1 Maxipime (cCefepime) Core Safety Profile Created from Maxipime SmPC for Hungary dated February 2009 4.3 Contraindications Maxipime Cefepime is contraindicated in patients who have had previous hypersensitivity reactions to any component of the formulation, the cephalosporin class of antibiotics, penicillins or other beta-lactam antibiotics. 4.4 Special warnings and precautions for use Warnings In patients with impaired renal function, such as reduction of urinary output because of renal insufficiency (creatinine clearance ≤ 50 mL/min) or other conditions that may compromise renal function, the dosage of Maxipime cefepime should be adjusted to compensate for the slower rate of renal elimination. Because high and prolonged serum antibiotic concentrations can occur from usual dosages in patients with renal insufficiency or other conditions that may compromise renal function, the maintenance dosage should be reduced when cefepime is administered to such patients. Continued dosage should be determined by degree of renal impairment, severity of infection, and susceptibility of the causative organisms (see sections 4.2 - Posology and method of administration and 5.2 - Pharmacokinetic properties). During postmarketing surveillance, the following serious adverse events have been reported: reversible encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, seizures (including nonconvulsive status epilepticus), and/or renal failure (see section 4.8 - Undesirable effects). Most cases occurred in patients with renal impairment who received doses of Maxipime cefepime that exceeded recommendations. In general, symptoms of neurotoxicity resolved after discontinuation of cefepime and/or after hemodialysis, however, some cases included a fatal outcome. Special precautions for use Antibiotics should be administered with caution to any patient who has demonstrated some form of allergy, particularly to drugs. If an allergic reaction to Maxipime cefepime occurs, discontinue the drug and treat the patient appropriately. Serious hypersensitivity reactions may require epinephrine and other supportive therapy. Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Maxipime cefepime, and may range in severity from mild diarrhea to fatal colitis. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Renal function should be monitored carefully if drugs with nephrotoxic potential, such as aminoglycosides and potent diuretics are administered with Maxipime cefepime. As with other antibiotics, use of Maxipime cefepime may result in overgrowth of nonsusceptible organisms. Should superinfection occur during therapy, appropriate measures should be taken. Geriatric use Of the more than 6400 adults treated with Maxipime cefepime e in clinical studies, 35 % were 65 years or older while 16% were 75 years or older. For geriatric patients in clinical studies, when geriatric patients who received the usual recommended adult dose, clinical efficacy and safety were comparable to clinical
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1
Maxipime (cCefepime) Core Safety Profile
Created from Maxipime SmPC for Hungary dated February 2009
4.3 Contraindications
Maxipime Cefepime is contraindicated in patients who have had previous hypersensitivity reactions to
any component of the formulation, the cephalosporin class of antibiotics, penicillins or other beta-lactam
antibiotics.
4.4 Special warnings and precautions for use
Warnings
In patients with impaired renal function, such as reduction of urinary output because of renal insufficiency
(creatinine clearance ≤ 50 mL/min) or other conditions that may compromise renal function, the dosage of
Maxipime cefepime should be adjusted to compensate for the slower rate of renal elimination. Because
high and prolonged serum antibiotic concentrations can occur from usual dosages in patients with renal
insufficiency or other conditions that may compromise renal function, the maintenance dosage should be
reduced when cefepime is administered to such patients. Continued dosage should be determined by
degree of renal impairment, severity of infection, and susceptibility of the causative organisms (see
sections 4.2 - Posology and method of administration and 5.2 - Pharmacokinetic properties). During
postmarketing surveillance, the following serious adverse events have been reported: reversible
encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma),
myoclonus, seizures (including nonconvulsive status epilepticus), and/or renal failure (see section 4.8 -
Undesirable effects). Most cases occurred in patients with renal impairment who received doses of
Maxipime cefepime that exceeded recommendations.
In general, symptoms of neurotoxicity resolved after discontinuation of cefepime and/or after
hemodialysis, however, some cases included a fatal outcome.
Special precautions for use
Antibiotics should be administered with caution to any patient who has demonstrated some form of
allergy, particularly to drugs. If an allergic reaction to Maxipime cefepime occurs, discontinue the drug
and treat the patient appropriately. Serious hypersensitivity reactions may require epinephrine and other
supportive therapy.
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial
agents, including Maxipime cefepime, and may range in severity from mild diarrhea to fatal colitis.
CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful
medical history is necessary since CDAD has been reported to occur over two months after the
administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not
directed against C. difficile may need to be discontinued.
Renal function should be monitored carefully if drugs with nephrotoxic potential, such as
aminoglycosides and potent diuretics are administered with Maxipime cefepime.
As with other antibiotics, use of Maxipime cefepime may result in overgrowth of nonsusceptible
organisms. Should superinfection occur during therapy, appropriate measures should be taken.
Geriatric use
Of the more than 6400 adults treated with Maxipime cefepime e in clinical studies, 35 % were 65 years or
older while 16% were 75 years or older. For geriatric patients in clinical studies, when geriatric patients
who received the usual recommended adult dose, clinical efficacy and safety were comparable to clinical
2
efficacy and safety in non-geriatric adult patients, unless the patients had renal insufficiency. There was a
modest prolongation in elimination half-life and lower renal clearance values compared to those seen in
younger persons. Dosage adjustments are recommended if renal function is compromised (see section 4.2
- Posology and administration and 5.2- Pharmacokinetic properties).
Cefepime is known to be substantially excreted by the kidney and the risk of toxic reactions to this drug
may be greater in patients with impaired renal function. Because elderly patients are more likely to have
decreased renal function, care should be taken in dose selection and renal function should be monitored
(see sections 4.8 Undesirable effects and 5.2 - Pharmacokinetic properties). Serious adverse events,
including reversible encephalopathy (disturbance of consciousness including confusion, hallucinations,
stupor, and coma), myoclonus, seizures (including nonconvulsive status epilepticus), and/or renal failure
have occurred in geriatric patients with renal insufficiency given the usual dose of cefepime (see section
4.8 - Undesirable effects).
4.5 Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed.
Positive Coombs’ test without hemolysis was detected in patients receiving Maxipime cefepime two
times daily (see section 4.8).
The result of glucose determination from urine may be false positive therefore glucose oxidase method is
suggested.
4.6 Pregnancy and lactation
Pregnancy
Reproductive studies in mice, rats, and rabbits showed no evidence of fetal damage, however there are no
adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not
always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Nursing Mothers
Cefepime is excreted in human breast milk in very low concentrations. Caution should be used when
cefepime is administered to a nursing woman.
4.7 Effects on ability to drive and use machines
The effects of medicinal product on ability to drive and use machines have not been studied. However,
possible adverse reactions like altered state of consciousness, dizziness, confusional state or
hallucinations may alter the ability to drive and use machines (see sections 4.4 Special warnings and
precautions for use, 4.8 Undesirable effects and 4.9 Overdose).
4.8 Undesirable effects
The table below includes all adverse events as currently listed in the CCDS†. The list is presented by
system organ class, MedDRA preferred term, and frequency using the following frequency categories:
very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to ≤1/100), rare (≥1/10000 to
≤1/1000), very rare (≤ 1/10000), and not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
TABLE 3 Adverse drug events reported during clinical or postmarketing experience
System Organ Class Frequency MedDRA Term
3
Infections and infestations Uncommon Oral candidiasis, vaginal infection
Rare Candidiasis
Blood and lymphatic system Very common Coombs test positive
disorders
Common Prothrombin time prolonged, partial
thromboplastin time prolonged,
anaemia, eosinophilia
Uncommon Thrombocytopenia, leukopenia,
neutropenia
Not known Aplastic anaemiaa, haemolytic
anaemiaa, agranulocytosis
Immune system disorders Rare Anaphylactic reaction
Not known Anaphylactic shock
Metabolism and nutrition Not known Urine glucose false positive
disorders
Psychiatric disorders Not known Confusional state, hallucination
Nervous system disorders Uncommon Headache
Rare Convulsion, paraesthesia, dysgeusia,
dizziness
Not known Coma, stupor, encephalopathy, altered
state of consciousness, myoclonus
Vascular disorders Common Infusion site phlebitis
Rare Vasodilation
Not known Haemorrhagea
Respiratory, thoracic and
mediastinal disorders
Rare Dyspnoea
Gastrointestinal disorders Common Diarrhoea
Uncommon Pseudomembranous colitis, colitis,
nausea, vomiting
Rare Abdominal pain, constipation
Not known Gastrointestinal disorder
Hepatobiliary disorders Common Alanine aminotransferase increased,
Aspartate aminotransferase increased,
Blood bilirubin increased
Skin and subcutaneous tissue Common Rash
disorders Uncommon Erythema, urticaria, pruritus
Not known Toxic epidermal necrolysisa , Stevens-
Johnson syndromea, erythema
multiformea
Renal and urinary disorders Uncommon Blood urea increased, blood
creatinine increased
Not known Renal failure, nephropathy toxica
Reproductive system and breast Rare Pruritus genital
disorders
General disorders and Common Infusion site reaction, injection site
administration site condition pain, injection site inflammation
Uncommon Pyrexia, infusion site inflammation
Rare Chills
Investigations Common Alkaline phosphatase increased
a:a Adverse reactions that are generally accepted as being attributable to other compounds in the class.
4
Pediatrics
The safety profile of Maxipime cefepime in infants and children is similar to that seen in adults. The most
frequently reported adverse event considered related to Maxipime cefepime in clinical trials was rash.
4.9 Overdose
In case of severe overdosage, especially in patients with compromised renal function, hemodialysis will
aid in the removal of cefepime from the body; peritoneal dialysis is of no value. Accidental overdosing
has occurred when large doses were given to patients with impaired renal function (see sections 4.2 -
Posology and administration and 4.4 - Special warnings and precautions for use). Symptoms of overdose
include encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and
coma), myoclonus, and seizures, and neuromuscular excitability (see section 4.8).
Opmerking [l1]: It is likely that the term "neuromuscular excitability" was
included as an adverse reaction in the
Overdosage section of the Maxipime SmPC for Slovenia as an inclusive term for the
events of myoclonus and seizures. This
occurred when the cefepime Company Core Data Sheet (CCDS) was revised in August
2000 to add post-marketing reports of
adverse reactions in patients with renal impairment. Our recent review of the
Safety database for cefepime revealed no
reports of "neuromuscular excitability" associated with the use of
cefepime. Therefore, BMS recommends
that this ADR be removed from the Maxipime SmPC for Slovenia. BMS
intends to revise the cefepime CCDS to
reflect this change.
cefepime 1/58 draft FAR PT/H/PSUR/0008/001
P-RMS FINAL
ASSESSMENT REPORT
Procedure number PT/H/PSUR/0008/001
Active substance Cefepime
Innovator name of product in the P-RMS Maxipime
Pharmaceutical form(s)/strength pó para solução injectável 1000 mg
Cefepime is indicated in adults for the treatment of the infections listed below when caused
by susceptible bacteria•
Lower respiratory tract infections, including pneumonia and bronchitis
Urinary tract infections, both complicated, including pyelonephritis, and uncomplicated
Skin and skin structure infections
Intra-abdominal infections, including peritonitis and biliary tract infections
Gynecologic infections
Septicemia
Empiric Therapy for Febrile Neutropenic Patients. Cefepime as monotherapy is indicated for
empiric treatment of febrile neutropenic patients. In patients at high risk for severe infection (for
example, patients with a history of recent bone marrow transplantation, with hypotension at
presentation, with an underlying hematologic malignancy, or with severe or prolonged neutropenia),
antimicrobial monotherapy may not be appropriate. Insufficient data exist to support the efficacy of
cefepime monotherapy in such patients.
Cefepime is also indicated for surgical prophylaxis in patients undergoing intra-abdominal surgery
Pediatrics
Cefepime is indicated in pediatric patients for the treatment of the infections listed below when caused by
susceptible bacteria:
Pneumonia
Urinary tract infections, both complicated, including pyelonephritis, and uncomplicated
Skin and skin structure infections 68,69,70
Septicemia
Empiric Therapy for Febrile Neutropenic Patients. Cefepime as monotherapy is indicated for empiric
treatment of febrile neutropenic patients. In patients at high risk for severe infection (for example, patients
with a history of recent bone marrow transplantation, with hypotension at presentation, with an underlying
hematologic malignancy, or with severe or prolonged neutropenia), antimicrobial monotherapy may not be
appropriate. Insufficient data exist to support the efficacy of cefepime monotherapy in such patients.
WORLDWIDE MARKETING AUTHORISATION STATUS AND UPDATE OF REGULATORY ACTIONS TAKEN FOR SAFETY REASONS (MAH, AUTHORITIES)
Has there been a change to the marketing authorisation status or have regulatory actions been taken for
safety reasons? Yes No
If yes, specify:
cefepime 3/58 draft FAR PT/H/PSUR/0008/001
PSUR Reported
Period Changes to CCDS
Regulatory Safety Changes
Fourteenth
PSUR
29 June 2006
and 28
December
2006
not revised due to safety issues. no actions pertaining to cefepime
are known to have been taken by
regulatory authorities
Fifteenth
PSUR
29 December
2006 and 28
June 2007
not revised due to safety issues. no actions pertaining to cefepime
are known to have been taken
Sixteen
PSUR
29 June 2007
and 28
December
2007
THERAPEUTIC INDICATIONS
Expanded text for indication of
empiric treatment
of febrile neutropenia.
POSOLOGY AND
METHOD OF ADMINISTRATION
Expanded text in
Table 3 for dosing patients with
febrile
neutropenia who have renal
impairment.
WARNINGS AND
PRECAUTIONS FOR USE
Addition of precautions
concerning
Clostridium difficile-
associated diarrhea.
PHARMACOLOGICAL PROPERTIES
Reformatted
PK/PD section and added
instruction to
obtain and take into account
information about
local bacterial resistance
patterns.
CLINICAL TRIAL
INFORMATION
Addition of information on
clinical studies in
patients with febrile
neutropenia.
REFERENCES
Added references for FN Indication
and CDAD
Warning. Renumbered
references.
FDA requested class labeling changes related
to Clostridium difficile associated diarrhea in
the WARNINGS section and
PRECAUTIONS
FDA requested BMS' position on a cefepime
meta-analysis publication (Yahav D, Paul M,
Fraser A, Sarid N, Leibovici L. Efficacy and
safety of cefepime: a systematic review and
meta-analysis. Lancet Infect Dis 2007;
7:338-48.)
New Zealand Health Authority (Medsafe)
request for BMS’ perspective on the
published meta-analysis for cefepime (Yahav
D, et.al., 2007).
Swiss Health Authority (SwissMedic)
requested an updated safety summary of
subjects who died while on cefepime therapy.
Dear Doctor/Pharmacist Letter (DDPL)
regarding the findings of the cefepime meta-
analysis (Yahav et al., 2007) was submitted
in German and French languages, to the
Swiss Health Authority (SwissMedic) and at
their request, mailed to all Swiss hospital
physicians, hospital pharmacists and
infectiologists
Finnish Health Authority, the National
Agency for Medicines requested BMS to
compile a report on potentially increased
mortality in patients taking cefepime
cefepime 4/58 draft FAR PT/H/PSUR/0008/001
Seventeenth
PSUR
29 December
2007 and 28
June 2008
The cefepime CCDS dated 09 November
2007 was not revised due to safety
issues.
BMS submitted an updated safety summary
of subjects who died while on cefepime therapy to the Swiss Health Authority (Swiss Medic).
A Dear Doctor/Pharmacist Letter (DDPL)
regarding the findings of the cefepime meta-
analysis (Yahav D, Paul M, Fraser A, Sarid
N, Leibovici L. Efficacy and safety of
cefepime: a systematic review and meta-
analysis. Lancet Infect Dis 2007; 7:338-48.)
was submitted in German and French
languages, to the Swiss Health Authority
(SwissMedic) and at their request, mailed to
all Swiss hospital physicians, hospital
pharmacists and infectiologists.
Finnish Health Authority, the National
Agency for Medicines requests BMS to
compile a report on potentially increased
mortality in patients taking cefepime in
response to the 2007 cefepime meta-analysis.
This response was submitted to the health
authority on 24 June 2008. Review of the
data is still ongoing.
29 June 2008
and 28 June
2009
The cefepime CCDS dated 09 November
2007 was not revised due to safety
issues.
France
August 2008: Variation was submitted to
amend the Summary of Product
Characteristics (SmPC) about Clostridium
difficile as a principal infectious cause of
antibiotic-associated diarrhea.
Canada
26 September 2008 and 3 October 2008:
Request for clarifications further to the
Yahav et al 2007 publication on 33 studies in
addition to those listed in the PSURs and
submitted during registration. Response
submitted 3 November 2008.
Slovenia
25 September 2008: A Type II variation with
SmPC safety update (addition of Febrile
Neutropenia and CDAD) was submitted to
HA and is still pending
Finland
Among other labeling updates requested, the
Finnish HA asked BMS to compile a report
of potentially increased mortality of the
patients treated with cefepime.
Poland
The Polish HA sent an assessment to BMS
and recommended the removal from the
Polish SmPC of the indication "Fever in
patients with neutropenia (empirical
treatment) for all age groups”.
cefepime 5/58 draft FAR PT/H/PSUR/0008/001
United States
17 June 2009: The FDA publicly informed
healthcare professionals through their
website, that it had performed meta analyses
based on additional data beyond those
included in the Yahav et al. publication
(Lancet Infect Dis, 2007). In the FDA
analyses, including data submitted by
Bristol-Myers Squibb, no statistically
significant increase in mortality was seen in
cefepime-treated patients compared to
comparator treated patients. Based on the
results of FDA's meta analyses, the FDA has
determined that cefepime remains an
appropriate therapy for its approved
indications.
On 25 June 2009, FDA required Bristol-
Myers Squibb to conduct an epidemiologic
study to compare the overall mortality among
hospitalized patients who were treated with
cefepime with those who received other
parenteral antibacterials.
SUMMARY OF RELEVANT PhVWP/CHMP DISCUSSIONS *, IF ANY:
Cefepime q (MAXIPIME®):
Results of a meta-analysis showing increased risk of all-cause mortality compared to other β-lactams (DE)
◦ Publication: Efficacy and safety of cefepime: a systematic review and meta-analysis. Yahav D et al. Lancet Infect Dis. 2007 May;7(5):338-48.
◦ Results from a systematic review of randomised trials that compared cefepime with another
beta-lactam antibiotic, alone or with the addition of a non-beta-lactam antibiotic to both study
groups showed that the all-cause mortality-the primary outcome-was higher with cefepime than
other beta-lactams (risk ratio [RR] 1.26 [95% CI 1.08-1.49]). Baseline risk factors for mortality
were similar. No significant differences between groups in treatment failure, superinfection, or
adverse events were found. This signal should be further investigated in the context of the
PSUR worksharing exercise (PT is the P-RMS for this substance). * During the period under review
CHANGES TO REFERENCE SAFETY INFORMATION
Is the CCDS the reference document? Yes No If not, please indicate which document is used as reference document: Date of the last reference document : 09 November 2007
Which sections of the reference safety document have been changed during the period covered by the PSUR? posology and method of administration (4.2) contraindications(4.3) special warnings and precautions for use(4.4)
cefepime 6/58 draft FAR PT/H/PSUR/0008/001
interaction with other medicinal products and other forms of interaction(4.5) pregnancy and lactation (4.6) effects on ability to drive and use machines(4.7) undesirable effects(4.8) overdose (4.9) Please specify the safety relevant changes:
PSUR Reported Period Changes to CCDS
Fourteenth PSUR 29 June 2006 and 28
December 2006
not revised due to safety issues.
Fifteenth PSUR 29 December 2006 and
28 June 2007
not revised due to safety issues.
Sixteen PSUR 29 June 2007 and 28
December 2007 THERAPEUTIC INDICATIONS
Expanded text for indication
of empiric treatment of febrile neutropenia.
POSOLOGY AND METHOD OF
ADMINISTRATION
Expanded text in Table 3 for dosing patients with febrile
neutropenia who have renal
impairment.
WARNINGS AND
PRECAUTIONS FOR USE
Addition of precautions concerning Clostridium
difficile-associated diarrhea.
PHARMACOLOGICAL
PROPERTIES
Reformatted PK/PD section
and added instruction to obtain
and take into account information about local
bacterial resistance patterns.
CLINICAL TRIAL INFORMATION
Addition of information on
clinical studies in patients with
febrile neutropenia.
REFERENCES
Added references for FN Indication and CDAD
Warning. Renumbered
references.
Seventeenth PSUR 29 December 2007 and
28 June 2008
The cefepime CCDS dated 09 November 2007 was
not revised due to safety issues.
29 June 2008 and 28
June 2009
The cefepime CCDS dated 09 November 2007 was
not revised due to safety issues.
Selected differences between RSI and proposed CSP:
cefepime 7/58 draft FAR PT/H/PSUR/0008/001
SUSPECTED ADVERSE DRUG REACTIONS (INNOVATOR) DURING THE PERIOD
SERIOUS CASES AND ADRs
Total number of serious cases, incl. fatalities 424
Number of fatal cases 1
SUSPECTED ADVERSE DRUG REACTIONS, overview
SUSPECTED ADVERSE DRUG REACTIONS (ADRs), Overview (29 Jun 2006 - 28 Jun 2009)*
Case Safety Reports During the period covered by these PSUR, 284 health care professional confirmed AE notifications have been reported. 231 ( 70,7%) were serious. 201 were spontaneous reports, 74 from the literature, 9 from clinical trials. A fatal outcome was reported in 49 reports. Adverse Events Reports, described in the chapter 6.3 of each MAH PSUR of the interest, from Non Health Care Professionals reported in this period were 3. Of these 2 were considered serious.(graph 1)
Source: MAH Cefipime PSUR – Chapter 6.3
Adverse Events by System Organ Class – Global Overview Since the beginning of commercialization of Cefepime the most frequent ADR´s reported by SOC were from Nervous System Disorders with 21,8%(n=612), General disorders 14,4%(n=404), Skin disorders with 10,5% (n=294), Blood disorders 8,2% (n=231) Psychiatric Disorders 6,6% (n=184), Investigations with 5,8%(n=164), respiratory disorders with 4,6% (n=128) and infections and infestactions disorders with 4,4% (n= 125) (graph 2).
cefepime 8/58 draft FAR PT/H/PSUR/0008/001
Source : Cefepime PSUR – annex 6.1 During the reported period, from june 2006 to june 2009, the most reported ADR were by SOC were Nervous
system disorders with 146 ADR, Skin disorders with 58, general disorders with 41, Investigations with 36,
infections with 34, blood disorders with 31, respiratory with 27, psychiatric disorders with 23 and renal
disorders with 20 (graph 3).
Source : Cefepime PSUR – annex 6.1
cefepime 9/58 draft FAR PT/H/PSUR/0008/001
Adverse Events by MedDra Preferred Term – Global Overview
ADR reports confirmed by health care professionals In the reported period the most frequent ADR reported by health care professionals were Convulsion (18 / 17 serious), Status Epilepticus (18 /18 serious), Encephalopathy (17 /17 serious), Rash (12/ 4 serious), Coma (11/ 11 serious); myoclonus ( 11/ 9 serious); depressed level of consciousness ( 10/ 10 serious), Confusional State ( 10/ 6 serious), Neutropenia (8 / 7), Sepsis (8/8), Aphasia (7/7 serious), Renal failure ( 7/ 7 serious).
ADR reports notified by non health care professionals In the period covered the PSUR the following adverse events were notified by non health care professionals, see table 1.
Table 1 – Absolute frequency of non health professionals ADR by reported during the period covered by this AR
MedDra Prefered term Serious
Non-Serious
Pyrexia 1
Muscle spasms-u 1
Hemiplegia-u 1
Speech disorder-u 1
Tremor-u 1
Hyperhidrosis-u 1
Flushing 1
Assessor, Comment :
During the period covered by this Assessment report the safety profile of cefepime in what concerns a global overview of the ADR reported by Soc and by preferred term is somewhat peculiar. There´s a higher proportion of ADR related with neurologic disorders by SOC and an elevated proportion of preferred terms also related with with nervous system and related terms. Of concern the proportion of convulsions, status epilepticus, encephalopathy, coma, myoclonus, depressed level of consciousness and confusional state. Of note the number of “neurologic ADR cases related with renal impairment and rebal failure, calling for a probable pharmacological mechanism linked to renal impairment and elevated cefime plasma concentration and the neurologic ADR, which need to be carefully monitorized by MAH.
cefepime 10/58 draft FAR PT/H/PSUR/0008/001
Detailed Analysis
Spontaneous, Literature reports and Clinical Trials We will analize in the following chapters four dimensions of ADR reported during this period in the following order: - absolute frequency; - the seriousness of the reported ADR;
In each SOC we will comment the data concerning the safety profile of cefepime looking at the proposed SPC and the data that was reported during this period.
Blood and lymphatic system disorders Table 1 - Summary ADR SOC Blood and Lymphatic System Disorders reported by health professionals
Events
Sp Lit CT all
PSUR Divergences*
S NS S NS S NS Total
Agranulocytosis 4 33
Disseminated intravascular coagulation 1 14
Eosinophilia 1 5
Febrile neutropenia 2 2 8
Leukopenia 1 2 1 31 26
Lymphopenia-u 1 2
Neutropenia 6 1 1 63 56
Neutrophilia 1 2
Pancytopenia 3 1 16
Thrombocytopenia 2 1 57
Sp – Spontaneous Events; Lit – Literature Events – CT – Clinical Trials and Post Marketing Studies U –
Unlisted events; *The total number of cumulative preferred terms between the different PSUR´s send by MAH are divergent – the figures in this columns signalize the differences between our own calculation and the information gave by the MAH
MAH SOC Assessment
Recommendation: Based on the information provided by these cases, no change to the CCDS is
recommended. The MAH will continue to closely monitor these events as part of routine safety
surveillance.
Assessor Comments: MAH had discussed one non serious case of neutrophilia and 2 cases of pancytopenia ( 1 serious and 1 non serious). In one case a causal relationship between pancytopenia and cefepime exposicion can not be excluded. The number of cases and the incidence rates of the events in this Soc does not have any new safety signal emerging in this period
cefepime 11/58 draft FAR PT/H/PSUR/0008/001
Cardiac disorders Table 2 - Summary table of ADR SOC Cardiac disorders ordered by absolute frequency of ADR reported by health professionals
Adverse Event Sp Lit CT PSUR
S NS S NS S NS S All
Cardiac arrest-u 1 15 1
Cardiac failure congestive-u 1 4
Cardiac failure-u 3 17 3
Cardio-respiratory arrest-u 2 7 2
Cyanosis 1 2 1
Myocarditis-u 1 2 1
Myocardial infarction-u 1 5
Tachycardia-u 1 12
Ventricular tachycardia-u 2 3 2
Recommendation: Based on the information provided by these cases, no change to the CCSI is
recommended. The MAH will continue to closely monitor these events as part of routine safety
surveillance.
Assessor Comments: MAH had discussed the cases of Cardiac arrest(1), Cardiac failure(1),Cardiac Failure Congestive (1) Cardiac failure acute, Cardio-respiratory arrest (1), In two cases the MAH causality assessment is not related. Of note the 5 cardiac events reported during the period covered by these period, all were literature cases. 8 cases ( 4 initial and 4 follow up), all fatal, were published by Sonck J et al in the Nephrol Dial transplant 2008 – 23:966-970. and relates patients with renal impairment treated with cefepime and all of them developed neurological signs ( coma , myoclonus, metabolic toxic disturbance on EEG, difuse slow wave activity on EEG, agitation,) the suggestive title of that article (“ The neurotoxicity and safety of treatment with cefepime in patients with renal failure”) precludes a concern that need an action.
Eye disorders Table 3 - Summary table of ADR SOC Eye Disorders ordered by absolute frequency of ADR reported by health professionals
All AEs in this SOC were reviewed by the product safety physician. Upon review of the PTs
included in this section, no cases warranted further discussion.
cefepime 12/58 draft FAR PT/H/PSUR/0008/001
Assessor Comments: The frequency and seriousness of the adverse events reported during this period are in line with the safety profile of this product and with what is expressed in the approved SPC
.
Gastrointestinal disorders Table 4 - Summary table of ADR SOC Gastrointestinal disorders ordered by absolute frequency of ADR reported by health professionals
Recommendation: Based on the information provided by these cases, no change to the CCDS is recommended. The MAH will continue to closely monitor these events as part of routine safety surveillance :
Assessor Comments MAH had discussed in this SOC the cases of Preferred Terms Gastrointestinal Haemorrhage (1 – possibly related by the reported physician, not possible to exclude a causal relationship by MAH) and neutropenic colitis (1 – multiple confounding factors) The number of cases and the incidence rates of the events is this Soc does not have any new safety signal emerging in this period. We agree with MAH that these events must continue to be monitorized.
General disorders and administration site conditions Table 5 - Summary table of ADR SOC General disorders and administration site conditions ordered by absolute frequency of ADR reported by health professionals
Cases of Fatal Outcome will be analyzed in the fatal cases section. Cases of drug Interactions were related in Drug Interactions section of this AR. MAH Assessment
Based on the information provided by these cases, no change to the CCDS is recommended. The MAH will continue to closely monitor these events as part of routine safety surveillance
Assessor Comments: The cases of drug ineffective (2 fatal), drug resistance (1 fatal) and multi-organ failure (1 case assessed by the physician as not related) were discussed by MAH The frequency and seriousness of the adverse events reported during this period are in line with the safety profile of this product and with what is expressed in the approved SPC
Hepatobiliary disorders Table 6 - Summary table of ADR SOC hepatobiliary disorders ordered by absolute frequency of ADR reported by health professionals
Upon review of the PTs included in this section, no cases warranted further discussion.
cefepime 14/58 draft FAR PT/H/PSUR/0008/001
Assessor Comments: The frequency and seriousness of the adverse events reported during this period are in line with the safety profile of this product and with what is expressed in the approved SPC.
Immune system disorders Table 7 - Summary table of ADR SOC immune system disorders ordered by absolute frequency of ADR reported by health professionals
*The total number of cumulative preferred terms between the different PSUR´s send by MAH are divergent – the figures in this columns signalize the differences between our own calculation and the information gave by the MAH MAH Assessment Anaphylactic reaction, anaphylactic shock and hypersensitivity are listed in the current CCDS of cefepime. Based on
the information provided by these reports, no change to the CCDS is recommended. The MAH will continue to monitor
these events as a part of routine safety surveillance
Assessor Comments: MAH discussed the cases of anaphylactic shock ( 2 cases both with a positive temporal relation, and positive biological plausibility and 1 case dubious) and anaphylactic reaction ( 1 case with + temporal association, one case possibly related, 1 case unlikely) and one case of hypersensivity The frequency and seriousness of the adverse events reported during this period are in line with the known safety profile of this product and with what is expressed in the approved SPC
Infections and Infestations Table 8 - Summary table of ADR SOC infections and infestations disorders ordered by absolute frequency of ADR reported by health professionals
Bronchopulmonary aspergillosis-u 1 3 Cytomegalovirus infection-u 1 1 Escherichia sepsis-u 1 2 Hepatosplenic candidiasis-u 1 1 Infection-u 1 5 Pneumonia-u 1 2 2 24 27 Pneumonia escherichia-u 1 1 Pneumonia necrotising-u 1 1 6 Pseudomembranous colitis 2 1 24 Sepsis-u 2 6 38 Septic shock-u 1 2 16 Tuberculosis-u 1 1 *The total figures of cumulative preferred terms between the different PSUR´s send by MAH are divergent – the figures in this columns signalize the differences between our own calculation and the information gave by the MAH
MAH Assessment
Upon review of the PTs included in this section, no cases warranted further discussion.
Assessor Comments: MAH discussed the cases of pneumonia ( 2 cases both with a positive temporal relation, and positive biological plausibility and 1 case dubious) . The frequency and seriousness of the adverse events reported during this period are in line with the known safety profile of this product and with what is expressed in the approved SPC
Injury, Poisoning and Procedural Complications Table 9 - Summary table of ADR SOC Injury, poisoning and procedural complications ordered by absolute frequency of ADR reported by health professionals
Events Sp Lit CT all
PSUR
Diver Gent*
S NS S NS S NS
Accidental overdose 1 5 Drug administration error 2 4 Medication error 1 9 Nerve injury-u 1 1 Overdose 3 1 23 Poor quality drug administered 3 3 *The total figures of cumulative preferred terms between the different PSUR´s send by MAH are divergent – the figures in this columns signalize the differences between our own calculation and the information gave by the MAH
cefepime 16/58 draft FAR PT/H/PSUR/0008/001
MAH Assessment
Upon review of the PTs included in this section, no cases warranted further discussion.
Assessor Comments: The frequency, the incidence rate and seriousness of the adverse events reported during this period are in line with the known safety profile of this product and with what is expressed in the approved SPC
Investigations Table 10 - Summary table of ADR SOC investigations ordered by absolute frequency of ADR reported by health professionals
*The total figures of cumulative preferred terms between the different PSUR´s send by MAH are divergent – the figures in this columns signalize the differences between our own calculation and the information gave by the MAH
Table 10 (cont) - Summary table of ADR SOC investigations ordered by absolute frequency of ADR reported by health professionals
Upon review of the PTs included in this section, no cases warranted further discussion.
cefepime 17/58 draft FAR PT/H/PSUR/0008/001
Assessor Comments: MAH discussed the cases of drug level increased ( 3 serious cases – in one case there was a neurotoxic syndrome that was assessed by the French Methodology as possible related with cefepime and in all these cases had a concomitant renal impairment) and the cases classified in the preferred term of drug level above therapeutic ( 14189369/CH – literature cases series ( 30 patients) related with cefepime levels variability dependent of the renal function in febrile neutropenic patients – in 40% of the cases cefepime blood levels were above 15mg/L and in 6 cases (20%) high cefepime levels were related with “neurological toxicity” and all these patients recovered after dose decrease or discontinuation. In the assessment of all the cases that MAH discusses the same conclusions were made namely concerning the information already described in the CCDS concerning renal impairment and dosing schedule and the warnings related with renal impairment and reversible encephalopathy and other neurologic adverse events. Although we can agree with MAH concerning the CCDS information we also reinforce that although that we still have reported cases related with the neurotoxicity of cefepime, namely in particular in people with renal impairment. This is a matter of concern.
Metabolism and nutrition disorders Table 11 - Summary table of ADR SOC Metabolism and nutrition disorders ordered by absolute frequency of ADR reported by health professionals
Based on the information provided by these cases, no change to the CCSI is recommended. The
MAH will continue to closely monitor these events as part of routine safety surveillance.
Assessor Comments MAH discussed one initial literature case ( 11794492/FR) of metabolic acidosis in a 31 year old male with acute monocytyc leukaemia ( coma, neutropenia, acute renal failure , confusional state, metabolic acidosis, renal tubular disorder and nephrogeic diabetes insipidus – temporal (+); biological plausibility (+/-); other confounding factors (+); dechallenge (?); Causality assessment by French Health Authority not reported) . The frequency and seriousness of the adverse events reported during this period are in line with the known safety profile of this product and with what is expressed in the approved SPC
cefepime 18/58 draft FAR PT/H/PSUR/0008/001
Musculoskeletal and connective tissue disorders Table12 - Summary table of ADR SOC Musculoskeletal and connective tissue disorders ordered by absolute frequency of ADR reported by health professionals
Upon review of the PTs included in this section, no cases warranted further discussion.
Assessor Comments The frequency, the incidence rate and seriousness of the adverse events reported during this period are in line with the known safety profile of this product and with what is expressed in the approved SPC
Neoplasms benign, malignant and unspecified Table 13 - Summary table of ADR SOC Neoplasms benign, malignant and unspecified ordered by absolute frequency of ADR reported by health professionals
Events Sp Lit CT all
PSUR
Diver Gent*
S NS S NS S NS
Leukaemia-u 1 1 Lymphoma-u 1 4 MAH Assessment
Upon review of the PTs included in this section, no cases warranted further discussion.
Clinical Assessor Comments: No safety signals arise in this SOC for this period
cefepime 19/58 draft FAR PT/H/PSUR/0008/001
Nervous system disorders Table 14 - Summary table of ADR SOC Nervous system disorders ordered by absolute frequency of ADR reported by health professionals
*The total figures of cumulative preferred terms between the different PSUR´s send by MAH are divergent – the figures in this columns signalize the differences between our own calculation and the information gave by the MAH
Table 14 (cont) - Summary table of ADR SOC Nervous system disorders ordered by absolute frequency of ADR reported by health professionals
o 17 narratives (2 follow up) ; 17 temporal (+); 3 dechallenge (+) ; 1 rechallenge (+) in one case; 6 in 10 cases reported presented concomitantly with renal impairment ; ; age » 75 = 8 cases in 14; age « 1 = 3 in 4 report related with children), 5 fatal cases in 17 reported cases.
- Altered level of conscience
o 2 cases : 91 and 81 years old age; temporal (+) in both cases
- Aphasia o 7 cases : temporal (+) : 7/7; dechallenge (+) 5; » 65 years old = 4 cases; renal impairment : 6 ;
metabolic toxic disturbance : 4 ;
- Apraxia; Choreoathetosis; Clonus ; Extrapiramidal disorder; generalized convulsive disorder ; complex partial seizures; hemiplegia; nervous system disorder; neurotocity – 1 narrative case of each PT
- Coma
o total cases : 14 ; temporal (+) : 14; dechallenge (+) : 7; » 65 years old = 11; renal impairment ; fatal cases 3.
o - Encephalophaty
o Total cases : 13; temporal (+) : 11; dechallenge (+) : 6 ; » 65 years old = 8/11; renal impairment : 8/13
- Epilepsy o Total cases . 4
- Metabolic Encephalopathy
o Total cases 4 ; renal impairment : 3 o
- Status Epilepticus
o Total cases : 18; temporal (+) : 14; dechallenge 7/9; renal impairment : 14; » 65 years old = 8/18
- Toxic Encephalopathy
o Total cases : 6/30; febrile neutropenic patients MAH Assessment General comment for toxic encephalopathy that can be applied for other adverse events reported in all the psur´s that were assessed concerning this SOC:
“ The information derived from this report is consistent with the known safety profile of cefepime.
According to the current CCDS, “During postmarketing surveillance, the following serious adverse
events have been reported: reversible encephalopathy (disturbance of consciousness including
confusion, hallucinations, stupor, and coma), myoclonus, seizures (including nonconvulsive status
hemiplegia, metabolic encephalopathy, toxic encephalopathy, status epilepticus are not listed but
coma, convulsion, encephalopathy, neurotoxicity are listed in the current CCDS of cefepime. Based
on the information provided by these reports, no change to the CCDS is recommended. The MAH
will continue to monitor this and similar events as part of routine safety surveillance.
mm
Clinical Assessor Comments: Although the current SPC recommends dose adjustments in patients with renal impairment the majority of the cases reported in all the assessed PSUR concerning what was called as neurotoxicity of cefepime (as Sonck J et al 2008 – “the neutoxicity and safety of treatment with cefepime in patients with renal failure – Nephrol Dial Transplant 2008; 23:966-970) and involved patients with renal impairment and aged patients. The frequency of the reported cases, the temporal relationship; the biologic plausibility; the age of the majority of the patients; the seriousness of some of reported cases, the proportion configures a consistent pattern of risk that probably can´t be solved only with the information in the SPC. Probably the best way to reduce the neurotoxic pattern of cefepime it will be to contra-indicated its use in aged persons with renal impairment.
Pregnancy, Puerperium and Perinatal Conditions
MAH has made a cumulative search of the safety database and identified 35 reports of cefepime. 7
were classified as serious cases. In all these reports there were 2 premature babies, 2 foetal distress
syndrome and two abortion, one induced. All the other cases were related with normal newborns.
Clinical Assessor Comments: No safety signals arise in this SOC for this period
Psychiatric Disorders Table 16 - Summary table of ADR SOC Psychiatric Disorders ordered by absolute frequency of ADR reported by health professionals
MAH had discussed the cases of Confusional state ( 1 serious case) and delirium ( 4 serious cases) ; MAH Assessment
Based on the information provided by these reports, no change to the CCDS is recommended. The
MAH will continue to monitor the event as a part of routine safety surveillance
Clinical Assessor Comments: We agree with MAH that these events must continue to be monitorized.
Renal and urinary disorders Table 17 - Summary table of ADR SOC Renal and urinary disorders ordered by absolute frequency of ADR reported by health professionals
*The total figures of cumulative preferred terms between the different PSUR´s send by MAH are divergent – the figures in this columns signalize the differences between our own calculation and the information gave by the MAH
The MAH will continue to closely monitor these events as part of routine safety surveillance.
Clinical assessor comments: The number of cases and the incidence rates of the events is this Soc does not have any new safety signal emerging in this period. We agree with MAH that these events must continue to be monitorized.
cefepime 23/58 draft FAR PT/H/PSUR/0008/001
Respiratory, thoracic and mediastinal disorders Table 18 - Summary table of ADR SOC Respiratory, thoracic and mediastinal disorders ordered by absolute frequency of ADR reported by health professionals
*The total figures of cumulative preferred terms between the different PSUR´s send by MAH are divergent – the figures in this columns signalize the differences between our own calculation and the information gave by the MAH
MAH Assessment
Upon review of the PTs included in this section, no cases warranted further discussion.
Clinical Assessor Comments: No new safety signals arise in this SOC for this period.
Skin and subcutaneous tissue disorders Table 19 - Summary table of ADR SOC Skin and subcutaneous tissue disorders ordered by absolute frequency of ADR reported by health professionals
Events Sp Lit CT all
PSUR
Diver Gent*
S NS S NS S NS
Drug rash with eosinophilia and systemic symp u 4 4 Dermatosis 1 Drug eruption 4 2 33 18 Erythema 2 21 14 Erythema multiforme 1 5 Generalised erythema 1 1 3 Hyperhidrosis-u Mucocutaneous ulceration-u 1 1 Petechiae-u 1 1 Prurigo 1 1 Pruritus 5 1 29 17
*The total figures of cumulative preferred terms between the different PSUR´s send by MAH are divergent – the figures in this columns signalize the differences between our own calculation and the information gave by the MAH
Table 19 (cont.) - Summary table of ADR SOC Skin and subcutaneous tissue disorders ordered by absolute frequency of ADR reported by health professionals
MAH had discussed the serious cases of Stevens-Johnson syndrome ( 4 serious cases: temporal (+) – 4;
dechallenge 2; biological plausibility 2) Toxic epidermal necrolysis ( 1 serious case); drug eruption ( 2 serious cases); skin exfoliation ( 1 serious cases) ; purpura ( 1 case) and 1 case of toxic skin eruption. MAH Assessment The MAH will continue to closely monitor these events as part of routine safety surveillance.
Clinical Assessor Comments: Purpura, drug eruption, skin exfoliation and toxic skin eruption are not listed events in the CCDS SJSyndrome and toxic epidermal necrolysis are listed in the CCDS We agree with MAH that these cases must be monitored.
cefepime 25/58 draft FAR PT/H/PSUR/0008/001
Vascular Disorders Table 20 - Summary table of ADR SOC Vascular Disorders ordered by absolute frequency of ADR reported by health professionals
MAH discussed the cases of Shock ( 2 cases – in 1 case that the causality assessment made by the phsycian states that the event was definitively related with cefepime administration and in another case a causality assessment is difficult to established due to scarcity of the information reported). MAH Assessment The MAH will continue to closely monitor these events as part of routine safety surveillance.
Clinical Assessor Comments: We agree with MAH that these events must continue to be monitorized.
cefepime 26/58 draft FAR PT/H/PSUR/0008/001
8. - Reports with a Fatal Outcome
A total of 49 fatal cases (25 spontaneous, 20 from literature and 4 from clinical studies) were reported .
o Age and sex ranged
1stPSUR 2nd PSUR 3rd PSUR Fourth PSUR Fifth PSUR
male 1 1
female 5 4
age mean 76 73 47,8 68 58
Age range 41 -95 59-83 0,66 - 77 30 - 84 0,22 - 87
Causes of death
Cardiac failure 4
Sepsis 4
Multi-organ failure 4
unknown 4
Coma 3
Pneumonia 3
treatment failure 3
Convulsion 2
Encephalopathy 2
Status Epilepticus 2
Aspergillosis 1
Cardiac Arrest 1
cardio-respiratory arrest 1
Drug level incresead 1
Infection 1
leukemia relapse 1
lymphoma 1
Multimorbidity 1
myocardial infarction 1
Pulmonary Embolism 1
Renal Failure 1
septic shock 1
septicemia 1
Clinical Assessor Comments: Of concern the number of cases of death related or associated with metabolic neurotoxicity (convulsions; depressed conscience; encephalopathy; status epilepticus ) that involved aged patients with renal impairment.
Met opmaak: Inspringing: Links: 1,9cm, Verkeerd-om: 0,63 cm, Metopsommingstekens + Niveau: 2 +Uitgelijnd op: 1,9 cm + Tab na: 2,54cm + Inspringen op: 2,54 cm
cefepime 27/58 draft FAR PT/H/PSUR/0008/001
CEFEPIME TABLE OF HEALTHCARE PROFESSIONAL CONFIRMED ADVERSE DRUG REACTIONS1,2
Serious Non-serious Total
System Organ Class (SOC) Listed Unlisted Listed Unlisted
Blood and lymphatic system disorders 28 2 4 1 33
Cardiac disorders 4 11 0 1 16
Congenital and familial and genetic
disorders 1 0 0 0 1
Ear and labyrinth disorders 0 0 0 0 0
Endocrine disorders 0 0 0 0 0
Eye disorders 0 3 0 0 3
Gastrointestinal disorders 2 3 4 2 11
General disorders and administration site
conditions 9 19 10 5 43
Hepatobiliary disorders 7 1 1 0 9
Immune system disorders 16 0 0 0 16
Infections and infestations 8 26 0 0 34
Injury poisoning and procedural
complications 5 1 6 0 12
Investigations 22 5 8 3 38
Metabolism and nutrition disorders 0 2 0 2 4
Musculoskeletal and connective tissue
disorders 2 2 0 1 5
Neoplasms benign, malignant and
unspecified 0 2 0 0 2
Nervous system disorders 122 21 7 5 155
Pregnancy, puerperium and perinatal
conditions 0 0 2 0 2
Psychiatric disorders 13 5 7 2 27
Renal and urinary disorders 10 7 1 2 20
Reproductive system and breast disorders 0 0 0 0 0
Respiratory thoracic and mediastinal
disorders 1 14 1 2 18
Social circumstances 0 0 0 0 0
Skin and subcutaneous tissue disorders 36 12 26 0 74
Surgical and medical procedure 0 0 0 0 0
Vascular disorders 3 1 2 2 8
Total 287 137 79 28 531 1All serious and non-serious, health professional confirmed spontaneous and literature adverse drug reactions.
2All serious and non-serious adverse drug reactions from serious Phase I-IV study cases (Not related study events are excluded from
the tabulations).
cefepime 28/58 draft FAR PT/H/PSUR/0008/001
TABLE OF SELECTED* SERIOUS UNLISTED ADRs :
* Selection is within the discretion of the P-RMS
SOC PSUR MEDDRA PREFERRED TERM SP-S L-S Study C&P-S
General disorders and administration site conditions 14 Death 1
15 Death 2
18 Death 1
14 Multi-organ failure 1
15 Multi-organ failure 2
18 Multi-organ failure 1
15 Multimorbidity 1
16 Drug resistance 1
18 Treatment failure 4
Hepatobiliary disorders 18 Liver injury 1
Infections and infestations 14 Cytomegalovirus infection- 1
14 Infection 1
14 Pneumonia 1
16 Pneumonia 2
14 Tuberculosis 1
16 Bronchopulmonary aspergillosis 1
18 Bronchopulmonary aspergillosis 1
16 Sepsis 1 1
17 Sepsis 1
cefepime 29/58 draft FAR PT/H/PSUR/0008/001
18 Sepsis 5
16 Septic shock 1
SOC PSUR MEDDRA PREFERRED TERM SP-S L-S Study C&P-S
17 Septic shock 1
18 Septic shock 1
17 Arthritis bacterial 1
17 Pneumonia escherichia 1
18 Bacteraemia 3
18 Bronchitis 1
18 Bronchopneumonia 1
18 Escherichia sepsis 1
18 Hepatosplenic candidiasis 1
18 Pneumonia necrotising 1
Injury, poisoning and procedural complications 16 Nerve injury 1
Investigations 15 Blood pressure decreased 1
16 Blood lactic acid increased 1
18 Liver function test abnormal 2
18 Transaminases increased 1
Metabolism and nutrition disorders 15 Metabolic acidosis 1
17 Apoptosis 1
Musculoskeletal and connective tissue disorders 14 Muscle spasms 1
14 Muscle twitching 1
18 Muscle twitching 1
18 Muscular weakness 1
Neoplasms benign, malignant and unspecified 18 Leukaemia 1
18 Lymphoma 1
Nervous system disorders 14 Convulsion 4 1
14 Dyskinesia 1
18 Dyskinesia 1
14 Hyperreflexia 1
14 Paraesthesia 1
17 Aphasia 3 2
18 Aphasia 1 2
17 Choreoathetosis 1
17 Dysarthria 1
18 Apraxia 1
18 Hemiplegia 1
18 Somnolence 2
cefepime 30/58 draft FAR PT/H/PSUR/0008/001
Nervous system disorders 14 Speech disorder- 1
15 Extrapyramidal disorder 1
SOC PSUR MEDDRA PREFERRED TERM SP-S L-S Study C&P-S
15 Nervous system disorder 1
16 Asterixis 1
16 Dyskinesia 1
Psychiatric disorders 14 Disorientation 1
14 Nervousness 1
Renal and urinary disorders 15 Haematuria 1
15 Nephrogenic diabetes insipidus 1
17 Nephritis interstitial 1
18 Renal failure acute 1
18 Renal failure chronic 1
Respiratory, thoracic and mediastinal disorders 14 Wheezing 1
15 Respiratory failure 1
18 Respiratory failure 1
16 Eosinophilic pneumonia 1
16 Interstitial lung disease 2
18 Interstitial lung disease 1
16 Non-cardiogenic pulmonary oedema 1
18 Pulmonary embolism 1
18 Respiratory disorder 1
Skin and subcutaneous tissue disorders 15 Mucocutaneous ulceration 1
15 Petechiae 1
16 Red man syndrome 1
16 Stevens-Johnson syndrome 1
18 Stevens-Johnson syndrome
18 Drug rash with eosinophilia and systemic 4
symptoms-
18 Purpura 1
Vascular disorders 16 Hypotension 1
cefepime 31/58 draft FAR PT/H/PSUR/0008/001
VALUABLE INFORMATION FROM PSURs FOR OTHER PRODUCTS AUTHORISED IN THE P-RMS
Do any of the PSURs for other products authorised in the P-RMS contain information not addressed in the PSUR for the originator product(s)?
Yes No
If yes, specify in table below:
TABLE OF SELECTED* SERIOUS UNLISTED ADRs IN OTHER PSURs AUTHORISED IN THE P-RMS
Serious unlisted ADRs (MedDRA PT in agreed SOC order)
Number of serious unlisted ADRs
* Selection is within the discretion of the P-RMS
Other information:
OVERALL ASSESSOR COMMENTS ON CASE REPORTS (INCL. LITERATURE CASES)
1.- Cardiac Events MAH had discussed the cases of Cardiac arrest(1), Cardiac failure(1),Cardiac Failure Congestive (1) Cardiac failure acute, Cardio-respiratory arrest (1), In two cases the MAH causality assessment is not related. Of note the 5 cardiac events reported during the period covered by these period, all were literature cases. 8 cases ( 4 initial and 4 follow up), all fatal, were published by Sonck J et al in the Nephrol Dial transplant 2008 – 23:966-970. and relates patients with renal impairment treated with cefepime and all of them developed neurological signs ( coma , myoclonus, metabolic toxic disturbance on EEG, difuse slow wave activity on EEG, agitation,) the suggestive title of that article (“ The neurotoxicity and safety of treatment with cefepime in patients with renal failure”) precludes a concern that need an action. 2.- investigations MAH discussed the cases of drug level increased ( 3 serious cases – in one case there was a neurotoxic syndrome that was assessed by the French Methodology as possible related with cefepime and in all these cases had a concomitant renal impairment) and the cases classified in the preferred term of drug level above therapeutic ( 14189369/CH – literature cases series ( 30 patients) related with cefepime levels variability dependent of the renal function in febrile neutropenic patients – in 40% of the cases cefepime blood levels were above 15mg/L and in 6 cases (20%) high cefepime levels were related with “neurological toxicity” and all these patients recovered after dose decrease or discontinuation. In the assessment of all the cases that MAH discusses the same conclusions were made namely concerning the information already described in the CCDS concerning renal impairment and dosing schedule and the warnings related with renal impairment and reversible encephalopathy and other neurologic adverse events. Although we can agree with MAH concerning the CCDS information we also reinforce that although that we still have reported cases related with the neurotoxicity of cefepime, namely in particular in people with renal impairment. This is a matter of concern
cefepime 32/58 draft FAR PT/H/PSUR/0008/001
3.- Nervous system disorders Although the current SPC recommends dose adjustments in patients with renal impairment the majority of the cases reported in all the assessed PSUR concerning what was called as neurotoxicity of cefepime (as Sonck J et al 2008 – “the neutoxicity and safety of treatment with cefepime in patients with renal failure – Nephrol Dial Transplant 2008; 23:966-970) and involved patients with renal impairment and aged patients. The frequency of the reported cases, the temporal relationship; the biologic plausibility; the age of the majority of the patients; the seriousness of some of reported cases, the proportion configures a consistent pattern of risk that probably can´t be solved only with the information in the SPC. Probably the best way to reduce the neurotoxic pattern of cefepime it will be to contra-indicated it´s use in aged persons with renal impairment. 4.- Reports with a Fatal Outcome Of concern the number of cases of death related or associated with metabolic neurotoxicity (convulsions; depressed conscience; encephalopathy; status epilepticus ) that involved aged patients with renal impairment.
OVERALL ASSESSOR COMMENTS ON MAH SPONSORED STUDIES
Describe and comment on studies of relevance to safety of the product(s)
OVERALL ASSESSOR COMMENTS ON STUDIES FROM THE LITERATURE
Food and Drug Administration from United States of America after the publication in the Lancet infectious diseases of one meta-analysis done by Yahav et al that noted an increased 30 day mortality associated with the use of cefepime vs other β lactams in the following indications : neutropenic fever, pneumonia, urinary tract/gynecologic infections and other mixed infections had done an analysis with several components
1 :
1.- The revision of all case report forms of all febrile neutropenia patients who died within 30 days of receiving cefepime or a comparator agent in the nine febrile neutropenia studies ( 7 comparative and 2 non-comparative studies ) submitted to the FDA by BMS in the initial process for the marketing authorization. This analysis was done to identify the most likely cause of death and the main factors that could contribute to each patient death. 2.- A data mining process to characterize the population that were involved in the nine febrile neutropenic studies; and to perform additional analysis of patient deaths to evaluate the association between these deaths and some Adverse events, patient co-morbid conditions and finally using the Bayesian meta – analytical methodology to assess potential causes of death (as developed by William DuMochel). 3.- a meta-analysis to assess if cefepime was associated with an excess risk of mortality vs comparator drugs. This review was done at a trial level ( 88 studies) with 9467 patients exposed to cefepime and 8288 patients exposed to comparators and at a patient level ( 35 studies) with 5058 patients exposed to cefepime and 3976 patients exposed to comparators and at a patient level. The primary endpoint was 30 day all – cause -mortality
1 Kim P. Cefepime clinical review. Food and Drug Administration 6/2009 in
http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/UCM167313.pdf acessed in 8/11/2009
In the overall analysis both analysis gave similar conclusions that cefepime was associated with greater mortality risk compared to comparator, although that difference was not found statistically significant.
In the overall analysis, both trial-level and patient-level analyses gave similar conclusions that cefepime was associated with greater mortality risk compared to comparator, however, this difference was not found to be statistically significant. The risk difference estimate for the trial-level analysis was 5.38 per 1000 population (95% CI: (-1.53, 12.28)), and for the patient-level analysis was 4.83 per 1000 population (95% CI: (-4.72, 14.38)).
OVERALL ASSESSOR COMMENTS ON NEW INFORMATION REGARDING
Special populations:
Pediatric Use
No safety signals
Elderly Use
n serious ADR total
1st PSUR 20 19 Depressed level of conscioussness 6
2nd PSUR
25
Convulsion 4
Encephalopathy 4
Status Epilepticus 4
Depressed level of conscioussness 2
3rd PSUR
13 10
Encephalopathy 1
Altered level of conscioussness 2
Epilepsy 1
Febrile Neutropenia 1
4rd PSUR
26 19
coma 4
death 3
Altered level of conscioussness 2
myoclonus 2
5th PSUR
49 41
Encephalopathy 6
hepatic function abnormal 5
Altered level of conscioussness 4
Status Epilepticus 4 Pregnancy/lactation:
No safety signals arise during this period Drug interaction:
No safety signals arise during this period
cefepime 34/58 draft FAR PT/H/PSUR/0008/001
Overdose: 1 acute renal failure 1 with cefepime – induced enecephalopathy; two cases with coma ;one fatal case. Abuse or misuse:
No safety signals arise during this period Medication errors:
No safety signals arise during this period Long-term treatment:
No safety signals arise during this period Off label use:
No safety signals arise during this period
COMMENTS ON ANY CHANGE OF THE RISK BENEFIT BALANCE
Patient treated for the indication of skin and skin structure infections:
According the FDA’s report, overall, there was not a statistically significant difference in 30 -day mortality for patients treated with
cefepime versus comparator agents in the analysis of 30-day mortality stratified by study drug and treatment indication. Aside from
the skin structure infection indication [which contained a relatively small number of patients and deaths (6 deaths for c efepime
versus 0 for comparators)], the analysis did not demonstrate a statistically significant difference in 30 -day mortality for cefepime
versus comparator agents for any of the other treatment indications analyzed. These data are not confirmed by the analysis conducted by BMS using the Solucient’s Hospital Drug Utilization Database (HDUD).
For more details please see the response to the question 2.
Patients with baseline pathogens resistant to study therapy:
On page 199 of FDA’s report, the M.O. commented that the data presented in Table 22 as follows: overall, the number of patients
with resistant pathogens at baseline who subsequently died was small. Regarding specific pathogens isolated at baseline in mo re
than one patient in either study arm in this subset, more cefepime patients died post isolation of the following organisms versus
comparator patients: Enterococcus sp. [cefepime: 9.0% (7/78) vs. comparator 3.2% (2/62)], S. aureus [cefepime: 28.6% (4/14) vs.
comparator 8.0% (2/25)], S. epidermidis [cefepime: 15.4% (2/13) vs. comparator 11.8% (2/17)], and P. aeruginosa [cefepime:
9.5% (2/21) vs. comparator 0% (0/15)]. The M.O. noted that cefepime is not typically used for treatment of infections due to
Enterococcus sp. or S. epidermidis. More control patients died post isolation of the following organisms versus cefepime patients:
K. pneumoniae [cefepime: 0% (0/1) vs. comparator 33.3% (2/6)].
BMS cannot identify these data regarding specific pathogens isolated at baseline in Table 22. Mortality Status Stratified by
Pathogen and Treatment Arm for 423 Patients with a “Resistant Pathogen at Baseline” (pages 198 and 199).
In addition, BMS reviewed the comments from the M.O. on CRFs of the 40 patients reported by BMS as having at least one
baseline pathogen resistant to study therapy and who died within 30 days post study therapy (pages 201-215).
Among these 40 patients, 16 were receiving cefepime and 15 were receiving therapy with cefepime in combination with amikacin
(14 patients) or vancomycin (1 patient).
From 16 CRFs with patients treated only with cefepime, there are no reports in which the M.O. considered cefepime treatment
failure as cause of the patient’s death.
ACTION PLAN AND CONCLUSIONS
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A CHANGES OF THE BENEFIT RISK BALANCE Has the benefit risk balance changed? No Yes , please specify: Concerning the FDA report the significant findings were : In what concerns the revision of all case report forms of all neutropenic patients (included in the clinical studies of febrile neutropenia – 2 non comparative and 7 comparative) who died within 30 days in order to identify the most likely cause of death and the main factors that could contribute to each patient death. The Medical Officer of FDA in his review states that in the seven comparative febrile neutropenia studies, there were 102/1402 deaths within 30 days of study therapy. Based on the treatment assignment 7.9% were cefepime patients and 6.0% were comparator patients. The MO of FDA revised all case report forms of all death cases of the neutropenia studies and in almost all the cases there was an alternative explanation for the death (underlying malignancy and or co-morbid condition) but in some cases is not possible to exclude a drug failure (24.6% cefepime patients and 24.4% of comparator patients), a resistant gram-positive pathogen (8.2% of the cefepime vs 4.9 comparator deaths) . The Multivariate Bayesian Logistic Regression data mining analysis of the 9 BMS sponsored febrile neutropenia studies cefepime used in the empiric treatment of febrile neutropenia showed that the cefepime exposure was not associated with a statistical significantly higher mortality rate vs comparator group. However that in some subgroups there were a trend related death, although small and not statistically relevant, on cefepime exposed patients namely in the following subgroups :
- oldest age group - white people - patients having received medications for a bone marrow transplant - patients with diabetes mellitus - patients with a baseline serum creatinine above 2.5mg/dL and neutrophil counts below 500 U/ul.
The overall conclusion of new meta-analysis done by FDA, states :
“Dr. Wu concluded in her meta-analysis that cefepime was not associated with a significantly higher
mortality rate versus the comparator group, i.e., she did not confirm the findings of Yahav et al.1
Dr. Wu
noted that her analysis was based on a broader spectrum of data sources and found that the mortality risk
difference in the cefepime group was greater, but this increase was not found to be statistically significant
in both trial-level and patient-level analyses. Additionally, she conducted subgroup analyses, most of which
did not demonstrate a significantly increased mortality associated with cefepime treatment. However,
significantly greater mortality was demonstrated for cefepime-treated patients in the following subgroups:
patients treated for the indication of skin and skin structure infections, patients with baseline pathogens
resistant to study therapy, and patients with febrile neutropenia with solid tumors at baseline. The numbers
of subjects available in these subgroups were very small, thus resulting in wide confidence intervals.
Therefore, significant findings from these subgroups would need to be re-examined if and when more data
are available.”
In the discussion of all data reviewed by FDA, the Medical Officer states that no biological plausible safety
signal has been identified to explain the increased mortality observed in the Yahav study, either specifically
among febrile neutropenia patients exposed to cefepime. And that only appropriated clinical trials could
explicitly answer to the question where cefepime patients were at an increased risk of death or not. Such
studies are not ethical possible.
Finally FDA is proposing a risk management plan concerning this issue:
cefepime 36/58 draft FAR PT/H/PSUR/0008/001
a) FDA will promote a postmarketing analysis of mortality associated with cefepime exposure by a
pharmacoepidemiological study that will be done in a clinical database.
b) BMS will perform a pharmacoepidemiological study in a drug utilization database
c) FDA is revising the data concerned with mean inhibitory concentration susceptibility breakpoints
for P aeruginosa an the Enterobacteriacea to improve consistency with EMEA product labels due
to change in bacterial resistance to cefepime.
d) The division may consider providing additional clarification in the “indications/usage section” of
the label for “empiric therapy for febrile neutropenic patients”
Assessor comments :
1) Concerning the data that was published namely the Yahav study and also the revision of all data done by FDA, we agree with MO of FDA in what concerns :
- The fact that in neutropenic studies in almost all the cases there was an alternative
explanation for the death ( underlying malignancy and co-morbid condition) but in some cases is not possible to exclude a drug failure (24.6% cefepime patients and 24.4% of comparator patients).
- The need to clarify “whether or not the use of cefepime is associated with increased mortality” and “the practical limitations of executing such trials using a mortality endpoint”.
- The data related with the subgroups analysis concerning “a significantly greater mortality was demonstrate for cefepime treated in the following subgroups : patient treated for the indication of skin and skin structure infections, patients with baseline pathogens resistant to study therapy, and patients with febrile neutropenia with solid tumor at baseline”
2) The data that we have received concerning the reported adverse drug reactions
does not appears to signalize new safety signal related with a significant change of the seriousness or the frequency of the listed ADR´s.
B CHANGES REQUIRED IN THE CSP Is the CSP acceptable? Yes No If not, specify the necessary changes (specific wordings): Please see attached document.
C REGULATORY ACTIONS * PROPOSED, IF ANY
* Regulatory options may include urgent safety restrictions, variations, suspension or revocation. Topics for close monitoring should be mentioned below in section E.
D SUMMARY OF COMMENTS FROM OTHER MSs
Member State Comment Agreed action e.g. updating CSP,
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close monitoring
AT CSP: Warning regarding symptoms of neurotoxicity
CSP Updating upon P-RMS decision: Patients should be instructed to contact their physician at once of any neurological signs and symptoms including encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus and seizures for immediate treatment, dosage adjustment, or discontinuation of cefepime
DE Section 4.4 of CSP: This section is not in line with SPC guideline, especially language should be more concise and subheadings (e.g. on renally impaired patients, hypersensitivity reactions) should be included. The warning on renally impaired patients should be strengthened as follows: Patients with decreased renal function In patients with impaired renal function, such as reduction of urinary output because of renal insufficiency (creatinine clearance ≤ 50 mL/min) or other conditions that may compromise renal function, the dosage of Maxipime cefepime should be adjusted to compensate for the slower rate of renal elimination. Because high and prolonged serum antibiotic concentrations can occur from usual dosages in patients with renal insufficiency or other conditions that may compromise renal function, the maintenance dosage should be reduced when cefepime is administered to such patients. Continued dosage should be determined by degree of renal impairment, severity of infection, and susceptibility of the causative organisms (see sections 4.2 - Posology and method of administration and 5.2 - Pharmacokinetic properties). During postmarketing surveillance, the following serious adverse events have been reported: reversible encephalopathy (disturbance of
The CSP should be updated accordingly.
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consciousness including confusion, hallucinations, stupor, and coma), myoclonus, seizures (including nonconvulsive status epilepticus), and/or renal failure (see section 4.8 - Undesirable effects). Most cases occurred in patients with renal impairment who received doses of Maxipime that exceeded recommendations. In general, symptoms of neurotoxicity resolved after discontinuation of cefepime and/or after hemodialysis, however, some cases included a fatal outcome. Special precautions for use Hypersensitivity reactions Antibiotics should be administered with caution to any patient who has demonstrated some form of allergy, particularly to drugs. If an allergic reaction to Maxipime occurs, discontinue the drug and treat the patient appropriately. Serious hypersensitivity reactions may require epinephrine and other supportive therapy. Geriatric use Of the more than 6400 adults treated with Maxipime in clinical studies, 35 % were 65 years or older while 16% were 75 years or older. For geriatric patients in clinical studies, when geriatric patients who received the usual recommended adult dose, clinical efficacy…
Section 4.6 of CSP: The german originator SPC mentions that cefepime passes the placental barrier and a link to section 5.3 is given. Additionally a warning on possible sensitisation and disturbances of gut flora in infants is given when breastfeeding is considered necessary. We therefore propose the following wording: Pregnancy Reproductive studies in mice, rats, and rabbits showed no evidence of fetal damage, however there are no adequate and well-controlled studies in
The CSP should be updated accordingly.
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pregnant women. Cefepime passes the placental barrier. Because animal reproduction studies (see section 5.3) are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers Cefepime is excreted in human breast milk in very low concentrations. Caution should be used when cefepime is administered to a nursing woman due to possible sensitisation and negative impact on the gut flora of the infants.
Section 4.7 of CSP: The german originator SPC mentions that due to some adverse reactions ability to drive and use machines may be impaired. We therefore propose the following wording: 4.7 Effects on ability to drive and use machines The effects of medicinal product on ability to drive and use machines have not been studied. However, possible adverse reactions like altered state of consciousness, dizziness, confusional state or hallucinations may alter the ability to drive and use machines.
The CSP should be updated accordingly.
Section 4.8 of CSP: The table format should be changed to display each frequency in a separate column since only this format enables a true two dimensional overview. The following adverse reactions should be included since being listed in the German originator SPC: Allergic reaction instead of anaphylactic reaction Tinnitus (rare) Arthralgia (rare)
The CSP should be updated accordingly. The MAH is also requested to comment if frequency of pseudomembranous colitis is correct since being less frequent labelled for other antibiotics.
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Oedema (rare) Additionally the footnotes should be formatted correctly. The section on paediatrics is not in line with SPC guideline and should be changed as follows: Pediatrics The safety profile of adverse reactions Maxipime in infants and children is similar to that seen in adults. The most frequently reported adverse reaction event considered related to Maxipime in clinical trials was rash.
Member State Comment Agreed action e.g. updating CSP, close monitoring
E POINTS TO BE ADDRESSED IN THE NEXT PSUR
1.- MAH should present comments on the safety issues that were described in this report, namely the data concerning the benefit –risk of the following indication :
- Empiric Therapy for Febrile Neutropenic Patients and
- Skin and skin structure infections 2.- MAH must propose a risk management plan tto clarify “whether or not the use of cefepime is associated with increased mortality” in empiric therapy for febrile neutropenic patients and skin and skin structures ( pharmacoepidemiological studies, information to health care professionals, SPC changes ).
F RFI / LoQ: REQUEST FOR FURTHER INFORMATION / LIST OF QUESTIONS
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QUESTION 1
Concerning the data that was published namely the Yahav study and also the revision of all data done by the Food and
Drug Administration (FDA), we ask the MAH to comment on the following points:
1. The fact that in neutropenic studies in almost all the cases there was an alternative explanation for the death (
underlying malignancy and co-morbid condition) but in some cases it is not possible to exclude a drug failure (24.6%
cefepime patients and 24.4% of comparator patients).
2. The need to clarify “whether or not the use of cefepime is associated with increased mortality” and “the practical
limitations of executing such trials using a mortality endpoint.”
3. The data related with the subgroups analysis concerning “a significantly greater mortality was demonstrate for
cefepime treated in the following subgroups: patient treated for the indication of skin and skin structure infections,
patients with baseline pathogens resistant to study therapy, and patients with febrile neutropenia with solid tumor at
baseline.”
MAH response: Cefepime is a broad-spectrum injectable antibiotic of the cephalosporin class. Cefepime is a fourth generation
cephalosporin which was approved in September 1996 in the U.S. It is currently indicated for empiric therapy of febrile
neutropenia and for the treatment of lower respiratory tract infections, urinary tract infections, skin and skin structure
infections, intra-abdominal infections, gynecologic infections and septicemia.1
In May 2007, a meta-analysis was published in The Lancet Infectious Diseases by Yahav et al.2 that reported an
increased risk of death for subjects treated with cefepime. Their meta-analysis was based on pooled study-level data from
published papers, abstracts, and personal communications. The meta-analysis included 57 randomized clinical trials
comparing cefepime to other β-lactam antibiotics. The primary outcome assessed was 30 day all-cause mortality only
available for 41 of the trials. Secondary outcomes were: clinical failure; microbiological failure; super-infections and
adverse events (AE). All cause mortality had a risk ratio [RR] of 1.26 (95% CI: 1.08-1.49). Subgroup analyses were
performed for febrile neutropenia, pneumonia, urinary tract/gynecological infections, and other/mixed infections. The
febrile neutropenia group presented with significant increase in overall mortality, i.e. RR=1.42 (95% CI: 1.09-1.84) and
in all the other groups the difference was not significant. There were no significant findings on the secondary outcomes2.
The study results should be interpreted with caution due to methodological limitations in the analysis which may lead to
unpredictable results. While meta-analyses provide some value in comparing several therapies, there are well known
challenges with metaanalyses. These include the varying quality of studies included in the meta-analysis, combining
studies assessing different indications, populations with dissimilar risks of interest, and publication bias3. Differences in
patient characteristics between treatment groups regarding disease severity, co-morbidities, and age, can also introduce
bias in meta-analysis. These issues may have impacted the absolute difference in mortality rates of the studies reported in
the meta-analysis by Yahav et al. In addition, many patients with febrile neutropenia in the studies selected by these
investigators had cancer with advanced diseases that could have contributed to the risk of mortality differently across
studies.
Regarding the 2009 FDA report4, the Medical Officer (M.O.) commented that the difference in the proportion of deaths
between cefepime and comparators in the 7 comparative studies was minimal, i.e., 1.4%. In the majority of the patients in
both groups, mortality appeared to be due to underlying malignancy and/or co-morbid conditions. Among those patients
that died, up to 24.6% of cefepime patients and 24.4% of comparator patients may have potentially died due to study drug
failure
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Since the publication by Yahav et al. in 2007, two separate independent groups have expressed viewpoints and reflections
to the published data in medical journals. A summary of these and the response to one of them by Yahav et al. are
provided below.
Towne TG et al.5, to better understand the differences of all-cause mortality between cefepime and other beta-lactam
antibiotics found in review by Yahav et al., and to determine if infectious or non-infectious causes impacted the mortality
results, reviewed 19 studies comparing the neutropenic fever subset of these data. Complete cause of death information
was obtained for 11 and partial cause of death information for two. These 13 studies included 64% of the all-cause
neutropenic deaths in Yahav publication. Review of causes of death among these patients found no marked differences
between cefepime and beta-lactam comparator for any infectious cause. This review did not find unrecognized cases of
non-convulsive status epilepticus/encephalopathy among the study patients (Yahav publication had proposed neurotoxic
effects of cefepime as a possible explanation for their results). A higher proportion of patients died secondary to
progression of their underlying disease in the cefepime arm compared with the other beta-lactam arm. Furthermore, no
patients were determined to have died directly as a result of receiving therapy with any agent, including cefepime.
Yahav et al.6 replied to this publication by Towne, in the same journal. They mention that all-cause mortality is the
primary outcome when assessing treatment of severe infections. They state that cause-specific mortality might have
delineated better differences between treatment regimens, avoiding dilution with outcomes that are unrelated to infection
and its consequences. However, the cause of death cannot be established clinically in most cases. The authors report that
patient allocation has not been unbalanced at baseline, since the only difference between trial arms was the antibiotic
given, which refute Towne and colleagues’ statement that more patients treated with cefepime died due to their
underlying disease. Although the authors could not explain the increased mortality, considering the significance of the
results and the wide variety of alternative antibiotic treatments, they believe that it is reasonable to reconsider the use of
cefepime until the US Food and Drug Administration reaches a definite conclusion concerning the safety of cefepime Since the publication by Yahav et al. in 2007, two separate independent groups have expressed viewpoints and reflections
to the published data in medical journals. A summary of these and the response to one of them by Yahav et al. are
provided below.
In another publication, Nguyen TD and colleagues7, selectively discussed 5 studies as possible confounding variables of
the meta-analysis performed by Yahav et al. In the meta-analysis, the 5 studies which demonstrated a notable difference
in the all-cause mortality rate in the subcategories “cefepime vs. piperacillin-tazobactam” and “neutropenic fever” were
the following: Bow et al., 2006; Sanz et al.,.2002 ; Gomez et al., 2001; Chandrasekar and Arnow, 2000; and Biron et al.,
1998. According to the authors, including or excluding the above-mentioned studies should affect the results of the
meta-analysis performed by Yahav et al. In their review of the method of the meta-analysis (e.g., the method of data
collection), Nguyen and colleagues raised questions about Yahav et al.’s conclusions, and called for additional review of
the clinical data before any effort is made to limit or eliminate cefepime from the current practice guidelines8.
P-RMS assessment and conclusion:
The literature data reported by MAH, concerning the studies published by Nguyen TD and Towne are in line with the results of FDA own data revision ( including their meta-analyses with 88 RCT that included the 38 trials of the Yahav meta-analysis) and also their revision at patients level . The FDA meta-analysis done at trials level included data on 88 clinical trials , that involved 9,467 cefepime exposed patients and 8,288 patients exposed to other comparators. At this leval no statistical difference was found concerning the all cause mortality at 30 days post-therapy – cefepime 5.98% and the compartors with 5.26% with an adjusted risk difference of - 2,83 per 1000 population (95% CI : -11,47, 5.80). At patient level, the meta-analysis included 35 clinical trials and the all cause mortality at 30 days post-therapy were 5,63% vs 5,68% for cepefime and compartors respectively with an adjusted risk difference of = 4.83 per 1000 population (95% C.I. : -4,72, 14,38). No statistical difference was demonstrated. The analysis at patient level of neutropenia trials did not also shown any statistical difference between cefepime and their comparators.
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Taking in account the comments of Yahav concerning Towve article and also the Nguyen conclusions and finally the conclusions of FDA, there is still a need to better understand this issue and a need to perform adiotional posmarketing studies of mortality associated with the use of cepefime. Namely the studies already proposed by FDA and also the need to developed similar in the European context that as we known is somewhat different from United States of America.
Patient treated for the indication of skin and skin structure infections: According the FDA’s report, overall, there was not a statistically significant difference in 30-day mortality for patients treated with cefepime versus comparator agents in the analysis of 30-day mortality stratified by study drug and treatment indication. Aside from the skin structure infection indication [which contained a relatively small number of patients and deaths (6 deaths for cefepime versus 0 for comparators)], the analysis did not demonstrate a statistically significant difference in 30-day mortality for cefepime versus comparator agents for any of the other treatment indications analyzed. These data are not confirmed by the analysis conducted by BMS using the Solucient’s Hospital Drug Utilization Database (HDUD). For more details please see the response to the question 2.
Patients with baseline pathogens resistant to study therapy: On page 199 of FDA’s report, the M.O. commented that the data presented in Table 22 as follows: overall, the number of patients with resistant pathogens at baseline who subsequently died was small. Regarding specific pathogens isolated at baseline in more than one patient in either study arm in this subset, more cefepime patients died post isolation of the following organisms versus comparator patients: Enterococcus sp. [cefepime: 9.0% (7/78) vs. comparator 3.2% (2/62)], S. aureus [cefepime: 28.6% (4/14) vs. comparator 8.0% (2/25)], S. epidermidis [cefepime: 15.4% (2/13) vs. Comparator 11.8% (2/17)], and P. aeruginosa [cefepime:
9.5% (2/21) vs. comparator 0% (0/15)]. The M.O. noted that cefepime is not typically used for treatment of infections due to Enterococcus sp. or S. epidermidis. More control patients
died post isolation of the following organisms versus cefepime patients: K. pneumoniae [cefepime: 0% (0/1) vs. comparator 33.3% (2/6)]. BMS cannot identify these data regarding specific pathogens isolated at baseline in Table 22. Mortality Status Stratified by Pathogen and Treatment Arm for 423 Patients with a “Resistant Pathogen at Baseline” (pages 198 and 199). In addition, BMS reviewed the comments from the M.O. on CRFs of the 40 patients reported by BMS as having at least one baseline pathogen resistant to study therapy and who died within 30 days post study therapy (pages 201-215). Among these 40 patients, 16 were receiving cefepime and 15 were receiving therapy with cefepime in combination with amikacin (14 patients) or vancomycin (1 patient). From 16 CRFs with patients treated only with cefepime, there are no reports in which the M.O. considered cefepime treatment failure as cause of the patient’s death.
Patients with febrile neutropenia with solid tumor at baseline: According to the FDA’s reports, overall, the analysis by malignancy type did not demonstrate a statistically significant difference in 30-day mortality between cefepime and comparator regimens. However, among the subset of patients with a solid tumor at baseline, 30-day mortality was higher among the cefepime patients. The level of confidence in this result is low given that the total number of patients who had a solid tumor was very small. These data are not confirmed by the analysis conducted by BMS using the Solucient’s Hospital Drug Utilization Database (HDUD). For more details please see the response to the question 2.
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QUESTION 2 MAH should present comments on the benefit –risk of the following indication: - Empiric therapy for febrile neutropenic patients - Skin and skin structure infections
MAH response: Since 2007, in order to further evaluate the findings described by Yahav et al., Bristol- Myers Squibb (BMS) diligently
worked with the FDA and key expert medical opinion leaders and conducted an internal meta-analysis of BMS sponsored
clinical trials. This internal meta-analysis aimed to explore the relationship between cefepime treatment and all-cause
mortality using data from 40 controlled randomized trials supported by BMS, utilizing patient-level data to explore the
role of potential prognostic factors, i.e. Baseline Patient Characteristics, Therapy Administration, and Post-baseline
Patient Factors. The result of this meta-analysis did not support the conclusions drawn by Yahav. The all cause mortality
rate observed for febrile neutropenia for the cefepime group was not statistically different from that of the comparator
group.
Additional work conducted by BMS using the Solucient’s Hospital Drug Utilization Database (HDUD) provided further
insights into the existing knowledge of patient experience on cefepime. The results from this study indicated no statistical
significant difference in the risk of all cause mortality between febrile neutropenia patients undergoing treatment with
cefepime and those undergoing treatment with ceftazidime [RR(95%CI): 1.12 (0.94, 1.34) or other parenteral antibiotics
(RR(95%CI): 0.90 (0.71,1.11)].
Results from the secondary analysis indicated no increased risk of cefepime when compared to ceftazidime or parenteral
antibiotics among patients treated for urinary tract infections, intra abdominal infections, complicated and uncomplicated
skin, septicemia, and other unspecified infections. Among patients with a diagnostic code for pneumonia, the risk of
cefepime was small but significant when compared to ceftazidime or other parenteral antibiotics. The risk versus other
combined cephalosporins was consistently higher for cefepime for all the different subgroups.
This study also used the number of drug administrations during the hospital stay as a proxy to study the relationship
between the risk of mortality and the cefepime administration, see Appendix I for results. Overall the analyses
consistently showed the the lack of a statistical significant association between the number of cefepime administration
and the risk of all cause mortality. These analyses were consistent among all the subgroups studied and comparisons to
cefepime.
The results of this observational study further supports the pooled analyses conducted by BMS and the FDA and do not
suggest any changes to the benefit risk profile of cefepime. The data presented in this report do not suggest an increase in
the all-cause mortality among patients undergoing treatment with cefepime for febrile neutropenia. The fact that this
finding was based on a comprehensive definition of febrile neutropenia; it was consistent regardless of statistical method
used; and was based on relatively good statistical power (~80%) provides reassurance around the benefit risk profile of
cefepime for the treatment of febrile neutropenia. The analyses also showed the risk of all-cause mortality did not
increase with elevations in the number of administrations of cefepime, potentially negating a dose response relationship
between increased cefepime dosage and mortality. This lack of a statistical difference between cefepime and ceftazidime;
and other parenteral antibiotics was replicated among patients with urinary tract infections, complicated and
uncomplicated skin infections, septicemia, intra abdominal infections and other unspecified infections. This further
supports the results from the pooled analyses conducted by BMS.
According to the integrated safety summary of clinical studies included in the original Marketing Authorization
Application for the indications of lower respiratory tract infections, urinary tract infections, skin/skin structure infections,
gynecological infections and septicemia, the frequency of death for cefepime was 5.5% (148/2707) versus 5.4%
(112/1842) for all comparators. When compared to ceftazidime, the frequency of death for cefepime was 5.4%
(110/2032) and 5.8% (85/1456) for ceftazidime. In noncomparative clinical trials the frequency of death for cefepime was
6% (98/1712). For the febrile neutropenia indication, all-cause mortality for cefepime was 8% (58/716) vs. 6% (35/582)
for all comparators. Primary infection was the cause of death in 1.7% (12/716) of cefepime- and 2.4% (14/582) of
comparator treated patients
BMS had proposed labeling changes to supplement the indication "empirical treatment of fever in patients with
neutropenia" with the statement that antimicrobial monotherapy may not be appropriate for patients with febrile
neutropenia at high risk for severe infections and that insufficient data exist to support the efficacy of cefepime
monotherapy in such patients.
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The results of the meta-analysis conducted by BMS on 40 controlled randomized trials and of the Hospital based
retrospective cohort study do not suggest any changes to the benefit risk profile of cefepime. BMS also recognizes the
importance of appropriate use of the product hence the proposed the labelling changes and potential future proposals
regarding dosage recommendation.
P-RMS assessment and conclusion: We agree that the results of the FDA evalution ( revision of individual case reports; the signal evaluation and also his own meta-analysis) associated with the results of the meta-analysis done by BMS and also the Solucient´s Hospital Drug Utilization confirms that the all cause mortality rate between cefepime and other comparators is similar, but we also agree that there is a need to reinforce the information to health professionals concerning the use of cefepime namely in patients with febrile neutropenia, and in that it is advisable note to use it in monotherapy.
QUESTION 3 The MAH is also requested to comment if the frequency of pseudomembranous colitis, in chapter 4.8, is correct, since being less frequent labelled for other antibiotics.
MAH response: The frequency of pseudomembranous colitis is estimated during the evaluation of the drug in Multiple - Dose Dosing
Regimens Clinical Trials conducted in North America. In all dosage groups (low, high) the incidence of this events was
less than 1%9.
P-RMS assessment and conclusion: The reference done by MAH is relate with it´s own information does not gives refrences to epidemiological studies or other published studies that can confirm this information. So MAH must support it´s information on adequate reference studies related with the incidence of pseudomenbranous colitis in patients exposed to cefepime and to other antibiotics.
QUESTION 4a
In Chapter 4.4 – Special warnings and precautions for use – reword is proposed in order to be more concise. Patients with decreased renal function In patients with impaired renal function, such as reduction of urinary output because of renal insufficiency (creatinine
clearance ≤ 50 mL/min) or other conditions that may compromise renal function, the dosage of Maxipime cefepime
should be adjusted to compensate for the slower rate of renal elimination. Because high and prolonged serum antibiotic
concentrations can occur from usual dosages in patients with renal insufficiency or other conditions that may compromise
renal function, the maintenance dosage should be reduced when cefepime is administered to such patients. Continued
dosage should be determined by degree of renal impairment, severity of infection, and susceptibility of the causative
organisms (see sections 4.2 - Posology and method of administration and 5.2 - Pharmacokinetic properties).
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During postmarketing surveillance, the following serious adverse events have been reported: reversible encephalopathy
(disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, seizures (including
nonconvulsive status epilepticus), and/or renal failure (see section 4.8 - Undesirable effects). Most cases occurred in
patients with renal impairment who received doses of Maxipime that exceeded recommendations.
In general, symptoms of neurotoxicity resolved after discontinuation of cefepime and/or after hemodialysis, however,
some cases included a fatal outcome.
Patients should be instructed to contact their physician at once of any neurological signs and symptoms including
encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus and
seizures for immediate treatment, dosage adjustment, or discontinuation of cefepime.
MAH response:
- BMS does not agree with the proposed revisions to this section of the CSP that is mandatory (essential) text in the
CCDS, which must be included in local labeling (in substance), although, not necessarily verbatim.
- Regarding the new proposed text on the patient’s instruction for neurological signs and symptoms of encephalopathy,
this text is more appropriate for Package Leaflet (PIL) than for CSP. BMS considers that, adverse events of neurological
signs and symptoms are sufficiently documented in the proposed CSP for cefepime (sections 4.4 Special warnings and
precautions for use, 4.8 Undesirable effects and 4.9 Overdose) to provide clinically significant information to the
prescribing healthcare professional.
Therefore, BMS does not agree with the addition of the new proposed text to the section 4.4 of proposed CSP for
cefepime.
P-RMS assessment and conclusion:
We don´t support the position of MAH, the reported cases that we have done during this assessement have enough concerns related these adverse events. We full support our position concerning a reinforcement of the information to the health professinonals and to the patients but a restriction on use of cepefipime in elderly patients with renal impairment, taking in account all the collected information that we had revised related with the reported period (proposed changes to section 4.3; and to section 4.4 geriartric use ).
QUESTION 4b
To change the subheading that states “Special precautions of use” to “Hypersensitivity reactions”
MAH response:
As the subheading “Special precautions of use” is not limited only to the hypersensitivity precautions (see proposed
CSP), the BMS does not agree to change this subheading to “Hypersensitivity reactions”.
P-RMS assessment and conclusion:
We agree with MAH
QUESTION 4c
In chapter 4.6 – add the underlined text.
cefepime 47/58 draft FAR PT/H/PSUR/0008/001
Pregnancy Reproductive studies in mice, rats, and rabbits showed no evidence of foetal damage, however there are no adequate and well-controlled studies in pregnant women. Cefepime passes the placental barrier. Because animal reproduction studies (see section 5.3) are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. And Nursing Mothers Cefepime is excreted in human breast milk in very low concentrations. Caution should be used when cefepime is administered to a nursing woman due to possible sensitisation and negative impact on the gut flora of the infants.
MAH response:
Two comprehensive literature searches were performed internally by the BMS investigating 1) In-Utero Cefepime
Exposure and 2) Breast-Milk Neonatal Cefepime Exposure.
1. In-Utero Cefepime Exposure
Background and Introduction: Reproductive studies in animals showed no evidence of fetal damage by in-utero cefepime exposure; however there are no
adequate and wellcontrolled studies in pregnant women. Against this background the BMS aimed to evaluate evidence in
support of cefepime crossing the placental barrier.
Methods:
A systemic search of PubMed was conducted with multiple combinations of the key terms, “cefepime”, “placenta” and
“fetal exposure”. The search period ranged from 1990 through 2010.
Results: There appeared a paucity of studies evaluating the possibility of cefepime crossing of the placental barrier. BMS
did not identify any article directly addressing inutero cefepime exposure in humans. Below one animal study is reported.
Shuich Kai and colleagues (1992) administered cefepime dihydrochloride to female rats during pregnancy for 14 days.
Their findings suggested that cefepime did not affect prenatal fetal development, and there was no effect on the
reproductive performance of the animals10.
Conclusion: This review suggested that no human studies of pregnancy outcomes after exposure to cefepime have been
published and there are no studies investigating whether cefepime crosses the human placental barrier. The study by
Shuich Kai et al. did not reveal any fetal toxicity by cefepime10.
2. Breast-Milk Neonatal Cefepime Exposure
Background and Introduction: Because cefepime passes into breast milk, there is a possibility of sensitization and
negative impact on the gut flora of the neonate. Against this background BMS conducted a literature review to evaluate
pertinent evidence in this area.
Objective: To find evidence in support of neonatal sensitization by breast-milk cefepime exposure.
Methods: A systemic search of PubMed was conducted with multiple combinations of the key terms, “cefepime”,
“lactation” and “neonate”. The search period ranged from 1990 through 2010.
Results: BMS did not identify any article directly addressing neonatal breast milk exposure to cefepime. One animal
study was identified and described below. Shuich Kai and co-workers (1992) administered cefepime to female rats during
the premating, mating, gestation, and lactation periods. They found that cefepime did not affect postnatal development of
the animals10.
Conclusion: This review suggested that there are no studies investigating neonatal breast-milk exposure to cefepime. The
study by Shuich Kai et al. did not reveal any neonatal toxicity by breast milk exposure to cefepime10.
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P-RMS assessment and conclusion:
We agree with MAH there is no evidence to support these proposals.
QUESTION 4d
Chapter 4.7. - add the underlined text.
Effects on ability to drive and use machines The effects of medicinal product on ability to drive and use machines have not been studied. However, possible adverse reactions like altered state of consciousness, dizziness, confusional state or hallucinations may alter the ability to drive and use machines.
MAH response:
BMS agrees to add the above mentioned text to the section 4.7 Effects on ability to drive and use machines with cross
referencing to the sections 4.4, 4.8 and 4.9 as follows: However, possible adverse reactions like altered state of
consciousness, dizziness, confusional state or hallucinations may alter the ability to drive and use machines (sections 4.4
Special warnings and precautions for use, 4.8 Undesirable effects and 4.9 Overdose).
P-RMS assessment and conclusion:
MAH agreed on our proposal.
QUESTION 4e
Chapter 4.8. - include the following adverse reactions Allergic reaction instead of anaphylactic reaction Tinnitus (rare) Arthralgia (rare) Oedema (rare)
MAH response: Tinnitus A comprehensive, cumulative search of the Bristol-Myers Squibb Company (BMS) safety database, CARES 2.07 was
performed. All reports were received by BMS from worldwide sources during the post marketing experience with
cefepime from the period covering cumulatively from 04 August 1984 to 02 April 2010.
During the reporting period, a total of 2 serious, spontaneous reports were received. The causality assessment done by the
reporting physician was not related and unknown. In one case other alternative explanation could be related with the
event, and in the other case a causal relationship with cefepime cannot be excluded altough other sk factors could also
explain the adverse events.
An extensive literature review was done by MAH concerning cefepime and tinnitus and in any of these published
revisions was found aor supposed na causal relation with tinnitus.
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Arthralgia During the reporting period, a total of 2 serious, spontaneous reports were received. One report was considered likely
related with cefepime exposition and another unknown. In one there´s a scarce information to do a causality assessement
andd in another case there was an anaphylactic shock related with cefepime.
An extensive literature review was done by MAH concerning cefepime and tinnitus and in any of these published
revisions was found aor supposed na causal relation with tinnitus.
Oedema
During the reporting period, a total of 12 reports (8 serious and 4 non serious) were received which included cefepime as
a suspect or interacting drug and met the criteria for inclusion in this report.
In two cases there´s a negative temporal relationship.
In eigth cases the oedema is related with a clinical context of anaphylactic shock.
In two cases oedema a causal relationship can not ruled out altough other risk factors could also explain the events.
MAH does not support the change of CSP they justify their position on the fact that, the reports of oedema described
above occurred in the context of anaphylactic reaction and anaphylactic shock that are already labeled. Addition of the
events of oedema therefore would not provide additional clinically significant information to the prescribing healthcare
professional.
P-RMS assessment and conclusion:
In what concrens tinnitus and artralgia we agree with MAH. Concerning Oedema the number of the cases, the seriousness and the clinical significance of oedema will represent a need to include this adverse event in chpater 4.8.
QUESTION 4f
Chapter 4.8 –the table format should be changed to display each frequency in a separate column since only this format enables a true two dimensional overview. Additionally the footnotes should be formatted correctly.
MAH response:
The September 2009 version of "A Guideline on Summary of Product Characteristics"16 does not prescribe an exact
format for the undesirable effects table, only the required elements. BMS has presented the table in the CCDSs and
SmPCs according to the format as shown in the proposed CSP and, for consistency, the BMS would like to maintain that
format. It presents exactly the same information. In addition, it can be debated whether the proposed revision to the table,
as presented in the preliminary assessment report, is easier to view.
P-RMS assessment and conclusion:
We agree with MAH
QUESTION 4g
Throughout the text, the MAH is requested to change the product's brand name and replace it with the active substance
MAH response:
MAH agrees to change the product's brand name and replace it with the active substance in the proposed CSP.
P-RMS assessment and conclusion: MAH agreed on our proposal.
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QUESTION 5 The following information is proposed to include in PIL
Patients should be instructed to contact their physician at once of any neurological signs and symptoms including encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus and seizures for immediate treatment, dosage adjustment, or discontinuation of cefepime.
MAH response:
BMS agrees to include text in the Patient Leaflet to address these potential side effects.
The text will be included in Section 4 of the leaflet. An example of the text follows:
Tell your doctor straight away if:
You have unexplained mental symptoms such as feeling confused and seeing or hearing
things that are not there (hallucinations). This could be a serious but very rare condition
called encephalopathy.
You have fits (convulsions).
P-RMS assessment and conclusion: M AH agreed on our proposal.
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FINAL CONCLUSION (SUMMARY OF A-F) 1. The literature data reported by MAH, concerning the studies published by Nguyen TD and Towne are in line with the results of FDA own data revision ( including their meta-analyses with 88 RCT that included the 38 trials of the Yahav meta-analysis) and also their revision at patients level . The FDA meta-analysis done at trials level included data on 88 clinical trials, that involved 9,467 cefepime exposed patients and 8,288 patients exposed to other comparators. At this level no statistical difference was found concerning the all cause mortality at 30 days post-therapy – cefepime 5.98% and the comparators with 5.26% with an adjusted risk difference of - 2,83 per 1000 population (95% CI : -11,47, 5.80). At patient level, the meta-analysis included 35 clinical trials and the all cause mortality at 30 days post-therapy were 5,63% vs. 5,68% for cefepime and comparators respectively with an adjusted risk difference of = 4.83 per 1000 population (95% C.I. : -4,72, 14,38). No statistical difference was demonstrated. The analysis at patient level of neutropenia trials did not also shown any statistical difference between cefepime and their comparators. Taking in account the comments of Yahav concerning Towve article and also the Nguyen conclusions and finally the conclusions of FDA, there is still a need to better understand this issue and a need to perform additional posmarketing studies of mortality associated with the use of cefepime. Namely the studies already proposed by FDA and also the need to develop similar in the European context that as we known is somewhat different from United States of America.
2. We agree that the results of the FDA evalution (revision of individual case reports; the signal evaluation and also his own meta-analysis) associated with the results of the meta-analysis done by BMS and also the Solucient´s Hospital Drug Utilization confirms that the all cause mortality rate between cefepime and other comparators is similar, but we also agree that there is a need to reinforce the information to health professionals concerning the use of cefepime namely in patients with febrile neutropenia, and in that it is advisable note to use it in monotherapy.
3. The reference done by MAH is relate with its own information does not gives references to epidemiological studies or other published studies that can confirm this information. So MAH must support its information on adequate reference studies related with the incidence of pseudomenbranous colitis in patients exposed to cefepime and to other antibiotics.
4. We don´t support the position of MAH, the reported cases that we have done during this assessement have enough concerns related these adverse events. We full support our position concerning a reinforcement of the information to the health professinonals and to the patients but a restriction on use of cepefipime in elderly patients with renal impairment, taking in account all the collected information that we had revised related with the reported period ( propose changes to section 4.3; and to section 4.4 geriartric use ).
5. In what concrens tinnitus and artralgia we agree with MAH. Concerning Oedema the number of the cases, the seriousness and the clinical significance of oedema will represent a need to include this adverse event in chpater 4.8.
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DATE AND CONCLUSION OF PHVWP DISCUSSION CONCERNING THIS PSUR, IF ANY:
In 2007 Yahav et al published a meta-analysis on the efficacy and safety of cefepime. This issue was
brought to the attention of the PhVWP by Germany in January 2008. The results from this systematic
review of randomised trials that compared cefepime with another beta-lactam antibiotic, alone or with
the addition of a non-beta-lactam antibiotic to both study groups showed that the all-cause mortality-the
primary outcome-was higher with cefepime than other beta-lactams (RR 1.26 [95% CI 1.08-1.49]).
Baseline risk factors for mortality were similar. No significant differences between groups in treatment
failure, super infection or adverse events were found. The PhVWP was of the opinion that this signal
should be further investigated in the context of the PSUR worksharing exercise with PT acting as PRMS
for this substance.
The PSUR Worksharing procedure for cefepime started on 14 October 2009 and the draft FAR was
circulated on 8 February 2011.
Following this assessment, the P-RMS proposed to include a new contraindication in the Core Safety
Profile (CSP) for this substance: use of cefepime in elderly patients with renal impairment. In line with
the Best Practice Guide for PSUR Worksharing, this subject was referred to the PhVWP for discussion.
On March 2011 PhVWP meeting, PT concluded that there was not strong body of evidence that supports
the existence of a higher risk of all cause mortality for cefepime vs. other antibiotics. However it was
noted that cefepime is used in empiric therapy for febrile neutropenic patients and most of the all-cause
mortality data focused on patients with an indication for febrile neutropenia. Hence, for precautionary
reasons PT stated that there was a need to reinforce the information to HCPs that use of cefepime
monotherapy in patients with febrile neutropenia at risk of severe infections might not be appropriate.
The PhVWP agreed that there was not sufficient body of evidence supporting a higher risk of all cause
mortality for cefepime vs. other antibiotics and considered that additional data from the MAH are
required, in relation to elderly population and ADR stratification according to the risk of renal chronic
failure would be useful. The PhVWP also recommended investigating efficacy/clinical failure, PK/PD in
compromised population with the Company and liaising with FDA. The PhVWP suggested that PT should
further assess these issues and present a report for adoption.
The attached report summarizes the analysis that was performed by a national group of experts on the
on association of cefepime with increased all-cause mortality compared to other β–lactam antibacterials,
and the proposed measures.
The data sources included in the analysis were meta-analysis of all-cause mortality of cefepime
compared to other antibiotics, the original research papers that were included in the meta-analysis,
comments published on the meta-analysis and the FDA requested study on the risk of all-cause mortality
among hospitalized patients treated with cefepime, ceftazidime, other cephalosporins or other parenteral
antibiotics in the United States.
In summary,
1. The MAH observational study using the HDUD database shows a higher risk for cefepime
compared to other cephalosporins. However residual confounding due to unrecorded/unobserved
variables is likely to be present.
2. There were several limitations to the Yahav et al study that favoured a risk for cefepime, which need
to be taken into account.
3. The meta-analysis performed by Kim et al, does not support a higher risk for all-cause mortality for
cefepime vs other antibiotics. This is highly relevant as the Kim et al meta-analysis included patient
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level data for 39 trials, which none of the previous studies collected.
4. No clear mechanism or cause of death is supported by any of the evidence addressed. Clinical
failure could be one reason.
In conclusion, there does not seem to be a sufficiently strong body of evidence that supports the
existence of a higher risk of all cause mortality for cefepime vs. other antibiotics.
Procedural context in which the issue has arisen:
Post-authorisation procedure: PSUR assessment under Work Sharing Procedure
Questions to the PRAC
Does the PRAC agree that there does not seem to be a sufficiently strong body of evidence that
supports the existence of a higher risk of all cause mortality for cefepime vs. other antibiotics?
Does the PRAC consider that additional data are required from the MAH on this issue?
Does the PRAC consider that the reinforcing the information to health professionals on the risk of
using monotherapy cefepime in febrile neutropenic patients is useful?
Does the PRAC see the need to further communicate these recommendations beyond the update
of the SmPC?
Discussion
In the light of the currently available data, PRAC does not consider there is a sufficiently strong body of
evidence that supports the existence of a higher risk of all cause mortality for cefepime vs. other
antibiotics. However, the committee considers this cannot be excluded. The PRAC considered it was too
premature to reinforce the information to health professionals on the risk of using monotherapy
cefepime in febrile neutropenic patients.
It was considered that requesting additional data from the MAH would not add any new data. However it
was proposed to address further questions to the FDA on their investigation to understand the rationale
behind their conclusions. Additionally it was considered appropriate to consult the Infectious Disease
Working Party to obtain their input on the use of monotherapy cefepime in febrile neutropenic patients.
Therefore the PRAC propose the following questions to IDWP and FDA respectively:#
PRAC Questions (adopted in January 2014) to the Infectious Disease Working Party (IDWP) including the IDWP responses
1. Based on PK/PD and clinical grounds and referring to existing therapeutic guidelines (notably EU
guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of
growing resistance. Haematologica 2013; 98 (12)], what is the position of the IDWP on the
adequacy of the use of cefepime monotherapy in patients with febrile neutropenia at high risk
for severe infections?
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IDWP answer
Cefepime has an antibacterial spectrum that includes Enterobacteriaceae, some non-fermenters
(including P. aeruginosa) and some Gram-positive organisms (including MSSA, pneumococci and beta-
haemolytic streptococci). It is not active against MRSA or enterococci. Its utility is affected by acquired
mechanisms of bacterial resistance in normally susceptible species. In particular, it is susceptible to
hydrolysis by many of the ESBLs that have become increasingly common in Gram-negative aerobes. In
contrast, it is a poor inducer of AmpC enzymes and is not a good substrate for these beta-lactamases.
These features are recognised in the publication quoted in the question, in which it is recommended that
the use of cefepime should be guided by knowledge regarding the risk of ESBL-producing pathogens.
Provided that the risk is perceived to be low then the need for combination therapy would mainly apply
when MRSA, enterococcal or pseudomonal infections are suspected.
2. To what extent those considerations also apply to cephalosporins of 3-4 generation, ceftazidime
notably?
IDWP answer
Ceftazidime is regarded as having little or no antibacterial activity against Gram-positive pathogens and
therefore monotherapy would not be appropriate unless there is already some laboratory evidence
available to guide therapy.
Ceftazidime is also susceptible to hydrolysis by many of the ESBLs and, unlike cefepime, it is hydrolysed
by AmpC enzymes.
Therefore the need for combination therapy is perceived to be higher for ceftazidime than for cefepime.
Most other injectable cephalosporins do not have clinically useful activity against non-fermenters and
some that were designed to have improved activity against Gram-negative organisms have lesser
activity against Gram-positive organisms. Generally they are susceptible to hydrolysis by a range of
ESBLs, although their affinity for specific enzymes is variable, and by AmpC enzymes.
3. What is your position on the strength of the signal derived from the literature of a higher risk of
all cause mortality of cefepime versus comparator in the neutropenic fever indication?
IDWP answer
The IDWP is not aware of data that would change the major conclusions drawn by the FDA review.
4. Would the IDWP consider that cefepime monotherapy should not be used in patients with febrile
neutropenia at high risk for severe infections, based on the signal raised?
IDWP answer
No. The IDWP agrees with the measured advice provided in the article quoted in Question 1.
5. To what extent such a recommendation, if drawn, should not be extended to other
cephalosporins?
IDWP answer
As mentioned, the injectable cephalosporins have a range of antibacterial spectra and also differ in their
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activity against normally susceptible species that have acquired various mechanisms of resistance. Many
of them would not even be considered for the management of febrile neutropenia due to perceived
deficiencies.
Hence it is not possible to provide a generic answer to this question; each drug has to be considered
separately.
The SmPCs in the EU should already contain advice to consult official guidance on appropriate use and
the physicians who manage the types of patients who are at risk of febrile neutropenia are especially
likely to be fully aware of national and international guidance. They are also very likely to be acutely
aware of problematic resistant organisms circulating in their institution and catchment areas and to have
a hierarchical approach to drug selection along the lines discussed in the article.
Discussion at PRAC in April 2014
From the FDA and IDWP consultation the PRAC concluded:
• there is no evidence that supports the existence of a higher risk of all cause mortality for
cefepime vs. other antibiotics;
• the SmPCs in the EU already contain advice to consult official guidance on appropriate use and
the physicians who manage the types of patients who are at risk of febrile neutropenia are
especially likely to be fully aware of national and international guidance. They are also very likely
to be acutely aware of problematic resistant organisms circulating in their institution and
catchment areas and to have a hierarchical approach to drug selection along the lines discussed
in the article Haematologica 2013; 98 (12)].
PRAC Advice – April 2014
• PT should conclude the assessment of the PSUR for cefepime, under PSUR synchronisation
scheme - Procedure number PT/H/PSUR/008/001 with the inclusion of the PRAC conclusions as
well as completing a CSP according to the updated information.
PT should also circulate the preliminary AR of the PSUR for cefepime, under PSUR synchronisation
scheme - Procedure number PT/H/PSUR/008/002, covering the period 29-06-2009 to 28-06-2012 taking
into account this PRAC Advice.
This AR fullfills the PRAC´s Advice, therefore, we give this issue as closed.
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Annex I : CSP In PAR: Proposed CSP with assessor comments, if any In Draft FAR: Proposed CSP with proposed comments In FAR: Agreed CSP
cefepime 57/58 draft FAR PT/H/PSUR/0008/001
Annex II:
PATIENT EXPOSURE (one annex for each PSUR of products authorised in the P-RMS)
Patient exposure in this PSUR : The total number of patients exposed during the period referenced above is estimated to be 3,507,948. This is an estimate and should be interpreted with caution, taking into account all of the above mentioned limitations. Methodology used for the exposure number calculation : Defined Daily Dose patients/day number of prescriptions number of doses Other (please specify)
Sales figures were received from IMS Global Services data sources for the period from 01 April 2006
to 31 March 2009, inclusive. No data is yet available for the second quarter of 2009. These figures,
which represent the bulk of BMS worldwide sales, remain an approximation of the total quantity sold,
since IMS does not have access to the total amount distributed in all countries. IMS sales data from
major countries are collected and maintained with the goal of capturing 85-90% of total world sales.
However, data may vary from one reporting period to another because of certain changes in
subscription agreements and the number of data channels available within a given country (i.e. direct to
consumer sales, hospital sales, home care sales, etc.).
Based on the above information, 49,111,273,990 mg were sold during the period referenced above.
The estimated sales and average dose and duration of treatment, based on the prescribing information,
are used to calculate the approximate number of patients treated; however, the dose and duration of
therapy depend on many factors including age (e.g., adult, pediatric), weight, renal function, specific
treatment indication, and the patient’s therapeutic response. Nevertheless, by making the following
assumptions regarding average dosage and duration of treatment, it is possible to arrive at an
approximation of the number of patients treated with cefepime during the period referenced above:
The patient was an adult who received 1000 mg of IV cefepime for the treatment of pneumonia;
The patient received this dose for every 12 hours for 7 days;
For a total dose of 14,000 mg.
The total number of 49,111,273,990 mg sold divided by the number of 14,000 mg each patient received
gives the total number of patients exposed.
49,111,273,990 14,000 = 3,507,948
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Annex III: COMMENTS ON THE PSUR (annex exclusively for innovator MAH)
Is the PSUR in accordance with international guidelines (CIOMS II, Volume 9A ) ? Yes No If not, specify non-conformance with the guidelines
