Zinforo

Zinforo

ceftaroline fosamil

Manufacturer:

Pfizer

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Ceftaroline fosamil.
Description
Each vial contains ceftaroline fosamil acetic acid solvate monohydrate equivalent to 600 mg ceftaroline fosamil.
After reconstitution, 1 mL of the solution contains 30 mg of ceftaroline fosamil.
Excipients/Inactive Ingredient: L-Arginine.
Action
Pharmacotherapeutic Group: Antibacterials for systemic use, other cephalosporins. ATC Code: J01DI02.
The active moiety after ceftaroline fosamil administration is ceftaroline.
Pharmacology: Pharmacodynamics: Mechanism of action Ceftaroline is a cephalosporin with activity against Gram-positive and Gram-negative bacteria. Invitro studies have shown that ceftaroline is bactericidal, due to inhibition of bacterial cell wall synthesis by binding to penicillin binding proteins (PBPs). Ceftaroline is also active against methicillin-resistant Staphylococcus aureus (MRSA) and penicillin non-susceptible Streptococcus pneumoniae (PNSP) due to its high affinity for the altered PBPs found in these organisms.
Pharmacokinetic/pharmacodynamic relationship: As with other beta-lactam antimicrobial agents, the percent time above the minimum inhibitory concentration (MIC) of the infecting organism over the dosing interval (%T >MIC) has been shown to best correlate with the antimicrobial activities for ceftaroline.
Mechanisms of resistance: Ceftaroline is not active against strains of Enterobacteriaceae producing extended-spectrum betalactamases (ESBLs) from the TEM, SHV or CTX-M families, serine carbapenemases (such as KPC), class B metallo-beta-lactamases or class C (AmpC cephalosporinases). Resistance may also be mediated by bacterial impermeability or drug efflux pump mechanisms. One or more of these mechanisms may co-exist in the same bacterium
Cross-resistance: Unlike other cephalosporins, ceftaroline is active against most MRSA and PNSP due to its ability to bind to the altered PBPs in these organisms that commonly confer insusceptibility to other beta-lactam agents.
Interaction with other antibacterial agents: In vitro studies have not demonstrated any antagonism between ceftaroline in combination with other commonly used antibacterial agents (e.g. amikacin, azithromycin, aztreonam, daptomycin, levofloxacin, linezolid, meropenem, tigecycline, and vancomycin).
Susceptibility testing: The prevalence of acquired resistance may vary geographically and with time for selected species. 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 is questionable.
The susceptibility to ceftaroline of a given clinical isolate should be determined by standard methods. Interpretations of test results should be made in accordance with local infectious diseases and clinical microbiology guidelines.
Clinical efficacy against specific pathogens: Efficacy has been demonstrated in clinical studies against pathogens listed under each indication that were susceptible to ceftaroline in vitro.
Complicated skin and soft tissue infections: Gram-positive organisms: Staphylococcus aureus (including methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus, (includes S. anginosus, S. intermedius, and S. constellatus), Streptococcus dysgalactiae.
Gram-negative -organisms: Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Morganella morganii.
Community-acquired pneumonia: Gram-positive organisms: Streptococcus pneumoniae (including cases with concurrent bacteraemia), Staphylococcus aureus (methicillin-susceptible strains only).
Gram-negative organisms: Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae.
Antibacterial activity against other relevant pathogens: Clinical efficacy has not been established against the following pathogens although in vitro studies suggest that they would be susceptible to ceftaroline in the absence of acquired mechanisms of resistance: Anaerobic Gram-positive organisms: Peptostreptococcus species.
Anaerobic Gram-negative organisms: Fusobacterium species.
Clinical efficacy and safety: Complicated skin and soft tissue infections: A total of 1396 adults with documented complicated skin and soft tissue infections were enrolled in two identical randomised, multi-centre, multinational, double-blind studies (CANVAS 1 and CANVAS 2) comparing ceftaroline fosamil (600 mg administered intravenously over 60 minutes every 12 hours) to vancomycin plus aztreonam (1 g vancomycin administered intravenously over 60 minutes followed by 1 g aztreonam administered intravenously over 60 minutes every 12 hours). Patients with deep/extensive cellulitis, a major abscess, a wound infection (surgical or traumatic), infected bites, burns or ulcers, or any lower extremity infection in patients with either pre-existing diabetes mellitus or peripheral vascular disease, were eligible for the studies. Treatment duration was 5 to 21 days. The modified intent-to-treat (MITT) population included all patients who received any amount of study drug according to their randomised treatment group. The clinically evaluable (CE) population included patients in the MITT population with sufficient adherence to the protocol.
The primary efficacy endpoint was the clinical response at the Test of Cure (TOC) visit in the coprimary populations of the CE and MITT patients in the table as follows. (See Table 1.)

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Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented as follows. (See Table 2.)

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Complicated skin and soft tissue infections with systemic inflammatory response or underlying comorbidities (COVERS): A total of 772 adults with cSSTI with evidence of systemic inflammation and/or underlying comorbidities were enrolled in a randomised, multi-centre, double-blind study (COVERS) comparing ceftaroline fosamil (600 mg administered intravenously over 120 minutes every 8 hours) to vancomycin plus aztreonam. The MITT population included all patients who received any amount of study drug according to their randomised treatment group; patients had an average area of lesion size of 400 cm2, 40% had SIRS, and 61% had elevated CRP (>50 mg/L). Treatment duration was 5 to 14 days. The CE population included patients in the MITT population with sufficient adherence to the protocol. The primary endpoint was clinical cure rate at the TOC visit in both the MITT and CE populations. (See Table 3.)

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Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented as follow. (See Table 4.)

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Community-acquired pneumonia: A total of 1240 adults with a diagnosis of CAP were enrolled in two randomized, multi-centre, multinational, double-blind studies (FOCUS 1 and FOCUS 2) comparing ceftaroline fosamil (600 mg administered intravenously over 60 minutes every 12 hours) to ceftriaxone (1 g ceftriaxone administered intravenously over 30 minutes every 24 hours). The studies were identical except in one respect, in FOCUS 1 both treatment groups received 2 doses of oral clarithromycin (500 mg every 12 hours) as adjunctive therapy starting on Day 1. No adjunctive macrolide therapy was used in FOCUS 2. Patients with new or progressive pulmonary infiltrate(s) on chest radiography with clinical signs and symptoms consistent with CAP with the need for hospitalisation and intravenous therapy were enrolled in the studies. Treatment duration was 5 to 7 days. The modified intent-to-treat efficacy (MITTE) population included all patients who received any amount of study drug according to their randomized treatment group and were in PORT Risk Class III or IV. The clinically evaluable (CE) population included patients in the MITTE population with sufficient adherence to the protocol.
The primary efficacy endpoint was the clinical response at the Test of Cure (TOC) visit in the coprimary populations of the CE and MITTE populations in the table as follows. (See Table 5.)

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Clinical cure rates at TOC by pathogens in the microbiologically evaluable patients are presented in the table as follows. (See Table 6.)

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Asia CAP Study: A total of 771 adults with a diagnosis of CAP were enrolled in a randomized, multi-centre, doubleblind study in Asia comparing ceftaroline fosamil (600 mg administered intravenously over 60 minutes every 12 hours) to ceftriaxone (2 g administered intravenously over 30 minutes every 24 hours). Treatment duration was 5 to 7 days. The primary objective was to determine the noninferiority in the clinical cure rate of ceftaroline treatment compared with that of ceftriaxone treatment at the TOC visit in the CE population of adult hospitalized patients with CAP (lower boundary of the 95% confidence interval for the difference in response rate [ceftaroline - ceftriaxone] greater than - 10%).
The non-inferiority of ceftaroline 600 mg versus ceftriaxone 2 g was demonstrated in both the CE and MITT populations (Tables 1 and 2). Furthermore, based on the pre-defined criteria (lower boundary of the 95% confidence interval for the difference in response rate greater than 0%), the superiority of ceftaroline 600 mg versus ceftriaxone 2 g was demonstrated in adult patients with PORT Risk Class III/IV CAP in Asia. (See Table 7, Table 8 and Table 9.)

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Pharmacokinetics: The Cmax and AUC of ceftaroline increase approximately in proportion to dose within the single dose range of 50 to 1000 mg. No appreciable accumulation of ceftaroline is observed following multiple intravenous infusions of 600 mg every 8 or 12 hours in healthy adults with normal renal function.
The systemic exposure (AUC), T½, and clearance of ceftaroline were similar following administration of 600 mg ceftaroline fosamil in a volume of 50 mL to healthy adult subjects every 8 hours for 5 days as 5 minute or 60 minute infusions, and the Tmax of ceftaroline occurred about 5 minutes after the end of the ceftaroline fosamil infusion for both infusion durations. The mean (SD) Cmax of ceftaroline was 32.5 (4.82) mg/L for the 5 minute infusion duration (n=11) and 17.4 (3.87) mg/L for the 60 minute infusion duration (n=12).
Distribution: The plasma protein binding of ceftaroline is low (approximately 20%) and ceftaroline is not distributed into erythrocytes. The median steady-state volume of distribution of ceftaroline in healthy adult males following a single 600 mg intravenous dose of radiolabeled ceftaroline fosamil was 20.3 L, similar to the volume of extracellular fluid.
Metabolism: Ceftaroline fosamil (prodrug) is converted into the active ceftaroline in plasma by phosphatase enzymes and concentrations of the prodrug are measurable in plasma primarily during intravenous infusion. Hydrolysis of the beta-lactam ring of ceftaroline occurs to form the microbiologically inactive, open-ring metabolite, ceftaroline M-1. The mean plasma ceftaroline M-1 to ceftaroline AUC ratio following a single 600 mg intravenous infusion of ceftaroline fosamil in healthy subjects is approximately 20-30%.
In pooled human liver microsomes, metabolic turnover was low for ceftaroline, indicating that ceftaroline is not metabolised by hepatic CYP450 enzymes.
Excretion: Ceftaroline is primarily eliminated by the kidneys. Renal clearance of ceftaroline is approximately equal, or slightly lower than the glomerular filtration rate in the kidney, and in vitro transporter studies indicate that active secretion does not contribute to the renal elimination of ceftaroline.
The mean terminal elimination half-life of ceftaroline in healthy adults is approximately 2.5 hours.
Following the administration of a single 600 mg intravenous dose of radiolabeled ceftaroline fosamil to healthy male adults, approximately 88% of radioactivity was recovered in urine and 6% in faeces.
Special populations: Patients with renal impairment: Dosage adjustment is required in patients with CrCL ≤50 ml/min (see Dosage & Administration).
Patients with hepatic impairment: The pharmacokinetics of ceftaroline in patients with hepatic impairment have not been established. As ceftaroline does not appear to undergo significant hepatic metabolism, the systemic clearance of ceftaroline is not expected to be significantly affected by hepatic impairment. Therefore, no dosage adjustment is recommended for patients with hepatic impairment.
Elderly patients: Following administration of a single 600 mg intravenous dose of ceftaroline fosamil, the pharmacokinetics of ceftaroline was similar between healthy elderly subjects (≥65 years of age), and healthy young adult subjects (18-45 years of age). There was a slight 33% increase in AUC0-∞ in the elderly that was mainly attributable to age-related changes in renal function. Ceftaroline fosamil dose adjustment is not required in elderly patients with creatinine clearance above 50 mL/min.
Paediatric population: The safety and efficacy of ceftaroline fosamil in children aged birth to <18 years have not yet been established.
Gender: The pharmacokinetics of ceftaroline were similar between males and females. No dose adjustment is required based on gender.
Race: Race was evaluated as a covariate in a population pharmacokinetic analysis on data from the clinical studies. No significant differences in ceftaroline pharmacokinetics were observed in Caucasian, Hispanic, Black, Asian or other subjects. No dosage adjustment is recommended based on race.
Toxicology: Preclinical safety data: The kidney was the primary target organ of toxicity in both the monkey and rat. Histopathologic findings included pigment deposition and inflammation of the tubular epithelium. Renal changes were not reversible but were reduced in severity following a 4 week recovery period.
Convulsions have been observed at relatively high exposures during single and multi-dose studies in both the rat and monkey (≥7 times to the estimated Cmax level of a 600 mg twice a day).
Other important toxicologic findings noted in the rat and monkey included histopathologic changes in the bladder and spleen.
Genetic toxicology: Ceftaroline fosamil and ceftaroline were clastogenic in an in vitro chromosomal aberration assay, however there was no evidence of mutagenic activity in an Ames, mouse lymphoma and unscheduled DNA synthesis assay. Furthermore, in vivo micronucleus assays in rat and mouse were negative. Carcinogenicity studies have not been conducted.
Reproductive toxicology: Reproductive studies in pregnant rabbits resulted in an increased foetal incidence of angulated hyoid alae, a common skeletal variation in rabbit foetuses, at exposures similar to 600 mg twice daily in humans. In the rat, no adverse effects were observed on embryofoetal development, fertility or postnatal development.
Indications/Uses
Ceftaroline fosamil is indicated in adults for the treatment of the following infections (see Precautions and Pharmacology: Pharmacokinetics under Actions): Complicated skin and soft tissue infections (cSSTI), Community-acquired pneumonia (CAP).
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
Dosage/Direction for Use
Posology: For the treatment of cSSTI and CAP, the recommended dose is 600 mg administered every 12 hours by intravenous infusion over 5 to 60 minutes in patients aged 18 years or older. The recommended treatment duration for cSSTI is 5 to 14 days and the recommended duration of treatment for CAP is 5 to 7 days.
Special populations: Elderly: No dosage adjustment is required for the elderly with creatinine clearance values > 50 ml/min (see Pharmacology: Pharmacokinetics under Actions).
Renal impairment The dose should be adjusted when creatinine clearance (CrCL) is ≤ 50 ml/min, as shown below (see Pharmacology: Pharmacokinetics under Actions). (See Table 10.)

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Hepatic impairment: No dosage adjustment is considered necessary in patients with hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
Paediatric population: The safety and efficacy of ceftaroline fosamil in children aged birth to < 18 years have not yet been established. No data are available (see Pharmacology: Pharmacokinetics under Actions).
Method of administration: Ceftaroline fosamil is administered by intravenous infusion over 60 minutes for all infusion volumes (50 ml, 100 ml or 250 ml) (see Description).
For instructions on reconstitution and dilution of the medicinal product before administration, see Description.
Overdosage
Intentional overdosing of ceftaroline fosamil is unlikely, although relative overdosing can occur particularly in patients with moderate to severe renal impairment. Limited data in patients receiving higher than recommended ceftaroline fosamil dosages show similar adverse reactions as observed in the patients receiving recommended dosages. Treatment under such circumstances should follow local standard medical practice.
Ceftaroline can be removed by haemodialysis; over a 4 hour dialysis session, approximately 74% of a given dose was recovered in the dialysate.
Contraindications
Hypersensitivity to ceftaroline fosamil or to any of the excipients listed in Description.
Hypersensitivity to cephalosporin class of antibacterials.
Immediate and severe hypersensitivity (e.g. anaphylactic reaction) to any other type of beta-lactam antibacterial agent (e.g. penicillins or carbapenems).
Special Precautions
Hypersensitivity reactions: As with all beta-lactam antibacterials, serious and occasionally fatal hypersensitivity reactions are possible (see Contraindications and Adverse Reactions).
Patients who have a history of hypersensitivity to cephalosporins, penicillins or other beta-lactam antibacterials may also be hypersensitive to ceftaroline fosamil. Before initiating therapy with ceftaroline fosamil, careful inquiry should be made concerning previous hypersensitivity reactions to beta-lactam antibacterials. If a patient developed an immediate and severe hypersensitivity (e.g. anaphylactic reaction) previously to any type of beta-lactam antibacterial, ceftaroline fosamil should not be administered (see Contraindications).
If a severe allergic reaction occurs, the medicinal product should be discontinued and appropriate measures taken.
Clostridium difficile-associated diarrhoea: Antibacterial-associated colitis and pseudomembranous colitis have been reported with nearly all anti bacterial agents, including ceftaroline fosamil, and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of ceftaroline fosamil (see section 4.8). In such circumstance, the discontinuation of therapy with ceftaroline fosamil and the use of supportive measures together with the administration of specific treatment for Clostridium difficile should be considered.
Patients with pre-existing seizure disorder: As with other cephalosporins, seizures have occurred in ceftaroline toxicology studies at 7-25 times human Cmax levels (see section 5.3). Clinical study experience with ceftaroline fosamil in patients with pre-existing seizure disorders is limited. Therefore, ceftaroline fosamil should be used with caution in this patient population.
Direct antiglobulin test (Coombs test) seroconversion: The development of a positive direct antiglobulin test (DAGT) may occur during treatment with cephalosporins. The incidence of DAGT seroconversion in patients receiving ceftaroline fosamil was 11.2% in the five pooled Phase 3 studies with administration every 12 hours (600 mg administered over 60 minutes every 12 hours) and 32.3% in a study in patients receiving ceftaroline fosamil every 8 hours (600 mg administered over 120 minutes every 8 hours). There was no evidence of haemolysis in any patient receiving ceftaroline fosamil who developed a positive DAGT.
cSSTI caused by (Staphylococcus aureus) S. aureus with an MIC >1 mg/L to ceftaroline: There are limited clinical data for ceftaroline in treating cSSTI in adults caused by S. aureus with an MIC >1 mg/L to ceftaroline and there are no clinical data for treating S. aureus with an MIC = 2 mg/L to 4 mg/L to ceftaroline. Therefore, the recommended dosages of ceftaroline fosamil to treat cSSTI caused by S. aureus with an MIC >1 mg/L to ceftaroline are based on pharmacokinetic/pharmacodynamic modelling and simulation (see Dosage & Administration).
Non-susceptible organisms: Superinfections may occur as with other antibacterial agents.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed. Dizziness may occur and this may have an effect on ability to drive and use machines (see Adverse Reactions).
Use In Pregnancy & Lactation
Pregnancy: No clinical data on pregnancies are available for ceftaroline. Animal studies with ceftaroline fosamil do not indicate harmful effects with respect to fertility, pregnancy, parturition or postnatal development (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Ceftaroline fosamil should not be used during pregnancy unless clearly necessary and only if the potential benefit outweighs the possible risk.
Lactation: It is not known whether ceftaroline is excreted in human milk, but because many beta-lactams are excreted in breast milk, women who are breast-feeding should be treated with ceftaroline fosamil only if clearly indicated. Interruption of breast-feeding is recommended.
Adverse Reactions
Pooled Phase III studies: Four phase 3 clinical trials (two in cSSTI and two in CAP) included 1305 adult patients treated with ceftaroline fosamil (600 mg administered over 60 minutes every 12 hours).
The incidences of treatment emergent adverse events in the pooled Phase 3 cSSTI and CAP studies were similar in ceftaroline and comparator groups (45.7% versus 46.7%, respectively). The most common adverse reactions occurring in ≥3% of patients treated with ceftaroline fosamil were diarrhoea, headache, nausea, and pruritus, and were generally mild or moderate in severity.
Additional Phase III studies: A study (Asia CAP) in Asia of 381 adult patients with CAP treated with ceftaroline fosamil (600 mg administered over 60 minutes every 12 hours) demonstrated that the safety profile of ceftaroline fosamil in these patients was similar to that observed in the pooled Phase 3 cSSTI and CAP studies.
A study (COVERS) was conducted of 506 adult patients with cSSTI treated with ceftaroline fosamil (600 mg administered over 120 minutes every 8 hours). The most common adverse reactions occurring in ≥3% of patients treated with ceftaroline fosamil were nausea, headache, and rash. The safety profile of ceftaroline fosamil was similar to that observed in previous pooled Phase III studies with the exception of both a greater incidence of rash in Asian patients (see below) and a greater incidence of DAGT seroconversion (see Precautions).
The following adverse reactions have been identified during clinical trials with ceftaroline fosamil. (See Table 11.)

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Description of selected adverse reactions: Rash: Rash was observed at a common frequency in the pooled Phase III studies in cSSTI with administration of ceftaroline fosamil every 12 hours (600 mg administered over 60 minutes every 12 hours) and the COVERS study in cSSTI with administration every 8 hours (600 mg administered over 120 minutes every 8 hours). However, the frequency of rash in the subgroup of Asian patients receiving ceftaroline fosamil every 8 hours (COVERS) was very common (18.5%).
Drug Interactions
No clinical drug-drug interaction studies have been conducted with ceftaroline fosamil.
The interaction potential of ceftaroline or ceftaroline fosamil on medicinal products metabolised by P450 enzymes is expected to be low since they are not inhibitors or inducers of P-450 enzymes in vitro. Ceftaroline or ceftaroline fosamil are not metabolised by P450 enzymes in vitro; therefore, co-administration with P450 inducers or inhibitors are unlikely to influence the pharmacokinetics of ceftaroline.
Ceftaroline is neither a substrate, nor an inhibitor of renal uptake transporters (OCT2, OAT1 and OAT3) in vitro. Therefore, interactions of ceftaroline with medicinal products that are substrates or inhibitors (e.g. probenecid) of these transporters would not be expected.
Caution For Usage
Special precautions for disposal and other handling: The powder must be constituted with water for injections and the resulting constituted solution must then be immediately diluted prior to use. The constituted solution is a pale yellow solution that is free of any particles.
Standard aseptic techniques should be used for solution preparation and administration.
Ceftaroline fosamil powder should be constituted with 20 ml sterile water for injections. The resulting constituted solution should be shaken prior to being transferred to an infusion bag or bottle containing one of the following diluents: sodium chloride 9 mg/ml (0.9%) solution for injection, dextrose 50 mg/ml (5%) solution for injection, sodium chloride 4.5 mg/ml and dextrose 25 mg/ml solution for injection (0.45% sodium chloride and 2.5% dextrose), Lactated Ringer's solution.
A 250 mL, 100 mL or 50 mL infusion bag can be used to prepare the infusion. The total time interval between starting constitution and completing preparation of the intravenous infusion should not exceed 30 minutes.
One mL of the constituted solution contains 30 mg of ceftaroline fosamil. For storage conditions of the constituted and diluted medicinal product, see Shelf-Life under Storage.
Each vial is for single use only.
Any unused product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: This medicinal product must not be mixed with other medicinal products except those previously mentioned in Special precautions for disposal and other handling.
Storage
Store below 30°C.
Store in the original package in order to protect from light.
For storage conditions of the constituted and diluted medicinal product, see Shelf-Life as follows.
Shelf-Life: After reconstitution: The reconstituted vial should be used immediately.
After dilution: Once the intravenous solution is prepared with diluents listed in Special precautions for disposal and other handling it should be administered within 6 hours of preparation. The chemical and physical in-use stability has been demonstrated for up to 24 hours at 2-8°C. Once removed from refrigeration to room temperature, the diluted product must be used within 6 hours.
From a microbiological point of view, the medicinal product should be used immediately, unless constitution and dilution has taken place in controlled and validated aseptic conditions. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.
MIMS Class
ATC Classification
J01DI02 - ceftaroline fosamil ; Belongs to the class of other cephalosporins and penems. Used in the systemic treatment of infections.
Presentation/Packing
Powd for infusion 600 mg (pale yellowish-white to light yellow powder in vial) x 10's.
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