4.1. Therapeutic indications

Zinforo is indicated for the treatment of the following infections in neonates, infants, children, adolescents and adults (see sections 4.4 and 5.1):

• 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.

4.2. Posology and method of administration

Posology

The recommended durations of treatment are 5-14 days for cSSTI and 5-7 days for CAP.

Table 1 Dosage in adults with normal renal function, creatinine clearance (CrCL) > 50 mL/min

Indications

Posology (mg/infusion)

Infusion time (minutes)/Frequency

Standard dosea

Complicated skin and soft tissue infections (cSSTI)

Community-acquired pneumonia (CAP)

600 mg

5 – 60b/every 12 hours

High doseb

cSSTI confirmed or suspected to be caused by S. aureus with an MIC = 2 mg/L or 4 mg/L to ceftarolinec

120/every 8 hours

a For patients with supranormal renal clearance receiving the standard dose, an infusion time of 60 minutes may be preferable.

b Infusion times of less than 60 minutes and high dose recommendations are based on pharmacokinetic and pharmacodynamic analyses only. See sections 4.4 and 5.1.

c For treatment of S. aureus for which the ceftaroline MIC is ≤ 1 mg/L, the standard dose is recommended.

Table 2 Dosage in paediatric patients with normal renal function, creatinine clearance (CrCL) > 50 mL/min*

Indications

Age group

Posology (mg/infusion)

Infusion time (minutes)/Frequency

Standard dosea

Complicated skin and soft tissue infections (cSSTI)

Community-acquired pneumonia (CAP)

Adolescents aged from 12 to < 18 years with bodyweight ≥ 33 kg

600 mg

5–60b/every 12 hours

Adolescents aged from 12 years to < 18 years bodyweight < 33 kg and children ≥ 2 years to < 12 years

12 mg/kg to a maximum of 400 mg

5–60b/every 8 hours

Infants ≥ 2 months to < 2 years

8 mg/kg

5–60b/every 8 hours

Neonates from birth to < 2 monthsb

6 mg/kg

60/every 8 hours

High doseb

cSSTI confirmed or suspected to be caused by S. aureus with an MIC = 2 mg/L or 4 mg/L to ceftarolinec

Children and adolescents aged from ≥ 2 years to < 18 years

12 mg/kg to a maximum of 600 mg

120/every 8 hours

Infants ≥ 2 months to < 2 years

10 mg/kg

120/every 8 hours

a For patients with supranormal renal clearance receiving the standard dose, an infusion time of 60 minutes may be preferable.

b Infusion times of less than 60 minutes, neonatal and high dose recommendations are based on pharmacokinetic and pharmacodynamic analyses only. See sections 4.4 and 5.1.

c For treatment of S. aureus for which the ceftaroline MIC is ≤ 1 mg/L, the standard dose is recommended.

* Calculated using the Schwartz formula (in mL/min/1.73 m2) for paediatric patients.

Special populations

Elderly

No dosage adjustment is required for the elderly with creatinine clearance values > 50 mL/min (see section 5.2).

Renal impairment

The dose should be adjusted when creatinine clearance (CrCL) is ≤ 50 mL/min, as shown in Tables 3 and 4 (see sections 4.9 and 5.2). The recommended durations of treatment are 5-14 days for cSSTI and 5-7 days for CAP.

Table 3 Dosage in adults with impaired renal function, creatinine clearance (CrCL) ≤ 50 mL/min

Indications

Creatinine clearance (mL/min)a

Posology (mg/infusion)

Infusion time (minutes)/Frequency

Standard dose

Complicated skin and soft tissue infections(cSSTI)

Community-acquired pneumonia (CAP)

> 30 to ≤ 50

400 mg

5–60c/every 12 hours

≥ 15 to ≤ 30

300 mg

ESRD, including haemodialysisb

200 mg

High dosec

cSSTI confirmed or suspected to be caused by S. aureus with an MIC = 2 mg/L or 4 mg/L to ceftarolined

> 30 to ≤ 50

400 mg

120/every 8 hours

≥ 15 to ≤ 30

300 mg

ESRD, including haemodialysisb

200 mg

a Calculated using the Cockcroft-Gault formula for adults. Dose is based on CrCL. CrCL should be closely monitored and the dose adjusted according to changing renal function.

b Ceftaroline is haemodialyzable; thus Zinforo should be administered after haemodialysis on haemodialysis days.

c Infusion times of less than 60 minutes and high dose recommendations are based on pharmacokinetic and pharmacodynamic analyses only. See sections 4.4 and 5.1.

d For treatment of S. aureus for which the ceftaroline MIC is ≤ 1 mg/L, the standard dose is recommended.

Dose recommendations for neonates, infants and children and adolescents are based on pharmacokinetic (PK) modelling.

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 2 to 12 years with End-stage renal disease (ESRD).

There is insufficient information to recommend dosage adjustments in paediatric patients < 2 years with moderate or severe renal impairment or ESRD.

Table 4 Dosage in paediatric patients with impaired renal function, creatinine clearance (CrCL) ≤ 50 mL/min

Indications

Age group

Creatinine clearance (mL/min)a

Posology

(mg/infusion)

Infusion time (minutes)/Frequency

Standard dose

Complicated skin and soft tissue infections (cSSTI)

Community-acquired pneumonia (CAP)

Adolescents aged from 12 to < 18 years with bodyweight ≥ 33 kg

> 30 to ≤ 50

400 mg

5–60c/every 12 hours

≥ 15 to ≤ 30

300 mg

ESRD, including haemodialysisb

200 mg

Adolescents aged from 12 years to < 18 years bodyweight < 33 kg and children ≥ 2 years to < 12 years

> 30 to ≤ 50

8 mg/kg to a maximum of 300 mg

5–60c/every 8 hours

≥ 15 to ≤ 30

6 mg/kg to a maximum of 200 mg

High dosec

cSSTI confirmed or suspected to be caused by S. aureus with an MIC = 2 mg/L or 4 mg/L to ceftarolined

Children and adolescents aged from ≥2 years to < 18 years

> 30 to ≤ 50

10 mg/kg to a maximum of 400 mg

120/every 8 hours

≥ 15 to ≤ 30

8 mg/kg to a maximum of 300 mg

a Calculated using the Schwartz formula for paediatric patients (in mL/min/1.73 m2). Dose is based on CrCL. CrCL should be closely monitored and the dose adjusted according to changing renal function.

b Ceftaroline is haemodialyzable; thus Zinforo should be administered after haemodialysis on haemodialysis days.

c Infusion times of less than 60 minutes and high dose recommendations are based on pharmacokinetic and pharmacodynamic analyses only. See sections 4.4 and 5.1.

d For treatment of S. aureus for which the ceftaroline MIC is ≤ 1 mg/L, the standard dose is recommended.

Hepatic impairment

No dosage adjustment is considered necessary in patients with hepatic impairment (see section 5.2).

Method of administration

Intravenous use. Zinforo is administered by intravenous infusion over 5 to 60 minutes for standard dose or 120 minutes for high dose (for cSSTI caused by S. aureus with MIC of 2 or 4 mg/L to ceftaroline) in infusion volumes of 50 mL, 100 mL or 250 mL (see section 6.6). Infusion related reactions (such as phlebitis) can be managed by prolonging the infusion duration.

Infusion volumes for paediatric patients will vary according to the weight of the child. The infusion solution concentration during preparation and administration should not exceed 12 mg/mL ceftaroline fosamil.

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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).

4.4. Special warnings and precautions for use

Hypersensitivity reactions

Serious and occasionally fatal hypersensitivity reactions are possible (see sections 4.3 and 4.8).

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) which can be life-threatening or fatal, have been reported in association with ceftaroline treatment (see section 4.8).

Acute generalised exanthematous pustulosis (AGEP) has been reported in association with beta-lactam antibiotics (including cephalosporins) treatment.

Patients should be advised of the signs and symptoms and monitored closely for skin reactions.

If signs and symptoms suggestive of these reactions appear, ceftaroline should be withdrawn immediately, and an alternative treatment considered.

If the patient has developed a severe skin reaction such as SJS, TEN or DRESS with the use of ceftaroline, treatment with ceftaroline must not be restarted in this patient at any time.

Patients who have a history of hypersensitivity to cephalosporins, penicillins or other beta-lactam antibacterials may also be hypersensitive to ceftaroline fosamil. Ceftaroline should be used with caution in patients with a history of non-severe hypersensitivity reactions to any other beta-lactam antibiotics (e.g. penicillins or carbapenems). If a severe allergic reaction or SCAR occurs during treatment with Zinforo, the medicinal product should be discontinued and appropriate measures taken.

With other beta-lactam antibiotics there have been reports of hypersensitivity reactions which progressed to Kounis syndrome (acute allergic coronary arteriospasm that can result in myocardial infarction, see section 4.8).

Clostridium difficile-associated diarrhoea

Antibacterial-associated colitis and pseudomembranous colitis have been reported with 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.

Non-susceptible organisms

Superinfections may occur during or following treatment with Zinforo.

Patients with pre-existing seizure disorder

Seizures have occurred in toxicology studies at 7-25 times human ceftaroline Cmax levels (see section 5.3). Clinical study experience with ceftaroline fosamil in patients with pre-existing seizure disorders is very limited. Therefore, Zinforo should be used with caution in this patient population.

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

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 pivotal 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). In clinical studies there was no evidence of haemolysis in patients who developed a positive DAGT 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 the clinical data

There is no experience with ceftaroline in the treatment of CAP in the following patient groups: the immunocompromised, patients with severe sepsis/septic shock, severe underlying lung disease (e.g. cystic fibrosis, see section 5.2), those with PORT Risk Class V, and/or CAP requiring ventilation at presentation, CAP due to methicillin-resistant S. aureus or patients requiring intensive care. Caution is advised when treating such patients.

There is no experience with ceftaroline in the treatment of cSSTI in the following patient groups: the immunocompromised, patients with severe sepsis/septic shock, necrotizing fasciitis, perirectal abscess and patients with third degree and extensive burns. There is limited experience in treating patients with diabetic foot infections. Caution is advised when treating such patients.

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 to 4 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 sections 4.2 and 5.1). Zinforo should not be used to treat cSSTI due to S. aureus for which the ceftaroline MIC is > 4 mg/L.

The recommended dosage of Zinforo shown in Table 2 for paediatric patients < 2 months of age are based on pharmacokinetic-pharmacodynamic modelling and simulation.

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

4.5. Interaction with other medicinal products and other forms of interaction

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 CYP450 enzymes is expected to be low since they are not inhibitors nor inducers of CYP450 enzymes in vitro. Ceftaroline or ceftaroline fosamil are not metabolised by CYP450 enzymes in vitro, therefore co-administered CYP450 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.

Paediatric population

As with adults, the interaction potential is expected to be low in paediatrics.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of ceftaroline fosamil in pregnant women. Animal studies conducted in rat and rabbit do not indicate harmful effects with respect to reproductive toxicity at exposures similar to therapeutic concentrations. Following administration throughout pregnancy and lactation in the rat, there was no effect on pup birth weight or growth, although minor changes in foetal weight and delayed ossification of the interparietal bone were observed when ceftaroline fosamil was administered during organogenesis (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of Zinforo during pregnancy unless the clinical condition of the woman requires treatment with an antibiotic with Zinforo's antibacterial profile.

Breast-feeding

It is unknown whether ceftaroline fosamil or ceftaroline is excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Zinforo therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

The effects of ceftaroline fosamil on fertility on humans have not been studied. Animal studies with ceftaroline fosamil do not indicate harmful effects with respect to fertility (see section 5.3).

4.7. Effects on ability to drive and 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 section 4.8).

4.8. Undesirable effects

Summary of the safety profile

The most common adverse reactions occurring in ≥ 3% of approximately 3242 patients treated with Zinforo in clinical studies were diarrhoea, headache, nausea, and pruritus, and were generally mild or moderate in severity. Clostridium difficile-associated disease (CDAD) and severe hypersensitivity reactions may also occur.

A greater incidence of rash in Asian patients (see below) and a greater incidence of DAGT seroconversion (see section 4.4) were observed in a study of adult patients with cSSTI conducted with Zinforo 600 mg administered over 120 minutes every 8 hours.

Tabulated list of adverse reactions

The following adverse reactions have been identified during clinical trials and post-marketing experience with Zinforo. Adverse reactions are classified according to System Organ Class and frequency. Frequency categories are derived according to the following conventions: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), not known (cannot be estimated from the available data).

Table 5 Frequency of adverse reactions by system organ class from clinical trials and post-marketing experience

System organ class

Very common

Common

Uncommon

Rare

Not known

Infections and infestations

Clostridium difficile colitis (see section 4.4)

Blood and lymphatic system disorders

Anaemia, leucopenia, neutropenia*, thrombocytopenia, prothrombin time (PT) prolonged, activated partial thromboplastin time (aPTT) prolonged, international normalized ratio (INR) increased

Agranulocytosis*, eosinophilia*

Immune system disorders

Rash, pruritus

Anaphylaxis, hypersensitivity (e.g. urticaria, lip and face swelling) (see sections 4.3 and 4.4)

Nervous system disorders

Headache, dizziness

Encephalopathy*,+

Vascular disorders

Phlebitis

Respiratory, thoracic and mediastinal disorders

Eosinophilic pneumonia*

Gastrointestinal disorders

Diarrhoea, nausea, vomiting, abdominal pain

Hepatobiliary disorders

Increased transaminases

Skin and subcutaneous tissue disorders

Stevens-Johnson syndrome (SJS)*, Toxic epidermal necrolysis (TEN)*, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)* (see section 4.4)

Renal and urinary disorders

Blood creatinine increased

General disorders and administration site conditions

Pyrexia, infusion site reactions (erythema, phlebitis, pain)

Investigations

Coombs Direct Test Positive (see section 4.4)

* Adverse Drug Reaction (ADR) identified post-marketing.

+ Risk of encephalopathy is higher in patients with renal impairment in whom the dose of ceftaroline has not been appropriately reduced (see sections 4.2 and 4.9).

Description of selected adverse reactions

Kounis Syndrome

Acute coronary syndrome associated with an allergic reaction (Kounis syndrome) has been reported with other beta-lactam antibiotics.

Rash

Rash was observed at a common frequency in both 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 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 was very common (18.5%).

Paediatric population

The safety assessment in paediatric patients is based on the safety data from 2 trials in which 227 patients aged from 2 months to 17 years with cSSTI or CAP received Zinforo. Overall, the safety profile in these 227 patients was similar to that observed in the adult population.

In addition, the safety assessment in neonates is based on the safety data from 2 trials in which 34 patients (age range from birth to less than 60 days) received Zinforo; 23 of these patients received only a single dose of Zinforo. Overall, the adverse events reported in these studies were consistent with the known safety profile for Zinforo.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Limited data in patients receiving higher than recommended Zinforo dosages show similar adverse reactions as observed in the patients receiving recommended dosages. Treatment of overdose should follow standard medical practice.

Patients with renal impairment

Relative overdosing could occur in patients with moderate 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 4.2).

Ceftaroline can be removed by haemodialysis; over a 4 hour dialysis period, approximately 74% of a given dose was recovered in the dialysate.