Zinforo

Zinforo

ceftaroline fosamil

Manufacturer:

Pfizer
Full Prescribing Info
Contents
Ceftaroline fosamil.
Description
Each vial contains ceftaroline fosamil 600 mg equivalent to ceftaroline 530 mg.
Excipients/Inactive Ingredients: L-arginine.
Action
Pharmacology: Pharmacodynamics: Mechanism of action: Ceftaroline is a cephalosporin with activity against Gram-positive and Gram-negative bacteria. In-vitro 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-nonsusceptible 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 beta-lactamases (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 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.
Gram-negative organisms: Escherichia coli; Klebsiella pneumoniae; Klebsiella oxytoca.
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 ZINFORO (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 co-primary populations of the CE and MITT patients in the table as follows. (See Table 1.)


Click on icon to see table/diagram/image


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


Click on icon to see table/diagram/image


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 administered over 60 minutes every 12 hours for up to 14 days in healthy adults with normal renal function.
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 moderate renal impairment (CrCL > 30 to 50 ml/min). There is insufficient data to make specific dosage adjustment recommendations for patients with severe renal impairment (CrCL ≤ 30 ml/min) and end-stage renal disease (ESRD), including patients undergoing haemodialysis.
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 ZINFORO, 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. ZINFORO dose adjustment is not required in elderly patients with creatinine clearance above 50 ml/min.
Paediatric patients: The safety and efficacy of ZINFORO in paediatric patients have not been established.
Gender: The pharmacokinetics of ceftaroline were similar between males and females. No dose adjustment is required based on sex.
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, or other patients. 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
ZINFORO is indicated for the treatment of adult (≥ 18 years of age) patients with complicated skin and soft tissue infections (cSSTI) caused by susceptible isolates of the designated microorganism: Staphylococcus aureus (including methicillin-susceptible and -resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Escherichia coli, Klebsiella pneumoniae and Klebsiella oxytoca.
Usage: To reduce the development of drug-resistant bacteria and maintain the effectiveness of ceftaroline and other antibacterial drugs, ceftaroline should be used to treat only cSSTI that are proven or strongly suspected to be caused by susceptible bacteria. Appropriate specimens for microbiological examination should be obtained in order to isolate and identify the causative pathogens and to determine their susceptibility to ceftaroline. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
Dosage/Direction for Use
The recommended dosage of ZINFORO is 600 mg administered every 12 hours by intravenous infusion over 60 minutes in patients ≥18 years of age for duration of 5-14 days. The duration of treatment should be guided by the severity of infection and the patient's clinical response.
Special populations: Patients with renal impairment: The following dose adjustment is recommended in patients with renal impairment (see Pharmacology: Pharmacokinetics under Actions and Precautions): (See Table 3.)


Click on icon to see table/diagram/image


Patients with hepatic impairment: No dosage adjustment is considered necessary in patients with hepatic impairment (see Pharmacology: Pharmacokinetics properties).
Elderly patients: No dosage adjustment is required for the elderly with creatinine clearance (CrCL) values > 50 ml/min (see Pharmacology: Pharmacokinetics properties).
Paediatric patients: Safety and efficacy in paediatric patients have not been established (see Pharmacology: Pharmacokinetics properties).
Constitution and compatibility: See Instructions for use, handling and disposal.
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 ZINFORO 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 the active substance or to any of its excipients.
Hypersensitivity to the 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 ZINFORO, 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 shoul dnot 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 ZINFORO, 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 Adverse Reactions). In such circumstance, the discontinuation of therapy with ZINFORO 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 Pharmacology: Toxicology: Preclinical safety data under Actions). Clinical study experience with ceftaroline in patients with pre-existing seizure disorders is limited. Therefore, ZINFORO 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 10.7% in the pooled Phase 3 studies. There was no evidence of haemolysis in any patient receiving ceftaroline fosamil who developed a positive DAGT.
Patients with renal impairment: Clinical study experience with ceftaroline in patients with severe renal impairment and ESRD is limited. Therefore, use of ZINFORO is not recommended in these patient populations (see Pharmacology: Pharmacokinetics under Actions).
Non-susceptible organisms: Superinfections may occur as with other antibacterial agents.
Effects on ability to drive and to use machines: Undesirable effects e.g. dizziness may occur and this may have an effect on the ability to drive and use of 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). ZINFORO 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 ZINFORO only if clearly indicated. Interruption of breast-feeding is recommended.
Adverse Reactions
The incidences of treatment emergent adverse events were similar in ceftaroline and comparator groups (45.7% vs 46.7%, respectively). The most common adverse reactions occurring in ≥ 3% of patients treated with ceftaroline were diarrhoea, headache, nausea, and pruritus, and were generally mild or moderate in severity.
The following adverse reactions have been identified during clinical trials with ZINFORO. Adverse reactions are classified according to frequency and System Organ Class. Frequency categories for the adverse events are defined according to the following conventions: Very common (≥ 1/10), Common (≥ 1/100, < 1/10), Uncommon (≥ 1/1000, < 1/100), Rare (≥ 1/10000, < 1/1000). (See Table 4.)


Click on icon to see table/diagram/image


Description of selected adverse reactions: Rash: Rash was observed at a common frequency in the pooled Phase III studies in cSSTI with administration of ZINFORO 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 ZINFORO every 8 hours (COVERS) was very common (18.5%).
Drug Interactions
No clinical drug-drug interaction studies have been conducted with ceftaroline.
The interaction potential of ceftaroline on drugs metabolised by CYP450 enzymes is expected to be low, since ceftaroline is not an inhibitor (CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4) nor an inducer (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4/5) of CYP450 enzymes in vitro. Ceftaroline is not metabolised by CYP450 enzymes in vitro, so co-administered CYP450 inducers or inhibitors are unlikely to influence the pharmacokinetics of ceftaroline.
In vitro, ceftaroline is not transported by efflux transporters P-gp or BCRP. Ceftaroline does not inhibit P-gp, therefore an interaction with substrates, such as digoxin, is not expected. Ceftaroline is a weak inhibitor of BCRP, but the effect is too small to be clinically relevant. In vitro studies demonstrated that ceftaroline is not a substrate of, nor did it inhibit the renal uptake transporters OCT2, OAT1, and OAT3; drug-drug interactions with drugs that inhibit active renal secretion (e.g. probenecid) or with drugs that are substrates of these transporters would therefore not be expected.
Caution For Usage
Instructions for use, handling and disposal: 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.
ZINFORO 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.
Routinely, a 250 ml infusion bag should be used to prepare the infusion and only in exceptional patients for whom there could be great concern over volumes infused should a 50 ml or 100 ml infusion bag be used. 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 mentioned in Instructions for use, handling and disposal as previously mentioned.
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: Dry powder: 3 years.
After constitution: The constituted vial should be used immediately (within 30 minutes).
After dilution: Once the intravenous solution is prepared with diluents listed in Instructions for use, handling and disposal under Cautions for Usage, 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 conc for soln for infusion (pale yellowish-white to light yellow in vial) 600 mg x 10's.
Register or sign in to continue
Asia's one-stop resource for medical news, clinical reference and education
Sign up for free
Already a member? Sign in