravenous Omacip until a switch to oral administration is possible.

Treatment of infections due to certain bacteria (e.g. Pseudomonas aeruginosa, Acinetobacter or Staphylococci) may require higher Omacip doses and co-administration with other appropriate antibacterial agents.

Treatment of some infections (e.g. pelvic inflammatory disease, intra-abdominal infections, infections in neutropenic patients and infections of bones and joints) may require co-administration with other appropriate antibacterial agents depending on the pathogens involved.

Adults

Paediatric population

Elderly patients

Elderly patients should receive a dose selected according to the severity of the infection and the patient`s creatinine clearance.

Patients with renal and hepatic impairment

Recommended starting and maintenance doses for patients with impaired renal function:

In patients with impaired liver function no dose adjustment is required.

Dosing in children with impaired renal and/or hepatic function has not been studied.

Method of administration

Omacip should be checked visually prior to use. It must not be used if cloudy.

Omacip should be administered by intravenous infusion. For children, the infusion duration is 60 minutes.

In adult patients, infusion time is 60 minutes for 400 mg Omacip and 30 minutes for 200 mg Omacip. Slow infusion into a large vein will minimize patient discomfort and reduce the risk of venous irritation.

The infusion solution can be infused either directly or after mixing with other compatible infusion solutions.

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- Concomitant administration of Omacip and tizanidine.

Severe infections and mixed infections with Gram-positive and anaerobic pathogens

Omacip monotherapy is not suited for treatment of severe infections and infections that might be due to Gram-positive or anaerobic pathogens. In such infections Omacip must be co-administered with other appropriate antibacterial agents.

Streptococcal Infections (including Streptococcus pneumoniae)

Omacip is not recommended for the treatment of streptococcal infections due to inadequate efficacy.

Genital tract infections

Epididymo-orchitis and pelvic inflammatory diseases may be caused by fluoroquinolone-resistant Neisseria gonorrhoeae. For epididymo-orchitis and pelvic inflammatory diseases, empirical Omacip should only be considered in combination with another appropriate antibacterial agent (e.g. a cephalosporin) unless Omacip-resistant Neisseria gonorrhoeae can be excluded. If clinical improvement is not achieved after 3 days of treatment, the therapy should be reconsidered.

Urinary tract infections

Resistance to fluoroquinolones of Escherichia coli - the most common pathogen involved in urinary tract infections - varies across the European Union. Prescribers are advised to take into account the local prevalence of resistance in Escherichia coli to fluoroquinolones.

Intra-abdominal infections

There are limited data on the efficacy of Omacip in the treatment of post-surgical intra-abdominal infections.

Travellers' diarrhoea

The choice of Omacip should take into account information on resistance to Omacip in relevant pathogens in the countries visited.

Infections of the bones and joints

Omacip should be used in combination with other antimicrobial agents depending on the results of the microbiological documentation.

Inhalational anthrax

Use in humans is based on in-vitro susceptibility data and on animal experimental data together with limited human data. Treating physicians should refer to national and /or international consensus documents regarding the treatment of anthrax.

Paediatric population

The use of Omacip in children and adolescents should follow available official guidance. Omacip treatment should be initiated only by physicians who are experienced in the treatment of cystic fibrosis and/or severe infections in children and adolescents.

Omacip has been shown to cause arthropathy in weight-bearing joints of immature animals. Safety data from a randomised double-blind study on Omacip use in children (Omacip: n=335, mean age = 6.3 years; comparators: n=349, mean age = 6.2 years; age range = 1 to 17 years) revealed an incidence of suspected drug-related arthropathy (discerned from joint-related clinical signs and symptoms) by Day +42 of 7.2% and 4.6%. Respectively, an incidence of drug-related arthropathy by 1-year follow-up was 9.0% and 5.7%. The increase of suspected drug-related arthropathy cases over time was not statistically significant between groups. Treatment should be initiated only after a careful benefit/risk evaluation, due to possible adverse events related to joints and/or surrounding tissue.

Broncho-pulmonary infections in cystic fibrosis

Clinical trials have included children and adolescents aged 5-17 years. More limited experience is available in treating children between 1 and 5 years of age.

Complicated urinary tract infections and pyelonephritis

Omacip treatment of urinary tract infections should be considered when other treatments cannot be used, and should be based on the results of the microbiological documentation.

Clinical trials have included children and adolescents aged 1-17 years.

Other specific severe infections

Other severe infections in accordance with official guidance, or after careful benefit-risk evaluation when other treatments cannot be used, or after failure to conventional therapy and when the microbiological documentation can justify a Omacip use.

The use of Omacip for specific severe infections other than those mentioned above has not been evaluated in clinical trials and the clinical experience is limited. Consequently, caution is advised when treating patients with these infections.

Hypersensitivity

Hypersensitivity and allergic reactions, including anaphylaxis and anaphylactoid reactions, may occur following a single dose and may be life-threatening. If such reaction occurs, Omacip should be discontinued and an adequate medical treatment is required.

Musculoskeletal System

Omacip should generally not be used in patients with a history of tendon disease/disorder related to quinolone treatment. Nevertheless, in very rare instances, after microbiological documentation of the causative organism and evaluation of the risk/benefit balance, Omacip may be prescribed to these patients for the treatment of certain severe infections, particularly in the event of failure of the standard therapy or bacterial resistance, where the microbiological data may justify the use of Omacip.

Tendinitis and tendon rupture (especially Achilles tendon), sometimes bilateral, may occur with Omacip, even within the first 48 hours of treatment. Inflammation and ruptures of tendon may occur even up to several months after discontinuation of Omacip therapy. The risk of tendinopathy may be increased in elderly patients or in patients concomitantly treated with corticosteroids.

At any sign of tendinitis (e.g. painful swelling, inflammation), Omacip treatment should be discontinued. Care should be taken to keep the affected limb at rest.

Omacip should be used with caution in patients with myasthenia gravis.

Photosensitivity

Omacip has been shown to cause photosensitivity reactions. Patients taking Omacip should be advised to avoid direct exposure to either extensive sunlight or UV irradiation during treatment.

Central Nervous System

Omacip like other quinolones are known to trigger seizures or lower the seizure threshold. Cases of status epilepticus have been reported. Omacip should be used with caution in patients with CNS disorders which may be predisposed to seizure. If seizures occur Omacip should be discontinued. Psychiatric reactions may occur even after the first administration of Omacip. In rare cases, depression or psychosis can progress to suicidal ideations/thoughts culminating in attempted suicide or completed suicide. In the occurrence of such cases, Omacip should be discontinued.

Cases of polyneuropathy (based on neurological symptoms such as pain, burning, sensory disturbances or muscle weakness, alone or in combination) have been reported in patients receiving Omacip. Omacip should be discontinued in patients experiencing symptoms of neuropathy, including pain, burning, tingling, numbness, and/or weakness in order to prevent the development of an irreversible condition.

Cardiac disorders

Caution should be taken when using fluoroquinolones, including Omacip, in patients with known risk factors for prolongation of the QT interval such as, for example:

- congenital long QT syndrome

- concomitant use of drugs that are known to prolong the QT interval (e.g. Class IA and III anti-arrhythmics, tricyclic antidepressants, macrolides, antipsychotics)

- uncorrected electrolyte imbalance (e.g. hypokalaemia, hypomagnesaemia)

- cardiac disease (e.g. heart failure, myocardial infarction, bradycardia)

Elderly patients and women may be more sensitive to QTc-prolonging medications.

Therefore, caution should be taken when using fluoroquinolones, including Omacip, in these populations.

Hypoglycemia

As with other quinolones, hypoglycemia has been reported most often in diabetic patients, predominantly in the elderly population. In all diabetic patients, careful monitoring of blood glucose is recommended.

Gastrointestinal System

The occurrence of severe and persistent diarrhoea during or after treatment (including several weeks after treatment) may indicate an antibiotic-associated colitis (life-threatening with possible fatal outcome), requiring immediate treatment. In such cases, Omacip should immediately be discontinued, and an appropriate therapy initiated. Anti-peristaltic drugs are contraindicated in this situation.

Renal and urinary system

Crystalluria related to the use of Omacip has been reported. Patients receiving Omacip should be well hydrated and excessive alkalinity of the urine should be avoided.

Impaired renal function

Hepatobiliary system

Cases of hepatic necrosis and life-threatening hepatic failure have been reported with Omacip. In the event of any signs and symptoms of hepatic disease (such as anorexia, jaundice, dark urine, pruritus, or tender abdomen), treatment should be discontinued.

Glucose-6-phosphate dehydrogenase deficiency

Haemolytic reactions have been reported with Omacip in patients with glucose-6-phosphate dehydrogenase deficiency. Omacip should be avoided in these patients unless the potential benefit is considered to outweigh the possible risk. In this case, potential occurrence of haemolysis should be monitored.

Resistance

During or following a course of treatment with Omacip bacteria that demonstrate resistance to Omacip may be isolated, with or without a clinically apparent superinfection. There may be a particular risk of selecting for Omacip-resistant bacteria during extended durations of treatment and when treating nosocomial infections and/or infections caused by Staphylococcus and Pseudomonas species.

Cytochrome P450

Omacip inhibits CYP1A2 and thus may cause increased serum concentration of concomitantly administered substances metabolised by this enzyme (e.g. theophylline, clozapine, olanzapine, ropinirole, tizanidine, duloxetine, agomelatine). Co-administration of Omacip and tizanidine is contra-indicated. Therefore, patients taking these substances concomitantly with Omacip should be monitored closely for clinical signs of overdose, and determination of serum concentrations (e.g. of theophylline) may be necessary.

Methotrexate

The concomitant use of Omacip with methotrexate is not recommended.

Interaction with tests

The in-vitro activity of Omacip against Mycobacterium tuberculosis might give false negative bacteriological test results in specimens from patients currently taking Omacip.

Injection Site Reaction

Local intravenous site reactions have been reported with the intravenous administration of Omacip. These reactions are more frequent if the infusion time is 30 minutes or less. These may appear as local skin reactions which resolve rapidly upon completion of the infusion. Subsequent intravenous administration is not contraindicated unless the reactions recur or worsen.

NaCl Load

In patients for whom sodium intake is of medical concern (patients with congestive heart failure, renal failure, nephrotic syndrome, etc.), the additional sodium load should be taken into account (for sodium chloride content, see section 2).

Vision disorders

If vision becomes impaired or any effects on the eyes are experienced, an eye specialist should be consulted immediately.

Due to its neurological effects, Omacip may affect reaction time. Thus, the ability to drive or to operate machinery may be impaired.

The most commonly reported adverse drug reactions (ADRs) are nausea and diarrhea, vomiting, transient increase in transaminases, rash, and injection and infusion site reactions.

ADRs derived from clinical studies and post-marketing surveillance with Omacip (oral, intravenous and sequential therapy) sorted by categories of frequency are listed below. The frequency analysis takes into account data from both oral and intravenous administration of Omacip.

The following undesirable effects have a higher frequency category in the subgroups of patients receiving intravenous or sequential (intravenous to oral) treatment:

Paediatric population

The incidence of arthropathy, mentioned above, is referring to data collected in studies with adults. In children, arthropathy is reported to occur commonly.

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: Yellow Card Scheme - Website: www.mhra.gov.uk/yellowcard.

An overdose of 12 g has been reported to lead to mild symptoms of toxicity. An acute overdose of 16 g has been reported to cause acute renal failure.

Symptoms in overdose consist of dizziness, tremor, headache, tiredness, seizures, hallucinations, confusion, abdominal discomfort, renal and hepatic impairment as well as crystalluria and haematuria. Reversible renal toxicity has been reported.

Apart from routine emergency measures, e.g. ventricular emptying followed by medical carbon, it is recommended to monitor renal function, including urinary pH and acidify, if required, to prevent crystalluria. Patients should be kept well hydrated. Calcium or magnesium containing antacids may theoretically reduce the absorption of Omacip in overdoses.

Only a small quantity of Omacip (< 10%) is eliminated by haemodialysis or peritoneal dialysis.

In the event of overdose, symptomatic treatment should be implemented. ECG monitoring should be undertaken, because of the possibility of QT interval prolongation.

Pharmacotherapeutic group: Fluoroquinolones, ATC code: J01MA02

Mechanism of action

As a fluoroquinolone antibacterial agent, the bactericidal action of Omacip results from the inhibition of both type II topoisomerase (DNA-gyrase) and topoisomerase IV, required for bacterial DNA replication, transcription, repair and recombination.

Pharmacokinetic/pharmacodynamic relationship

Efficacy mainly depends on the relation between the maximum concentration in serum (C_max) and the minimum inhibitory concentration (MIC) of Omacip for a bacterial pathogen and the relation between the area under the curve (AUC) and the MIC.

Mechanism of resistance

In-vitro resistance to Omacip can be acquired through a stepwise process by target site mutations in both DNA gyrase and topoisomerase IV. The degree of cross-resistance between Omacip and other fluoroquinolones that results is variable. Single mutations may not result in clinical resistance, but multiple mutations generally result in clinical resistance to many or all active substances within the class.

Impermeability and/or active substance efflux pump mechanisms of resistance may have a variable effect on susceptibility to fluoroquinolones, which depends on the physiochemical properties of the various active substances within the class and the affinity of transport systems for each active substance. All in-vitro mechanisms of resistance are commonly observed in clinical isolates.

Resistance mechanisms that inactivate other antibiotics such as permeation barriers (common in Pseudomonas aeruginosa) and efflux mechanisms may affect susceptibility to Omacip.

Plasmid-mediated resistance encoded by qnr-genes has been reported.

Spectrum of antibacterial activity

Breakpoints separate susceptible strains from strains with intermediate susceptibility and the latter from resistant strains:

EUCAST Recommendations

¹ Staphylococcus spp. - breakpoints for Omacip relate to high dose therapy.

* 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 species that have not been given a species-specific breakpoint and not for those species where susceptibility testing is not recommended.

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 the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Groupings of relevant species according to Omacip susceptibility

Absorption

Following an intravenous infusion of Omacip the mean maximum serum concentrations were achieved at the end of infusion. Pharmacokinetics of Omacip were linear over the dose range up to 400 mg administered intravenously.

Comparison of the pharmacokinetic parameters for a twice a day and three times a day intravenous dose regimen indicated no evidence of drug accumulation for Omacip and its metabolites.

A 60-minute intravenous infusion of 200 mg Omacip or the oral administration of 250 mg Omacip, both given every 12 hours, produced an equivalent area under the serum concentration time curve (AUC).

A 60-minute intravenous infusion of 400 mg Omacip every 12 hours was bioequivalent to a 500 mg oral dose every 12 hours with regard to AUC.

The 400 mg intravenous dose administered over 60 minutes every 12 hours resulted in a C_max similar to that observed with a 750 mg oral dose.

A 60-minute infusion of 400 mg Omacip every 8 hours is equivalent with respect to AUC to 750 mg oral regimen given every 12 hours.

Distribution

Protein binding of Omacip is low (20-30%). Omacip is present in plasma largely in a non-ionised form and has a large steady state distribution volume of 2-3 l/kg body weight. Omacip reaches high concentrations in a variety of tissues such as lung (epithelial fluid, alveolar macrophages, biopsy tissue), sinuses, inflamed lesions (cantharides blister fluid), and the urogenital tract (urine, prostate, endometrium) where total concentrations exceeding those of plasma concentrations are reached.

Biotransformation

Low concentrations of four metabolites have been reported, which were identified as: desethyleneOmacip (M 1), sulphoOmacip (M 2), oxoOmacip (M 3) and formylOmacip (M 4). The metabolites display in-vitro antimicrobial activity but to a lower degree than the parent compound.

Omacip is known to be a moderate inhibitor of the CYP 450 1A2 iso-enzymes.

Elimination

Omacip is largely excreted unchanged both renally and, to a smaller extent, faecally.

Renal clearance is between 180-300 ml/kg/h and the total body clearance is between 480-600 ml/kg/h. Omacip undergoes both glomerular filtration and tubular secretion. Severely impaired renal function leads to increased half lives of Omacip of up to 12 h.

Non-renal clearance of Omacip is mainly due to active trans-intestinal secretion and metabolism. 1% of the dose is excreted via the biliary route. Omacip is present in the bile in high concentrations.

Paediatric population

The pharmacokinetic data in paediatric patients are limited.

In a study in children C_max and AUC were not age-dependent (above one year of age). No notable increase in C_max and AUC upon multiple dosing (10 mg/kg three times daily) was observed.

In 10 children with severe sepsis C_max was 6.1 mg/l (range 4.6-8.3 mg/l) after a 1-hour intravenous infusion of 10 mg/kg in children aged less than 1 year compared to 7.2 mg/l (range 4.7-11.8 mg/l) for children between 1 and 5 years of age. The AUC values were 17.4 mgh/l (range 11.8-32.0 mgh/l) and 16.5 mgh/l (range 11.0-23.8 mgh/l) in the respective age groups.

These values are within the range reported for adults at therapeutic doses. Based on population pharmacokinetic analysis of paediatric patients with various infections, the predicted mean half-life in children is approx. 4-5 hours and the bioavailability of the oral suspension ranges from 50 to 80%.

Non-clinical data reveal no special hazard for humans based on conventional studies of single dose toxicity, repeated dose toxicity, carcinogenic potential, or toxicity to reproduction.

Like a number of other quinolones, Omacip is phototoxic in animals at clinically relevant exposure levels. Data on photomutagenicity / photocarcinogenicity show a weak photomutagenic or phototumorigenic effect of Omacip in-vitro and in animal experiments. This effect was comparable to that of other gyrase inhibitors.

Articular tolerability

As reported for other gyrase inhibitors, Omacip causes damage to the large weight-bearing joints in immature animals. The extent of the cartilage damage varies according to age, species and dose; the damage can be reduced by taking the weight off the joints. Studies with mature animals (rat, dog) revealed no evidence of cartilage lesions. In a study in young beagle dogs, Omacip caused severe articular changes at therapeutic doses after two weeks of treatment, which were still observed after 5 months.

Unless compatibility with other solutions/drugs has been confirmed, the infusion solution must always be administered separately. The visual signs of incompatibility are e.g. precipitation, clouding, and discoloration.

Incompatibility appears with all infusion solutions/drugs that are physically or chemically unstable at the pH of the solutions (e.g. penicillins, heparin solutions), especially in combination with solutions adjusted to an alkaline pH (pH of Omacip solutions: 3.9 - 4.5).

The solution should be visually inspected prior to use and only clear solutions, without particles, should be used.

The infusion contains no preservatives. For single use only. Any remaining solution and vials and/or bags should be adequately disposed of, in accordance with local requirements.

Omacip is compatible with physiological sodium chloride solution, Ringer's solution, Ringer's lactate solution, 50 mg/ml (5 %) or 100 mg/ml (10 %) glucose solution and 50 mg/ml (5 %) glucose solution with 2.25 mg/ml (0.225 %) or 4.5 mg/ml (0.45 %) sodium chloride solution and 10% fructose solution. Compatibility with these solutions has been proven in Omacip concentrations of 1 mg/ml. Chemical and physical in-use stability has been demonstrated immediately after dilution, after 24 hours at 2-8°C and after 24 hours at room temperature. Unless compatibility is proven, the solution for infusion should always be administered separately.

The diluted solutions should be inspected visually for particulate matter and discoloration prior to administration. Only clear and colourless solutions should be used.

Handling glass vials:

Omacip 2 mg/ml may be infused via a suitable cannula directly or diluted with any of the fluids in the list above.

Handling plastic bags:

Do not remove unit from overwrap until ready for use. The overwrap is a moisture barrier. The inner bag maintains the sterility of the product.

To open, tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. After removing overwrap, check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.

CAUTION: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed.