PART VI. SUMMARY OF THE RISK MANAGEMENT PLAN Summary of risk management plan for ZINFORO

Transcription

1 PART VI. SUMMARY OF THE RISK MANAGEMENT PLAN Summary of risk management plan for ZINFORO This is a summary of the risk management plan (RMP) for ZINFORO. The RMP details important risks of ZINFORO, how these risks can be minimised, and how more information will be obtained about ZINFORO's risks and uncertainties (missing information). ZINFORO's SmPC and its package leaflet give essential information to healthcare professionals and patients on how ZINFORO should be used. This summary of the RMP for ZINFORO should be read in the context of all this information including the assessment report of the evaluation and its plain-language summary, all which is part of the European Public Assessment Report (EPAR). Important new concerns or changes to the current ones will be included in updates of ZINFORO's RMP. I. The Medicine and What It Is Used For ZINFORO's is authorised for complicated skin and soft tissue infections (cssti) and community-acquired pneumonia (CAP). It contains ceftaroline fosamil as the active substance and it is given by infusion. Further information about the evaluation of ZINFORO s benefits can be found in ZINFORO's EPAR, including in its plain-language summary, available on the EMA website, under the medicine s webpage uman_med_ jsp&mid=wc0b01ac058001d124 II. Risks Associated with the Medicine and Activities to Minimise or Further Characterise the Risks Important risks of ZINFORO, together with to minimise such risks and the proposed studies for learning more about ZINFORO's risks, are outlined below. Measures to minimise the risks identified for medicinal products can be: Specific Information, such as warnings, precautions, and advice on correct use, in the package leaflet and SmPC addressed to patients and healthcare professionals Important advice on the medicine s packaging; The authorised pack size the amount of medicine in a pack is chosen so to ensure that the medicine is used correctly; The medicine s legal status the way a medicine is supplied to the public (e.g. with or without prescription) can help to minimise its risks.

2 Together, these constitute routine risk minimisation. In addition to these, information about adverse events is collected continuously and regularly analysed, including PSUR assessment, so that immediate action can be taken as necessary. These constitute routine pharmacovigilance activities. If important information that may affect the safe use of ZINFORO is not yet available, it is listed under missing information below. II.A. List of Important Risks and Missing Information Important risks of ZINFORO are risks that need special risk management activities to further investigate or minimise the risk, so that the medicinal product can be safely administered. Important risks can be regarded as identified or potential. Identified risks are concerns for which there is sufficient proof of a link with the use of ZINFORO. Potential risks are concerns for which an association with the use of this medicine is possible based on available data, but this association has not been established yet and needs further evaluation. Missing information refers to information on the safety of the medicinal product that is currently missing and needs to be collected (eg, on the long-term use of the medicine). The MAH proposes to reclassify Hypersensitivity/anaphylaxis and CDAD, from important identified risks to risks not important, and therefore to remove them from the list of safety concerns. Table 1. Important identified risks Important potential risks Missing information List of Important Risks and Missing Information CDAD Hypersensitivity/anaphylaxis None Bacterial resistance development Convulsions/seizures Drug induced liver injury Haemolytic anaemia Renal impairment (including potential drug interactions with nephrotoxic agents) Potential for off-label use Immunocompromised population Lactation Paediatric population exposure Pre-existing seizure disorder Pre-existing significant hepatic disease Pregnancy exposure Efficacy in MRSA CAP CAP = Community-acquired pneumonia; CDAD = Clostridium difficile associated diarrhoea; DILI = Drug-induced liver injury; MRSA = Methicillin-resistant Staphylococcus aureus. Strikethrough text: important identified risks reclassified as not important, and therefore removed from the list of safety concerns. II.B. Summary of Important Risks The following 2 safety concerns, previously considered important identified risks, are proposed to be reclassified as not important (strikethrough text in tables below):

3 Clostridium difficile associated diarrhoea (Table 2) Hypersensitivity/anaphylaxis (Table 3) Table 2. Important Identified Risk - Clostridium difficile associated diarrhoea The MAH considers that CDAD can be re-categorised not important, being an adverse reaction with clinical consequences, even serious, but occurring with a low frequency and considered to be acceptable in relation to the severity of the indication treated; in addition, CDAD is a known risk that does not impact on the benefit-risk balance of the product. Chief risk factors include: prior antibiotic exposure, hospitalisation; and age >65 years. Outpatient populations should also be recognised as being at potential risk. Cephalosporins (especially second and third-generation) are among the most common antibiotics implicated in CDAD. RMMs: the risk is communicated through the label in SmPC Section 4.4 (Special warnings and precautions for use) and Section 4.8 (Undesirable effects) CDAD = Clostridium difficile associated diarrhoea; MAH = Marketing authorisation holder; RMM = Risk minimisation measure; SmPC = Summary of product characteristics. Table 3. Important Identified Risk - Hypersensitivity/Anaphylaxis The MAH believes that Hypersensitivity/anaphylaxis can be reclassified as not important because it is an adverse reaction already well-known to health professionals, that does not require additional pharmacovigilance activities or additional risk minimisation, and it has no impact on public health. The most important risk factor for allergy to cephalosporins is a history of hypersensitivity to penicillins or cephalosporins. Atopic individuals, especially those with asthma, may be predisposed to more severe and even fatal reactions in the event of anaphylaxis; however, a history of atopy (allergic rhinitis, asthma, or atopic dermatitis) by itself does not seem to be an independent risk factor for the development of an allergy to β-lactam antibiotics. 1 Routine RMMs: the risk is communicated through the label in SmPC Section 4.3 (Contraindications), Section 4.4 (Special warnings and precautions for use), and Section 4.8 (Undesirable effects). MAH = Marketing authorisation holder; RMM = measure; SmPC = Summary of product characteristics. Table 4. Important Potential Risk Bacterial Resistance Development Bacterial resistance development has been observed in nonclinical studies, and reports indicative of bacterial resistance development have been received in the post-marketing setting.

4 Table 4. Important Potential Risk Bacterial Resistance Development Additional pharmacovigilance activities Factors that may contribute to the development of resistance include inadequate infection control, high antibiotic use in a specific geographic area per unit time, increased use for prophylaxis, increased use for empiric polymicrobial therapy, greater severity of illness of hospitalised patients, more severely immunocompromised patients, devices and procedures, agricultural use of antimicrobials, social factors, international travel, and evolution of pathogens. Evidence suggests that a causal relationship exists between antimicrobial usage and antimicrobial resistance (e.g., hospitals with high antibiotic use have high rates of resistance; changes in antimicrobial usage in such settings are often accompanied by changes in resistance patterns and an increased duration of antimicrobial exposure is accompanied by an increased risk of colonisation with resistant organisms). 2 Routine RMMs: the risk is communicated through the label in SmPC Section (4.1 Therapeutic indications) and Section 5.1 (Pharmacodynamic properties) Additional pharmacovigilance activities: Resistance surveillance programme. See section II.C of this summary for an overview of the post-authorisation development plan. RMM = measure; SmPC = Summary of product characteristics. Table 5. Important Potential Risk Convulsions/Seizures Convulsions/seizures is a recognised class effect and it has been observed in nonclinical studies; reports indicative of convulsions/seizures have been received in clinical trials and in the post-marketing setting. Risk factors include advanced age, history of head trauma or neurologic disease, stroke, brain tumours, renal failure or genetic predisposition. Abnormal neurological status, defined as abnormal neurological examination, abnormal CT brain scan, remote symptomatic aetiology or neurological deficits from birth, is considered one of the most important risk factors for recurrence of seizure. Seizures have also been reported with use of a number of antimicrobial agents, including penicillins, cephalosporins, carbapenems and fluoroquinolones. A review study on antibiotic-induced convulsions suggested that risk factors for antibiotic-induced seizures include renal insufficiency, pre-existing CNS disease (including seizure disorder), cardiopulmonary bypass, sepsis and endocarditis. 3 RMMs: the risk is communicated through the label in SmPC Section 4.4 (Special warnings and precautions for use) CNS = Central nervous system; CT = Computed tomography; RMM = measure; SmPC = Summary of product characteristics. Table 6. Important Potential Risk Drug-Induced Liver Injury DILI is a recognised class effect and it has been observed nonclinical studies; reports indicative of DILI have been received in clinical studies and in the postmarketing setting. History of alcohol use, pre-existing liver disease, concomitant use of other hepatotoxic drugs and infections.

5 Table 6. Important Potential Risk Drug-Induced Liver Injury Routine RMMs: the risk is communicated through the label in SmPC Section 4.8 (Undesirable effects) DILI = Drug induced liver injury; RMM = measure; SmPC = Summary of product characteristics. Table 7. Important Potential Risk Haemolytic Anaemia Haemolytic anaemia is a recognised class effect and it has been observed nonclinical studies; reports indicative of haemolytic anaemia have been received in clinical studies and in the post-marketing setting. Risk factors include autoimmune disease, haematologic neoplasm, immunodeficiency disease, family history of haemolytic disease, and recent viral infections. RMMs: SmPC Section 4.4 (Special warnings and precautions for use) and Section 4.8 (Undesirable effects) RMM = measure; SmPC = Summary of product characteristics. Table 8. Important Potential Risk Renal Impairment (Including Potential Drug Interactions with Nephrotoxic Agents) Renal impairment is a recognised class effect and it has been observed nonclinical studies; reports indicative of renal impairment have been received in clinical studies and in the post-marketing setting. Risk factors include: advanced age, severe life-threatening systemic infections, circulatory, respiratory and renal compromise, trauma, history of diabetes mellitus, hypertension, heart failure, hepatic disease and concomitant nephrotoxic drugs. Clinical use of second- and third-generation cephalosporins has not produced clear evidence of significant nephrotoxicity. Decreases in glomerular filtration rate of about 10 ml/minute were seen after ceftazidime treatment courses ranging from 4-31 days. For many other cephalosporins comparable data are lacking. 4 Drug interactions that may potentially increase the risk of nephrotoxicity cited in the literature mainly relate to the use of older 1st generation cephalosporins (ie, cephaloridine and cefalotin) with either loop diuretics such as furosemide or aminoglycosides. 4 Conflicting data exist concerning the effect of furosemide on the PK of cephalosporins. 5 An increase in aminoglycoside nephrotoxicity has only been documented with cefalotin and cephaloridine. 4 Routine RMMs: the risk is communicated through the label in SmPC Section 4.2 (Posology and method of administration), Section 4.8 (Undesirable effects), and Section 5.2 (Pharmacokinetic properties) PK = Pharmacokinetics; RMM = measure; SmPC = Summary of product characteristics.

6 Table 9. Important Potential Risk Potential for off-label use AMR data was used to identify off-label activities in tigecycline. There is no literature evaluating any off-label use that would be relevant here. Reports indicative of off-label use have been received in the post-marketing setting. Patients with infections who are unresponsive and/or resistant to conventional antibiotic therapy or patients with life-threatening infections where no alternative therapy exists. RMMs: the risk is communicated through the label in SmPC Section 4.1 (Therapeutic indications) and Section 4.2 (Posology and method of administration) AMR = Arlington Medical Resources; PK = Pharmacokinetics; RMM = measure; SmPC = Summary of product characteristics. Table 10. Missing Information - Immunocompromised population Routine RMMs: the risk is communicated through the label in SmPC Section 4.4 (Special warnings and precautions for use) RMM = measure; SmPC = Summary of product characteristics. Table 11. Missing Information - Lactation Routine RMMs: the risk is communicated through the label in SmPC Section 4.6 (Pregnancy and lactation) RMM = measure; SmPC = Summary of product characteristics. Table 12. Missing Information - Paediatric population exposure Additional pharmacovigilance activities Routine RMMs: the risk is communicated through the label in SmPC Section 4.2 (Posology and method of administration) and Section 5.2 (Pharmacokinetic properties) Additional pharmacovigilance activities: Evaluation of the safety data from completed and ongoing PIP studies. See section II.C of this summary for an overview of the post-authorisation development plan. PIP = Paediatric investigation plan; RMM = measure; SmPC = Summary of product characteristics. Table 13. Missing Information - Pre-existing seizure disorder Routine RMMs: the risk is communicated through the label in SmPC Section 4.4 (Special warnings and precautions for use) RMM = measure; SmPC = Summary of product characteristics.

7 Table 14. Missing Information - Pre-existing significant hepatic impairment Routine RMMs: the risk is communicated through the label in SmPC Section 4.2 (Posology and method of administration), Section 4.8 (Undesirable effects), and Section 5.2 (Pharmacokinetic properties) RMM = measure; SmPC = Summary of product characteristics. Table 15. Missing Information - Pregnancy exposure Routine RMMs: the risk is communicated through the label in SmPC Section 4.2 (Posology and method of administration) and Section 5.2 (Pharmacokinetic properties) RMM = measure; SmPC = Summary of product characteristics. Table 16. Missing Information - Efficacy in MRSA CAP Routine RMMs: the risk is communicated through the label in SmPC Section 4.4 (Special warnings and precautions for use) RMM = measure; SmPC = Summary of product characteristics. II.C. Post-Authorisation Development Plan II.C.1. Studies which are Conditions of the Marketing Authorisation There are no studies which are conditions of the marketing authorisation or specific obligation of ZINFORO. II.C.2. Other Studies in Post-Authorisation Development Plan The following category 3 studies are additional pharmacovigilance activities planned or ongoing to address use in paediatric population, (including term and pre-term neonates) and bacterial resistance development. D3720C00009/C /P (PIP) - A multi-centre, open-label study to evaluate the safety, tolerability, PK and efficacy of ceftaroline plus ampicillin plus optional aminoglycoside in term and pre-term neonates with LOS. Purpose of the study: To evaluate the safety, tolerability, PK and efficacy of ceftaroline plus ampicillin plus optional aminoglycoside in term and pre-term neonates with LOS; to evaluate the safety, tolerability, efficacy, and PK of ceftaroline fosamil versus comparator in paediatric subjects with complicated cssti. D3720C00017/C (PIP) - A Phase 4, multi-centre, randomised, observer-blinded study to evaluate the safety, tolerability, efficacy, and PK of ceftaroline fosamil versus comparator in paediatric subjects with cssti.

8 Purpose of the study: To evaluate the safety, tolerability, efficacy, and PK of ceftaroline fosamil versus comparator in paediatric subjects with complicated cssti. Resistance surveillance programme Purpose of the study: To track the longitudinal in-vitro activity of ceftaroline and comparator agents against relevant clinical isolates (those pathogens identified in the SmPC with demonstrated clinical efficacy) in cssti, and LRTI.

9 Risk Management Plan Ceftaroline fosamil References March 2018 REFERENCES Kelkar P, Li J. Cephalosporin allergy. N Engl J Med 2001;345: Stein GE. Antimicrobial resistance in the hospital setting: Impact, trends, and infection control. Pharmacotherapy 2005;25(10 Pt 2):44S- 54S. Wallace KL. Antibiotic-induced convulsions. Crit Care Clin 1997;13(4): Aronson JK. Meyler s side effects of drugs: The international encyclopedia of adverse drug reactions and interactions. 15th ed. Oxford (UK): Elsevier; Cephalosporins. p Furosemide. p Pea F, Furlanut M. Pharmacokinetic aspects of treating infections in the intensive care unit: Focus on drug interactions. Clin Pharmacokinet 2001;40(11):