affidavit -1 - Seniors at Risk

Transcription

Affidavit # 1 of R. Tisdell
Sworn SeptemberLl, 20100F
NO. 080327
VICTORlA REGISTRY
IN THE SUPREME COURT OF BRlTISH COLUMBIA
IN THE MATrER OF THE PATIENTS PROPERTY ACT
RS.B.C. 1996, CHAPTER 349 AND AMENDMENTS THERETO
-ANDIN THE MATTER OF KATHLEEN PALAMAREK, PATIENT
AFFIDAVIT
T, Ronald II. Tisdell of 201 Westbury Lane, in the City of Georgetovm, Williamson
County in the State of Texas, United States of America, MAKE OATH AND SAY as follows:
I.
I am a Toxicologist, the principal of Toxicology Litigation Consultants, Inc. in Texas,
and a Liccnsed Pharmacist in the Province of Alberta, Canada. As such, I have personal
knowledge of the matters to which I depose, except where the same are said to be made on
information and belief, in which case I verily believe them to be true.
2.
A toxicologist is one who studies and treats the effects of drugs and poisons.
3.
1 have more than thirty years of experience as a toxicologist and licensed phannacist and
have acquired the requisite knowledge, training, skill and ability to understand the nature
and effects of drugs and poisons on patients. I have participated in the care and treatment
of poisoned patients and those suffering from the adverse side effects of medication.
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4.
I have participated in the care and treatment of patients who have received antipsychotic
medications, antidepressants, benzodiazepines, antihypertensive medications and others of
the kind and class referred to herein.
5.
I have testified as an expert in Toxicology in Texas, Arkansas, Oklahoma and Nevada
and at a coroner's inquest in Yellowknife, NWT. I have testified in more than 30 civil and
criminal cases in those jurisdictions and have never been disqualified as an expert.
6.
A copy of my curriculum vitae is attached hereto as Exhibit"A".
Documents Reviewed and Information Gathered
7.
I have reviewed medical records ofKathIeen Palamarek dated up until September of
2008. The records reviewed included her medical records while at Saanich Peninsula
Hospital ("SPH"), The Lodge at Broadmead (to September, 2008), and PharmaNet
medication records.
8.
I have reviewed the articles from the peer reviewed scientific literature that are cited in
this affidavit, and attached hereto as Exhibits.
9.
I have reviewed the medication prescribing infonnation and warnings that were available
to physicians, nurses and pharmacists during the initiation and continuance of Mrs.
Palarnarek's treatment at SPH and Broadmead.
10. I have reviewed the Safety Warnings and Recall Bulletins issued by Health Canada and
other anthorities regarding defective and dangerous fentsnyl transderrnal patches, and
increased drug related morbidity and mortality in elderly patients in general, and in those
elderly patients with dementia.
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11. I have examined photographs provided to me by Lois Sampson, offentanyl transdermal
patches that were applied to Mrs. Palamarek's body at Broadmead.
12. I have reviewed the Practice Guidelines for Medication Administration published by the
College of Licensed Practical Nurses of British Columbia They are attached hereto as
Exhibit "B".
13.
I personally met with Mrs. Palamarek and Lois Sampson on March 22, 2009 at The
Lodge at Broadmead to speak with and observe Mrs. Palamarek in her surroundings with
her daughter Lois.
S!UII1!/llTII of Facts and Information
14. Mrs. Palamarek is an 88 year old mother of four living children. She is predeceased by
her husband of 59 years.
15. Prior to entering SPH on November 22, 2006 Mrs. Palamarek lived in her own home with
her son and danghter-in-Iaw.
16. During my visit with Mrs. Palamarek on March 22, 2009 it was evident that Mrs.
Palamarek suffered from a hearing disability. She was unable to communicate at my voice
level. But with the assistance of her daughter Lois, repeating what I had said to her, Mrs.
Palamarek was able to respond and engage in conversation appropriately.
17. Mrs. Palamarek was a pleasant and engaging lady who was fully oriented to person, place
and time. She was not combative argumentative or hostile and showed no evidence of
delusional ideations or hallucinations. She was busy reading the newspaper upon our
arrival. Our visit was limited to one hour. Mrs. Palamarek exhibited mild hand tremors,
nervousness and impaired hearing.
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18. Mrs. Palamarek was admitted to Saanich Peninsula Hospital (SPH) on November 22,
2006 with gastrointestinal bleeding.
19. Following hcr admission to SPH it was discovered that she had also sustained an acute
myocardial infarction.
20. Dr. Koziol's consultation report dated November 22, 2006, a eopy ofwhieh is attached
hereto as Exhibit "COl, identifies the medications Mrs. Palamarek was taking prior to
admission.
21. Dr. Koziol has identified Aspirin and Plavix® as the likely cause of the gastrointestinal
bleeding, and Actonel as a possible cause of esophagitis, and states, "1 have obviously
discontinued her Aspirin and Plavix and ..... would hold some ofher antipsychotics as they
are known to cause cardiovascular dy~fimction. " Dr. Koziol' 8 clinical "Impreasion" is
included in Exhibit "C", attached hereto.
22. The medications prescribed for Mrs. Palamarek prior to her admission to SPH caused or
contributed to her injuries from a fall, gastrointestinal bleeding and cardiovascular
instability, giving rise to her hospitalization on November 22, 2006.
23. Aspirin and Plavix® (clopidogrel) are antiplatelet drugs used in the prophylaxis against
stroke and myocardial infarction. On March 16, 2006 Bhatt, et al. published the results of
their study of 15,603 patients receiving aspirin plus c1opidogrel or aspirin plus placebo.
There was no significant therapeutic benefit from the combination of aspirin and
c\opidogrel over monotherapy with low dose aspirin.
(Reference: Bhatt, D.L., et ai. Clopidogrel and Aspirin versus Aspirin Alone for the
Prevention ofAtherothrombotic Events, N Engl J Med; 354, 2006).
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24. Aspirin and Plavix® when administered together increase the risk and occurrence of
major bleeding.
25. Mrs. Palamarek was taking Aspirin and Plavix® prior to her admission to SPH for
gastrointestinal bleeding.
26. While under the care of Dr. Prowse, Mrs. Palamarek was placed on Reminyl®
(galantamine) on August 26,2005.
27. Galantamine is a cholinergic drug (cholinesterase inhibitor) used in the treatment of
Alzheimer's disease.
28. A study published in the Archives ofInternal Medicine, 2009:169:867-873, a copy of
which is attached as Exhibit "D", reflects the fIndings of a joint Canada and USA stndy
regarding the adverse effects of cholinesterase inhibitors such as galantamine when
administered to elderly patients. Syncopal episodes and accompanying personal injury
(fractures) have been linked to the use of galantamine, in elderly patients with dementia.
29. Hypotension caused by blood loss from gastrointestinal bleeding increased Mrs.
Palamarek's risk of a fall.
30.
Celexa®, Zyprexa®, Reminyl® and Ebixa® are, individually and in combination,
capable of impairing mental and physical faculties that are necessary to avoid falls.
Antipsvchotic Medication
31. Mrs. Palamarek has not been diagnosed as a schizophrenic nor docs she suffer from
manic depressive (bipolar) disease, yet she has received continuous treatment with
antipsychotic medications including Seroquel® and Zyprexa® that are indicated only for
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treatment of schizophrenia and bipolar disease, as evidenced in the the monographs for
Seroquel® (quetiapine) and Zyprexa® (olanzapine) (also referenced by the brand name
Zydis® in the medical record), and attached hereto as Exhibit "E" (Seroquel) and Exhibit
"F" (Zyprexa).
32. Mrs. Palamarek is a member of a class of patients who have been found to be at an
increased risk of death from antipsychotic medication.
33. Schneeweiss et al. performed a retrospective cohort study in British Columbia, Canada
of 37,241 adults 65 years of age or older, who were prescribed conventional (12,882) or
atypical (24,359) antipsychotic medications for any reason between January 1996 and
December 2004. 'The investigators compared the l80-day all cause mortality with use of a
conventional antipsychotic versus an atypical antipsychotic. They found that the risk of
death in the group of patients treated with conventional antipsychotic medications was
comparable to, or possibly greater than, the risk of death in the group of patients treated
with atypical antipsychotic medications. The causes of death with the highest relative risk
were cancer and cardiac disease. (Reference: Schneeweiss, et a1. Risk ofdeath associated
with the use ofconventional versus atypical antipsychotic drugs among elderly patients.
CMAJ. 2007; 176:627-632.)
34. Geriatric patients receiving antipsychotic drugs for dementias are at a very high risk of
death (approximately double) when compared to patients who do not receive antipsychotic
medications. Although the precise reason for this phenomenon is unknown, the results
have been epidemiologically studied and proven to the satisfaction of Health Canada and
the Food and Drug Administration, resulting in the warning incorporated in Exhibit "G".
35. In April 2005, the Food and Drug Administration (FDA) informed healthcare
professionals and the public about the increased risk of death in elderly patients receiving
atypical antipsychotic drugs to treat dementia-related psychosis (April 2005 Public Health
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Achisory and Informationfor Healthcare Profossionals). At that time, the analyses of 17
placebo controlled trials that enrolled 5377 elderly patients with dementia-related
behavioral disorders revealed a risk of death in the drug-treated patients of between 1.6 to
1.7 times that seen in plaeebo-treated patients.
36. Gill, et al. perfonned a retrospective cohort study in Ontario, Canada of27,259 adults, 66
years of age or older, with a diagnosis of dementia between April 1997 and March 2002.
The investigators compared the risk for death with use of an atypical antipsychotic versus
no antipsychotic and the risk for death with use of a conventional antipsychotic versus an
atypical antipsychotic. They found that atypical antipsychotics were associated with
increased mortality as compared to no antipsychotic use as early as 30 days and persisting
until study end at 180 days. The causes of death were not reported in this study.
(Reforence: Gill SS, et al. Antipsychotic drug use and mortality in older adults with
dementia. Annals of Internal Medicine 146: 775-786. 2007)
37. Zyprexa®, Seroquel® and Risperdal® (risperidone) are arttipsychotic drugs indieated
only for treatment of schizophrenia and manic depressive (bipolar) psychiatric disorders.
Antipsychotic medications are contraindicated in elderly patients with dementia including
Alzheimer's dementia, vascnlar dementia and mixed Alzheimer's and vascular dementia
because these drugs are known to contribute to a 1.6 to 1.7 fold increase in death in these
patients.
38. Mrs. Palamarek's physicians knew, or should have known that their decision to
administer antipsychotic medications to Mrs. Palamarek would significantly increase the
probability of her early death because the warnings are published in peer reviewed medical
and scientific literature and is readily accessible in the prescribing information and
warnings carried in The Compendium ofPhannaceuticals and Specialties (CPS).
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39. Mrs. Palamarek has not been diagnosed as a schizophrenic nor does she suffer from
manic depressive (bipolar) disease, yet she has received continuous treatment with
antipsychotic medications including Seroquel® and Zyprexa® as an outpatient, as a patient
at SPH, and as a resident at The Lodge at Broadmead, with little apparent regard for their
indications and contraindications.
40. On December 18, 2006 at Saanich Peninsula Hospital, Dr. Prowse wrote the following
order. "Quetiapine 25mg t.i.d and may give 25mg q4hjor agitation or aggressive behavior
otherwise unmanageable. "
Translated, this prescription means that Mrs. Palamarek
must be given 25 milligrams of Seroquel® three times daily, and 25 milligrams every 4
hours "as needed" or PRN.
41. Mrs. Palamarek was not previously characterized as an aggressive or unmanageable
patient, and I would respectfully advise the court as a pharmacist, that antipsychotic drugs
have been routinely and for many years used in elder care facilities to "chemically
restrain" elderly patients for the convenience of the staff, and where there is otherwise no
evidence based rationale for their therapeutic usc.
42. Professor David 1. Sackett, et ai, of the NHS Research and Development Centre for
Evidence Based Medicine in Oxford supplies the essential elements of evidence based care
in the following excerpts from his pUblication in the British Medical Journal, attached
hereto as Exhibit "H". He states the following. (Emphasis added)
"Evidence based medicine is the conscientious. explicit. and judicious usc of current
best evidence in making decisions about the care of individual patients."
"The practice of evidence based medicine means integrating individual clinical
expertise with the best available external clinical evidence trom systematic research. By
individual clinical expertise we mean the proficiency and judgment that individual
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clinicians acquire through clinical experience and clinical practice. Increased expertise is
reflected in many ways, but especially in more effective and efficient diagnosis and in the
more thoughtfol identification and compassionate use ofindividual patients'
predicaments, rights, and preferences in making clinical decisions about their care.
"By best available extemai clinical evidence we mean clinically relevant research, ...
especially from patient centered clinical research into the accuracy and precision of
diagnostic tests (including the clinical examination), the power of prognostic markers,
and the efficacy and safety oftherapeutic. rehabilitative, and preventive regimens.
(Reference: Sackett, D.L. et al.; British Medical Journal 312: 71-72, January 13, 1996.)
43. Antipsychotic drugs including Seroquel®, Zyprexa® and Risperdal® produce physically
and emotionally disabling side effects including pseudo Parkinsonism (extrapyramidal
symptoms), akathisia (an unpleasant sensation of "inner restlessness" that manifests as an
inability to remain motionless), endocrine disturbances (hyperglycemia, dyslipidemias and
diabetes mellitus), intense sedation, disordered sleep, and orthostatic hypotension (causing
fall related injuries), somnolence (resulting in disordered cognitive abilities and slip and
fall risks), and dystonic reactions ( sudden loss of muscle tone and control).
44. The medicai records reflect that Mrs. Palamarek has developed hyperglycemia,
extrapyramidal symptoms, declining cognition, hypotension, fall related injuries, disturbed
sleep, abnormal triglyceride levels and unusual dreams. These drug induced problems
have, in my opinion, caused her care providers to "paint a picture" of a debilitated and
declining Kathleen Palamarek who is unable to perform well on subjective and objective
tests of her true cogniti ve abilities.
45. Mrs. Palamarek will continue to appear incompetent in the eyes of her medical team,
legal representative, and respectfully, in the eyes of the Court as long as she is receiving
antipsychotic medications that impair her mental and physical faculties. Antipsychotic
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medications dull mental and physical faculties. If given to a patient with mild dementia,
antipsychotic medications become an aggravating factor of dementia symptotns.
46. Anxiety, agitation, panic attacks, insonmia, irritability, hostility, aggressiveness,
impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been
reported in adults being treated ,vith citalopram. (Reference: British Journal ofPsychiatry,
154, 672-676, 1989.)
47. Citalopram is an antidepressant under the brand name Celexa® administered to Mrs.
Palamarek for depression. Its side effects are probable contributors to perceived behavioral
and cognitive deterioration.
48.
Respectfully, I would advise the Court that a woman who is hearing impaired, drugged
with narcotics and antipsychotic medications, and attempting to cope with adverse drug
reactions and medication induced illnesses cannot reasonably be expected to perform well
during oral or written assessments of her cognitive abilities (e.g. MMSE exam). Mrs.
Palamarek has been repeatedly tested under these conditions.
Fentanyl Transdemwl Pain Management
49. Fentanyl is a synthetic opiate with potency that is sixty to one hundred times greater than
morphine. It is available as a transdermal patch, intended for treatment of chronic
moderate to severe pain that has not responded to continuous treatments with more
traditional opiates such as codeine, morphine, hydrocodone, oxycodone and others.
Patients who have received continual treatment with more traditional opiates are
considered "opiate tolerant'. Those who have not are considered "opiate naive".
50. Opiate naive patients, when treated with the fentanyl transdermal patch, are placed at risk
of death resulting from fentanyl induced respiratory arrest.
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51.
Mrs. Palamarek was "opiate naive" when her doctors started preseribed fentanyl
transdermal patches.
52. The equipotent doses of more traditional opiates required prior to placing a patient on
fentanyl transdermal is found in the document entitled, "Health Canada Endarsed
Important Safety Information on Fentanyl Transdermal Systems ", attached hereto as
Exhibit "P'.
53. There are no indications for 12 mcglhour fentanyl because the same level of analgesia
can be more safely delivered with other opiates with a shorter halflife.
54. Mrs. Palamarek has been treated with a modified fentanyl delivery system in an attempt
to reduce the amount of fentanyl delivered from a 25 mcg/hour patch to 12 to 12,5 mcg per
hour. The lower photograph in Exhibit "K" attached hereto demonstrates the modified
delivery system.
55, The modified delivery system applied to Mrs, Palamarek is not approved, is not safe, and
results in the availability of large amounts of residual fentanyl in every patch that is
removed from her body. The residual narcotic is never accounted for and there are no
safeguards to prevent diversion of this highly sought after narcotic.
56, Fentanyl 12 mcglhr patches are available to supplement the minimum recommended
starting dose of 25 mcglhr in opiate tolerant patients. The 12 mcglhr patches are not
intended for use as a starting dose because the same analgesic effect can be established
using recommended doses of safer opiates.
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57. Exhibit "J" attached hereto contains excerpts from Mrs. Palamarek's record at
Broadmead. It shows that fentanyl patches were missing from her body on at least 9 (nine)
different occasions.
58. On February 6, 2009 at 8:00 PM a Ranbaxy brand of25 mcg/hr fentanyl transdermal
patch was applied to Mrs. Palamarek. A photograph of that patch, taken by Lois Sampson,
is attached as Exhibit "K". The annotations on the photograph are mine.
59. The patch is defective as evidenced by bubbles that have fonned on the adhesive edge of
the patch. The bubbles represent fentanyl that has leaked out of the controlled release
reservoir to an area of direct skin contact due to a defect or cut in the patch.
60. Exhibit "L" is a photograph provided to me by Lois Sampson. It is provided for
comparison to demonstrate the appearance of a normal patch.
61. One year prior to the defective patch being applied to Mrs. Palamarek, Health Canada
issued a voluntary recall on all Ranfentanyl® and Duragesic® brand transdermal
25mcg/hour patches. A copy of the recall is attached as Exhibit "M".
llUltlequate Tracking ofFentanyl Patches
62. Fentanyl transdermal patches prescribed for Mrs. Palamarek were missing on nine
separate occasions as evidenced by the excerpts from the Lodge at Broadmead nursing
notes attached hereto as Exhibit "J".
63. Fentanyl patches are a valued target of narcotic diversion. I have seen no evidence that
The Lodge at Broadmead has ever conducted an investigation to determine the
whereabouts of these missing narcotics, nor is there any evidence that the nurses,
physicians and/or pharmacists ever conducted a medication review to determine whether or
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not these patches were applied to persons for whom they were not prescribed.
64. The missing patches represent a significant potential risk to Mrs. Palamarek and other
residents, and visitors to the Lodge due to their ability to rapidly induce loss of
consciousness and respiratory arrest.
Qualifications ofLPN's to Distinguish Adverse Drug Effects
65. LPN's with minimal understanding of the safe and effective use of drugs or their adverse
effects, have been permitted to exercise significant control over the administration and
monitoring of Mrs. Palamarek's medications, including "as needed" antipsychotic
medications, and to opine as to the causes ofmental status changes and behavioral
changes that are known, and have been shown herein to be adverse events caused by
medication.
66. The documented and contributory adverse side effects of these drugs including sleep
disturbances, confabulation, anxiety, hostility, sadness, apathy and somnolence have been
attributed by nursing staff to be caused by family discord, outings, family visits and other
environmental factors without considering the contribution of the adverse effects of her
medication.
67. A "Fall Risk Assessment" dated December 28, 2006 and attached hereto as Exhibit "N",
is a nursing assessment. Mrs. Palamarek's "Neurologic Diagnosis" is recorded as the
largest contributing mctor to her risk of fulls while her medication is recorded among the
lowest contributing mctors.
68. Mrs. Palarnarek's medications are a major risk factor, and probable cause of her fulls
because they cause dizziness, gait disturbances, somnolence, restless motion, orthostatic
hypotension, cardiovascular instability and disturbances of mental and physical faculties
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that are essential to avoiding hazards when carrying out divided attention tasks. An
example of a divided attention task is one in which a patient searches for her room nwnber
while at the same time maintaining balance, direction and forward motion. Drug impaired
patients who attempt to carry out divided attention tasks are at a high level of risk of
injuries from accidental causes. Divided attention disorders are highly sensitive indicators
of drug impairment and are among the first disorders to develop in patients receiving
psychotropic medication including antipsychotics, narcotics, benzodiazepines and
antidepressants.
69. Medication induced injuries in elder care facilities are prevalent, and elderly patients who
receive mood and mind altering drugs that cause sonmolence, altered perception,
disordered sleep, and other effects discussed herein share the same disability exhibited by
drug impaired drivers. The cause and outcomes are the same.
Hypotensive EvenJ: Caused by Metoprolol andAccupril
70. Metoprolol and accupril are antihypertensive medications that are commonly used to
reduce afterload (arterial pressure against which the heart must contract), in patients with
and without congestive heart failure. Metoprolol is a beta adrenergic blocking agent.
Sudden and abrupt withdrawal of metoprolol is capable of causing undesirable cardiac
events.
71.
The medical records contain specific instructions to the health care staff to hold Mrs.
Palamarek's accupril ifher systolic blood pressure fell to less than 100 mm Hg. I find no
record of orders instructing her nursing staff on the monitoring parameters to be used to
ensure safe and effective metoprolol therapy. It appears that Mrs. Palamarek's health
care providers failed to adequately monitor her blood pressure in a fashion necessary to
determine ifher blood pressure had fallen below 100 mm Hg, or if her heart rate was in
any way compromised by her medications. As a resnlt, her blood pressure was allowed
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to fall to dangerously low pressures on several occasions and she developed marked sinus
bradycardia, a known toxic effect of beta blocking agents that required abrupt
discontinuance of metoprolol.
72.
Mrs. Palamarek's metoprolol was ''held'' on May 25th and abruptly discontinued on May
26'& 2007.
73. Myocardial infarction and ventricular arrhythmias can occur unexpectedly and without
warning following abrupt discontinuation of metoprolol.
74. As a result, Mrs. Palamarek was placed at a higher level of risk for adverse cardiac events
than she would have been with adequate monitoring.
Opinions and Conclusions
75. Mrs. Palamarek's mental and physical faculties are adversely and mmecessarily impaired
by the medication she is receiving. Her baseline competence cannot be truthfully evaluated
while she is receiving psychotropic medications of the kind she has been receiving.
76. Mrs. Palamarek has repeatedly been placed at risk of injury and potentially fatal
consequences because her health care providers including her physicians, pharmacists and
legal representative have ignored prescribing guidelines and warnings that were readily
available to them, which prove that she was at an iocreased risk of morbidity and mortality
from treatment with antipsychotics because of her diagnosis of dementia.
77. Mrs. Palamarek's physicians failed to comply with warnings intended to protect patients
from harm when they prescribed fentanyl transdermal therapy while she was not opiate
tolerant.
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CURRICULUM VITAE
Ronald H. Tisdell
BIOGRAPHICAL:
Mailing Address: 201 Westbury Lane
Georgetown, Texas 78633
Telephone: (254) 760-9721
E-Mail: rtisdell@verizon.net
EDUCATION:
1967 - 1970
University of Alberta
Faculty of Science
B.Sc (Biology)
1971 - 1976
Faculty of Pharmacy
B.Sc (Pharmacy)
1976 - 1978
Clinical Pharmacy
University of Texas
Graduate School of
Biomedical Sciences
Health Science Center at San Antonio
1984 - 1986
South Texas College of Law
Houston, Texas
TEACHING EXPERIENCE:
1996 - 1997
Law
Toxicology Instructor
Scott & White Hospitals
EM S Education Department
1990 - 1992
Clinical Instructor, Drug Information
Canadian Society of Hospital Pharmacy
1988 - 1992
Clinical Instructor
Faculty of Pharmacy
University of Alberta Hospitals
1986 - 1987
Toxicology Seminars for Medical Students
University of Texas Medical Branch
Galveston, Texas
1976 - 1978
Graduate Teaching Assistant
University of Texas Health Sciences Center
San Antonio, Texas
Exhibit "A"
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1974-1976
COMMITTEE ACTIVITIES:
1995 - 1996
Teaching Assistant
B iopharmaceutics
Faculty of Pharmacy and Pharmaceutical Sciences
Scientific Review Committee
American Association of Poison Control Centers
1993 - 1994
Chairman
Pharmacy and Therapeutics Committee
Fort McMurray Regional Hospital
1992
Executive Council Member
Health Sciences Association of Alberta
1992
By Laws and Policies Committee
1992
Finance Committee
1991 - 1992
Alberta Pharmaceutical Association
Committee on Pharmaceutical Technologists
1991 - 1992
Ex-officio Member
Non-Formulary Drug Task Force
1991 - 1992
Task Force on Cardiovascular Drugs
1990 - 1992
Editorial Board
Pharmacotherapeutics Newsletter
Department of Pharmacy
1989
Canadian Society of Hospital Pharmacists
Western Branch
Upjohn Hospital Pharmacy Residency Award Program
1989 - 1992
Management Committee
1989 - 1992
Clinical Committee
University of Albelta Hospitals
18
1989 - 1992
Chairman
Formulary Review Committee
1989 - 1992
Secretary
Antibiotic Subcommittee of Pharmacy &
Therapeutics Committee
1988 - 1989
Chairman
Medication Administration Planning Committee
1988 - 1989
Secretary
Adverse Drug Reaction Committee
1987 - 1988
Alberta Representative
Executive Council
1988
Professional Bargaining Committee
1983
Texas Conference on Disease Prevention & Health
Promotion
Toxic Substances Control Committee: 1990
Objectives
Texas Department of Health
PROFESSIONAL EXPERIENCE:
1997 - Present
Toxicologist
Toxicology Litigation Consultants, Inc
1995 - 1996
Toxicologist
Scott and White Hospital
Temple, Texas
1992 - 1994
Director of Pharmacy
Fort McMurray Regional Hospital
1988 - 1992
Director, Drug Information and
Drug Utilization Review
1987 - 1989
Coordinator, Special Services
19
1978 - 1987
LICENSURE &
CERTIFICATION:
Toxicologist
Texas State Poison Center
University of Texas Medical Branch
Galveston, Texas
Registered Pharmacist
Alberta College of Pharmacists
License Number 2742
Certified Toxicologist
American Association of Poison Control Centers
(1983)
(Recertified 1995)
Certified IAQ Specialist
Texas Tech University (2000)
PROFESSIONAL & SCIENTIFIC SOCIETIES:
1982 - 1997
American Academy of Clinical Toxicologists
1993 - Present
Canadian College of Clinical Pharmacy
1989 - 1992
Alberta Society of Clinical & Forensic Toxicologists
1987 - Present
Canadian Society of Hospital Pharmacists
1979 - Present
Southwestern Association of Toxicologists
1977 - 1987
American Society of Hospital Pharmacists
1976 - Present
Canadian Pharmaceutical Association
1976 - Present
Alberta Pharmaceutical Association
2000- Present
Alberta College of Pharmacists
2007-Present
American College of Forensic Examiners Institute
REFEREE & EDITORIAL ACTIVITIES:
1980 - 1987
Referee, American Journal of Hospital Pharmacy
1985
Reviewer, Toxicology: The Basic Science of Poisons
2nd Edition. Ed. Doun, Klaassen, Amdur. Macmil1an
Publishing Co., Inc. 1980
1996
Poisoning and Toxicology
Lexi-Comp Clinical Reference Library
PUBLICATIONS:
Taylor, G.D., Kibpsey, P., Tisdell, R.H., Blondel-Hi1l, E. Friesen, E., Vaudry, W.
:Containing Cefoxitin Costs Through a Program to Curtail Usage in Surgical
Prophylaxis. Canadian Journal ofInfectious Diseases, 1993: 4(6)
Legatte,D. and Tisdell, R.H. Ethylene Glycol Quantitation: Avoid Propylene Glycol as
an InternatStandard. Clinical Chemistry 1990: 136;54
20
Ellis, E.N., Brouhard, B.H., , Lynch, R.E., Dawson, E.B., Tisdell, R.H., Nichols, N.M., and
Ramirez, F. Studies of the Effects of Hemodialysis and Dimercaprol in Acute Sodium
Dichromate_Poisoning. J. Toxicology: Clinical Toxicology 1982, 19(3): 249-258.
Ells, 1 T., McMartin, K.E., Black, K., Virayotha, Y., Tisdell, R. H. , and Tephly, T. R.
Formaldehyde Poisoning: Rapid Metabolism to Formic Acid. J.A.M.A. 1981,246(11):
1237 - 1238.
Teat, D. W., Stramoski, E. 1., and Tisdell, R. H. Paraquat Intoxication. U.S. Pharmacist
1979,4(5)
Tisdell, R. H., Tricyclic Antidepressant In the Treatment of Intractable Pain. Drugdex
Publications, Micromedex Inc., Denver Colorado. December, 1979
ABSTRACTS & PRESENTATIONS:
Tisdell, R. H., Pharmacological Considerations in Treatment of the Geriatric Patient,
East Central Educators Group. LIoydminster, Alberta. May, 1990
Tisdell, R.H., Drug Therapy in Alzheimers Dementia. Alberta Hospital Association
Teleconference Network. March, 1990.
Tisdell, R. H., Toxicology of Commonly Used Street Drugs. University of Alberta
Hospitals, Emergency Medicine Grand Rounds. October, 1989.
Tisdell, ,R.H., Iacobucci, M.A. and Snodgrass, W.R. Caffeine Poisoning in an Adult:
Survival With a Serum Caffeine Concentration of 400mg/L and Need for Adenosine
Agonist Antidotes. Vet. Human Toxicol1986, 28(5):492
Tisdell, R.H., Quality Improvement and Cost Avoidance Strategies in the Clinical Use
of Omeprazole, A Novel Intragastric pH Modifier. Canadian Society of Hospital
Pharmacists, Western Branch Annual Conference. Banff, Alberta 1991.
Tisdell, R.H., Rational Methods of Antimicrobial Selection Through Drug Utilization
Review Programs. Sponsored through a grant from Lederle Pharmaceuticals, May, 1991.
Tisdell, R.H., Thallium Poisoning in Southeast Texas. Southwest Associan of Toxicologists,
Neurotoxicology Symposium. Dallas, Texas. 1986.
Tisdell, R.H., Efficacy of Hemodialysis and Chelation Therapy in Acute Chromate
Poisoning. Annual Meeting of the American Association of Poison Control Centers, 1983.
Tisdell, R.H., Pharmacokinetic Profile of Formaldehyde and Formic Acid: A Case Report.
Annual Meeting ofthe American Association of Poison Control Centers, 1981.
Richard, lL., Smiley, G.C. Platner, R.D. & Tisdell, R.H., A Case for the Potential for
Aerosol Exposure to Ochratoxin. Annual Meeting of the American Phytopathological
Society. Milwaukee, Wisconsin. July 27,2002.
21
Suite 260 - 3480 Gilmore Way
Burnaby BC V5G 4Y1
Tel: 778.373.3100
Fax: 778.373.3102
College of Licensed Practical Nurses
Toll Free in BC: 1.877.373.2201
Email: info@clpnbc.org
of British Columbia
www.clpnbc.org
Ensuring safe, competent, and ethical nursing practice.
PRACTICE GUIDELINE: MEDICATION ADMINISTRATION
As regulated professionals, individual LPNs undertake only those roles, functions, and activities for which they have
demonstrated the required competencies. The responsibility for determining those competencies rests with the nurse and the
nurse's employer.
Definition: Medication administration is a nursing intervention which involves the preparation, administration, evaluation,
and documentation of ordered medications.
Foundations of Practice
An LPN draws upon knowledge of human biological sciences, pharmacology, and health-promotion and prevention strategies,
while formulating and implementing the nursing care plan, as indicated by:
•
Assessing the appropriateness of the medication for a particular client. For example: reason for medication; and
knowledge of the action, interactions, usual dose, route, client's allergies, sensitivities, and previous adverse
reactions.
•
Understanding the indications and contraindications of the medication; risk(s) involved, including the potential risks
involved in administering the initial dose; and the expected therapeutic outcome(s) of the medication.
•
Understanding the factors that might affect the safety and effectiveness of drug treatment for clients, including: past
health history, current health history, current medications, and lifestyle.
•
Understanding the client's health habits which may impact the effectiveness of medications. Does the client have
drug sensitivities? Is the client involved in treatment of allergies, alternative self-administered medications, alcohol,
street drugs, and/or the use of naturopathic and herbal remedies?
•
Performing the appropriate assessments prior to, and after, the administration of medications.
•
Diligently completing a minimum of three "checks" between the physician's order, the medication administration
record, and medication label; and adhering to the "rights" of medication administration:
1. right
2. right
3. right
4. right
5. right
6. right
7. right
8. right
9. right
10. right
reason
client
medication
dose
route
frequency/time
evaluation
documentation
of the client to be educated when deemed able to participate
of the client to refuse when deemed able to do so
1
Exhibit liB"
22
•
Determining the appropriate dose from an available range dose to achieve a therapeutic effect for the client. An order
change is required if a range dose is unavailable. Record the dose, route, and time on the medication administration
record.
Collaborative Practice
An LPN collaborates with clients, families, and members of the health-care team to promote best client outcomes during
medication administration, as indicated by:
•
Remaining with the client to ensure the medication is consumed or ingested.
•
Monitoring the client for response to the medication during and after administration.
•
Communicating with other members of the health-care team regarding outcomes of medication administration, as
necessary.
•
Contacting the prescriber regarding the need for medication order changes and/or clarification as necessary.
Professional Practice
An LPN maintains standards of professional nursing practice, professional conduct, and safety in the practice setting during
medication administration, as indicated by:
•
Administering medications according to health authority, facility, agency and/or departmental policy. Baseline
competencies permit an LPN to administer medications via routes including oral, rectal, vaginal, intramuscular,
subcutaneous, aural (eardrops), ophthalmic (eye drops), intradermal, topical, nasal, sublingual, inhalation,
nasogastric tube, jejunostomy tube, and gastrostomy tube. An LPN may administer medications via intravenous route
with the appropriate education, as determined by the employer. (*See CLPNBC Peripheral Infusion Therapv Practice
GUideline)
•
Assessing one's own knowledge, skill, and jUdgment to competently carry out medication administration; to use
medication equipment; and to intervene during an adverse reaction.
•
Seeking assistance in response to the recognition of personal limitations in the safe administration of medications.
•
Being aware of agency policies and expectations with regard to independently double-checking high-risk medication
preparations.
•
Withholding the medication and following up with a prescriber in a timely manner in the event that a medication order
is incomplete, unclear, inappropriate, or misunderstood.
Ethical Practice
An LPN understands and adheres to the ethical obligations and requirements of the profession during medication
administration, as indicated by:
•
Demonstrating respect for the right of choice and personal freedoms held by clients and acknowledging that clients
are integral partners in the decision-making process.
•
In the event of a medication error:
o checking the client immediately by assessing all parameters and documenting according to agency
policy.
o assessing for effects of the drug.
o contacting respective practitioners and completing forms according to agency policies.
o monitoring client carefully.
2
23
Exhibit liB"
o critically self-reflecting to prevent future errors.
•
Maintaining the confidentiality and privacy of a client's medication profile.
•
Maintaining a quality practice environment for medication administration where all safeguards are utilized to minimize
and/or eliminate errors.
Legal Practice
An LPN understands and adheres to the legal obligations and requirements of the profession during medication
administration, as indicated by:
•
Administering medications in a manner that enables the LPN to function in compliance with the scope of practice for
LPNs as set out in the Nurses (Licensed Practical) Regulation under the Health Professions Act, and the CLPNBC
Standards of Practice and Code of Ethics.
•
Administering medications as ordered by regulated members of health professions authorized by the employing
agency to prescribe medications.
•
Documenting accurately and recording only medications administered. Medications withheld, omitted, or refused
must be documented with the rationale for the action, such as: medications administered by the client/family while on
pass, or a change in client condition contraindicating administration of the medication.
•
Documenting medication administration and pertinent data immediately following administration. Pertinent data may
include: dose (if there is a range); route (if there is an option); vital signs/blood glucose (if there are parameters);
injection site (as appropriate); exact administration time of STAT and PRN medications; reason and reaction (as
appropriate); and medications held or refused.
Key Strategies/Actions for Ensuring Safe and Competent Practice
On an individual basis, nurses can practise safely by implementing the following strategies:
•
Advocating for systemic changes that improve the safety of medication preparation and administration.
•
Requesting a change in an order for dosages that are expressed in package units or volume.
•
Promoting the use of a zero before the decimal point. Suspect a missed decimal if the dose requires more than three
dosing units.
•
Reviewing the dosage, having another practitioner check the original order, recalculating formulas, and confirming the
dosage with the prescriber, if the dose requires use of multiple dosage units or very small fractions of a dosage unit.
•
Repeating a telephone/verbal order, haVing the medication name and dosage spelled out to avoid sound-alike
confusion, and following up with the prescriber regarding any concerns or questions about the medication.
References
College and Association of Registered Nurses of Alberta. (2005). Medication Administration: Guidelines for Registered
Nurses. Edmonton.
College of Licensed Practical Nurses of British Columbia. (2009). Entry-Level Competencies for Licensed Practical Nurses'
Professional Practice. Burnaby.
College of Licensed Practical Nurses of British Columbia. (2006). Medication Administration (Practice Directive). Burnaby.
3
Exhibit "B"
24
College of Licensed Practical Nurses of British Columbia. (2010). Professional Standards of Practice for Licensed Practical
Nurses. Burnaby.
College of Nurses of Ontario. (2008). Medication (Practice Standard). Toronto.
College of Registered Nurses of British Columbia. (2005). Administration of Medications (Practice Standard). Vancouver.
4
hibit 118"
25
"--/'1.0'
~
Name:
MRN:
ENC#:
VANCOUVER ISLAND
'.'
/
"--,,.
health~
authority
(South Island)
PHN:
Transcription Services
Health Records
r
DaB:
4;,'
Palamarek, Kathleen
05876982
92002471690
15-Jul-1922
9052-095-051
Exhibit ((("
i
,
....
Con· s u i t a t
o n
Document Type: Gastroenterology Consult
Dictated By: Koziol, Kathie Anne Stephanie
Date of Consult: November 22, 2006
Ms. Kathleen Palamarek is an 84 year old widow living at home with her son and daughter-in-law who came
into hospital this morning with complaints of chest tightness, chills, diaphoresis, headache, nausea and
severe low back pain after falling. Her troponin from noon at about 1230 hrs was 0.17 which is obviously
positive and a 12 lead cardiogram shows normal sinus rhythm with a few PVCs and slight ST segment
depression in the inferior and anterior leads. Her hemoglobin was 56.
Her past medical history is as follows:
1. Myocardial infarction in 1996 and other years; she has also had left ventricular ejection fraction done in
1997 which was 25%, normal being over 55%.
2. Hypertension, strokes, hyperlipidemia, carotid stenosis and congestive heart failure.
3. Osteoporosis.
4. Depression and early dementia for which she was seen by Dr. Art Prowse .
5. Remote Hepatitis B.
6. GI bleed in 1987 secondary to Aspirin.
7. Cataract resected in August 2000.
•
MEDICATIONS:
Nitroglycerin patch 0.4 mg on for 12 hours/off for 12 hours, Pravastatin 20 mg hs, Aspirin 81 mg ad, Accupril
20 mg od, Plavix 75 mg od, Actonel 35 mg qweekly, Citalopram 20 mg od, Zyprexa 2.5 rng od, Ebixa
(Memantine) 10 mg po bid, Seroquel25 mg 1600 hrs pm.
This lady used ,to smoke a pack of cigarettes a day but quit in the 1970s and drinks rare alcohol.
She normally says her bowel habit is passing one stool a day which is formed and brown. Over the last
three days, she has had black and tarry stools up to three times a day. She had felt tremendous low back
pain across her kidneys. She has also fallen twice, once a week ago and once last night with a large bruise
over her right hip.
She is not eating well. She has had some nausea but no vomiting. She denies any early satiety. When I
asked her about heartburn, she complained of burning epigastric pain but it was more like a chest tightness
and squeezing across her retrosternal area. She has a little difficulty swallowing. She has lost 10 Ibs over a
month, probably because she has not been eating well she says.
•
Pt.Loc: SPHAC ER-S
Print Date: 27-Nov-2006
Print Time: 14:55
Chart Section: 2
Discharge Date: 22-Nov-2006
26
Page 1 of 2
Name:
MAN:
ENC#:
Palamarek, Kathleen
05876982
92002471690
Exhibit "(II
.-::....
Document Type: Gastroenterology Consult
Dictated By: Koziol, Kathie Anne Stephanie
On examination today, Ms. Palamarek was alert and oriented to time and place. Her blood pressure was
88/67 in the left arm lying. I did not stand her or sit her up. Her heart rate was 82 and slightly irregular. She
had some PVCs. She had pale conjunctiva. Her chest was clear to her bases. Cardiovascular exam
revealed a possible S4 though heart sounds were faint. She had no murmurs. I could not detect a heave or
a thrill and I did not feel that her apex was displaced although I would expect it to be. Abdomen was soft
and obese with epigastric tenderness. She had no enlarged liver or spleen. Rectal exam revealed black
but not melena stool. Evaluation of the extremities revealed tremors in both hands which have been present
for about year and a right buttock bruise.
Laboratory data on admission revealed a white count of 15.1, hemoglobin of 66 and MCV of 96. Her
electrolytes were normal save for her CO2 which was 23. Her urea was 22.4 going along with an upper GI
bleed and her creatinine was 96. Her albumin was low at 32.
.'
IMPRESSION:
This lady present with gastrointestinal bleeding which is likely Aspirin and Plavix induced gastric erosion,
gastric ulcer or duodenal ulcer. She could also have esophagitis caused by the Actonel. She has a fresh
myocardial infarction which is complicated by underlying poor left ventricular function. I obviously am not
able to do a gastroscopy at this time. I have asked Dr. Ray Seigo to see her with regards to her myocardial
infarction. We will transfuse her as appropriate to greater than 100 and watch for congestive heart failure. I
would keep her on clear fluids and a Pantoloc infusion. I have obviously discontinued her Aspirin and Plavix
andwould hold some of her antipsychotics as they are known to cause cardiovascular dysfunction.
THIS DOCUMENT HAS BEEN
DICTATED AND ACCEPTED BY:
"----"
Dr. Kathie Anne Stephanie Koziol
D: 22-NOY-2006 19:31 T: 27-NOY-2006 14:37 JL
26219
cc: Dr. Christopher Michael James
cc: Dr. Miguel Angel Lipka
.'
"--../
27
Page 2 of 2
Arch Intern Med -- Abstract: Sy...
Page 1 of2
Page 1 of2
Exhibit 110"
ALMED C
Online Only
Vol. 169 No.9, May 11, 2009
• Online First Table of
Contents
Original Investigation
• Online Features
Syncope and Its Consequences in Patients With
Dementia Receiving Cholinesterase Inhibitors
This Article
A Population-Based Cohort Study
Sudeep S. Gill, MD, MSc; Geoffrey M. Anderson, MD, PhD; Hadas D. Fischer, MD;
Chaim M. Bell, MD, PhD; Ping Li, PhD; Sharon-Lise T. Normand, PhD;
Paula A. Rochon, MD, MPH
Arch Intern Med. 2009;169(9):867-873.
Background Cholinesterase inhibitors are commonly prescribed to treat dementia,
but their adverse effect profile has received little attention. These drugs can provoke
symptomatic bradycardia and syncope, which may lead to permanent pacemaker
insertion. Drug-induced syncope may also precipitate fall-related injuries, including
hip fracture.
Methods In a population-based cohort study, we investigated the relationship
between cholinesterase inhibitor use and syncope-related outcomes using health care
databases from Ontario, Canada, with accrual from April 1, 2002, to March 31, 2004.
We identified 19 803 community-dwelling older adults with dementia who were
prescribed cholinesterase inhibitors and 61 499 controls who were not.
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Results Hospital visits for syncope were more frequent in people receiving
cholinesterase inhibitors than in controls (31.5 vs 18.6 events per 1000 person-years;
adjusted hazard ratio [HR], 1.76; 95% confidence interval [CI], 1.57-1.98). Other
syncope-related events were also more common among people receiving
cholinesterase inhibitors compared with controls: hospital visits for bradycardia (6.9
vs 4.4 events per 1000 person-years; HR, 1.69; 95% CI, 1.32-2.15), permanent
pacemaker insertion (4.7 vs 3.3 events per 1000 person-years; HR, 1.49; 95% CI,
Social
1.12-2.00), and hip fracture (22.4 vs 19.8 events per 1000 person-years; HR, 1.18;
Bookmarking
95% CI, 1.04-1.34). Results were consistent in additional analyses in which subjects
c .-" ~ ¢l
were either matched on their baseline comorbidity status or matched using propensity
What's thlS 7
scores.
IElI
Conclusions Use of cholinesterase inhibitors is associated with increased rates of syncope, bradycardia,
pacemaker insertion, and hip fracture in older adults with dementia. The risk of these previously
underrecognized serious adverse events must be weighed carefully against the drugs' generally modest
benefits.
Author Affiliations: Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada (Drs Gill,
Anderson, Fischer, Bell, Li, and Rochon); Department of Medicine, Queen's University, Kingston, Ontario
(Dr Gill); Departments of Medicine and Health Policy, Management, and Evaluation, University of Toronto,
Toronto (Drs Anderson, Bell, and Rochon); and Harvard Medical School and Harvard School of Public
Health, Boston, Massachusetts (Dr Normand).
28
http://archinte.ama-assn.orglcgilcontentlshort/16919/867
Tuesday, September 14,2010
Arch Intern Med -- Abstract: Sy...
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RELATED LETTERS
Adverse Events in Patients Receiving Cholinesterase Inhibitors Due to Dissimilar Follow-up
Periods
Mark Chan
Arch Intern Med. 2009;169(18):1724.
EXTRACT
I
FULL TEXT
Periods- Reply
Sudeep S. Gill, Chaim M. Bell, and Paula A. Rochon
Arch Intern Med. 2009;169(18):1724-1725.
EXTRACT
I
FULL TEXT
RELATED ARTICLE
In This Issue of Archives of Internal Medicine
Arch Intern Med. 2009;169(9):827.
FULL TEXT
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Roman et al.
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ABSTRACT
I
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Cautionary Tales in the Interpretation of Clinical Studies Involving Older Persons
Scott and Guyatt
Arch Intern Med 2010;170:587-595.
ABSTRACT
I
FULL TEXT
Periods
Chan
Arch Intern Med 2009;169:1724-1724.
FULL TEXT
Periods--Reply
Gill et al.
Arch Intern Med 2009;169:1724-1725.
FULL TEXT
Exhibit liD"
HOME
I CURRENT ISSUE I
PAST ISSUES
I TOPIC
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I
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I CONTACT US I SITE MAP
HELP
PRIVACY POLICY
© 2009 American Medical Association. All Rights Reserved.
29
http://archinte.ama-assn.org/cgi/content/short/169/9/867
Tuesday, September 14,2010
May 20. 009 - Cholinesterase inhibitors are associated with pre',10usly underrecognized serious ad erse events
in older adults with dementia. which must be carefull balanced against the generall l modest benefits of these
drugs, according to the results of a population-based cohort study reported in the Il'lay 11 issue of the rcl1l'les 0'
In'e nal MediCine
'Cholinesterase inhibitors are cOll1monlJ~ prescribed to treat dementia. but their ad' erse effect profile has received
little attention" write udee S Gill, 1'.1 ,M c from the Institute for Clinical Evaluative Sciences in Toronto,
Ontario, Canada, and colleagues. 'These drugs can pro oke sy'mptomatic bradycardia and Sl ncope which may
lead to permanent pacemaker insertion, Drug-induced s ncope ma' also precipitate fall-related injuries. including
hip fracture"
To e' aluate the association between use of cholinest rase i h' ito sand Sl' co e- e ate
ute
the
investigators used healthcare databases from Ontario. Canada. '",ith enrollment from April 1. 2002, to March 31.
2004 The study cohort consisted of 19,803 community-dwelling older adults with dementia 'Nho were prescribed
cholinesterase inhibitors and 61 499 control subjects who were not using these medications
Compared with control subjects, patients who were prescribed cholinesterase inhibitors had more frequent hospital
visits for syncope (31 5 'IS 18.6 events per 1000 person-years adjusted hazard ratio HR]. 1 6 95% confidence
interval [CI] 1 5 - 1 98) Partici ,ants receiving cholinesterase inhibitors also had a higher frequency of other
s ncope-related e' ents ,·s control subjects
These events included hospital visits for bradycardia (6.9 s 4.4 e',/ents per 1000 person-years; HR, 1 69.95% CI
1 32 - 215). permanent pacemaker insertion (4 'IS 3 3 events per 1000 person-years HR. 149,95% CI, 1.12
.00) and hip fracture 22.4 'IS 19' 8 events per 1000 person-years, HR. 118 95% CI, 1 04 - 1 34)
A.dditional analy'ses in ,vhich participants were matched either on their baseline comorbidity status or use of
propensit scores yielded similar findings .
. Use of cholinesterase inhibitors is associated with increased rates of s Inca e brad cardia acemaker insertion
and hip fracture in older adults with dementia" the study authors write. 'The risk of these previousl\
underrecognized serious adverse e"ents must be weighed carefully against the drugs' generally modest benefits ..
Limitations of this stud include retrospecti e. obsel' ational design additional risk factors for syncope in many
patients, possible residual confounding and hidden bias; failure to compare individual cholinesterase inhibitors or to
examine dose-response relationships lack of e aluation of fall-related injuries other than hip fracture. and exclusion
of r::atients with a recent history of syncope
The I,'n/cal eachers ssoc,'a"'on of ueen' Endo ',rmen Fund and a hr. 71 Disease ,\Iew Emergt ,g ea
program fa 'rom he anadli'/!7 Ins lues of ee) f:<esearcr ( U-f,C?j s' p oded h,.s s udy. The Nerl E .ergl g
Team program recelyes Jom sponsorslilp 'rom he ,anadlan DIO' e e
ssocla 10/i, lie Kidney FoundO'!Jon of
<anada, !he Hearl and S roke Founda Ion of .anada, end he IHR Ins t u es of Nul ,'on, Me!e ollsm and
la eLs, and /feu/a 'ory and Resp/I'a ory eal h. Some of he s udy au'hors ,a e dlsc,losed varwus fmanclal
re}a IOnshlps WI h Bayer
anada. he
11 ano Mims ry of ,'1eal 17, he
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f oranio. al1
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Arch In em Med 2009,169,867-8 3
EXh\b\t "0"
30
I
Health
sante
Canada Canada
Health Products and Food Branch
Direction generale des produits de sante et des aliments
The Health Produ cts and Food Branch (H PFB) posts on the Health Ca nada web site safety alerts, public health
advisories, press releases and other notices as a service to health professionals, consumers, and other interested
parties. These advisories may be prepared with Directorates in the HPFB which includes pre-market and post
market areas as well as market authorization holders and other stakeholders. Although the HPFB grants market
authorizations or licenses for therapeutic products, we do not endorse either the product or the company. Any
questions regarding product information should be discussed with your health professional.
This is duplicated text of a letter from Janssen-Ortho Inc.
Contact the company for a copy of any references, attachments or enclosures.
Health Canada Endorsed Important Safety Information on
REMINYL* (galantamine hydrobromide)
~ JANSSEN-ORTHO
April 18, 2005
Subject:
Safety Information from Investigational Studies with REMINYL*
(galantamine hydrobromide) in Mild Cognitive Impairment (MCI)
Dear Health Care Professional,
Janssen-Ortho Inc., in consultation with Health Canada, would like to inform you of important
safety information regarding REMINYL* (galantamine hydrobromide). In January 2005,
Janssen-Ortho Inc., in consultation with Health Canada, issued a public advisory regarding the
results of two investigational trials in patients with MCI. REMINYL is approved for the
symptomatic treatment of patients with mild to moderate dementia of the Alzheimer's type. No
indication is being sought for the treatment of individuals with MCI.
The REMINYL Product Monograph has been revised to include information regarding the
results of the studies in MCI.
Changes to the REMINYL Product Monograph will include:
Information under WARNINGS AND PRECAUTIONS regarding a difference in mortality with
REMINYL (13 fatalities; n=1026) compared to placebo (1 fatality; n=1022) in two investigational
trials in MCI. The reason for this difference is currently unknown. This difference in mortality has
not been observed in REMINYL studies in Alzheimer's Disease.
In these trials, REMINYL was not shown to be effective in patients with MCI.
There is no evidence of an increased risk of mortality when REMINYL is used in patients with mild
to moderate Alzheimer's Disease.
A reminder to health care professionals under DOSAGE AND ADMINISTRATION that REMINYL is
not indicated for use in patients with MCI.
31
WARNINGS AND PRECAUTIONS, Special Populations
Exhibit "0"
Patients with Mild Cognitive Impairment (MCI):
Mortality in Investigational Trials in Mel
Two randomized, double-blind, placebo-controlled efficacy and safety studies of 2 years'
duration were completed in non-demented subjects with MCI. Individuals with MCI demonstrate
isolated memory impairment greater than expected for their age and education, but do not meet
current diagnostic criteria for Alzheimer's Disease. In these trials, REMINYL was not shown to
be effective in patients with MCI. In the double-blind portion of these two trials, a total of 13
deaths in subjects on REMINYL (n=1 026) were recorded and 1 death in subjects on placebo
(n=1022); the reason for this difference is currently unknown. This difference in mortality has
not been observed in REMINYL studies in Alzheimer's Disease. Approximately half of the
REMINYL deaths appeared to have resulted from various vascular causes (myocardial
infarction, stroke, and sudden death); other deaths appeared to have resulted from infection,
suicide and cancer. There is no evidence of an increased risk of mortality when REMINYL is
used in patients with mild to moderate Alzheimer's Disease.
DOSAGE AND ADMINISTRATION
REMINYL (galantamine hydrobromide) and REMINYL ER are not indicated for use in
patients with mild cognitive impairment (see WARNINGS AND PRECAUTIONS, Special
Populations, Patients with Mild Cognitive Impairment (MCI):, Mortality in Investigational
Trials in MCI).
The use of REMINYL is not advised outside of its approved indication. Patients should be
treated according to the approved Canadian prescribing information.
Please refer to the attached highlighted copy of the Prescribing Information for the revisions to
the Product Monograph. Please insert this revised Prescribing Information in your copy of the
Compendium of Pharmaceuticals and Specialties (CPS) and use when prescribing or
dispensing REMINYL. The revised Product Monograph is also available on the Janssen-Ortho
website at www.janssen-ortho.com.
Janssen-Ortho Inc. continues to work closely with Health Canada to monitor ongoing clinical
trials, and worldwide pharmacovigilance reports. Janssen-Ortho Inc. will continue to provide
you with the most current and complete product information available for the management of
patients receiving REMINYL.
The identification, characterization, and management of marketed health product-related
adverse reactions are dependent on the active participation of health care professionals in
adverse drug reaction reporting programmes. Any occurrences of serious and/or unexpected
adverse reactions in patients receiving REMINYL should be reported to Janssen-Ortho Inc. or
the Marketed Health Products Directorate at the following addresses:
32
Exhibit "0"
Janssen-Ortho Inc.
19 Green Belt Drive
Toronto, Ontario
M3C 1L9
Or call toll free at 1-800-567-3331
Or email todsscan@joica.jnj.com
Or toll free fax to 1-866-767-5865
Any suspected adverse reaction can also be reported to:
Canadian Adverse Drug Reaction Monitoring Program (CADRMP)
Marketed Health Products Directorate
HEALTH CANADA
Address Locator: 0701 C
OTTAWA, Ontario, K1A OK9
Tel: (613) 957-0337 or Fax: (613) 957-0335
To report an Adverse Reaction, consumers and health professionals may call toll free:
Tel: 866234-2345
Fax: 866 678-6789
cadrmp@hc-sc.gc.ca
For other inquiries, please refer to contact information:
Bureau of Cardiology, Allergy and Neurological Sciences
bca ns_en qui ri es@hc-sc.gc.ca
Tel: (613) 941-1499
Fax: (613) 941-1668
The AR Reporting Form and the AR Guidelines can be found on the Health Canada web site or in The Canadian
Compendium of Pharmaceuticals and Specialties.
http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/adverse_e.htm I
http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dptladr_guideline_e.htm I
Your professional commitment in this regard has an important role in protecting the well-being
of your patients by contributing to early signal detection and informed drug use.
Should you have any questions or require additional information regarding the use of
REMINYL, please contact Janssen-Ortho Inc. Medical Information Department at 1-800-567
3331 from 9:00 am to 5:00 pm Monday to Friday Eastern Standard Time (EST) or by facsimile
at 416-449-5248. A copy of this letter is also available on the Janssen-Ortho website at
www.janssen-ortho.com and on the Health Canada website at www.hc-sc.gc.ca/hpfb
dgpsa/tpd-dpt/index_e.html.
Sincerely,
original signed by
Wendy Arnott, Pharm.D.
Vice President
Regulatory, Safety and Quality
*AII trademark rights used under license.
33
Exhibit liE"
SEROQUEL@
quetiapine fumarate immediate-release tablets
quetiapine 25, 100, 200 and 300 mg
Antipsychotic Agent
PART I: HEALTH PROFESSIONAL INFORMATION
SUMMARY PRODUCT INFORMATION
Route of
Administration
Dosage Form / Strength
Nonmedicinal Ingredients
oral
immediate-release tablet /
25, 100,200 and 300 mg
The core of the tablet contains the excipients
calcium hydrogen phosphate dihydrate,
lactose monohydrate, magnesium stearate,
microcrystalline cellulose, povidone, and
sodium starch glycolate type A. The coating
of the tablet contains hydroxypropyl
methylcellulose 2910, polyethylene glycol
400, red ferric oxide (25 mg tablets), titanium
dioxide, and yel10w ferric oxide (25 mg and
100 mg tablets).
INDICATIONS AND CLINICAL USE
Adults:
Schizophrenia
SEROQUEL (quetiapine fumarate immediate-release) is indicated for the management of the
manifestations of schizophrenia. The antipsychotic efficacy of SEROQUEL was established
in short-term (6-week) controlled inpatient trials (see Part II: CLINICAL TRIALS). The
efficacy of SEROQUEL in long-term use, that is, for more than 6 weeks, has not been
systematically evaluated in controlled trials of patients with manifestations of schizophrenia.
Bipolar Disorder
SEROQUEL is indicated as monotherapy for the:
•
Acute management of manic episodes associated with bipolar disorder.
•
Acute management of depressive episodes associated with bipolar I and bipolar II
disorder.
COPYRIGHT 1998,2006,2008
34ASTRAZENECA CANADA INC.
Page 3 of 50
The efficacy of SEROQUEL in bipolar mania was established in two 12-week clinical trials of
bipolar patients (see Part II: CLINICAL TRIALS). The safety and effectiveness of
SEROQUEL for long-term use, and for prophylactic use in bipolar mania has not been
evaluated.
The efficacy of SEROQUEL in bipolar depression was established in four 8-week clinical
trials that included either bipolar I or bipolar II patients (see Part II: CLINICAL TRIALS).
Geriatrics (>65 years of age): SEROQUEL is not indicated in elderly patients with
dementia. See WARNINGS AND PRECAUTIONS, Serious Warnings and Precautions Box
and Special Populations.
Pediatrics «18 years of age): The safety and efficacy of SEROQUEL in children under the
age of 18 years have not been established.
CONTRAINDICATIONS
SEROQUEL (quetiapine fumarate immediate-release) is contraindicated in patients with a
known hypersensitivity to this medication or any of its ingredients. For a complete listing, see
DOSAGE FORMS, COMPOSITION AND PACKAGING.
WARNINGS AND PRECAUTIONS
Serious Warnings and Precautions
Increased Mortality in Elderly Patients with Dementia
Elderly patients with dementia treated with atypical antipsychotic drugs are at an
increased risk of death compared to placebo. Analyses of thirteen placebo controlled
trials with various atypical antipsychotics (modal duration of 10 weeks) in these patients
showed a mean 1.6 fold increase in death rate in the drug-related patients. Although the
causes of death were varied, most of the deaths appeared to be either cardiovascular
(e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature (see
WARNINGS AND PRECAUTIONS, Special Populations, Use in Geriatric Patients with
Dementia).
General
Body Temperature Regulation: Although not reported with SEROQUEL (quetiapine
fumarate immediate-release) disruption of the body's ability to reduce core body temperature
has been attributed to antipsychotic agents. Appropriate care is advised when prescribing
SEROQUEL for patients who will be experiencing conditions which may contribute to an
elevation of core temperature, e.g., exercising strenuously, exposure to extreme heat, receiving
concomitant medication with anticholinergic activity, or being subject to dehydration.
Acute Withdrawal (discontinuation) Symptoms: Acute discontinuation symptoms such as
insomnia, nausea, headache, diarrhea, vomiting, dizziness and irritability, have been described
COPYRIGHT 1998,2006,2008
35 ASTRAZENECA CANADA INC.
Page 4 of 50
after abrupt cessation of antipsychotic drugs including SEROQUEL. Gradual withdrawal over
a period of at least one to two weeks is advisable. Symptoms usually resolved after I week
post-discontinuation.
Carcinogenesis and Mutagenesis
For animal data, see Part II: TOXICOLOGY.
Cardiovascular
Hypotension and Syncope: As with other drugs that have high aj adrenergic receptor
blocking activity, SEROQUEL may induce orthostatic hypotension, dizziness, and sometimes
syncope, especially during the initial dose titration period. These events may lead to falls.
Syncope was reported in 1% (35/4083) of patients treated with SEROQUEL, compared with
0.3% (3/1 006) on placebo, and 0.4% (2/527) on active control drugs. The risk of hypotension
and syncope may be reduced by more gradual titration to the target dose (see DOSAGE AND
ADMINISTRATION). SEROQUEL should be used with caution in patients with known
cardiovascular disease (e.g., history of myocardial infarction or ischemic heart disease, heart
failure or conduction abnormalities), cerebrovascular disease, or other conditions predisposing
to hypotension (e.g., dehydration, hypovolemia and treatment with antihypertensive
medications) (see OVERDOSAGE).
Cholesterol and Triglyceride Elevations: Very common (2: 10%) cases of elevations in
serum triglyceride levels (2:2.258 mmol/L on at least one occasion), elevations in total
cholesterol (predominantly LDL cholesterol) (2:6.2064 mmol/L on at least one occasion), and
decreases in HDL cholesterol «1.025 mmol/L males; <1.282 mmol/L females at any time)
have been observed during treatment with quetiapine in clinical trials (see ADVERSE
REACTIONS). Lipid changes should be managed as clinically appropriate.
In short-term placebo-controlled schizophrenia trials, SEROQUEL-treated patients showed
mean increases from baseline in cholesterol and triglyceride of 11 % and 17%, respectively,
compared to mean decreases in the placebo-treated patients. LDL cholesterol was not
measured in these trials.
In short-term placebo-controlled bipolar depression trials, SEROQUEL-treated patients had
decreases from baseline in mean cholesterol and increases from baseline in mean triglyceride
of 0.7% and 12%, respectively, compared to decreases in mean cholesterol and increases in
mean triglyceride of 1.8% and 2% respectively for placebo-treated patients.
QT Prolongation: In clinical trials, quetiapine was not associated with a persistent increase in
absolute QT intervals. However, in post-marketing experience, there were cases reported of
QT prolongation with overdose (see OVERDOSAGE). As with other antipsychotics, caution
should be exercised when quetiapine is prescribed in patients with cardiovascular disease or
family history of QT prolongation. Also caution should be exercised when quetiapine is
prescribed either with medicines known to increase QT interval or with concomitant
neuroleptics, especially for patients with increased risk of QT prolongation, i.e., the elderly,
COPYRIGHT 1998,2006,2008
Page 5 of 50
patients with congenital long QT syndrome, congestive heart failure, heart hypertrophy,
hypokalemia, or hypomagnesemia (see DRUG INTERACTIONS).
Endocrine and Metabolism
Hyperglycaemia: As with some other antipsychotics, hyperglycaemia and diabetes mellitus
(including exacerbation of pre-existing diabetes, diabetic ketoacidosis, and diabetic coma
including some fatal cases) in the aggregate have been reported rarely (20.01% - <0.1%)
during the use of SEROQUEL in post-marketing experience, sometimes in patients with no
reported history of hyperglycaemia (see ADVERSE REACTIONS, Post-Market Adverse
Drug Reactions).
Increases in blood glucose and hyperglycaemia, and occasional reports of diabetes, have been
observed in clinical trials with quetiapine (see ADVERSE REACTIONS, Abnormal
Hematologic and Clinical Chemistry Findings).
Assessment of the relationship between atypical antipsychotic use and glucose abnormalities
is complicated by the possibility of an increased background risk of diabetes mellitus in
patients with schizophrenia and the increasing incidence of diabetes mellitus in the general
population. Given these confounders, the relationship between atypical antipsychotic use and
hyperglycaemia-related adverse events is not completely understood. However,
epidemiological studies suggest an increased risk of treatment-emergent hyperglycaemia
related adverse events in patients treated with the atypical antipsychotics. Precise risk
estimates for hyperglycaemia-related adverse events in patients treated with atypical
antipsychotics are not available.
Any patient treated with atypical antipsychotics should be monitored for symptoms of
hyperglycaemia including polydipsia, polyuria, polyphagia, and weakness. Patients who
develop symptoms of hyperglycaemia during treatment with atypical antipsychotics should
undergo fasting blood glucose testing. In some cases, hyperglycaemia has resolved when the
atypical antipsychotic was discontinued; however, some patients required continuation of anti
diabetic treatment despite discontinuation of the suspect drug. Patients with risk factors for
diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with
atypical antipsychotics should undergo fasting blood glucose testing at the beginning of
treatment and periodically during treatment. Patients with an established diagnosis of diabetes
mellitus who are started on atypical antipsychotics should be monitored regularly for
worsening of glucose control.
Hyperprolactinemia: During clinical trials with quetiapine, elevation in prolactin levels
occurred in 3.6% (158/4416) of patients treated with quetiapine compared to 2.6% (51/1968)
on placebo (see ADVERSE REACTIONS).
Increased prolactin levels with quetiapine were observed in rat studies. As is common with
compounds which stimulate prolactin release, the administration of SEROQUEL resulted in
an increase in the incidence of mammary neoplasms in rats. The physiological differences
between rats and humans with regard to prolactin make the clinical significance of these
COPYRIGHT 1998,2006,2008
Page 6 of 50
findings unclear. To date, neither clinical nor epidemiological studies have shown an
association between chronic administration of drugs that stimulate prolactin release, and
mammary tumourigenesis. Tissue culture experiments, however, indicate that approximately
one third of human breast cancers are prolactin dependent in vitro; a factor of potential
importance if prescription of these drugs is contemplated in a patient with previously detected
breast cancer.
Possible manifestations associated with elevated prolactin levels are amenorrhea, galactorrhea,
and menorrhagia.
In the multiple fixed-dose schizophrenia clinical trial there were no differences in prolactin
levels at study completion for SEROQUEL, across the recommended dose range, and placebo.
Hypothyroidism: Clinical trials in schizophrenia demonstrated that SEROQUEL is
associated with a dose-related decrease in total and free thyroxine (T4 ). On average
SEROQUEL was associated with about a 20% mean reduction in thyroxine levels (both total
and free). Forty-two percent ofSEROQUEL-treated patients showed at least a 30% reduction
in total T4 and 7% showed at least a 50% reduction. Maximum reduction of thyroxine levels
generally occurred during the first two to four weeks of treatment with SEROQUEL. These
reductions were maintained without adaptation or progression during longer term treatment.
Decreases in T4 were not associated with systematic changes in TSH or clinical signs or
symptoms of hypothyroidism. Approximately 0.4% (12/2595) of patients treated with
SEROQUEL (schizophrenia and bipolar mania studies combined) experienced persistent
increases in TSH, and 0.25% of patients were treated with thyroid replacement.
Weight Gain: In controlled schizophrenia clinical trials (up to 6 weeks), mean weight gain
was approximately 2.3 kg compared to a mean weight gain of 0.1 kilograms in patients taking
placebo (n=427). In open-label extension trials, after 9 to 13 weeks of SEROQUEL
monotherapy, the mean weight increase was 1.58 kg (n=170). After 53 to 78 weeks of
treatment, the mean weight increase was 1.98 kg (n=137). These data are obtained from
uncontrolled, open-label trials; the relevance of these findings to clinical practice is unknown.
Weight change over time appeared to be independent of quetiapine dose (see ADVERSE
REACTIONS).
In the acute placebo-controlled bipolar mania clinical trials (up to 12 weeks) mean weight
gain in patients taking SEROQUEL was 1.8 kg compared to a mean weight loss of 0.1 kg in
patients taking placebo. In patients completing the entire 12 weeks of treatment mean weight
gain in patients taking SEROQUEL was 2.8 kg.
In the acute placebo-controlled bipolar depression clinical trials (8 weeks) mean weight gain
in patients taking SEROQUEL was 1.15 kg compared to a mean weight gain of 0.1 kg in
patients taking placebo. During maintenance treatment, patients treated with SEROQUEL 300
mg or placebo lost on average 0.1 kg and 0.6 kg, respectively, while patients treated with
SEROQUEL 600 mg gained on average 0.8 kg. In patients who completed 40 and 54 weeks of
maintenance treatment a small mean decrease was seen in the SEROQUEL 300 mg group
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Page 70f50
(-0.2 kg) and placebo group (-0.8 kg) while patients in the SEROQUEL 600 mg group showed
a mean weight gain of 1.2 kg (see ADVERSE REACTIONS).
Based on the cumulative acute placebo-controlled clinical trial database, weight gain (based
on ?7% increase in body weight from baseline) was reported in 9.6% in quetiapine-treated
patients and 3.8% in placebo-treated patients, which occurs predominantly during the early
weeks of treatment in adults (see ADVERSE REACTIONS).
Gastrointestinal
Antiemetic Effect: Consistent with its dopamine antagonist effects, SEROQUEL may have
an antiemetic effect. Such an effect may mask signs of toxicity due to overdosage of other
drugs, or may mask symptoms of disease such as brain tumour or intestinal obstruction.
Dysphagia and Aspiration Pneumonia: Dysphagia and aspiration have been reported with
quetiapine. Although a causal relationship with aspiration pneumonia has not been
established, SEROQUEL should be used with caution in patients at risk for aspiration
pneumonia. See WARNINGS AND PRECAUTIONS, Special Populations and ADVERSE
REACTIONS.
Hematologic
Neutropenia: Severe neutropenia «0.5 x 109/L) has been uncommonly reported in
quetiapine clinical trials. There was no apparent dose relationship. Possible risk factors for
leucopenia and/or neutropenia include pre-existing low white cell count (WBC) and history of
drug induced leucopenia and/or neutropenia. SEROQUEL should be discontinued in patients
with a neutrophil count <1.0 x 109/L. These patients should be observed for signs and
symptoms of infection and neutrophil counts followed (until they exceed 1.5 x 109/L). (See
ADVERSE REACTIONS, Abnormal Hematologic and Clinical Chemistry Findings and Post
Market Adverse Drug Reactions).
Hepatic
Hepatic Impairment: Decreased clearance of SEROQUEL was observed in patients with
mild hepatic impairment (see ACTIONS and CLINICAL PHARMACOLOGY, Special
Populations and Conditions). Patients with mild hepatic impairment should be started on 25
mg/day. The dose should be increased daily in increments of25 to 50 mg/day to an effective
dose, depending on the clinical response and tolerability in the individual patient. No
pharmacokinetic data are available for any dose of SEROQUEL in patients with moderate or
severe hepatic impairment. However, should clinical judgement deem treatment with
SEROQUEL necessary, the drug should be used with great caution in patients with moderate
or severe hepatic impairment (see ACTIONS AND CLINICAL PHARMACOLOGY, Special
Populations and Conditions and DOSAGE AND ADMINISTRATION).
Transaminase Elevations: During premarketing clinical trials, therapy with SEROQUEL
was associated with elevation of hepatic transaminases, primarily ALT. Within a clinical trial
database of 1892 SEROQUEL-treated schizophrenia patients, with baseline ALT levels <60
COPYRIGHT 1998,2006,2008
Page 8 of 50
lUlL, 5.3% (101/1892) had treatment-emergent ALT elevations to > 120 lUlL, 1.5% (29/1892)
had elevations to >200 lUlL, and 0.2% (3/1892) had elevations to >400 lUlL. No patients had
values in excess of 800 lUlL. None of the SEROQUEL-treated patients who had elevated
transaminase values manifested clinical symptomatology associated with liver impairment.
The majority of transaminase elevations were seen during the first two months of treatment.
Most elevations were transient (80%) while patients continued on SEROQUEL therapy. Of
the 101 SEROQUEL-treated patients whose enzyme levels increased to> 120 lUlL, 40
discontinued treatment while their ALT values were still raised. In 114 SEROQUEL-treated
patients whose baseline ALTwas >90 lUlL, only 1 experienced an elevation to >400 lUlL.
In the bipolar disorder trials, the proportions of patients with transaminase elevations of> 3
times the upper limits of the normal reference range, was approximately 1% for both
SEROQUEL-treated and placebo-treated patients.
Precautions should be exercised when using SEROQUEL in patients with pre-existing hepatic
disorders, in patients who are being treated with potentially hepatotoxic drugs, or if treatment
emergent signs or symptoms of hepatic impairment appear.
For patients who have known or suspected abnormal hepatic function prior to starting
SEROQUEL, standard clinical assessment, including measurement of transaminase levels is
recommended. Periodic clinical reassessment with transaminase levels is recommended for
such patients, as well as for patients who develop any signs and symptoms suggestive of a
new onset liver disorder during SEROQUEL therapy.
Neurologic
Neuroleptic Malignant Syndrome (NMS): Neuroleptic Malignant Syndrome is a potentially
fatal symptom complex that has been reported in association with antipsychotic drugs,
including SEROQUEL.
The clinical manifestations ofNMS are hyperthermia, muscle rigidity, altered mental status,
and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia,
diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine
phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure.
In arriving at a diagnosis, it is important to identify cases where the clinical presentation
includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated
or inadequately treated extrapyramidal signs and symptoms. Other important considerations
in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and
primary central nervous system pathology.
The management ofNMS should include immediate discontinuation of antipsychotic drugs,
including SEROQUEL, and other drugs not essential to concurrent therapy; intensive
symptomatic treatment and medical monitoring; and treatment of any concomitant serious
medical problems for which specific treatments are available. There is no general agreement
about specific pharmacological treatment regimens for uncomplicated NMS.
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Page 90f50
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential
reintroduction of drug therapy should be carefully considered. The patient should be carefully
monitored since recurrences ofNMS have been reported.
Tardive Dyskinesia (TD) and Extrapyramidal Symptoms (EPS): Tardive Dyskinesia is a
syndrome of potentially irreversible, involuntary, dyskinetic movements that may develop in
patients treated with antipsychotic drugs including quetiapine. Although the prevalence of the
syndrome appears to be highest among the elderly, especially elderly women, it is impossible
to rely upon estimates to predict which patients are likely to develop the syndrome.
In placebo-controlled clinical trials for schizophrenia and bipolar mania the incidence
of EPS was no different from that of placebo across the recommended therapeutic dose
range. It has been hypothesized that agents with a lower EPS liability may also have a
lower liability to produce TD. This relationship predicts that quetiapine should have
less potential than typical antipsychotic agents to induce TD in schizophrenia and
bipolar mania patients. In short-term, placebo-controlled clinical trials for bipolar
depression, the incidence ofEPS was higher in quetiapine treated patients than in
placebo treated patients. See ADVERSE REACTIONS.
The risk of developing TD and the likelihood that it will become irreversible are believed to
increase as the duration of treatment and the total cumulative dose of antipsychotic drugs
administered to the patient increase. However, the syndrome can develop, although much less
commonly, after relatively brieftreatment periods at low doses.
There is no known treatment for established cases ofTD, although the syndrome may remit,
partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment,
itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome
and thereby may possibly mask the underlying process. The effect that symptomatic
suppression has upon the long-term course of the syndrome is unknown.
Given these considerations, SEROQUEL should be prescribed in a manner that is most likely
to minimize the occurrence ofTD. Chronic antipsychotic treatment should generally be
reserved for patients who appear to suffer from a chronic illness that is known to respond to
antipsychotic drugs, and for whom alternative, equally effective, but potentially less harmful
treatments are not available or appropriate. In patients who do require chronic treatment, the
smallest dose and the shortest duration of treatment producing a satisfactory clinical response
should be sought. The need for continued treatment should be reassessed periodically.
If signs and symptoms of TD appear in a patient on SEROQUEL, dose reduction or drug
discontinuation should be considered. Some patients may require treatment with SEROQUEL
despite the presence of the syndrome. The symptoms of TD can worsen or even arise after
discontinuation of treatment (see ADVERSE REACTIONS).
Seizures: In controlled schizophrenia clinical trials, there was no difference in the incidence
of seizures in patients treated with SEROQUEL or placebo (incidence of 0.4% or 3 events per
100 patient years in patients given SEROQUEL, compared with 0.5% or 6.9 events per 100
COPYRIGHT 1998,2006,2008
Page LO of 50
patient years for placebo). Nevertheless, as with other antipsychotics, caution is
recommended when treating patients with a history of seizures or with conditions associated
with a lowered seizure threshold (see ADVERSE REACTIONS).
Potential Effect on Cognitive and Motor Performance: Somnolence was a very commonly
reported adverse event in patients treated with SEROQUEL, especially during the initial dose
titration period. Since SEROQUEL may cause sedation and impair motor skill, patients
should be cautioned about performing activities requiring mental alertness, such as operating a
motor vehicle or hazardous machinery, until they are reasonably certain that SEROQUEL
therapy does not affect them adversely. Somnolence may lead to falls.
Ophthalmologic
Cataracts: The development of cataracts was observed in association with quetiapine
treatment in chronic dog studies at 4 times the recommended human dose. Lens changes
have also been observed in patients during long-term SEROQUEL treatment, but a
causal relationship to SEROQUEL use has not been established. The possibility of
lenticular changes during long-term use of SEROQUEL in man, thus can not be
excluded at this time. Eye examinations (e.g., slit lamp exam) prior to or shortly after
initiation of treatment with SEROQUEL and at 6 month intervals thereafter, are
recommended. If clinically significant lens changes associated with SEROQUEL use are
observed, discontinuation of SEROQUEL should be considered.
Psychiatric
Suicide/ suicidal thoughts or clinical worsening: Depressive episodes are associated with
an increased risk of suicidal thoughts, self-harm and suicide (suicide-related events). This risk
persists until significant remission of depression occurs. As improvement may not occur
during the first few weeks or more of treatment, patients should be closely monitored until
such improvement occurs. It is general clinical experience that the risk of suicide may increase
in the early stages of recovery. In addition to depressive episodes associated with bipolar
disorder, depression may be co-morbid with schizophrenia.
Schizophrenia as well as manic episodes associated bipolar disorder, can also be associated
with an increased risk of suicide-related events, and thus close supervision and appropriate
clinical management of high risk patients should accompany drug therapy.
Patients with a history of suicide-related events are also known to be at a greater risk of
suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment.
In placebo-controlled bipolar depression clinical trials with SEROQUEL, the incidence of
treatment emergent suicidal ideation or suicidal behaviour, as measured by the Columbia
Analysis of Suicidal Behaviour, was 1.5% for SEROQUEL treated patients and 2.0% for
placebo-treated patients.
COPYRIGHT 1998, 2006, 2008
Page II of 50
Renal
There is little experience with SEROQUEL in patients with renal impairment, except in a low
(subclinical) single dose study (see ACTIONS AND CLINICAL PHARMACOLOGY,
Special Populations and Conditions). SEROQUEL should thus be used with caution in
patients with known renal impairment, especially during the initial dosing period (see
DOSAGE AND ADMINISTRATION).
Special Populations
Pregnant Women: Patients should be advised to notify their physician if they become
pregnant or intend to become pregnant during treatment with SEROQUEL. The safety and
efficacy of SEROQUEL during human pregnancy have not been established. Therefore,
SEROQUEL should only be used during pregnancy if the expected benefits justify the
potential risks.
Nursing Women: The degree to which quetiapine is excreted into human milk is unknown.
Women who are breast-feeding should therefore be advised to avoid breast-feeding while
taking SEROQUEL.
Pediatrics « 18 years of age): The safety and efficacy of SEROQUEL in children under the
age of 18 years have not been established.
Geriatrics (~ 65 years of age): The number of patients 65 years of age or over, with
schizophrenia or related disorders, exposed to SEROQUEL, during clinical trials was limited
(n=38). When compared to younger patients the mean plasma clearance of quetiapine was
reduced by 30% to 50% in elderly subjects. In addition, as this population has more frequent
hepatic, renal, central nervous system, and cardiovascular dysfunctions, and more frequent use
of concomitant medication, caution should be exercised with the use of SEROQUEL in the
elderly patient (see DOSAGE AND ADMINISTRATION).
Use in Geriatric Patients with Dementia:
Overall Mortality: Elderly patients with dementia treated with atypical antipsychotic
drugs showed increased mortality compared to placebo in a meta-analysis of 13
controlled trials of various atypical antipsychotic drugs. In two placebo-controlled trials
with oral SEROQUEL in this population, the incidence of mortality was 5.5% for
SEROQUEL-treated patients compared to 3.2% for placebo-treated patients.
SEROQUEL is not indicated in elderly patients with dementia.
Cerebrovascular adverse events: An increased risk of cerebrovascular adverse events has
been seen in the dementia population with some atypical antipsychotics. The mechanism for
this increased risk is not known. There is insufficient data with quetiapine to know if there is
an increased risk of cerebrovascular events associated with quetiapine. An increased risk,
however, cannot be excluded. SEROQUEL is not indicated in patients with dementia.
Vascular disease: SEROQUEL should be used with caution in patients with risk factors for
stroke or with a history of stroke.
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Exhibit "F"
Efficacy was established in three I-day trials in adults. (143)
HIGHLIGHTS OF PRESCRIBING INFORMATION
As ZYPREXA and Fluoxetine in Combinationfor the:
Treatment of depressive episodes associated with bipolar 1 disorder.
These highlights do not include all the information needed to use
ZYPREXA safely and effectively. See full prescribing information for
ZYPREXA.
( 1.5)
• Efficacy was established with Symbyax (olanzapine and fluoxetine in
combination) in adults; refer to the product label for Symbyax.
Treatment of treatment resistant depression (major depressive disorder
in patients who do not respond to 2 separate trials of different
antidepressants of adequate dose and duration in the current episode).
(1.6)
Efficacy was established with Symbyax (olanzapine and fluoxetine in
combination) in adults; refer to the product label for Symbyax.
ZYPREXA (olanzapine) Tablet for Oral use
ZYPREXA ZYDIS (olanzapine) Tablet, Orally Disintegrating for Oral
use
ZYPREXA IntraMuscular (olanzapine) Injection, Powder, For Solution
for Intramuscular use
Initial U.S. Approval: 1996
----------------------- DOSAGE AND ADMINISTRA nON ---------------------
WAR ING: INCREASED MORTALITY IN ELDERLY PATIENTS
WITH DEMENTIA-RELATED PSYCHOSIS
See full prescribing information for complete boxed warning.
Elderly patients with dementia-related psychosis treated with
antipsychotic drugs are at an increased risk of death. ZYPREXA is
not approved for the treatment of patients with dementia-related
psychosis. (5.1, 5.14, 17.2)
When using ZYPREXA and fluoxetine in combination, also refer to
the Boxed Warning section of the package insert for Symbyax.
I
--------------------------- RECENT MAJOR CHANGES -------------------------
Ind ications and Usage:
Schizophrenia (1.1)
12/2009
Bipolar 1 Disorder (Manic or Mixed Episodes) (1.2)
L2/2009
Special Considerations in Treating Pediatric
Schizophrenia and Bipolar I Disorder (1.3)
12/2009
ZYPREXA IntraMuscular: Agitation Associated with
Schizophrenia and Bipolar 1 Mania (1.4)
L2/2009
Dosage and Administration:
Schizophrenia (2.1)
12/2009
Bipolar I Disorder (Manic or Mixed Episodes) (2.2)
12/2009
Warnings and Precautions:
Orthostatic Hypotension (5.8)
05/2010
Leukopenia, Neutropenia, and Agranulocytosis (5.9)
08/2009
Hyperprolactinemia (5.15)
OJ/2010
Oral: Start at 5-10 mg once daily;
Target: 10 mglday within several days
Schizophrenia in adolescents (2.1)
Oral: Start at 2.5-5 mg once daily;
Target: 10 mg/day
Bipolar I Disorder (manic or mixed
episodes) in adults (2.2)
Oral: Start at 10 or 15 mg once daily
Bipolar LDisorder (manic or mixed
episodes) in adolescents (2.2)
Oral: Start at 2.5-5 mg once daily;
Target: 10 mg/day
Bipolar I Disorder (manic or mixed
episodes) with lithium or valproate
in adults (2.2)
Oral: Start at LO mg once daily
Agitation associated with
Schizophrenia and Bipolar I Mania
in adults (2.4)
1M: 10 mg (5 mg or 7.5 mg when
clinically warranted)
Assess for orthostatic hypotension
prior to subsequent dosing (max. 3
doses 2-4 hrs apart)
Depressive Episodes associated
with Bipolar I Disorder in adults
(2.5)
Oral in combination with fluoxetine:
Start at 5 mg of oral olanzapine and
20 mg offluoxetine once dailv
Treatment Resistant Depression in
adults (2.6)
Oral in combination with fluoxetine:
Start at 5 mg of oral olanzapine and
20 mg of fluoxetine once daily
Lower starting dose recommended in debilitated or
pharmacodynamically sensitive patients or patients with predisposition
to hypotensive reactions, or with potential for slowed metabolism. (2.1)
Olanzapine may be given without regard to meals. (2.1)
----------------------------I.NDlCAT10NS AND USAGE --------------------------
ZYPREXA and Fluoxetine in Combination:
Dosage adjustments, if indicated, should be made with the individual
components according to efficacy and tolerability. (2.5, 2.6)
Olanzapine mono therapy is not indicated for the treatment of depressive
episodes associated with bipular Ldisorder or treatment resistant
depression. (2.5, 2.6)
Safety of co-administration of doses above 18 mg olanzapine with
75 mg fluoxetine has not been evaluated. (2.5,2.6)
ZYPREXA" (olanzapine) is an atypical antipsychotic indicated:
As oralformulationfor the:
Treatment of schizophrenia. (II)
Adults: Efficacy was established in three clinical trials in patients
with schizophrenia: two 6-week triaLs and one maintenance
triaL (14.1)
Adolescents (ages 13-17): Efficacy was established in one 6-week
trial in patients with schizophrenia (14.1). The increased potential (in
adolescents compared with adults) for weight gain and
hyperlipidemia may lead clinicians to consider prescribing other
drugs first in adolescents. (1.1)
Acute treatment of manic or mixed episodes associated with bipolar 1
disorder and maintenance treatment of bipolar I disorder. (1.2)
Adults: Efficacy was established in three clinical trials in patients
with manic or mixed episodes of bipolar 1disorder: two 3- to 4-week
trials and one maintenance triaL (14.2)
Adolescents (ages 13-17): Efficacy was established in one 3-week
trial in paticnts with manic or mixed episodes associated with bipolar
1 disorder (14.2). The increased potential (in adolescents compared
with adults) for weight gain and hyperlipidemia may lead clinicians
to consider prescribing other drugs first in adolescents. (1.2)
Medication therapy for pediatric patients with schizophrenia or bipolar I
disorder should be undertaken only after a thorough diagnostic
evaluation and with careful consideration of the potential risks. (1.3)
Adjunct to valproate or lithium in the treatment of manic or mixed
episodes associated with bipolar 1 disorder. (1.2)
Efficacy was established in two 6-week clinical trials in adults (14.2).
Maintenance efficacy has not been systematically evaluated.
As ZYPREXA IntraMuscular for the:
Treatment of acute agitation associated with schizophrenia and bipolar I
mania. (1.4)
Schizophrenia in adults (2.1)
---------------------- DOSAGE FORMS AND STRE GTHS --------------------
Tablets (not scored): 2.5, 5, 7.5, 10, 15,20 mg (3)
Orally Disintegrating Tablets (not scored): 5, 10, 15,20 mg (3)
Intramuscularlnjection: 10 mg vial (3)
------------------------------- CONT RA IND ICA TlONS -----------------------------
None with ZYPREXA monotherapy.
When using ZYPREXA and fluoxetine in combination, also refer to the
Contraindications section of the package insert for Symbyax'~. (4)
When lIsing ZYPREXA in combination with lithium or valproate, refer
to the Contraindications section of the package inserts for those
products. (4)
44
------------------------ WARNINGS AND PRECA UnONS ----------------------
Elderly Patients with Dementia-Related Psychosis: rncreased risk of
death and increased incidence of cerebrovascular adverse events (e.g.,
stroke, transient ischemic attack). (5.1)
Suicide: The possibility of a suicide attempt is inherent in schizophrenia
and in bipolar I disorder, and close supervision of high-risk patients
should accompany drug therapy; when using in combination with
fluoxetine, also refer to the Boxed Warning and Warnings and
Precautions sections of the package insert for Symbyax. (5.2)
Neuroleptic Malignant Syndrome: Manage with immediate
discontinuation and close monitoring. (5.3)
2
Manic or Mixed Episodes Bipolar I Disorder (Adolescents) - sedation,
weight increased, increased appetite, headache, fatigue, dizziness, dry
mouth, abdominal pain, pain in extremity (6.1)
Hype/glycemia: In some cases extreme and associated with ketoacidosis
or hyperosmolar coma or death, has been reported in patients taking
olanzapine. Patients taking olanzapine should be monitored for
symptoms of hyperglycemia and undergo fasting blood glucose testing
at the beginning of, and periodically during, treatment. (5.4)
Hyperlipidemia: Undesirable alterations in lipids have been observed.
Appropriate clinical monitoring is recommended, including fasting
blood lipid testing at the beginning of, and periodically during,
treatment. (5.5)
Weight Gain: Potential consequences of weight gain should be
considered. Patients should receive regular monitoring of weight. (5.6)
Tardive Dyskinesia: Discontinue ifclinically appropriate. (5.7)
Orthostatic Hypotension: Orthostatic hypotension associated with
dizziness, tachycardia, bradycardia and, in some patients, syncope, may
occur especially during initial dose titration. Use caution in patients with
cardiovascular disease, cerebrovascular disease, and those conditions
that could affect hemodynamic responses. (5.8)
Leukopenia, Neutropenia, and Agranulocytosis: Has been reported with
antipsychotics, including ZYPREXA. Patients with a history of a
clinically significant low white blood cell count (WBC) or drug induced
leukopenia/neutropenia should have their complete blood count (CBC)
monitored frequently during the first few months of therapy and
discontinuation of ZYPREXA should be considered at the first sign of a
clinically significant decline in WBC in the absence of other causative
factors. (5.9)
Seizures: Use cautiously in patients with a history of seizures or with
conditions that potentially lower the seizure threshold. (5.1 J)
Potentialjor Cognitive and Motor Impairment: Has potential to impair
judgment, thinking, and motor skills. Use caution when operating
machinery. (5.12)
Hyperprolactinemia: May elevate prolactin levels. (5.15)
Use in Combination with Fluoxetine, Lithium or Valproate: Also refer to
the package inserts for Symbyax, lithium, or valproate. (5.16)
LaboratDlY Tests: Monitor fasting blood glucose and lipid profiles at the
beginning of, and periodically during, treatment. (5.17)
Combination ojZYPREXA and Lithium or Valproate:
Manic or Mixed Episodes, Bipolar I Disorder (Adults) - dry mouth,
weight gain, increased appetite, dizziness, back pain, constipation,
speech disorder, increased salivation, amnesia, paresthesia (6.1)
ZYPREXA and Fluoxetine in Combination: Also refer to the Adverse
Reactions section of the package insert for Symbyax. (6)
ZYPREXA IntraMuscular jor Injection:
Agitation with Schizophrenia and Bipolar I Mania (Adults) somnolence (6.1)
To report SUSPECTED ADVERSE REACTJONS, contact Eli Lilly and
Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-I088
or www.fda.gov/medwatch
------------------------------- DRU G INTERA CTIONS -----------------------------
Diazepam: May potentiate orthostatic hypotension. (7.1, 7.2)
Alcohol: May potentiate orthostatic hypotension. (7.1)
Carbamazepine: Increased clearance ofolanzapine. (7.1)
Fluvoxamine: May increase olanzapine levels. (7.1)
ZYPREXA and Fluoxetine in Combination: Also refer to the Drug
Interactions section of the package insert for Symbyax. (7.1)
CNS Acting Drugs: Caution should be used when taken in combination
with other centrally acting drugs and alcohol. (7.2)
Antihypertensive Agents: Enhanced antihypertensive effect. (7.2)
Levodopa and Dopamine Agonists: May antagonize levodopaldopamine
agonists. (7.2)
Lorazepam (1M): Increased somnolence with 1M olanzapine. (7.2)
Other Concomitant Drug Therapy: When using olanzapine in
combination with lithium or valproate, refer to the Drug Interactions
sections of the package insert for those products. (7.2)
------------------------ USE IN SP EC IFIC POPULA TI 0 NS ----------------------
Pregnancy: ZYPREXA should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus. (8.1)
Nursing Mothers: Breast-feeding is not recommended. (8.3)
Pediatric Use: Safety and effectiveness ofZYPREXA in children <13
years of age have not been established. (8.4)
------------------------------- ADV ERSE REA cn 0 NS -----------------------------
Most common adverse reactions
associated with:
(~5%
and at least twice that for placebo)
OralOlanzapine Monotherapy:
Schizophrenia (Adults) - postural hypotension, constipation, weight
gain, dizziness, personality disorder, akathisia (6.1)
Schizophrenia (Adolescents) - sedation, weight increased, headache,
increased appetite, dizziness, abdominal pain, pain in extremity, fatigue,
dry mouth (6.1)
Manic or Mixed Episodes, Bipolar 1 Disorder (Adults) - asthenia, dry
mouth, constipation, increased appetite, somnolence, dizziness, tremor
(6. J)
See 17 for PATIENT COUNSELING INFORMATION and FDA
approved Medieation Guide
Revised: OS/2010
2.7
FULL PRESCRIBING INFORMATION: CONTENTS*
ZYPREXA and Fluoxetine in Combination: Dosing in Special
Populations
WARNING: INCREASED MORTALITY IN ELDERLY PATIE TS
WiTH DEMENTIA-RELATED PSYCHOSIS
3
I
4
CONTRA INDICA TIONS
5
WARNINGS AND PRECAUTIONS
5.1
Elderly Patients with Dementia-Related Psychosis
5.2
Suicide
5.3
Neuroleptic Malignant Syndrome (NMS)
5.4
Hyperglycemia
5.5
Hyperlipidemia
5.6
Weight Gain
5.7
Tardive Dyskinesia
5.8
Orthostatic Hypotension
5.9
Leukopenia, Neutropenia, and Agranulocytosis
5.10 Dysphagia
5.11
Seizures
5.12 Potential for Cognitive and Motor Impairment
5.13
Body Temperature Regulation
5.14
Use in Patients with Concomitant TIlness
5.15
Hyperprolactinemia
5.16
Use in Combination with Fluoxetine, Lithium, or Valproate
5.17 Laboratory Tests
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Vital Signs and Laboratory Studies
2
INDICATIONS A D USAGE
J.I
Schizophrenia
1.2
Bipolar I Disorder (Man ic or Mixed Episodes)
l.3
Special Considerations in Treating Pediatric Schizophrenia and
Bipolar I Disorder
1.4
Schizophrenia and Bipolar I Mania
1.5
ZYPREXA and Fluoxetine in Combination: Depressive
Episodes Associated with Bipolar I Disorder
1.6
ZYPREXA and Fluoxetine in Combination: Treatment Resistant
Depression
DOSAGE AND ADMINISTRATION
2.1
Schizophrenia
2.2
Bipolar I Disorder (Manic or Mixed Episodes)
2.3
Administration ofZYPREXA ZYDIS (olanzapine orally
disintegrating tablets)
2.4
Schizophrenia and Bipolar 1 Mania
2.5
ZYPREXA and Fluoxetine in Combination: Depressive
Episodes Associated with Bipolar I Disorder
2.6
ZYPREXA and Fluoxetine in Combination: Treatment Resistant
Depression
45
DOSAGE FORMS AND STRENGTHS
3
6.3
7
14.3
Postmarketing Experience
16
DRUG INTERACTIONS
7.1
7.2
8
17
USE IN SPECIFIC POPULATIONS
8. I
8.2
8.3
8.5
9
17.3
[74
17.5
17.6
17.7
[7.8
[7.9
17. [0
17.11
17.12
17. [3
17. [4
DRUG ABUSE AND DEPENDENCE
9.3
Dependence
OVERDOSAGE
10
10.1
10.2
Human Experience
Management of Overdose
II
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1
122
12.3
13
Mechanism of Action
Pharmacodynamics
Pharmacokinetics
NONCLINICAL TOXICOLOGY
13.1
13.2
14
Carcinogenesis, Mutagenesis, Impairment of Fertility
Animal Toxicology and/or Pharmacology
Information on Medication Guide
Elderly Patients with Dementia-Related Psychosis: Increased
Mortality and Cerebrovascular Adverse Events (CYAE),
Including Stroke
Neuroleptic Malignant Syndrome (NMS)
Hyperglycemia
Hyperlipidemia
Weight Gain
Orthostatic Hypotension
Potential for Cognitive and Motor Impairment
Body Temperature Regulation
Concomitant Medication
Alcohol
Phenylketonurics
Use in Specific Populations
Need for Comprehensive Treatment Program in Pediatric
Patients
'Sections or subsections omitted from the full prescribing information are not
listed
CLINICAL STUDIES
14.1
14.2
How Supplied
Storage and Handling
PATIENT COUNSELING INFORMATION
17.1
[7.2
Pregnancy
Labor and Delivery
Nursing Mothers
Pediatric Use
Geriatric Use
84
HOW SUPPLIED/STORAGE AND HA DLI G
16.1
162
Potential for Other Drugs to Affect Olanzapine
Potential for Olanzapine to Affect Other Drugs
Agitation Associated with Schizophrenia and Bipolar I Mania
Schizophrenia
Bipolar [Disorder (Manic or Mixed Episodes)
FULL PRESCRIBING INFORMATION
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.
Analyses of seventeen placebo-controlled trials (modal duration oflO weeks), largely in patients taking atypical
antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in
placebo-treated patients. Over the course of a typical lO-week controlled trial, the rate of death in drug-treated patients
was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of
the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.
Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic
drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be
attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. ZYPREXA
(olanzapine) is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions
(5.1, 5.14) and Patient Counseling Tnformation (J7.2)].
When using ZYPREXA and fluoxetine in combination, also refer to the Boxed Warning section of the package
insert for Symbyax.
1
1.1
INDICAnONS AND USAGE
Schizophrenia
Oral ZYPREXA is indicated for the treatment of schizophrenia. Efficacy was established in three clinical trials in adult
patients with schizophrenia: two 6-week trials and one maintenance trial. In adolescent patients with schizophrenia (ages 13-(7),
efficacy was established in one 6-week trial [see Clinical Studies (14./)).
When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential
(in adolescents as compared with adults) for weight gain and hyperlipidemia. Clinicians should consider the potential long-term risks
when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents [see
Warnings and Precautions (5.5.5.6)).
1.2
Bipolar I Disorder (Manic or Mixed Episodes)
Monotherapy - Oral ZYPREXA is indicated for the acute treatment of manic or mixed episodes associated with bipolar [
disorder and maintenance treatment of bipolar r disorder. Efficacy was established in three clinical trials in adult patients with manic
or mixed episodes of bipolar I disorder: two 3- to 4-week trials and one monotherapy maintenance trial. In adolescent patients with
manic or mixed episodes associated with bipolar r disorder (ages 13-(7), efficacy was established in one 3-week trial [see Clinical
Studies (J4.2)}.
46
Public Health Advisories (Drug...
Page 1 of 1
Page 1 of 1
Exhibit "G"
U.S. Food and Drug Administration
Home> Drugs> Drug Safety and Availability> Postmarket Drug Safety Information for Patients and Providers
Drugs
Public Health Advisory: Deaths with Antipsychotics in Elderly Patients with Behavioral Disturbances
The issues described in this communication have been addressed in product
labeling (see Drugs@FDA1 ).
4/11/2005
The Food and Drug Administration has determined that the treatment of behavioral disorders in elderly patients with dementia with atypical (second
generation) antipsychotic medications Is associated with increased mortality. Of a total of seventeen placebo controlled trials performed with
olanzapine (Zyprexa), aripiprazole (Abilify), risperidone (Risperdal), or quetiapine (Seroquel) in elderiy demented patients with behavioral
disorders, fifteen showed numerical Increases in mortality In the drug-treated group compared to the piacebo-treated patients, These studies enrolled
total of 5106 patients, and several analyses have demonstrated an approximately 1.6-1.7 fold increase in mortality in these studies. Examination of
the specific causes of these deaths revealed that most were either due to heart related events (e,g., heart failure, sudden death) or Infections (mostly
pneumonia),
The atypical antipsychotics fall into three drug classes based on their chemical structure, Because the Increase in mortality was seen with atypical
antipsychotic medications in all three chemical classes, the Agency has concluded that the effect is probably related to the common pharmacologic
effects of ali atypical antipsychotic medications, including those that have not been systematically studied in the dementia population, In addition to
the drugs that were studied, the atypical antipsychotic medications include c10zapine (Clozaril) and ziprasidone (Geodon), All of tvhe atypical
antipsycll0tics are approved for the treatment of schizophrenia. None, however, is approved for the treatment of behavioral disorders in patients with
dementia, Because of these findings, the Agency will ask the manufacturers of these drugs to include a Boxed Warning in their labeling describing this
risk and noting that these drugs are not approved for this indication, Symbyax, a combination product containing olanzapine and fluoxetine, approvec
for the treatment of depressive episodes associated with bipolar disorder, will also be included in the request,
The Agency is also considering adding a similar warning to the labeling for older antipsychotic medications because the limited data available suggest
similar increase in mortality for these drugs.
i
Related Information
• Atypical Antipsychotic Drugs Information 2
Links on this page:
1, http://www ,accessdata ,fda.gov/scripts/cder/drugsatfda/index,cfm
2, http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetylnformationforPatientsandProviders/ucm094303.htm
47
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetylnformati... Tuesday, September 14, 2010
Exhibit "Gil
1+1
Health Sante
Canada Canada
Health Products and Food Branch
Direction generale des produits de sante et des aliments
The Health Products and Food Branch (HPFB) posts on the Health Canada web site safety alerts, public health
advisories, press releases and other notices as a service to health professionals, consumers, and other interested
parties. These advisories may be prepared with Directorates in the HPFB which includes pre-market and post-market
areas as well as market authorization holders and other stakeholders. Although the HPFB grants market
authorizations or licenses for therapeutic products, we do not endorse either the product or the company. Any
questions regarding product information should be discussed with your health professional.
Health Canada Endorsed Important Safety Information on
Atypical Antipsychotic Drugs and Dementia
June 22, 2005
Subject:
Increased Mortality Associated with the Use of Atypical Antipsychotic
Drugs in Elderly Patients with Dementia
Dear Health Care Professional,
Health Canada is advising Canadians that treatment with atypical antipsychotic medication of
behavioral disorders in elderly patients is associated with an increased risk for all-cause
mortality. Except for risperidone (RISPERDAL), these medications are not approved for use in
elderly demented patients.
Of a total of 13 placebo-controlled studies performed with risperidone (RISPERDAL), quetiapine
(SEROQUEL) and olanzapine (ZYPREXA) in elderly demented patients with behavioral
disorders, 10 studies showed numerical increases in all-cause mortality in the drug-treated
groups compared to the placebo-treated groups. Overall, these studies enrolled a total of 3965
patients, showed a mean 1.6 fold-increase in death rate in the drug-treated patients. Most of the
deaths were either due to heart related events (e.g., heart failure, sudden death) or infections
(mostly pneumonia).
All atypical antipsychotic drugs are approved for the treatment of schizophrenia. Risperidone
(RISPERDAL) is also approved for the "short-term symptomatic management of inappropriate
behavior due to aggression and/or psychosis in patients with severe dementia". There are no
studies with c10zapine (CLOZARIL) in elderly demented patients.
Because of the findings in the 13 studies, Health Canada is requesting that all manufacturers of
atypical antipsychotic drugs include a warning of this risk in their Product Monograph describing
this risk and noting that these drugs (except for RISPERDAL) are not approved for treating
behavioral disorders in elderly patients with dementia.
The incidence of all-cause mortality observed in placebo-controlled clinical studies in behavioral
disorders in elderly patients with dementia are:
48
Exhibit "G"
Mortality Incidence in Elderly Subjects with Dementia in Placebo-Controlled Studies
Clozapine
(CLOZARIL)
Number of Studies
Incidence
mortality: all causes/
Number of all treated
patients
(#/N)
Percentage (%)
Placebo
-
Dru!l
Risperidone
IRISPERDALl
Placebo
Quetiapine
ISEROQUELl
6
Placebo
Olanzapine
IZYPREXA)
2
Placebo
5
-
-
40/1009
22/712
20/365
7/217
42/1184
7/478
-
-
4
3.1
5.51
3.2
3.5
1.5
-No studies have been performed
The identification, characterization, and management of marketed health product-related
adverse reactions are dependent on the active participation of health care professionals in
adverse reaction reporting programmes. Any serious and/or unexpected reactions in patients
should be reported to Health Canada at the following address:
Canadian Adverse Drug Reaction Monitoring Program (CADRMP)
HEALTH CANADA
Address Locator: 0701C
OTTAWA, Ontario, K1A OK9
Tel (613) 957-0337 or Fax (613) 957-0335
Tel: 866234-2345
Fax: 866678-6789
cadrmp@hc-sc.gc.ca
For other inquiries: please refer to contact information.
Bureau of Cardiology, Allergy and Neurological Sciences (BCANS)
BCANS enquiries@hc-sc.gc.ca
Tel: (613) 941-1499
Fax (613) 941-1668
The AR Reporting Form and the AR Guidelines can be found on the Health Canada web site or in The Canadian
Compendium of Pharmaceuticals and Specialties.
http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/adverse_e.html
http://wwwhc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/adr_guideline_e.html
49
Postmarket Drug Safety Inform...
1......lDh~
Page 1 of 1
Page 1 of 1
U.S. Food and Drug Administration
Home> Drugs> Drug Safety and Availability> Postmarket Drug Safety Information for Patients and Providers
Drugs
Information on Antipsychotics
FDA ALERT [6/16/2008]: FDA is notifying healthcare professionals that both conventional and atypical anti psychotics are associated
with an increased risk of mortality in elderly patients treated for dementia-related psychosis.
In April 2005, FDA notified healthcare professionals that patients with dementia-related psychosis treated with atypical antipsychotic
drugs are at an increased risk of death. Since issuing that notification, FDA has reviewed additional information that indicates the risk
is also associated with conventional anti psychotics.
Antipsychotics are not indicated for the treatment of dementia-related psychosis.
This Information reflects FDA's current analysis of data available to FDA concerning this drug. FDA intends to update this when additional information (
analyses become available.
• Conventional Antipsychotic Drugs:
Compazine (prochlorperazine)
Haldol (haloperidol)
Loxitane (Ioxapine)
Mellaril (thioridazine)
Moban (rnolindone)
Navane (thlthixene)
Orap (plmozide)
Prolixin (fluphenazine)
Stelazine (trifluoperazine)
Thorazine (chlorpromazine)
• Trilafon (perphenazine)
To report any serious adverse events associated with the use of these drugs, please contact the FDA MedWatch program using the contact information
at the bottom of thiS sheet.
Related Information
• Information for Healthcare Professionals: Conventional Antipsychotics 1
(6/16/200B)
• FDA Requests Boxed Warnings on Older Class of Antipsychotic Drugs 2
FDA news release (6/16/200B)
Contact Us
• Report a Serious Problem
• 1-BOO-332-10BB
• 1-BOO-FDA-017B Fax
MedWatch Online 3
Regular Mail: Use postage-paid FDA Form 3500'
Mail to: MedWatch 5600 Fishers Lane
Rockville, MD 20857
Links on this page:
1. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetylnformationforPatientsandProviders/ucm124830.htm
2. http://www. fda .gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm 116912.htrn
3. http://www.fda .govhttps: / /www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm
4. http://www.fda .gov/ downloads/Safety/MedWatch/DownloadForms/UCM082 725. pdf
50
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformati... Tuesday, September 14, 2010
competition maintain that the NHS should do the same.
'"':"'nese developments have been reinforced by concerns
about the increase in management costs associated with the
introduction of competition.
Estimates suggest that the NHS reforms may have resulted
in up to £lbn extra being spent on administration, although
changes in definitions make it difficult to be precise. This is
because of the need to employ staff to negotiate and monitor
contracts and to deal with the large volumes of paperwork
involved in the contracting system. Ministers have responded
to these concerns by streamlining the organisation of the NHS
and introducing tight controls over management costs. They
have also encouraged the use oflong term contracts in order to
reduce the transaction costs of the new arrangements.
Out of the ashes of competition has arisen a different policy
agenda. This owes less to a belief in market forces than a
desire to use the NHS reforms to achieve other objectives.
The current agenda centres on policies to improve the health
of the population, give greater priority to primary care, raise
standards through the patient's charter, and ensure that
medical decisions are evidence based. These policies hinge on
effective planning and coordination in the NHS and all have
been made more salient by the separation of purchaser and
provider roles on which the reforms are based.
In particular, the existence of health authorities able to take
an independent view of the population's health needs without
being beholden to particular providers has changed the way in
which decisions are made. To this extent the organisational
changes introduced in 1991 have served to refocus attention
on those whom the NHS exists to serve, even though the
effects were neither anticipated nor intended when the
reforms were designed. like a potter moulding clay, only in
the process of creation has the shape of the product become
apparent. The effect of this policy shift has been to open up
common ground between Labour and the Conservatives,
notwithstanding the differences that remain.
Yet before the obituary of competition is written, the
consequences of a return to planning need to be thought
through. The NHS was reformed precisely because the old
command and control system had failed to deliver acceptable
planning must also be ackn
IS a
reforming strategy may have
Exhibit "H"
ess
elements of this strategy v
~ot
least, the stimulus to impro".. p",UUCluance wnlch arises from
the threat that contracts may be moved to an alternative
provider should not be lost. The middle way between
planning and competition is a path called contestability. This
recognises that health care requires cooperation between
purchasers and providers and the capacity to plan develop
ments on a long term basis. At the same time, it is based on the
premise that performance may stagnate unless there are
sufficient incentives to bring about continuous improvements.
Some of these incentives may be achieved through manage
ment action or professional pressure, and some may derive
from political imperatives.
In addition, there is the stimulus to improve performance
which exists when providers know that purchasers have
alternative options. This continues to be part ofthe psychology
of NHS decision making, even though ministers seem
reluctant to use the language of markets. It is, however, a
quite different approach than competitive tendering for
clinical services, which would expose providers to the rigours
of the market on a regular basis.
The essence of contestability is that planning and com
petition should be used together, with contracts moving only
when other means of improving performance have failed. Put
another way, in a contestable health service it is the possibility
that contracts may move that creates an incentive within the
system, rather than the actual movement of contracts. Of
course for this to be a real incentive then contracts must shift
from time to time, but this is only one element in the process
and not necessarily the most important. As politicians prepare
their plans for the future it is this path that needs to be
explored.
l
CHRIS HAM
Director
Health Sexvices Management Centre,
Birmingham B15 2RT
I Smith R. William Waldegrave: thinking beyond the new NHS. 8M] 1990;301:711-4.
2 Bottomley V. The tltw NHS: ccmrinuiryand clumge. London: Department of Health, 1995.
Evidence based medicine: what it is and what it isn't
It's about integrating individual clinical expertise and the best external evidence
Evidence based medicine, whose philosophical origins extend
back to mid-19th century Paris and earlier, remains a hot
topic for clinicians, public health practitioners, purchasers,
planners, and the public. There are now frequent workshops
in how to practice and teach it (one sponsored by the EM]
will be held in London on 24 April); undergraduate' and
postgraduate' training programmes are incorporating ie (or
pondering how to do so); British centres for evidence based
practice have been established or planned in adult medicine,
child health, surgery, pathology, pharmacotherapy, nursing,
general practice, and dentistry; the Cochrane Collaboration
and Britain's Centre for Review and Dissemination in York
are providing systematic reviews of the effects of health care;
new evidence based practice journals are being launched; and
it has become a common topic in the lay media. But
enthusiasm has been mixed with some negative reaction.4-6
Criticism has ranged from evidence based medicine being old
hat to it being a dangerous innovation, perpetrated by the
RMT
vrH TTI\A" ~
1?
1~
TANTTAI>V
1 QQf\
arrogant to serve cost cutters and suppress clinical freedom.
As evidence based medicine continues to evolve and adapt,
now is a useful time to refine the discussion of what it is and
what it is not.
Evidence based medicine is the conscientious, explicit, and
judicious use of current best evidence in making decisions
about the care of individual patients. The practice of evidence
based medicine means integrating individual clinical expertise
with the best available external clinical evidence from syste
matic research. By individual clinical expertise we mean the
proficiency and judgment that individual clinicians acquire
through clinical experience and clinical practice. Increased
expertise is reflected in many ways, but especially in more
effective and efficient diagnosis and in the more thoughtful
identification and compassionate use of individual patients'
predicaments, rights, and preferences in making clinical
decisions about their care. By best available external clinical
51evidence we mean clinically relevant research, often from the
71
Ui:1.,J\".
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ULlL
~"YC\"'Ji:lU'y
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clinical rCClp.arch into the accuracy and precision of diagnostic
teslS (including the clinical examination), the power of
prognostic markers, and the efficacy and safety of therapeutic,
rehabilitative, and preventive regimens. External clinical
evidence both invalidates previously accepted diagnostic tests
and treatments and replaces them with new ones that are more
powerful, more accurate, more efficacious, and safer.
Good doctors use both individual clinical expertise and the
best available external evidence, and neither alone is enough.
Without clinical expertise, practice risks becoming tyrannised
by evidence, for even excellent external evidence may be
inapplicable to or inappropriate for an individual patient.
Without current best evidence, practice risks becoming
rapidly out of date, to the detriment ofpatients.
This description of what evidence based medicine is helps
clarify what evidence based medicine is not. Evidence based
medicine is neither old hat nor impossible to practice. The
argument that "everyone already is doing it" falls before
evidence of striking variations in both the integration of
patient values into our clinical behaviour? and in the rates with
which clinicians provide interventions to their patients." The
difficulties that clinicians face in keeping abreast of all the
medical advances reported in primary journals are obvious
from a comparison of the time required for reading (for
general medicine, enough to examine 19 articles per day,
365 days per year') with the time available (well under an hour
a week by British medical consultants, even on self reports 10).
The argument that evidence based medicine can be con
ducted only from ivory towers and armchairs is refuted by
audits from the front lines of clinical care where at least some
inpatient clinical teams in general medicine," psychiatry a R
Geddes et ai, Royal College of Psychiatrists winter meeting,
January 1996), and surgery (P McCulloch, personal com
munication) have provided evidence based care to the vast
majority of their patients. Such studies show that busy
clinicians who devote their scarce reading time to selective,
efficient, patient driven searching, appraisal, and incor
poration of the best available evidence can practice evidence
based medicine.
Evidence based medicine is not "cookbook" medicine.
Because it requires a bottom up approach that integrates
the best external evidence with individual clinical expertise
and patients' choice, it cannot result in slavish, cookbook
approaches to individual patient care. External clinical
evidence can inform, but can never replace, individual clinical
expertise, and it is this expertise that decides whether the
external evidence applies to the individual patient at all and, if
so, how it should be integrated into a clinical decision.
Similarly, any external guideline must be integrated with
individual clinical expertise in deciding whether and how
it matches the patient's clinical state, predicament, and
preferences, and thus whether it should be applied. Clinicians
who fear top down cookbooks will find the advocates of
evidence based medicine joining them at the barricades.
Some fear that evidence based medicine will be hijacked by
purchasers and managers to cut the costs of health care. This
would not only be a misuse of evidence based medicine but
suggests a fundamental misunderstanding of its financial
consequences. Doctors practising evidence based medicine
will identify and apply the most efficacious interventions to
maximise the quality and quantity of life for individual
patients; this may raise rather than lower the cost of their care.
Evidence based medicine is not restricted to randomised
trials and meta-analyses. It involves tracking down the best
external evidence with which to answer our clinical questions.
To find out about the accuracy of a diagnostic test, we need to
find proper cross sectional studies of patients clinically
"U"YC\".LCU VI. Ui:1J.UVUJ.J1J.1S
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.I.ll;;Jll;;Yi:1UL UJ.,U.l.Ull;;.I.,
UVL
e:t .I.i:lUUV
mised trial. For a question about prognosis, we need proper
follow up studies of patients assembled at a uniform, early
point in the clinical course oftheir disease. And sometimes the
evidence we need will come from the basic sciences such as
genetics or immunology. It is when asking questions about
therapy that we should try to avoid the non-experimental
approaches, since these routinely lead to false positive
conclusions about efficacy. Because the randomised trial, and
especially the systematic review of several randomised trials,
is so much more likely to inform us and so much less likely to
mislead us, it has become the "gold standard" for judging
whether a treatment does more good than harm. However,
some questions about therapy do not require randomised
trials (successful interventions for otherwise fatal conditions)
or cannot wait for the trials to be conducted. And if no
randomised trial has been carried out for our patient's
predicament, we must follow the trail to the next best external
evidence and work from there.
Despite its ancient origins, evidence based medicine
remains a relatively young discipline whose positive impacts
are just beginning to be validated,12 13 and it will continue
to evolve. This evolution will be enhanced as several under
graduate, postgraduate, and continuing medical education
programmes adopt and adapt it to their learners' needs. These
programmes, and their evaluation, will provide further
information and understanding about what evidence based
medicine is and is not.
DAVID L SACKETT
Professor
NHS Research and Development Centre for Evidence Based Medicine,
Oxford Radcliffe NHS Trust,
Oxford OX3 9DU
WIll.IAM M C ROSENBERG
Clinical tutor in medicine
Nuffield Department of Clinical Medicine,
University of Oxford,
Oxford
JA MUIR GRAY
Director of research and development
Anglia and Oxford Regional Health Authority,
Milton Keynes
R BRIAN HAYNES
Professor of medicine and clinical epidemiology
McMaster University,
Hamilton, Ontario
Canada
W SCOTT RICHARDSON
Clinical associate I'rofessor of medicine
University of Rochester School of Medicine and Dentistry,
Rochester, New York,
USA
1 British Medical Association. Report of"" working fJ4Tfy OIl nudi<aI education. London: BMA, 1995.
2 Standing Committee on Poslgnduale Medical and Denlal Education. C...aJing a btlUr leaming
mtJiron",.", in hospitals. I. readling hospital doaon and dmtisu to u(J(;h. London: SCOPME, 1994.
3 General Medical Council. Education commiau rtpon. London: GMC, 1994.
4 Graham..Smirh D. Evidence based medicine: Socratic diasenl. 8MJ 1995;310:1126-7.
5 Evidence based medicine; in iu place [editorial]. Lance, 1995;346:785.
6 Corre.pondence. Evidence based medicine. Lanai 1995;346: 1171-2.
7 WearheralJ DJ: The inhumanity of medicine. 8MJ 1994;309;1671-2.
8 House of CommoDs Health Committee. Priority sminK in tJu NHS: purchasing. Fint rtport sessions
199~95. London: HMSO. 1995. (HC 134-1.)
9 DavidoffF, Haynes B, Sackett D, Smirh R Evidence based medicine: a new joumallo help doctors
identify rhe information rhey need. 8MJ 1995;310:1085-6.
10 Sackett D1- Surveys of self-rq>otted reading times of consullanls in Ozford, Birmingham, Mil,On
Keynes, Bristol, Leicester, and Glasgow. In: Rosenberg WMC, Richardson WS, Haynes RB,
Sackett D1- Evidm",-based medicine. London: Churchill Livinplone (in pres.).
11 Ellis J, MuUigan I, Rowe J, Sackett OL. Inpatient general medicine is evidence based. Lancet
1995;346:407-10.
12 Bennert RJ. Sackert DL, Hayne. RB, Neufeld VR. A controlled !rial of reaching critical appraisal
ofrhe clinicallilerarure 10 medicalsrudenrs.JAMA 1987;2S7:2451-4.
13 Shin JH, Flayncs RB, Johnston ME. Effect of problem-based, sclf-direeted undergraduate
education on life-long learning. Can MedAssoc J 1993;148:969-76.
For details of the international conference on evidence based
medicine to be held in London on Wednesday 24 April 1996, contact
the BMNBM] Conference Unit, telephone 0171 383 6605, fax
5201713836663.
Exhibit "H"
7'1
__ ...• Tr' ..
r ....'
100;;
Janssen-Ortho Inc.
Cobalt Pharmaceuticals Inc.
Novopharm Limited
Ranbaxy Pharmaceuticals Canada Inc.
ratiopharm inc.
Exhibit "I"
•
I
January 2, 2009
Dear Health Care Professional:
SUBJECT:
Important Changes to the Dose Conversion Guidelines for Fentanyl Transdermal
Systems
The manufacturers of Fentany I Transdermal Systems (FTS), in collaboration with Health Canada wish to
provide you with important information regarding changes to the Dose Conversion Guidelines (Table
1.1) and to the analgesic equivalency table: Opioid Analgesics: Parenteral/Oral/Rectal Equianalgesic
Potency Conversion (Table 1.2) in the Dosage and Administration section of the Canadian Product
Monographs for FTS. The Dose Conversion Guidelines are to be used to convert adult patients from
their current oral or parenteral opioid therapy to the fentanyl transdermal patch. The analgesic
equivalency table Opioid Analgesics: Parenteral/Oral/Rectal Equianalgesic Potency Conversion,
may be used for adult patients taking opioids or doses not listed in Table 1.1, using the conversion
methodology outlined for Table 1.1 with Table 1.2.
The revised Dose Conversion Guidelines and Opioid Analgesics: Parenteral/Oral/Rectal
Equianalgesic Potency Conversion Table are attached for your reference and should be retained for
future consultation. Changes have been highlighted for ease of reference.
Serious or life-threatening hypoventilation can result if appropriate conversions are not used.
Based on clinical experience in patients with chronic pain:
•
The conversion from 1M/IV morphine to the fentanyl transdermal patch has been revised to
reflect a conversion ratio of 1:2 and 1:3 of parenteral morph ine to oral morphine.
•
The conversion from IV hydromorphone to the fentanyl transdermal patch has been revised to
reflect a conversion ratio of 1:2 of parenteral hydromorphone to oral hydromorphone.
The use of fentanyl transdermal systems in opioid-na'ive patients and in patients with acute or
postoperative pain is contraindicated.
]n addition, the analgesic equivalency table 1.2 has been revised to remove the data equating 10 mg
parenteral morphine to 60 mg oral morphine derived from single or intermittent dosing studies. Data
referring to IM//IV oxycodone and to 1M meperidine have been removed from both Tables 1.1 and 1.2 as
the former drug is not marketed in Canada as an Injectable, and the latter drug causes CNS toxicity if used
by the parenteral route chronically.
53
Exhibit "l"
Manufacturers of all fentanyl transdermal patches are working with Health Canada to include this safety
information in the Dosage and Administration section in all Canadian Product Monographs for Fentanyl
Transdennal Systems:
Duragesic® (fentanyl transdermal system)
CO Fentanyl
Novo-fentanyl
RAN-fentanyl transdermal system
ratio-FENTANYL Transdermal System
Managing marketed health product-related adverse reactions depends on health care professionals and
consumers reporting them. RepOlting rates determined on the basis of spontaneously reported post
marketing adverse reactions are generally presumed to underestimate the risks associated with health
product treatments. Any serious or unexpected adverse reactions in patients receiving fentanyl
transdemlal systems should be reported to the manufacturers or Health Canada at the following addresses:
Janssen-Ortho Inc.
Drug Safety Department
19 Green Belt Drive
Toronto, Ontario M3C 1L9
Telephone: (800) 567-3331 or Fax: (866) 767-5865
dsscan@joica.jnj.com
Cobalt Pharmaceuticals Inc.
6500 Kitimat Road
Mississauga, Ontario L5N 2B8
Telephone: 1-866-254-6111
Fax: 905-542-0478
Novopharm Limited
Pharmacovigilance and Drug Safety
30 Novopharm Court
Toronto, Ontario M I B 2K9
Telephone: 416-291-8888 ext. 5005
Fax: 416-335-4472
E-mail: PhV(a)Novopharm.com
2680 Matheson Blvd. East, Suite 200
Mississauga, Ontario L4W OA5
Telephone: 1-866-840-1340
Fax: 905-602 4216
ratiopharm inc.
17800 Lapointe
Mirabel, Quebec 17J IP3
Telephone: 1-800-337-2584
Fax: 1-800-313-7673
www.ratiopharm.ca
E-mail: drugsafety@ratiopharm.ca
54
Exhibit "\"
Any suspected adverse reaction can also be reported to:
Canada Vigilance Program
HEALTH CANADA
Address Locator: 0701 C
Ottawa, Ontario, KIA OK9
Tel: 613-957-0337 or Fax: 613-957-0335
Tel: 866-234-2345
Fax: 866-678-6789
CanadaVigilance@hc-sc.gc.ca
The AR Reporting Form and the AR Guidelines can be found on the Health Canada web site or in The
Canadian Compendium ofPharmaceuticals and Specialties.
http://www.hc-sc.gc.ca/dhp-mps/medeff/report-declaration/form/ar-ei form e.html
http://www.hc-sc.gc.caJdhp-mps/medeff/report-declaration/guide/ar-eiguide-ldire.html
For other inquiries related to this communication, please contact Health Canada at:
E-mail: mhpd_dpsc@hc-sc.gc.ca
Tel: 613-954-6522
Fax: 613-952-7738
Please contact the appropriate manufacturer with any questions or concerns.
Authorized by:
lanssen-Ortho Inc.
Cobalt Pharmaceuticals Tnc.
Novopharm Limited
ratiopharm inc.
References
Johnson BL, Gross 1. Chapter 8, Phannacological Treatment of Cancer Pain in Handbook of Oncology
Nursing, Jones & Bartlett Publishers, 1998. p.313-327
Ripamont, C, Pharmacology ofOpioid Analgesia: Clinical Principles in Cancer Pain: Assessment and
Management, edited by Bruera E and Portenoy RK. Cambridge University Press, 2003. p.124
55
EXhibit 111'1
Attachment
DOSAGE CONVERSION GUIDELINES FOR FENTANYL TRANSDERMAL SYSTEMS
Table 1.1 1 #
From Current Opioid to DURAGES1C or other Fentanyl Transdermal Systems (FTS):
Dose Conversion Guidelines
Daily Dosage (mg/d)
Current Analgesic
Oral morphine
60-134
135-179
180-224
225-269
270-314
315-359
360-404
1\1/1\' morphine!
30-66
67-9U
91-111
112-13"
135-157
158-179
180-202
Oral oxycodone
30-66
67-90
91-112
113-134
135-157
158-179
180-202
Oral codeine
150-447
448-597
598-747
748-897
898-1047
1048-1197
1198-1347
8-16
17-22
23-28
29-33
34-39
40-45
46-51
".0-8."
8.5-11'"
11.5-1 .....
....5-16.5
16.6- 19.5
19.6-22.5
22.6-25.5
Oral hydromorphone
IV hydromorphone
J
U
Recommended
Fentanyl Transdermal
System (FTS) Dose
25 mcg/h
U
37 mcg/h
U
50 mcg/h
U
62 mcg/h
U
75 mcg/h
U
U
87 mcg/h
100 mcg/h
Alternatively, for adult patients taking opioids or doses not listed in Table 1.1, use the conversion methodology outlined
above with Table 1,2,
# 12 mcglh dose is not included in this table because it generally should not be used as the initiating dose, except in
the case of patients for whom clinical judgment deems it appropriate to start DURAGESIC and other FTS at less
than 25 mcglh; DURAGESIC and other FTS at any dose is contraindicated in opioid-naive patients (see
CONTRAINDICATlONS).
'Table 1.1 should not be used to convert from DURAGESIC and other FTS to other therapies because this
conversion to DURAGESIC and other FTS is conservative. Use of Table 1.1 for conversion to other analgesic
therapies can overestimate the dose ofthe new agent. Overdosage ofthe new analgesic agent is possible (see
DOSAGE AND ADMINISTRATION, Safe Use of Tables 1.1, 1.2, and 1.3).
2 Based on clinical experience in patients with chronic pain, the conversion ratio of 10 mg parenteral morphine is
equal to approximately 20 - 30 mg oral morphine. In the table above, calculation is based on a 1:2 parenteral to
oral dose ratio. For some patients, a 1:3 parenteral to oral dose ratio (10 mg parenteral morphine = 30 mg oral
morphine) may be more appropriate. The respective 1M/IV morphine equivalents for the various fentanyl
transdermal doses with a 1:3 ratio are:
1M/IV morphine
(mg/d) at
20-....
"5-60
61-75
76-90
91-10"
105 -119
120-134
25 mcg/h
37 mcg/h
50 mcg/h
62 mcg/h
75 mcg/h
87 mcg/h
100 mcg/h
1:3 parenteral to
oral dose ratio
Recommended
FTS Dose
56
Exhibit "'"
3 The
conversion ratio of parenteral hydromorphone to oral hydromorphone of 1:2 is based on clinical experience in
patients with chronic pain. Reference: Parenteral Drug Therapy Manual, Vancouver General Hospital,
Pharmaceutical Sciences Clinical Services.
57
Exhibit "III
OPIOID ANALGESICS: PARENTERALIORALIRECTAL
EQUIANALGESIC POTENCY CONVERSION
Table 1.2
Opioid Analgesics: Parenteral/OralJRectal Equianalgesic Potency Conversion
DRUG
Equivalent Dose (mgi 2)
(compared to morphine 10 mg 1M)
Parenteral
Strong Opioid Agonists:
Morphine (repeated dosing)
Hydromorphone
Anileridine
Levorphanol
Oxymorphone
Methadone(4)
10
1.5
25
2
1
Weak Opioid Agonists:
Codeine
Oxycodone
130
Propoxyphene
50
(I)
(I)
Duration of Action
(hours)
Oral
20-30
7.5
75
4
10 (rectal)
3-4
2-4
2-3
4-8
3-4
200
30
100
3-4
2-4
2-4
(3)
References:
Foley K.M. Cancer, Principles and Practice ofOnco]ogy, 4th Ed., V.T. Devita, Jr., S. Hellman, S.A.
Rosenberg (Ed.), 1.E. Lippincott Co., Philadelphia: 1993. p. 2417-2448.
Foley K. M. The Treatment of Cancer Pain, New Eng!. 1. Med. 313(2): 84-95, 1985.
AronoffG.M Evans, W.O., Evaluation and Treatment of Chronic Pain, 2nd Ed., G.M. Aronoff(Ed.),
Williams and Wilkins, Baltimore, p. 359-368,1992.
Cherny N.I,Portenoy, R.K., Textbook ofPain, 3rd Ed., P.O. Wall and R. Melzack (Eds.), Churchill
Livingstone, London, p. 1437-1467, 1994.
(2)
(3)
Most of these data were derived from single-dose, acute pain studies and should be considered an
approximation for selection of doses when treating chronic pain.
The conversion ratio of 10 mg parenteral morphine = 20 - 30 mg oral morphine is based on clinical
experience in patients with chronic pain.
Reference:
Skaer TL. Practice Guidelines for Transdermal Opioids in Malignant Pain. Drugs: 64 (23) 2629 - 2638,
2004.
Berdine HJ, Nesbit SA. Equianalgesic Dosing of Opioids. Journal of Pain & Palliative Care
Pharmacotherapy: 20 (4) 79 - 84, 2006.
(4) Extremely variable equianalgesic dose. Patients should undergo personalized titration starting at an
equivalent to 1/10 of the morphine dose.
58
Fentanyl transdermal patches prescribed for Mrs. Palamarek were missing on nine
separate occasions as evidenced by the following nursing notes.
9/17/2008 22:11
Type: General Narrative Note
Note Text: Fentanyl patch that was due yesterday(Sep16) was not applied. Writer removed old patch(Sep13) and applied new
one.
Transcriber: Hyun Ju Kim Interdisciplinary Team - LPN, Lodge Signature:
Nurse
1/19/2008 22:00
Note Text: .No fentanyl patch found on resident this evening. New fentanyl applied this evening.
Transcriber: Jennifer Guther Interdisciplinary Team - LPN,
Lodge Nurse
5/171200822:31
Signature:
Note Text: Unable to find old Fentanyl patch. New one on. H.J.Kim/LPN
Transcriber: Hyun Ju Kim Interdisciplinary Team· LPN.
Nurse
odge
Signature:
12/281200708:09 Type: General Narrative Note
Note Tellt:
Note Text: In the past week two incident reports have been completed re missing Durageslc patches which were
not on Mrs. Palamarek's person on change day. Writer suspects Kay is removing these herself. Note left in MAR to
secure new patches on her upper back to hopefully reduce their accessabllity.
Transcriber: Debbie McMahon Interdisciplinary Team - Care
Coordinator
10/21/200721 :40
Signature:
Type: General Narrative Nole
Note Text: Unable to locate duragesic patch @ hs.
Transcriber: Julie Swan Interdisciplinary Team - Lodge Nurse
9/27/200722: 19
Signature:
Note Text: Unable to locate duragesic patch at hs.
9112/200721:05
Signature:
Note Text: Unable to locate duragesic patch at hs. new patch applied to right shoulder.
Transcriber: Julie Swan Interdisciplinary Team· Lodge Nurse
81161200722:16
Signature:
Note Text: Writer unable to locate duragesic patch from August 13107. New patch applied to upper back.
12/231200721 :03
Signature:
Note Text: Patch change: No duragesic patch found at hs.
Transcriber: Julie Swan Interdisciplinary Team - lodge Nurse
Signature:
59
Exhibit "K"
Defective Ranbaxy 25 mcgjhr Fentanyl Patch
Defective Fentanyl Patch applied over reddened, excoriated skin.
Excoriated skin
extends under patch
Abnormal bubbles in
adhesive layer
indicate a defective
patch
Adhesive edge
Fentanyl reservoir
Tegaderm barrier
added to modify
delivery rate
60
Exhibit "K"
AdhesIVe
Layer
BUbbles in adhesive
layer indicates leak from
reselVOlr
Fentanyl
ReselVoir
lBubbles in adhesive border suggests that a leaking fentanyl transderrnal patch
(Ranbaxy 25 mcg/hr) was placed on Mrs. Palamarek at 8:00 PM on February 6, 2009.
61
Normal Fentanyl Patch
Note the absence of bubbles in the adhesive area.
Exhibit "l"
62
Exhibit "M"
I I
I
C
da
Sante
Cana a
a a
Fentanyl Transdermal Pain Patches recalled due to health risk
Advisory
2008-29
February 14, 2008
For immediate release
OTTAWA - Health Canada is advising Canadians not to use 25 mcgjhr Duragesic (fentanyl
transdermal system) patches sold by Janssen-Ortho Inc. and 25 mcgjhr Ran Fentanyl Transdermal
System patches sold by Ranbaxy. Duragesic and Ran Fentanyl Transdermal System 25 mcgjhr
patches are being voluntarily recalled by the manufacturer because they may have a cut along one
side of the patch which could result in leaking of the fentanyl gel from the patch.
Duragesic and Ran Fentanyl Transdermal System patches are prescription medications containing
a strong narcotic for use in the management of persistent, moderate to severe chronic pain.
Exposure to fentanyl gel that has leaked from the patch may lead to increased skin absorption and
could result in serious, potentially life-threatening adverse events, including respiratory depression
(slowed breathing) and possible overdose, which may be fatal.
Patients or caregivers should return the product to their pharmacy for safe disposal. Patches
should not be handled directly. Health Canada advises consumers who have been using these
products (25 mcgjhr strength of Duragesic or Ranbaxy Fentanyl patch) to contact their treating
physician for advice on a suitable alternative product for their medical condition.
Anyone who comes into contact with fentanyl gel that has leaked from a patch should thoroughly
rinse exposed skin with large amounts of water only; do not use soap or alcohol. Health Canada
advises consumers who have used this product and are concerned about their health to contact a
health practitioner for advice.
Signs of fentanyl overdose include difficult or shallow breathing, tiredness, extreme sleepiness or
sedation; inability to think, talk or walk normally; and feeling faint, dizzy or confused. Patients and
their caregivers should be aware of the signs and symptoms of fentanyl overdose, and should seek
medical attention immediately if any of these side effects are noted. Patches with a cut edge that
have leaked gel may not proVide effective pain relief.
To report a suspected adverse reaction to this product, please contact the Canada Vigilance
Program of Health Canada by one of the following methods:
Telephone: 1-866-234-2345
Facsimile: 1-866-678-6789
Canada Vigilance Program
Ottawa, Ontario, AL 0701C
K1A OK9
E-mail: CanadaViqilance@hc-sc.Qc.ca
The Canada Vigilance adverse reaction reporting form, including a version that can be completed
and submitted online, is located in the MedEffect area of the Health Canada Web site.
Consumers requiring more information about this adVisory can contact Health Canada's public
enquiries line at (613) 957-2991, or toll free at 1-866-225-0709.
63
Exhibit liN"
PAl,. M1 A R[ !( I
Q ,»)
c: :.') "');'}
, . -\ ~) (.
t.. A THUt
.)!)
1~MJUl-192c
.. Tpur
FALL RISK
Risk Factor Assessment
Risk Factor
J.
~J i. 0VJ S;~
~
o •
1,8...
Cognitive Dysfunction
2
I
~"
Neurological Diagnosis
5
5
~
Previous History of Falls
1
Impaired Mobility
1
I
1
General Debility
1
\
1
\~
\
I
I
Cardiovascu Iar\
Respiratory Insufficiency
,----,.
d'l
rf. hu, l (
·.t
1100
1
I 0
1
l
I
,
0 l) 2 [{\.) 5S
ASSESSME~T[lq~.l:1
",C'
" 2a.,O(C -;FH) h
Score
Medications in past 24 hrs·
~
Date
Time
Alterations in Elimination
n fi:) HAW,
:; 2:J
.~
1
.\
I
,
I
Bill.
Risk Assessment
TOTAL SCORE
Nurse initial
,., benzodlazeplnes, tranquilizers, narcotics. anaesthetic, laxative. diuretic
KEY
IRisk Level
Fall Risk Score
0-2
2-4
Low risK
Mooerate....8Jsk
(.~;gh
' .1
•
64
::;;.'.'
)
, .;:>"

affidavit -1 - Seniors at Risk

Transcription

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