Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Correvio, 15 Rue du Bicentenaire, 92800 Puteaux, France, Phone number: +44 (0)203 002 8114, Email: medinfo@cardiome.com
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).
As with all beta-lactam antibacterial agents, serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported. In case of severe hypersensitivity reactions, treatment with Zevtera must be discontinued immediately and adequate emergency measures must be initiated.
Before beginning treatment, it should be established whether the patient has a history of severe hypersensitivity reactions to Zevtera, to other cephalosporins or to any other type of beta-lactam agent. Caution should be used if Zevtera is given to patients with a history of non-severe hypersensitivity to other beta-lactam agents.
There is no clinical experience with Zevtera doses higher than the recommended 500 mg administered every eight hours.
Seizures have been associated with the use of Zevtera. Seizures occurred most commonly in patients with pre-existing CNS/seizure disorders during treatment with Zevtera. Therefore caution is advised when treating these patients.
Antibacterial agent-associated colitis and pseudomembranous colitis have been reported with the use of Zevtera and may range in severity from mild to life-threatening. This diagnosis should be considered in patients with diarrhoea during or subsequent to the administration of Zevtera (see section 4.8). Discontinuation of therapy with Zevtera and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.
The use of Zevtera may result in overgrowth of non-susceptible organisms, including fungi. Appropriate measures should be taken if evidence of superinfection occurs during therapy.
In animals, reversible renal toxicity was observed at high doses of Zevtera and was associated with precipitation of drug-like material in the distal tubules (see section 5.3). Although the clinical significance of this observation is unknown, it is advisable to correct hypovolaemia to maintain normal urinary output in patients receiving Zevtera.
Precipitation can occur when Zevtera is mixed with calcium-containing solutions in the same intravenous administration line. Therefore, Zevtera and calcium-containing solutions, except Lactated Ringer’s solution for injection, must not be mixed or administered simultaneously in the same intravenous line (see section 6.2).
There is no experience with ceftobiprole in the treatment of HAP (excluding VAP) and CAP in HIV-positive patients, patients with neutropenia, immunocompromised patients, and patients with myelosuppression. Caution is advised when treating such patients.
Zevtera has not been shown to be effective in the treatment of patients with VAP. Zevtera should not be initiated in patients with VAP (see Section 5.1). In addition, on the basis of a post-hoc analysis showing a trend in favour of ceftobiprole, it is recommended that in patients with hospital-acquired pneumonia (HAP) who subsequently require ventilation, Zevtera should be used with caution.
Ceftobiprole, like other cephalosporins is susceptible to hydrolysis that may be produced by Enterobacteriaceae including many of the extended-spectrum beta-lactamases (ESBLs), serine carbapenemases, class B metallo-beta-lactamases (among others). Therefore, information on the prevalence of Enterobacteriaceae producing extended-spectrum beta-lactamases (ESBLs) should be taken into consideration when selecting Zevtera for treatment (see section 5.1).
The development of a positive direct antiglobulin test may occur during treatment with a cephalosporin. In clinical studies there was no evidence of haemolytic anaemia. However, the possibility that haemolytic anaemia may occur in association with Zevtera treatment cannot be ruled out. Patients experiencing anaemia during or after treatment with Zevtera should be investigated for this possibility.
It is not known whether ceftobiprole, like some other cephalosprins, interferes with the alkaline picrate assay to measure serum creatinine (Jaffé reaction), which may lead to erroneously high creatinine measurements. During treatment with Zevtera it is recommended that an enzymatic method of measuring serum creatinine be used.
During treatment with Zevtera it is recommended that an enzymatic method to detect glucosuria be used, because of potential interference with tests using the copper reduction technique.
This medicinal product contains approximately 1.3 mmol (29 mg) sodium per dose. To be taken into consideration by patients on a controlled sodium diet.
In vitro studies have been carried out to investigate potential interactions at the level of CYP enzymes. However, as the concentrations of ceftobiprole used in these studies were limited by solubility, the potential for CYP drug interactions cannot be ruled out.
In vitro studies showed that ceftobiprole inhibits OATP1B1 and OATP1B3 with IC50s of 67.6 μM and 44.1 μM, respectively. Zevtera may increase concentrations of drugs eliminated by OATP1B1 and OATP1B3, such as statins (pitavastin, pravastatin, rosuvastatin), glyburide, and bosentan.
No clinical interaction studies have been performed. Caution is advised when Zevtera is administered together with drugs with narrow therapeutic index.
There are no adequate and well-controlled studies with Zevtera in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).
As no data in exposed human pregnancies are available, Zevtera should not be used during pregnancy unless strictly necessary.
Animal studies have shown the excretion of ceftobiprole/metabolites in milk at low concentrations. It is unknown whether ceftobiprole is excreted in human milk and the risk of diarrhoea and fungal infection of the mucous membranes in the breast-fed infant cannot be excluded. The possibility of sensitisation should be taken into account. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Zevtera therapy, taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
The effects of ceftobiprole medocaril on fertility in humans have not been studied. Animal studies with ceftobiprole medocaril do not indicate harmful effects with respect to fertility.
No studies on the effects on the ability to drive and use machines have been performed. However, since dizziness is a common undesirable effect, driving and using machines is not recommended while on treatment with Zevtera.
In therapeutic clinical studies, 1,668 subjects received Zevtera. Within these trials there were a total of 1,239 subjects (696 subjects in community-acquired pneumonia and nosocomial pneumonia, and 543 subjects in complicated skin and soft tissue infections, cSSTIs) who received 500 mg three times daily, 389 subjects (cSSTIs) who received 500 mg twice daily and 40 subjects (cSSTIs) who received 750 mg twice daily.
The most common adverse reactions occurring in ≥3% of patients treated with Zevtera were nausea, vomiting, diarrhoea, infusion site reactions, hypersensitivity (including urticaria, pruritic rash and drug hypersensitivity) and dysgeusia.
Less frequently reported, but more serious, adverse reactions include thrombocytopenia, agranulocytosis, anaphylaxis, Clostridium difficile, colitis, convulsion, agitation (including anxiety, panic attacks and nightmares), and renal failure.
The following adverse reactions were reported during therapy and during follow-up with frequencies corresponding to 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); very rare (<1/10,000); not known (cannot be estimated from the available data):
Adverse reactions from clinical studies and post-marketing reports:
Common: Fungal infection (including vulvovaginal, oral and cutaneous fungal infections)
Uncommon: Clostridium difficile colitis**
Uncommon: Eosinophilia***, leukopenia, anaemia, thrombocytosis, thrombocytopenia
Not known: Agranulocytosis*
Common: Hypersensitivity (including urticaria, pruritic rash and drug hypersensitivity)
Uncommon: Anaphylaxis**
Common: Hyponatraemia
Uncommon: Hypokalaemia
Uncommon: Insomnia, agitation (including anxiety, panic attacks and nightmares)
Common: Dysgeusia, headache, dizziness, somnolence***
Not known: Convulsions*,**
Uncommon: Dyspnoea, pharyngolaryngeal pain***, asthma
Common: Nausea, vomiting, diarrhoea, abdominal pain, dyspepsia
Common: Hepatic enzymes increased (including AST, ALT, LDH and alkaline phosphatase)
Common: Rash (including macular, papular, maculo-papular and generalised rash), pruritus
Uncommon: Muscle spasms***
Uncommon: Renal failure
Common: Infusion site reactions
Uncommon: Peripheral oedema
Uncommon: Blood triglycerides increased, blood creatinine increased, blood glucose increased
Not known: Coombs Direct Test Positive (see section 4.4)
* Based on post-marketing reports. Since these reactions were spontaneous reports post-marketing, it is not possible to reliably estimate their frequency which is therefore categorised as not known.
** See section 4.4
*** Seen in cSSTI studies only
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 Yellow Card Scheme, web site: www.mhra.gov.uk/yellowcard.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
This medicinal product must not be mixed or administered simultaneously with calcium-containing solutions (except Lactated Ringer’s solution for injection). See sections 4.2, 4.4, 6.6.
This medicinal product should not be simultaneously administered via a Y site with:
Acyclovir sodium, Amikacin sulphate, Amiodarone hydrochloride, Amphotericin B (colloidal), Calcium gluconate, Caspofungin acetate, Ciprofloxacin, Cisatracurium besylate, Diazepam, Diltiazem hydrochloride, Diphenhydramine hydrochloride, Dobutamine hydrochloride, Dopamine hydrochloride, Esomeprazole sodium, Famotidine, Filgrastim, Gentamicin sulphate, Haloperidol lactate, Hydromorphone hydrochloride, Hydroxyzine hydrochloride, Insulin human regular, Insulin lispro, Labetalol hydrochloride, Levofloxacin, Lidocaine hydrochloride, Magnesium sulphate, Meperidine hydrochloride, Metoclopramide hydrochloride, Midazolam hydrochloride, Milrinone lactate, Morphine sulphate, Moxifloxacin hydrochloride, Ondansetron hydrochloride, Pantoprazole sodium, Potassium phosphates, Promethazine hydrochloride, Remifentanil hydrochloride, Sodium phosphates, Tobramycin sulphate.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
