Ceftaroline fosamil

The dose should be adjusted when creatinine clearance (CrCL) is ≤50 mL/min, as shown in Tables 1 and 2. The recommended durations of treatment are 5-14 days for cSSTI and 5-7 days for CAP.

Table 1. Dosage in adults with impaired renal function, creatinine clearance (CrCL) ≤50 mL/min:

^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 ceftaroline fosamil 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.
^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 2. Dosage in paediatric patients with impaired renal function, creatinine clearance (CrCL) ≤50 mL/min:

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

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 ceftaroline fosamil, the medicinal product should be discontinued and appropriate measures taken.

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

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.

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

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 ceftaroline fosamil 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.

Undesirable effects e.g. dizziness may occur and this may have an effect on the ability to drive and use of machines.

Summary of the safety profile

The most common adverse reactions occurring in ≥ 3% of approximately 3242 patients treated with ceftaroline fosamil 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 were observed in a study of adult patients with cSSTI conducted with ceftaroline fosamil 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 ceftaroline fosamil. 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).

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

^* 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.

Description of selected adverse reactions

Severe Cutaneous Adverse Reactions

SCARs (Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, acute generalised exanthematous pustulosis) have been reported with beta-lactam antibiotics, including cephalosporins.

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 ceftaroline fosamil 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 ceftaroline fosamil 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 ceftaroline fosamil. 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 ceftaroline fosamil; 23 of these patients received only a single dose of ceftaroline fosamil. Overall, the adverse events reported in these studies were consistent with the known safety profile for ceftaroline fosamil.