"NARRATIVES
OF SERIOUS ADVERSE EVENTS
Selected clinical summaries of serious
adverse events are provided below. Deaths are listed first
followed by other serious events grouped by organ system.
The order in which the organ systems are listed is based
on the clinical significance of the adverse events. Psychiatric
adverse events were the most frequent and most clinically
significant serious adverse events. The clinical manifestations
of the most frequent serious adverse events appeared to
be similar across treatment groups. The rarer adverse
events did not appear to be specific to any treatment
group. The clinical descriptions of these events were
consistent with those of adverse events previously reported
in the literature for interferon alfa and described in
the drug label.
Deaths
Suicide: Patient 148 was a 42 year-old
woman on PEG-IFN 0.5pg/kg for 25 weeks who died by self-inflicted
gunshot wound. Of note is the lack of history of depression.
No symptoms or signs of depression were noted by the patient's
physicians.
Suicide, murder, paranoid reaction
in the post-treatment period: Patient 598 was
a 41 year-old man on IFN for 1 year and a history of depression,
antisocial behavior, and drug abuse.
Sudden death associated with
straining at stool: Patient 406 was a 59 year-old
man on IFN for 21 weeks. Myocardial infarction was suspected
as cause of death. There were neither history nor symptoms
of cardiovascular disease and the study ECG was normal.
No postmortem examination was performed.
Psychiatric
Adverse Events
The narratives of the psychiatric adverse events
indicate that suicidal behavior, namely ideation, attempt,
or completed suicide, was commonly (but by no means invariably)
associated with a previous history of depression or other
psychiatric diagnoses. Depression and other psychiatric
disorders occurred both during the interferon-treatment
period and in the post-treatment period.
Abuse of illicit drugs or ethanol was
reported. Very frequently drug abuse represented a relapse
of drug addiction and was often associated with development
of depression. Overdoses of illicit drugs were also reported.
These events did not appear to be a manifestation of suicidal
behavior.
Suicide attempt: Patient
057 was a 49 year-old woman who completed PEG-IFN 1.5
pg/kg for 1 year and attempted suicide (venisection and
intake of 24 g of acetaminophen) in the post-treatment
period. The patient had a history of depression and anxiety.
Suicide attempt, depression,
addiction relapse: Patient 371 was a 33 year-old
man who completed treatment with PEG-IFN 1.5 pg/kg. The
suicide attempt occurred in the post-treatment period;
depression and addiction relapse were also diagnosed at
that time. There was a previous history of suicide attempt,
depression, and drug abuse.
Suicidal gesture, depression,
anxiety, agitation: Patient 053 was a 53-year-old
man on PEG-IFN 1 pg/kg for 1 year and a history of depression
and drug abuse.
Suicidal/ ideation, depression,
aggressive reaction: Patient 139 was a 40 year-old
man on IFN-alfa-2b for 36 weeks and a history of depression.
Suicidal ideation, depression
aggravated: Patient 824 was a 43 year-old woman
on PEG-IFN 0.5 pg/kg for 1 year and a history of depression.
Suicidal ideation, depression,
addiction relapse: Patient 96 was a 40 year-old
woman on PEG-IFN 1.5 pg/kg for 8 weeks who became depressed
with suicidal thoughts and resumed ethanol abuse. Patients
had a history of suicidal attempts, depression and alcoholism.
Suicidal ideation, depression,
aggressive moods: Patient 411 was a 29 year-old
man, on PEG-IFN 1 pg/kg for 5 months. There was no previous
history of depression.
Suicidal ideation, depression:
Patient 012 was a 39 year-old man. PEG-IFN was discontinued
after 42 weeks for severe depression and suicidal thoughts.
There was no previous history of depression.
Suicidal ideation, depression:
Patient 465 was a 33 year-old man; PEG-IFN 1 .Opg/kg was
discontinued after 8 months for severe depression and
suicidal thoughts. There was no previous history of depression.
Suicidal ideation, emotional
lability, depression: Patient 304 was a 34 year-old
woman who was discontinued from PEG-IFN 0.5 yg/kg after
about 10 months due to suicidal ideation. There was no
previous history of depression.
Suicidal ideation:
Patient 288 was a 39 year-old woman on PEG-IFN 1.5pg/kg
and no previous history of depression. The event resolved
with treatment and IFN was continued.
Depression: Patient
084 was a 37 year-old man on PEG-IFN 0.5 pg/kg for 9 months
and a history of depression and drug abuse.
Addiction relapse/overdose:
Patient 084 following discontinuation of PEG-IFN due to
depression was hospitalized for respiratory failure and
required assisted ventilation. A drug screen was positive
for amphetamine, benzodiazepine, pentobarbital, marijuana
and ethanol.
Depression, drug abuse:
Patient 086 was a 34 year-old woman who completed PEG-IFN
1.5 pg/kg treatment. Depression developed and was followed
by use of illicit drugs. The patient had a history of
depression.
Depression, anxiety, addiction
relapse: Patient 024 was a 28 year-old man on
PEG-IFN 1.5 pg/kg for 2 months who became anxious, severely
depressed an restarted IV drug abuse.
Depression: Patient
089 was a 59 year-old woman on IFN for 2 months who developed
severe depression, fatigue and somnolence; previous history
of depression.
Depression: Patient
638 was a 43 year-old man who completed one year of treatment
with PEG-IFN 0.5 pg/kg. Depression began within 1 month
of treatment and waxed and waned in severity. In the post-treatment
period the patient was hospitalized for severe depression.
Addiction relapse/overdose,
depression, agitation, hypothyroidism: Patient
517 was a 47 year-old man on PEG-IFN 0.5 pg/kg for 37
weeks. He became depressed, agitated, irritable and overdosed
on diazepam (#50 10 mg tabs), hydrocodone and dalmane.
He developed hypothyroidism requiring treatment. There
was a previous history of depression and drug abuse.
Substance abuse, injury accidental:
Patient 097 was a 47 year-old man who completed PEG-IFN
0.5 pg/kg treatment. The patient sustained a crush injury
with pelvic and rib fractures and bladder injury. During
hospitalization for the multiple trauma he developed ethanol
withdrawal syndrome.
Addiction relapse:
Patient 107 was a 31 year-old man on IFN for 11 months.
The patient had history of drug abuse and depression and
was hospitalized for detoxification from benzodiazepines.
Addiction relapse, overdose:
Patient 306 was a 35 year-old man completed 1 year of
treatment with PEG-IFN 0.5 pg/kg. He was hospitalized
for an episode of loss of consciousness diagnosed as drug
abuse and unintended overdose of lorazepam and valoron.
There was a history of drug abuse.
Addiction relapse:
Patient 297 a 35 year-old man discontinued IFN treatment
after 6 months due to relapse of heroin abuse.
Cardiovascular
Adverse Events
Myocardial infarction, septal, age undetermined, cardiomyopathy,
severe depression of left ventricular systolic function:
Patient 053 was a 53 year old man on PEG-IFN 1 pg/kg for
1 year. He became symptomatic and was diagnosed in the
post IFN-treatment period.
Additional evidence of association
of ischemic events with IFN consists of one case of myocardial
infarction in study C97-058-01 (a PK study), two cases
of retinal ischemia in the phase 3 study (see "Ophthalmic"
narratives below), and post-marketing reports of ischemic
colitis associated with interferon alfa-2b.
Renal
Adverse Events
Nephrotic syndrome, interstitial nephritis:
Patient 087 was a 42 year old man who completed 1 year's
treatment with PEG-IFN 0.5 f_r.g/kg. Dramatic increase
in body weight and edema were first noted 1 month after
the end of IFN treatment. At 3 months post-treatment heavy
proteinuria (6g/24 hrs) was documented with normal urine
microscopy, hematology and clinical chemistries. At 4
months post- treatment interstitial nephritis was diagnosed
on renal biopsy (focal segmental glomerulosclerosis was
included in the differential diagnosis) and corticosteroid
treatment was begun for the nephrotic syndrome.
Hematologic
Adverse Events
Autoimmune thrombocytopenia: Patient
0002 was a 58 year-old man who received PEG-IFN 1 .O yglkg
for 16 weeks. IFN was stopped when the platelet count
dropped to 65x10' from 370x10' at baseline. Other hematology
parameters including bone marrow aspirate were normal.
Anti-platelet glycoprotein Ilb/llla was negative at baseline
and elevated during treatment. Increased gingival bleeding
was the only clinical manifestation of the cytopenia.
Platelet count normalized on corticosteroid treatment.
After several months of treatment corticosteroids were
tapered off without recurrence of thrombocytopenia.
Autoimmune thrombocytopenia,
epistaxis: Patient 157 was a 59 year-old woman
who received PEG-IFN 1 .O pg/kg for 3 months. While on
study, Parkinson's disease, gastritis, anxiety, and flu-like
syndrome were diagnosed and were treated with biperiden,
madopar, famotidine, acetaminophen, and a benzodiazepine.
IFN was discontinued due to severe thrombocytopenia (27
xl 0'). Anti-platelet glycoprotein la/lla and ANA became
weakly positive whereas they were negative at baseline.
Bone marrow was not examined. Corticosteroid treatment
was deemed unnecessary. Three months after discontinuation
of IFN the platelet count was 102 xl 0'.
Ophthalmic
Adverse Events
Retinal ischemia, decreased visual Acuity, cotton
wool spots: Patient 021 was a 58 year-old man
on IFN for 3 months. At 4 weeks of treatment he began
to complain of decreased vision at night that progressively
grew worse. There was no history of diabetes or cardiovascular
disease. Ophthalmologic exam at 3 months showed cotton
wool spots in the right eye and microvacular ischemia
was documented by angiography. IFN was stopped and ophthalmologic
changes were reported to be normal 8 weeks later.
Retinal vein thrombosis, vision
disorder: Patient 361 was a 48 year-old woman
on IFN for 7 months. Evaluation for scotomas in the right
eye revealed a thrombosis of the upper temporal pole of
the retinal vein with no involvement of the central vein.
Endocrine
Adverse Events
Autoimmune thyroiditis mya/gia,asthenia:
Patient 049 was a 30 year-old man, on PEG-INF 1.5 f_rg/kg
for 3 months. He developed asthenia, diarrhea, headaches,
myalgia, low TSH, elevated T3 and T4 and positive anti-peroxidase
antibodies. IFN was discontinued and carbimazole treatment
was begun.
lnfections
Because of the bone marrow suppressive effect of interferons
alfa, serious infections were reviewed for unusual clinical
manifestations or outcomes. The following events were
described. Two cases of pneumonias presumed to be bacterial;
one case of each of the following: appendicitis; peri-appendiceal
abscess with peritonitis; retrouterine abscess in the
presence of an IUD; oral abscess following dental extractions;
labial abscess associated with controlled diabetes; tonsillitis
presumed to be bacterial; erysipelas originating from
a wound in the popliteal fossa; aseptic meningitis. The
adverse events were not associated with clinically significant
decreases in neutrophil counts and patients appeared to
recover with treatment. An unusual finding was the presence
(in patient 206 on PEG-IFN 0.5 yglkg) of necrotizing epithelioid
granulomas in the post-treatment liver biopsy. A diagnosis
of mycobacterium infection was considered but was not
confirmed.
Neuroloqic
Adverse Events
Left-sided facial paralysis associated with neutropenia
and thrombocytopenia: Patient 022 was a 62 year-old man
on PEG-IFN 1 .O pg/kg for 3 months. Bell's palsy developed
while WBC was 0.81 x10' and the platelet count was 81
x10'. Paralysis and cytopenias resolved after discontinuation
of IFN. Left-sided facial paralysis: Patient 347 was a
53 year-old woman on PEG-IFN 1 ug/kg for two months and
a history of diabetes. Severe Bell's palsy developed,
IFN was stopped and corticosteroids begun; 15 weeks later
mild facial drooping remained.
Oculomotor nerve paralysis,
diplopia: Patient 577 was a 48 year-old man with
insulin-controlled diabetes. IFN treatment was discontinued
after 5 months because of double vision, and drooping
left eyelid. Partial oculomotor nerve palsy was attributed
to vasculitis caused by diabetes or IFN.
Hearing loss: Patient
068 was a 36 year-old woman who completed 1 year treatment
with PEG-IFN 1.5 yglkg. The patient complained of hearing
loss and an audiogram showed a bilateral 30% loss of hearing
(30 dB in the 1000 and 2000 Hz frequencies) that remained
stable on continued IFN treatment.
Dermatologic
Adverse Events
Psoriasis aggravated: Patient 149 was
a 37 year-old woman on IFN for 3 weeks and a history of
mild psoriasis controlled with topical coal extract. The
patient developed a severe flare of psoriasis affecting
the extremities and associated with arthralgias and eye
irritation. IFN was stopped and cyclosporine and calcipotriene
were required to control the psoriasis. Exacerbations
of psoriasis recurred in the post-treatment period.
Generalized urticaria:
Patient 318 was a 54 year-old woman on PEG-IFN 0.5 pg/kg
who developed injection site erythema after the third
dose. With the fourth dose the patient developed urticaria
that began at the injection site and became generalized.
IFN was discontinued and the patient was treated with
corticosteroids.
Autoimmune
Adverse Events
Systemic lupus erythematosus-like syndrome, Patient 327
was a 71 year-old woman who completed a 1 year course
of PEG-IFN 1.5 ug/kg. Six weeks post- treatment the patient
developed dyspnea, fever, and thoracic pain. Pericarditis
with effusion and pleurisy were diagnosed and diclofenac
was administered. GI bleeding occurred, was attributed
to diclofenac and was treated with transfusion. A respiratory
infection was treated with a cepahalosporin. Serologic
testing was positive at high titer for ANA, DS-DNA, TPO,
and for thyroid, spleen, thymus, and smooth muscle. No
treatment for the autoimmune disorder was considered necessary.
To the SLE case should be added the following autoimmune
adverse events described above: aggravated psoriasis,
thyroiditis, thrombocytopenia, and nephritis. In addition
ulcerative colitis (presenting with fever, abdominal pain,
and bloody diarrhea) has been associated with interferon
alfa by postmarketing adverse event reports."
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