Consumer medicine information

Zinforo

Ceftaroline fosamil

BRAND INFORMATION

Brand name

Zinforo

Active ingredient

Ceftaroline fosamil

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Zinforo.

What is in this leaflet

This leaflet answers some common questions people ask about Zinforo. It does not contain all the available information. It does not take the place of talking to your/your child's doctor, nurse or pharmacist.

All medicines have risks and benefits. Your/your child's doctor will have weighed the risks of taking Zinforo against the benefits they expect it will have for you/your child.

If you/your child have any concerns about taking this medicine, ask the doctor, nurse or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Zinforo is used for

Zinforo is an antibiotic used to treat serious infections caused by bacteria (germs), such as:

  • infections of the skin and tissue below the skin
  • infection of the lungs (pneumonia).

Zinforo will not work against fungal or viral infections (such as colds or the flu).

Zinforo belongs to a group of antibiotics called cephalosporins. These antibiotics work by killing the bacteria that are causing the infection.

Zinforo is given by injection and is mostly given in hospital. Some patients may also be given Zinforo in "hospital in the home". It is available only with a doctor's prescription.

Ask your/your child's doctor if you/your child have any questions about why this medicine has been prescribed. The doctor may have prescribed it for another reason.

This medicine is not addictive.

The side effects of this medicine may affect the ability to drive a car or operate machinery.

Before Zinforo is given

When you/your child must not be given it

Do not take Zinforo if you have/your child has an allergy to:

  • any medicine containing ceftaroline, the active ingredient in Zinforo
  • L-arginine (inactive ingredient in Zinforo)
  • other cephalosporin antibiotics.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not take Zinforo if you have/your child has had a serious allergy to penicillins or beta-lactam antibiotics (e.g., carbapenems). You/your child may be more likely to have an allergic reaction to Zinforo if you/your child have had an allergic reaction to these other antibiotics.

The hospital staff will check that the expiry date printed on the pack has not passed and that the packaging is not torn or showing signs of tampering.

If you are not sure whether you/your child should be given this medicine, talk to the doctor, pharmacist or nurse.

Before you/your child are given it

Tell the doctor or nurse if you/your child have any type of allergic reaction to penicillin or beta-lactam antibiotics (e.g., carbapenems). You/your child may be more likely to have an allergic reaction to Zinforo if you/your child are allergic to these other antibiotics.

Tell the doctor or nurse if you/your child have allergies to any other medicines, foods, preservatives or dyes.

Tell the doctor or nurse if you/your child have or have had any of the following medical conditions:

  • kidney problems
  • fits (seizures/convulsions)
  • severe diarrhoea after taking any antibiotics.

Tell the doctor if you are pregnant or plan to become pregnant or are breast-feeding. The doctor can discuss with you/your child the risks and benefits involved.

If you/your child have not told the doctor about any of the above, tell him/her before you/your child are given Zinforo.

Taking other medicines

Tell the doctor, nurse or pharmacist if you/your child are taking any other medicines, including any that you get without a prescription from the pharmacy, supermarket or health food shop.

The doctor, nurse and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How Zinforo is given

Zinforo treatment is mostly given in hospital. Some patients may also be given Zinforo in "hospital in the home". It is given as a slow injection (infusion) directly into a vein, which usually takes 60 minutes.

It must only be given by a doctor or nurse.

How much will be given

The doctor will decide what dose of Zinforo you/your child will need depending on certain factors such as the type of infection, age and bodyweight (for children) and if you/your child have kidney problems.

Adults (18 years and over):

The usual adult dose is 600 mg every 12 hours.

Children (2 months to 17 years):

The dose in children varies depending on body weight, and is given every 8 hours. Older children (12 to 17 years) over a certain body weight may be given the adult dose (every 12 hours). Your child's doctor will decide what dose needs to be given.

People with kidney problems

If you/your child (from 24 months of age) have kidney problems, the doctor may lower the dose depending on the severity of your/your child's kidney problems.

How long will Zinforo need to be given

Zinforo needs to be given as a series of slow injections (infusions) over a few days. The doctor will decide how many days you/your child will need to be given Zinforo.

Ask the doctor, nurse or pharmacist if you have any questions including how this medicine is prepared, how it will be given to you/your child or how long it will need to be given.

If you/your child have missed a dose

If you are concerned that a dose of Zinforo may have missed, tell the doctor or nurse straight away.

If too much has been given (overdose)

As Zinforo is given under the close supervision of the doctor or nurse, it is unlikely that you/your child will be given too much. If you are concerned that too much has been given, tell the doctor, nurse or pharmacist immediately.

While using Zinforo

Things you/your child must do

If the symptoms of the infection do not improve within a few days, or if they become worse, tell the doctor.

If you/your child get severe diarrhoea tell the doctor, pharmacist or nurse immediately. Do this even if it occurs several weeks after Zinforo has been stopped. Diarrhoea may mean that there is a serious condition affecting the bowel. You/your child may need urgent medical care. Do not take/give your child any diarrhoea medicine without first checking with the doctor.

If any new medicines are about to be started remind the doctor, nurse and pharmacist that you are/your child is taking Zinforo.

Tell any other doctors (including surgeons and anaesthetists), dentists, nurses and pharmacists who treat you/your child that you/your child are being treated with this medicine.

If you find out you are pregnant while taking this medicine, tell the doctor immediately.

If you/your child are about to have any blood tests, tell the doctor or nurse that you are/your child is taking this medicine. Zinforo may affect the results of a test called “DAGT” or “Coombs”, which is a test for antibodies that fight against your red blood cells. It may also affect the test which measure how well your blood clots.

Side effects

Tell the doctor, nurse or pharmacist as soon as possible if you/your child do not feel well while taking Zinforo.

This medicine helps most people with serious infections, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You/your child may need medical attention if you/your child get some of the side effects.

Do not be alarmed by the following lists of side effects. You/your child may not experience any of them.

Ask the doctor, nurse or pharmacist to answer any questions you may have.

Tell the doctor, nurse or pharmacist if you/your child notice any of the following and they worry you/your child:

  • diarrhoea (mild – see next section if severe diarrhoea or if it doesn't go away), stomach pain
  • headache
  • feeling sick (nausea) or being sick (vomiting)
  • itching, skin rash
  • feeling dizzy
  • fever.

The above list includes the more common side effects this medicine. They are usually mild and short-lived.

Other side effects (e.g., redness, pain and swelling) may occur where the injection was given.

If any of the following happen, tell the doctor or nurse immediately, or if not in hospital already go to Accident and Emergency at your nearest hospital:

  • sudden swelling of the lips, face, throat or tongue, a severe rash, swallowing or breathing problems. These may be signs of a severe allergic reaction (anaphylaxis) and may be life-threatening.
  • diarrhoea that becomes severe or does not go away, or stools that contains blood or mucus.
    Do not take any diarrhoea medicine without checking with the doctor.
  • increase in enzymes produced by your liver (as shown in blood tests)
  • an increase in the level of creatinine in your blood. Creatinine shows how well your kidneys are working
  • severe skin reaction such as painful red areas, large blisters, peeling of your skin, and bleeding in the lips, eyes, mouth, nose and genitals.
    Your doctor may need to stop your treatment with Zinforo and change to another antibiotic if this occurs.
  • anaemia
  • pain and irritation of the veins
  • bleeding or bruising more than usual
  • sudden fever, chills, weakness in your limbs, sore throat, mouth or gums including mouth ulcers or bleeding gums
  • coughing, wheezing, feeling short of breath or difficulty breathing
  • difficulty concentrating, confusion, disorientation; muscle twitching, spasms or trembling, poor coordination; fainting, feeling weak and tired, difficulty speaking or swallowing, abnormal eye movements, seizures.

The above list includes very serious side effects. You/your child may need urgent medical attention or hospitalisation.

Occasionally, Zinforo may be associated with changes in the blood, such as an increase in some white blood cells that may require the doctor or nurse to do certain blood tests.

Tell the doctor, nurse or pharmacist if you/your child notice anything that is making you/your child feel unwell. Other side effects not listed above may also occur in some people.

After finishing Zinforo

Tell the doctor immediately if you/your child notice watery or severe diarrhoea (which may also contain blood or mucus), particularly if it occurs several weeks after stopping treatment with Zinforo.

You/your child may have a serious condition affecting the bowel which may need urgent medical attention.

Do not take/give your child any diarrhoea medicine without first checking with the doctor.

Storage

The hospital and/or pharmacy staff will store Zinforo vials in a safe place at a temperature below 25°C and away from light. They will also prepare and store the infusion bags/bottles ready for the injection.

Product description

What it looks like

Zinforo vials contain a pale yellowish-white to light yellow powder. The hospital and/or pharmacy staff dissolves the powder in water for injection, then transfer to an infusion bag/bottle containing certain solutions (e.g., normal saline) ready for the injection.

Ask the doctor, nurse or pharmacist if you/your child have any questions about how they prepare the injection.

Ingredients

Zinforo contains 600 mg of ceftaroline fosamil as the active ingredient.

It also contains L-arginine (an amino acid) as the inactive ingredient.

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Supplier

Pfizer Australia Pty Ltd
Sydney NSW.
Toll Free Number: 1800 675 229.
www.pfizer.com.au.

This leaflet was prepared in May 2020.

Australian Registration Number:

AUST R 192260.

® Registered trademark.

© Pfizer Australia Pty Ltd 2020.

Published by MIMS July 2020

BRAND INFORMATION

Brand name

Zinforo

Active ingredient

Ceftaroline fosamil

Schedule

S4

 

1 Name of Medicine

Ceftaroline fosamil monoacetate monohydrate.

2 Qualitative and Quantitative Composition

Each vial contain 600 mg of the prodrug, ceftaroline fosamil (equivalent to 530 mg active ceftaroline).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for injection.
Zinforo is a sterile, pyrogen-free pale yellowish-white to light yellow powder.
The reconstituted diluted solution is a pale yellow solution that is free of any particles.

4 Clinical Particulars

4.1 Therapeutic Indications

Zinforo is indicated for the treatment of patients with the following infections proven or strongly suspected to be caused by designated susceptible bacteria:
complicated skin and soft tissue infections (cSSTI);
community acquired pneumonia (CAP).

4.2 Dose and Method of Administration

Dosage.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Zinforo and other antibiotics, Zinforo should be used to treat only cSSTI or CAP that are proven or strongly suspected to be caused by designated 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 antibiotic therapy. In the absence of such data, local epidemiology and susceptibility patterns using local Antimicrobial Stewardship (AMS) recommendations and Therapeutic Guidelines must be used.
The recommended dosage of Zinforo, the frequency of dosing and infusion times are summarised in Table 1. The duration of treatment should be guided by the type of infection to be treated, its severity, and the patient's clinical response.

Method of administration.

Intravenous (IV) infusion.
Standard aseptic techniques should be used for solution preparation and administration.
Zinforo powder should be reconstituted with 20 mL of sterile water for injections and the resulting reconstituted solution must then be immediately diluted prior to use. The resulting reconstituted 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 (0.45% sodium chloride and 2.5% dextrose) solution for injection;
lactated Ringer's solution.
It must not be mixed with any other medications.
A 250 mL, 100 mL or 50 mL infusion bag can be used to prepare the infusion.
The total time interval between starting reconstitution and completing preparation of the IV infusion should not exceed 30 minutes.
One mL of the reconstituted solution contains 30 mg of ceftaroline fosamil.
Infusion volumes for children/adolescents will vary according to the weight of the child/adolescent. The infusion solution concentration during preparation and administration should not exceed 12 mg/mL ceftaroline fosamil.
Each Zinforo vial is for single use in one patient only.

Stability after reconstitution and dilution.

After reconstitution.

The reconstituted vial must be diluted immediately prior to use.

After dilution.

To reduce microbial hazard, the Zinforo IV infusion solution should be administered as soon as practicable after preparation. If storage is necessary, hold at 2 to 8°C (Refrigerate. Do not freeze) for not more than 24 hours, or not more than 6 hours at room temperature (including infusion time). The chemical and physical in-use stability has been demonstrated for up to 24 hours at 2 to 8°C, and up to 6 hours at room temperature.
If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

Dosage adjustment.

Renal impairment.

The dose should be adjusted when creatinine clearance (CrCl) is ≤ 50 mL/min (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties, Renal impairment), as shown in Table 2. The recommended durations of treatment are the same as those shown in Table 1.
Dose recommendations for children and adolescents are based on PK modelling.
For end stage renal disease (ESRD), there is insufficient information to recommend dosage adjustments in adolescents aged from 12 to < 18 years with bodyweight < 33 kg and in children aged from 24 months to 12 years. There is insufficient information to recommend dosage adjustments in children aged from 2 to < 24 months with moderate or severe renal impairment or ESRD.

Hepatic impairment.

No dosage adjustment is considered necessary in patients with hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties, Renal impairment).

Elderly (> 65 years old).

No dosage adjustment is required for the elderly with CrCl values above 50 mL/min (see Section 5.2 Pharmacokinetic Properties, Elderly (> 65 years)).

Paediatric patients < 2 months of age.

There are limited clinical data in patients less than 2 months of age. Therefore, the recommended dosage of Zinforo shown in Table 1 for paediatric patients < 2 months of age is based on pharmacokinetic-pharmacodynamic modelling and simulation (see Section 4.2 Dose and Method of Administration).

4.3 Contraindications

Hypersensitivity to ceftaroline fosamil or L-arginine (excipient).
Hypersensitivity to the cephalosporin class of antibiotics.
Immediate and severe hypersensitivity (e.g. anaphylactic reaction) to any other type of β-lactam antibiotic (e.g. penicillins or carbapenems).

4.4 Special Warnings and Precautions for Use

Hypersensitivity reactions.

As with all β-lactam antibiotics, serious and occasionally fatal hypersensitivity reactions are possible (see Section 4.3 Contraindications; Section 4.8 Adverse Effects (Undesirable Effects)).
Patients who have a history of hypersensitivity to cephalosporins, penicillins or other β-lactam antibiotics may also be hypersensitive to ceftaroline fosamil. Before initiating therapy with Zinforo, careful inquiry should be made concerning previous hypersensitivity reactions to β-lactam antibiotics. If a patient developed an immediate and severe hypersensitivity (e.g. anaphylactic reaction) previously to any type of β-lactam antibiotic, ceftaroline fosamil should not be administered (see Section 4.3 Contraindications).
If a severe allergic reaction occurs, Zinforo should be discontinued and appropriate measures taken.

Clostridium difficile associated diarrhoea.

Antibacterial associated colitis and pseudomembranous colitis have been reported with nearly all antibacterial 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 Zinforo (see Section 4.8 Adverse Effects (Undesirable Effects)). 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.

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. As with other cephalosporins, seizures have occurred in ceftaroline toxicology studies at 7-25 times human Cmax levels.

Coombs test (direct antiglobulin test) seroconversion and potential risk of haemolytic anaemia.

The development of a positive Coombs test (direct antiglobulin test) may occur during treatment with cephalosporins. The incidence of Coombs test seroconversion in patients receiving ceftaroline fosamil was 11.2% in the five pooled pivotal 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). See Section 4.8 Adverse Effects (Undesirable Effects). In clinical studies there was no evidence of haemolysis in patients who developed a positive Coombs test on treatment. However, the possibility that haemolytic anaemia may occur in association with cephalosporins including Zinforo treatment cannot be ruled out. Patients experiencing anaemia during or after treatment with Zinforo should be investigated for this possibility.

Limitations of clinical data.

cSSTI caused by S. aureus with an MIC > 1 mg/L to ceftaroline.

There are limited clinical trial data on the use of ceftaroline to treat cSSTI caused by S. aureus with an MIC of > 1 mg/L. The recommended dosages of Zinforo shown in Tables 1 and 2 for the treatment of cSSTI caused by S. aureus with ceftaroline MIC of 2 or 4 mg/L are based on pharmacokinetic-pharmacodynamic modelling and simulation (see Section 4.2 Dose and Method of Administration; Section 5.1 Pharmacodynamic Properties, Clinical trials, Complicated skin and soft tissue infections with systemic inflammatory response or underlying comorbidities (COVERS)). Zinforo should not be used to treat cSSTI due to S. aureus for which the ceftaroline MIC is > 4 mg/L.

Infusion times of less than 60 minutes.

Infusion times of less than 60 minutes are based on pharmacokinetic and pharmacodynamic analyses only.

Severe cutaneous adverse reactions.

Severe cutaneous adverse reactions (SCAR), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalised exanthematous pustulosis (AGEP) have been reported in patients taking beta-lactam antibiotics. When SCAR is suspected, ceftaroline should be discontinued immediately and an alternative treatment should be considered.

Appropriate use of antibiotics.

Consideration should be given to official guidance on the appropriate choice and dose of antibiotics using AMS and Therapeutic Guidelines (also see Section 4.2 Dose and Method of Administration; Section 5.1 Pharmacodynamic Properties, Susceptibility testing).

Nonsusceptible organisms.

Superinfections may occur as with other antibiotics.

Neurotoxicity.

There have been reports of neurotoxicity associated with cephalosporin treatment. Symptoms of neurotoxicity include encephalopathy, seizures and/or myoclonus. Risk factors for developing neurotoxicity with cephalosporin treatment include being elderly, renal impairment, central nervous system disorders and intravenous administration. Withdrawal of the medicine should be considered if there are signs of neurotoxicity.

Use in renal impairment.

Dosage adjustments are required in adults, adolescents and children with creatinine clearance (CrCl) ≤ 50 mL/min (see Section 4.2 Dose and Method of Administration, Renal impairment).
There is insufficient information to recommend dosage adjustments in adolescents with ESRD aged from 12 to < 18 years and with bodyweight < 33 kg and in children with ESRD aged from 24 months to < 12 years. There is insufficient information to recommend dosage adjustments in children aged < 24 months with moderate or severe renal impairment or ESRD.
Relative overdosing could occur in patients with moderate to severe renal impairment. Neurological sequelae, including encephalopathy, have been noted in cases where beta-lactam antibiotics (including cephalosporins) have been given to patients with impaired renal function without reducing the dose (see Section 4.9 Overdose).

Use in the elderly.

No dose adjustment is required in the elderly with CrCl values > 50 mL/min (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Paediatric use.

Dose adjustments are required for neonates, infants, children and for adolescents aged 12 to < 18 years with bodyweight < 33 kg (see Section 4.2 Dose and Method of Administration).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No clinical drug-drug interaction studies have been conducted with ceftaroline.
The interaction potential of ceftaroline on drugs metabolised by P450 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 P450 enzymes in vitro. Ceftaroline is not metabolised by P450 enzymes in vitro, so coadministered P450 inducers or inhibitors are unlikely to influence the pharmacokinetics of ceftaroline.
In vitro, ceftaroline is not transported by efflux transporters P-gp and 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.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No adverse effects were observed on fertility of male and female rats given up to 450 mg/kg/day (approximately 4-fold higher than the maximum recommended human dose based on body surface area).
(Category B1)
No clinical data on pregnancies are available for ceftaroline. Zinforo should not be used during pregnancy unless clearly necessary and only if the potential benefit outweighs the possible risk.
Animal studies with ceftaroline fosamil do not indicate harmful effects with respect to pregnancy, parturition or postnatal development. Reproductive studies in pregnant rabbits resulted in an increased foetal incidence of angulated hyoid alae, a common skeletal variation in rabbit foetuses, at systemic exposures around 0.6 times those produced in humans dosed at 600 mg twice daily. In the rat, no adverse effects were observed on embryofoetal or postnatal development at systemic exposures around 2-4 times those produced in humans dosed at 600 mg twice daily.
 It is not known whether ceftaroline is excreted in human milk. As many β-lactams are excreted in breast milk, women who are breastfeeding should be treated with Zinforo only if clearly indicated and interruption of breastfeeding is recommended.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed. Undesirable effects may occur which may have an effect on ability to drive and use machines (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

Clinical trial experience.

Adults. The four phase 3 clinical trials (two in cSSTI and two in CAP) included 1305 adult patients treated with Zinforo (600 mg administered over 60 minutes every 12 hours).
The safety profile of Zinforo is consistent with that expected of a cephalosporin antibiotic. The incidences of treatment emergent adverse events in the initial pooled phase 3 cSSTI and CAP trials were similar in Zinforo (ceftaroline fosamil) and comparator groups (45.7% versus 46.7%, respectively). The most common adverse reactions occurring in ≥ 3% of patients treated with Zinforo in these initial trials were diarrhoea, headache, nausea, rash and pruritus, and were generally mild or moderate in severity.
The treatment emergent adverse events that occurred in at least 1% of patients in the phase 3 cSSTI and initial CAP active comparator trials are listed in Table 3 regardless of causality.
Infusion site reactions (erythema, phlebitis and pain) were commonly reported with use of Zinforo and comparator groups.
In addition, a study in Asia of 381 adult patients with CAP treated with Zinforo (600 mg administered over 60 minutes every 12 hours) demonstrated that the safety profile of Zinforo in these patients was similar to that observed in the pooled phase 3 cSSTI and initial CAP studies. In addition, dyspepsia, asthenia, abnormal hepatic function, urinary tract infection and decreased appetite were commonly reported in the Zinforo group.
A study (COVERS) was conducted of 506 adult patients with cSSTI treated with Zinforo (600 mg administered over 120 minutes every 8 hours). The most common adverse reactions occurring in ≥ 3% of patients treated with Zinforo were nausea, headache, and rash. The safety profile of Zinforo was similar to that observed in previous pooled Phase III studies with the exception of both a greater incidence of rash in Asian patients and a greater incidence of DAGT seroconversion (see Section 4.4 Special Warnings and Precautions for Use).
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%).

Adverse reactions.

The following adverse drug reactions have been observed with Zinforo during the phase 3 clinical trials (including the phase 3 CAP study in Asia). See Table 4.
Kounis syndrome. Acute coronary syndrome associated with an allergic reaction (Kounis syndrome) has been reported with other beta-lactam antibiotics.
Children and adolescents. The safety assessment in children and adolescents is based on the safety data from 2 clinical trials in which 227 patients aged from 2 months to 17 years with cSSTI or CAP received ceftaroline in which the safety profile was similar to that observed in the adult population. In addition, 30 patients received ceftaroline in a complicated CAP study and 62 patients received a single dose of ceftaroline in PK studies and no additional safety concerns were identified from these supportive studies.
In addition, the safety assessment in neonates (age range from birth to less than 2 months) is based on the safety data from 2 trials in which 11 patients with late-onset sepsis received ceftaroline fosamil at 4 or 6 mg/kg as a 60 minute infusion every 8 hours (q8h) and 23 patients with a suspected or confirmed bacterial infection received only a single dose of ceftaroline fosamil at 8 mg/kg as a 60 minute infusion. Overall, the adverse events reported in these studies were consistent with the known safety profile for Zinforo.

Post-marketing experience.

Blood and lymphatic system disorders.

Eosinophilia.

Skin and other subcutaneous tissue disorders.

Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalised exanthematous pustulosis (AGEP) have been reported in beta-lactam antibiotics. Also see Section 4.4 Special Warnings and Precautions for Use, Severe cutaneous adverse reactions.

Nervous system disorders.

Encephalopathy, seizures, myoclonus.

Respiratory, thoracic and mediastinal disorders.

Eosinophilic pneumonia.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

Signs and symptoms.

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.

Recommended treatment.

Ceftaroline can be removed by haemodialysis over a 4 hour dialysis session. Approximately 74% of a given dose was recovered in the dialysate.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Ceftaroline fosamil is a semi-synthetic prodrug from the cephalosporin class of β-lactam antibiotics.
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 non-susceptible Streptococcus pneumoniae (PNSP) due to its affinity for the altered PBPs found in these organisms.

Pharmacokinetic/pharmacodynamic relationship.

As with other β-lactam antibiotics, 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 activity of ceftaroline.

Mechanisms of resistance.

Ceftaroline is not active against strains of Enterobacterales producing extended spectrum β-lactamases (ESBLs) from the TEM, SHV or CTX-M families, serine carbapenemases (such as KPC), class B metallo-β-lactamases or class C (AmpC cephalosporinases). One or more of these mechanisms may coexist 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 β-lactam agents.

Interaction with other antibiotics.

In vitro studies have not demonstrated any antagonism between ceftaroline in combination with other commonly used antibiotics (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 important. 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.
As detailed in Section 5.1 Pharmacodynamic Properties, Clinical trials, efficacy has been demonstrated in clinical studies against the pathogens listed under each indication that were susceptible to ceftaroline in vitro.
Complicated skin and soft tissue infection (cSSTI). Also see Table 7.

Gram positive aerobes.

S. aureus (including methicillin resistant strains), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group (includes S. anginosus, S. intermedius and S. constellatus) and Streptococcus dysgalactiae.

Gram negative aerobes.

Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Morganella morganii.
Community acquired pneumonia (CAP). Also see Table 11 and Table 13.

Gram positive aerobes.

S. pneumoniae (including cases with concurrent bacteraemia) and S. aureus (methicillin susceptible strains only as MRSA was an exclusion criterion). See Section 5.1 Pharmacodynamic Properties, Clinical trials for details.

Gram negative aerobes.

E. coli, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae.
In vitro susceptibility. Clinical efficacy has not been established against the following relevant pathogens, although in vitro studies suggest that they would be susceptible to ceftaroline in the absence of acquired mechanisms of resistance.

Gram positive anaerobes.

Peptostreptococcus spp.

Gram negative anaerobes.

Fusobacterium spp.
In vitro data indicate that the following species are not susceptible to ceftaroline: Chlamydophila spp., Legionella spp., Mycoplasma spp. and Pseudomonas aeruginosa.
Australian antibiotic resistance prevalence data. A surveillance study was conducted to examine the susceptibility of ceftaroline tested against contemporary clinical isolates collected from Australia in 2010. A total of 1523 isolates were collected from 6 sites in 6 different states/territories across the country. Sources of isolates were specimens obtained from patients with infections of the blood stream (22.9%), skin/soft tissue (33.0%), respiratory tract (38.4%), urinary tract (3.4%) or other (2.4%) infection types. Where applicable, susceptibility interpretive criteria applied were Clinical Laboratory Standards Institute (CLSI) M100-S21 (2011). Data are summarised in Table 5.
A surveillance study was conducted to examine the susceptibility of ceftaroline tested against contemporary clinical isolates collected from Australia in 2015. A total of 766 isolates (including paediatric isolates: 21 from ≤ 1 year old and 74 from 2-17 years old) were collected from 5 sites in 4 different states across the country.
Overall, the 2015 surveillance study showed similar susceptibility results as in 2010. There were no significant changes in the MIC range (mg/L) and the MIC90 results did not vary by more than 2-3 fold dilution for each genus/species evaluated. With respect to total S. aureus tested, there was a notable increase in the incidence of MRSA isolated in 2015 (62% or 149/237) vs (28% or 131/466) isolated in 2010, however the MIC90 of 1 mg/L for MRSA remained the same in both study years. The Streptococci species (including the Pneumococcal isolates) and the Gram-negative fastidious pathogens (H. influenzae and M. catarrhalis) remained highly susceptible to ceftaroline. For Enterobacterale, the non-ESBL phenotypes of E. coli, Klebsiella species, and P. mirabilis had reported MIC90s of ≤ 0.5 mg/L that were within the CLSI and EUCAST susceptible breakpoints. In 2015, ceftaroline showed variable activity against M. morganii with an MIC range of 0.12 to > 32 mg/L that was comparable to 2010. During this 5 year surveillance period, ceftaroline tested with expected potency against the prescribed pathogens isolated in Australia.
The surveillance study conducted in 2016 to examine the susceptibility of ceftaroline against contemporary clinical isolates were collected from 5 sites in 4 different states across Australia. A total of 1145 isolates (including paediatric isolates: 44 from ≤ 1 year old and 85 from 2-17 years old) were collected. No major differences were found in ceftaroline activity between LRTI, SSTI and blood subsets as well as from subsets from paediatric and adult patients and the population as a whole except for K. oxytocoa where ceftaroline activity against SSTI isolates were greater against the general population (MIC90 > 128 mg/L), M. morganii where ceftaroline activity against SSTI isolates was greater than against the general population (MIC90 of 128 mg/mL) and P. mirabilis where ceftaroline activity against LRTI isolates was greater than against the entire collection (MIC90 16 mg/L versus > 128 mg/L). Longitudinal analysis of data from 2012 through 2016 showed no notable decreasing trends in ceftaroline susceptibility of any species at CLSI, EUCAST or PK/PD breakpoints.
Longitudinal analysis of ceftaroline in vitro activity in Australia from 2012 to 2019 is presented in Table 5. The in vitro data in Table 5 were conducted on a total of 12,196 isolates collected between 2004 to 2019 from 16 investigative sites across the country. Ceftaroline had good activity against S. aureus clinical isolates, with an overall MIC90 value of 1 mg/L and 90.6% of isolates susceptible to ceftaroline. The activity of ceftaroline was greater against the MSSA than the MRSA isolates with MIC90 values 0.25 and 1 mg/L, respectively. Potent activity was observed against S. pneumoniae, with a ceftaroline MIC90 of 0.12 mg/L. Reduced penicillin susceptibility had an impact on the ceftaroline MIC distribution as the compound displayed MIC90 values of 0.015, 0.12, and 0.25 mg/L against penicillin-susceptible, -intermediate and -resistant strains, respectively.

Clinical trials.

Complicated skin and soft tissue infections (cSSTI). The efficacy and safety of Zinforo in cSSTI was established in 2 identical randomised, multicentre, multinational, double blind studies (CANVAS 1 and 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). Treatment duration was 5 to 21 days.
A total of 1396 adults with documented cSSTI were enrolled. The majority of patients had deep/extensive cellulitis or a major abscess. Other infections included wound infections (surgical or traumatic), infected bites, burns or ulcers or any lower extremity infection in patients with either pre-existing diabetes mellitus (DM) or peripheral vascular disease (PVD). Key exclusion criteria included third degree burns (or burns covering > 5% body surface area), diabetic foot ulcer or foot ulcer associated with PVD (and accompanied by osteomyelitis), immunosuppressed patients, patients with severe sepsis/septic shock, necrotizing fasciitis and perirectal abscess. Approximately 46% of patients had either pre-existing DM and/or PVD or presented with either bacteraemia or systemic inflammatory response syndrome (SIRS). The median age of patients was 48 years old; of which approximately 18% were 65 years or older. The median treatment duration was 7.0 (range: 1-22) and 8.0 (range: 1-21) days for Zinforo and vancomycin/aztreonam respectively, with the majority of patients receiving 5 to 10 days treatment.
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.
Zinforo demonstrated high clinical cure and microbiological success rates (see Table 6) and was efficacious against cSSTI caused by MRSA and other common cSSTI pathogens (see Table 7). Clinical cure rates were similar across infection types and between patients with common comorbidities (such as DM and PVD).
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, multicentre, 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, approximately 40% of patients had SIRS, 86% had ≥ 2 severe local signs and/or symptoms or fever or elevated WBC, and > 60% had CRP > 50 mg/L, which was consistently higher than patients in the Phase 3 q12 hour cSSTI pool studies (CANVAS Studies). 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 Tables 8 and 9.
Community acquired pneumonia (CAP). The efficacy and safety of Zinforo in CAP was established in 2 randomised, multicentre, multinational, double blind, studies (FOCUS 1 and 2) comparing Zinforo (600 mg administered intravenously over 60 minutes every 12 hours) to ceftriaxone (1 g 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. Treatment duration was 5-7 days.
A total of 1240 adults with new or progressive pulmonary infiltrate(s) on chest radiography with clinical signs and symptoms consistent with CAP of the Pneumonia Outcomes Research Team (PORT) risk class III or IV with the need for hospitalization (but not admitted to ICU) and IV therapy were enrolled in the studies. A key exclusion criterion included patients infected with pathogens known or suspected to be resistant to ceftaroline and ceftriaxone, such as atypical pathogens or Pseudomonas spp. In addition, patients with suspected or confirmed MRSA infections were excluded due to lack of activity of ceftriaxone against this pathogen. Other exclusion criteria included immunosuppressed patients, patients with severe sepsis/septic shock and patients with severe underlying lung disease. Approximately 38% of patients had a PORT score of IV and 30% had severe CAP as per the modified American Thoracic Society (ATS) criteria. The majority of patients (75%) had SIRS, with 36% with hypoxia, 19% with pleural effusion and 28% with multilobar infiltrates. The most common comorbid conditions were structural lung disease (~ 25%), diabetes (~ 15%), cardiac impairment (~ 33%) and renal impairment (~ 50%; CrCl ≤ 80 mL/min). Approximately 48% of patients were 65 years or older. The median treatment duration was 7.0 days (range: 1-8) in both treatment arms, with the majority of patients receiving 5-7 days treatment.
The modified intent to treat efficacy (MITTE) population included all patients who received any amount of study drug according to their randomised treatment group and were in PORT risk class III or IV. The CE population included patients in the MITTE population with sufficient adherence to the protocol. The primary efficacy endpoint was the clinical response at the TOC visit in the coprimary populations of the CE and MITTE populations.
Zinforo demonstrated high clinical cure and microbiological success rates (see Table 10) and was efficacious against CAP caused by S. pneumoniae and other common CAP pathogens (see Table 11).
In addition, the efficacy and safety of Zinforo in Asian patients (including China, India, Korea, Taiwan and Vietnam) with CAP was established in a randomised, multicentre, double blind study in comparing Zinforo (600 mg administered intravenously over 60 minutes every 12 hours) to ceftriaxone (2 g administered intravenously over 30 minutes every 24 hours). The study design was similar to the initial phase 3 CAP studies, with no adjunctive macrolide therapy as per FOCUS 2. Treatment duration was 5 to 7 days.
A total of 771 adults (385 and 386 in ceftaroline and ceftriaxone groups, respectively) with CAP as defined by radiographic and microbiologic inclusion criteria and whose severity of disease was a PORT Risk class III or IV were randomised in the study. Patients also need to have acute illness of ≤ 7 days duration with at least 3 clinical signs or symptoms consistent with a lower respiratory tract infection. Key exclusion criterion were similar to the initial CAP studies, including patients infected with pathogens known or suspected to be resistant to ceftaroline and ceftriaxone (e.g. Pseudomonas spp), and patients with suspected or confirmed MRSA infections (due to lack of activity of ceftriaxone against this pathogen).
Approximately 32% of patients had a PORT score of IV and ~ 60% of patients were 65 years or older. A high percentage of patients had a history of underlying lung disease: COPD (~ 28%), asthma (~ 6%), tuberculosis (~ 7%), chronic bronchitis (~ 4%), and bronchiectasis (~ 3%) and a low percentage (< 25%) of patients had received prior systemic antibacterial medication.
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 hospitalised patients with CAP (lower boundary of the 95% confidence interval for the difference in response rate [ceftaroline-ceftriaxone] greater than -10%).
The noninferiority of ceftaroline 600 mg versus ceftriaxone 2 g was demonstrated in both the CE and MITT populations (Table 12). Furthermore, based on the predefined 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 or IV CAP in Asia.
Zinforo was efficacious against CAP caused by S. pneumoniae and other common CAP pathogens (see Table 13).
Children and adolescents.

Complicated skin and soft tissue infections.

The cSSTI paediatric trial was a randomised, parallel-group, active controlled trial in paediatric patients 2 months to < 18 years of age. A total of 163 children from 2 months to < 18 years of age with clinically documented cSSTI were enrolled in a randomised, multicentre, multinational, parallel group, active controlled trial comparing ceftaroline fosamil to vancomycin or cefazolin (each with optional aztreonam). Treatment duration was 5 to 14 days. A switch to oral therapy with either cephalexin, clindamycin, or linezolid after Study Day 3 was allowed. The Modified Intent-to-Treat (MITT) population included all patients who received any amount of study drug with a confirmed diagnosis of cSSTI. The primary objective was to evaluate the safety and tolerability of ceftaroline fosamil.
The study was not powered for comparative inferential efficacy analysis, and no efficacy endpoint was identified as primary. Clinical cure rates at test of cure (8 to 15 days after the end of therapy) in the MITT population were 94.4% (101/107) for ceftaroline fosamil and 86.5% (45/52) for the comparator, with a treatment difference of 7.9 (95% CI -1.2, 20.2).

Community acquired pneumonia.

A study was conducted in paediatric patients aged 2 months to < 18 years with CAP. The primary objective was to evaluate the safety and tolerability of ceftaroline versus ceftriaxone, with 107 patients in the ceftaroline arm and 36 patients in the ceftriaxone arm (MITT population).
The CAP paediatric trial was a randomised, parallel-group, active controlled trial in paediatric patients 2 months to < 18 years of age. A total of 161 children with a diagnosis of CAP were enrolled in a randomised, multicentre, multinational, active controlled trial comparing ceftaroline fosamil with ceftriaxone. Patients with new or progressive pulmonary infiltrate(s) on chest radiography and signs and symptoms consistent with CAP including acute onset or worsening symptoms of cough, tachypnoea, sputum production, grunting, chest pain, cyanosis, or increased work of breathing with the need for hospitalisation and IV therapy were enrolled in the trial. Treatment duration was 5 to 14 days. A switch to oral therapy with amoxicillin clavulanate was allowed after Study Day 3. The Modified Intent-to-Treat (MITT) population included all randomised patients who received any amount of study drug with a confirmed diagnosis of CAP. The primary objective was to evaluate the safety and tolerability of ceftaroline fosamil. The study was not powered for comparative inferential efficacy analysis, and no efficacy endpoint was identified as primary.
Clinical cure rates at test of cure (8 to 15 days after final dose of study drug) in the MITT population were 87.9% (94/107) for ceftaroline fosamil and 88.9% (32/36) for the comparator, with a treatment difference of -1.0 (95% CI -11.5, 14.1).

5.2 Pharmacokinetic Properties

Absorption.

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 IV infusions of 600 mg administered over 60 minutes every 8 or 12 hours for up to 14 days 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 Cmax (SD) 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 is not distributed into erythrocytes. The median steady-state volume of distribution of ceftaroline in healthy adult males following a single 600 mg IV dose of radiolabelled ceftaroline fosamil was 20.3 L, similar to extracellular fluid volume.

Metabolism.

Ceftaroline fosamil (prodrug) is converted into the active ceftaroline in plasma by a phosphatase enzyme and concentrations of the prodrug are measurable in plasma primarily during IV infusion. Hydrolysis of the β-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 IV 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 IV dose of radiolabelled ceftaroline fosamil to healthy male adults, approximately 88% of radioactivity was recovered in urine and 6% in faeces.

Special populations.

Elderly (> 65 years).

Following administration of a single 600 mg IV 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 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 (CrCl) values above 50 mL/min.

Children and adolescents.

Dose adjustments are required for children aged from 2 months to < 12 years and for adolescents aged 12 to < 18 years with bodyweight < 33 kg (see Section 4.2 Dose and Method of Administration). See Section 4.4 Special Warnings and Precautions for Use, Paediatric use.

Gender.

The pharmacokinetics of ceftaroline were similar between males and females. No dose adjustment is required based on gender.

Renal impairment.

Dosage adjustments are required in adults, adolescents and children with creatinine clearance (CrCl) ≤ 50 mL/min (see Section 4.2 Dose and Method of Administration).
There is insufficient information to recommend dosage adjustments in adolescents with end stage renal disease (ESRD) aged from 12 to < 18 years and with bodyweight < 33 kg and in children with ESRD aged from 24 months to < 12 years. There is insufficient information to recommend dosage adjustments in children aged < 24 months with moderate or severe renal impairment or ESRD.

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.

5.3 Preclinical Safety Data

Genotoxicity.

Ceftaroline fosamil and ceftaroline were clastogenic in an in vitro chromosomal aberration assay, however there was no evidence of mutagenic activity in Ames and mouse lymphoma assays. Furthermore, in vivo micronucleus assays in rat and mouse were negative.

Carcinogenicity.

Carcinogenicity studies have not been conducted.

6 Pharmaceutical Particulars

6.1 List of Excipients

L-arginine.

6.2 Incompatibilities

Zinforo must not be mixed with any other medications.Also see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Vials.

Store below 25°C. Store in the original package in order to protect from light.

After reconstitution.

The powder for injection should be reconstituted and then diluted with diluents listed in Section 6.6, immediately prior to use. The total time interval between starting reconstitution and completing preparation of the intravenous infusion should not exceed 30 minutes.

After dilution.

To reduce microbial hazard, Zinforo intravenous infusion should be administered as soon as practicable after preparation. If storage is necessary, hold at 2 to 8°C (Refrigerate. Do not freeze) for not more than 24 hours or not more than 6 hours at room temperature (including infusion time). The chemical and physical in-use stability has been demonstrated for up to 24 hours at 2 to 8°C, and up to 6 hours at room temperature.
If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

6.5 Nature and Contents of Container

Available as 10 x 20 mL glass (Type 1) vials closed with a rubber (halobutyl) stopper and aluminium seal with blue flip-off cap.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.


The chemical name of ceftaroline fosamil monoacetate monohydrate is (6R, 7R)-7-{(2Z)-2-(ethoxyimino)-2-[5-phosphonoamino)-1,2,4-thiadiazol-3-yl]acetamido}}-3-{[4-(1-methylpyridin-1-ium-4-yl)-1,3-thiazol-2-yl]sulfanyl}8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate monoacetate monohydrate.
The molecular formula of the solvate hydrate form is C24H27N8O11PS4 and the molecular mass is 762.75.
The molecular formula of the solvent and water free form is C22H21N8O8PS4 and the molecular mass is 684.68.
The solubility of ceftaroline fosamil in water is 8.6 mg/mL. Its solubility is increased in the IV infusion by inclusion of L-arginine as an alkalising agent. The pH of the IV infusion is in the range of 5.0 to 7.0.
Ceftaroline has one strongly acidic proton and one moderately acidic proton on the phosphoamino group (pKa 1.22 and 5.10), a strongly acidic carboxylic acid group (pKa 1.79) and a pKa associated with the secondary amide adjacent to the β-lactam (pKa 10.9).

CAS number.

C24H27N8O11PS4 (solvate hydrate form): 400827-55-6.
C22H21N8O8PS4 (solvent and water free form): 229016-73-3.

7 Medicine Schedule (Poisons Standard)

Prescription only medicine, Schedule 4.

Summary Table of Changes