"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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