Review of Schering Plough's
application for PEG-Intron
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
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
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.
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
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.
depression, aggressive reaction: Patient 139 was a 40
year-old man on IFN-alfa-2b for 36 weeks and a history of depression.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Patient 089 was a 59 year-old woman on IFN for 2 months who
developed severe depression, fatigue and somnolence; previous
history of 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.
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.
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.
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.
Patient 297 a 35 year-old man discontinued IFN treatment
after 6 months due to relapse of heroin abuse.
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
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.
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.
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
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
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.
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