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Center of Biologics Evaluation and Research
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 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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