FDA label f80518dd-eca6-4b0b-bd85-bec5712800de

WARNING Alpha interferons, including INTRON® A, cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Patients with persistently severe or worsening signs or symptoms of these conditions should be withdrawn from therapy. In many but not all cases these disorders resolve after stopping INTRON A therapy. See WARNINGS and ADVERSE REACTIONS .

WARNINGS General Moderate to severe adverse experiences may require modification of the patient's dosage regimen, or in some cases termination of INTRON® A therapy. Because of the fever and other "flu-like" symptoms associated with INTRON A administration, it should be used cautiously in patients with debilitating medical conditions, such as those with a history of pulmonary disease (e.g., chronic obstructive pulmonary disease) or diabetes mellitus prone to ketoacidosis. Caution should also be observed in patients with coagulation disorders (e.g., thrombophlebitis, pulmonary embolism) or severe myelosuppression. Cardiovascular Disorders INTRON A therapy should be used cautiously in patients with a history of cardiovascular disease. Those patients with a history of myocardial infarction and/or previous or current arrhythmic disorder who require INTRON A therapy should be closely monitored (see PRECAUTIONS, Laboratory Tests ). Cardiovascular adverse experiences, which include hypotension, arrhythmia, or tachycardia of 150 beats per minute or greater, and rarely, cardiomyopathy and myocardial infarction have been observed in some INTRON A-treated patients. Some patients with these adverse events had no history of cardiovascular disease. Transient cardiomyopathy was reported in approximately 2% of the AIDS-Related Kaposi's Sarcoma patients treated with INTRON A. Hypotension may occur during INTRON A administration, or up to 2 days post-therapy, and may require supportive therapy including fluid replacement to maintain intravascular volume. Supraventricular arrhythmias occurred rarely and appeared to be correlated with preexisting conditions and prior therapy with cardiotoxic agents. These adverse experiences were controlled by modifying the dose or discontinuing treatment, but may require specific additional therapy. Cerebrovascular Disorders Ischemic and hemorrhagic cerebrovascular events have been observed in patients treated with interferon alpha-based therapies, including INTRON A. Events occurred in patients with few or no reported risk factors for stroke, including patients less than 45 years of age. Because these are spontaneous reports, estimates of frequency cannot be made and a causal relationship between interferon alpha-based therapies and these events is difficult to establish. Neuropsychiatric Disorders DEPRESSION AND SUICIDAL BEHAVIOR INCLUDING SUICIDAL IDEATION, SUICIDAL ATTEMPTS, AND COMPLETED SUICIDES, HOMICIDAL IDEATION, AND AGGRESSIVE BEHAVIOR SOMETIMES DIRECTED TOWARDS OTHERS, HAVE BEEN REPORTED IN ASSOCIATION WITH TREATMENT WITH ALPHA INTERFERONS, INCLUDING INTRON A THERAPY. If patients develop psychiatric problems, including clinical depression, it is recommended that the patients be carefully monitored during treatment and in the 6-month follow-up period. INTRON A should be used with caution in patients with a history of psychiatric disorders. INTRON A therapy should be discontinued for any patient developing severe psychiatric disorder during treatment. Obtundation and coma have also been observed in some patients, usually elderly, treated at higher doses. While these effects are usually rapidly reversible upon discontinuation of therapy, full resolution of symptoms has taken up to 3 weeks in a few severe episodes. If psychiatric symptoms persist or worsen, or suicidal or homicidal ideation or aggressive behavior towards others is identified, discontinue treatment with INTRON A and follow the patient closely, with psychiatric intervention as appropriate. Narcotics, hypnotics, or sedatives may be used concurrently with caution and patients should be closely monitored until the adverse effects have resolved. Suicidal ideation or attempts occurred more frequently among pediatric patients, primarily adolescents, compared to adult patients (2.4% versus 1%) during treatment and off-therapy follow-up. Cases of encephalopathy have also been observed in some patients, usually elderly, treated with higher doses of INTRON A. Treatment with interferons may be associated with exacerbated symptoms of psychiatric disorders in patients with co-occurring psychiatric and substance use disorders. If treatment with interferons is initiated in patients with prior history or existence of psychiatric condition or with a history of substance use disorders, treatment considerations should include the need for drug screening and periodic health evaluation, including psychiatric symptom monitoring. Early intervention for re-emergence or development of neuropsychiatric symptoms and substance use is recommended. Bone Marrow Toxicity INTRON A therapy suppresses bone marrow function and may result in severe cytopenias including aplastic anemia. It is advised that complete blood counts (CBC) be obtained pretreatment and monitored routinely during therapy (see PRECAUTIONS, Laboratory Tests ). INTRON A therapy should be discontinued in patients who develop severe decreases in neutrophil (less than 0.5 × 10 9 /L) or platelet counts (less than 25 × 10 9 /L) (see DOSAGE AND ADMINISTRATION, Guidelines for Dose Modification ). Ophthalmologic Disorders Decrease or loss of vision, retinopathy including macular edema, retinal artery or vein thrombosis, retinal hemorrhages and cotton wool spots; optic neuritis, papilledema, and serous retinal detachment may be induced or aggravated by treatment with interferon alfa-2b or other alpha interferons. All patients should receive an eye examination at baseline. Patients with preexisting ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive periodic ophthalmologic exams during interferon alpha treatment. Any patient who develops ocular symptoms should receive a prompt and complete eye examination. Interferon alfa-2b treatment should be discontinued in patients who develop new or worsening ophthalmologic disorders. Endocrine Disorders Infrequently, patients receiving INTRON A therapy developed thyroid abnormalities, either hypothyroid or hyperthyroid. The mechanism by which INTRON A may alter thyroid status is unknown. Patients with preexisting thyroid abnormalities whose thyroid function cannot be maintained in the normal range by medication should not be treated with INTRON A. Prior to initiation of INTRON A therapy, serum TSH should be evaluated. Patients developing symptoms consistent with possible thyroid dysfunction during the course of INTRON A therapy should have their thyroid function evaluated and appropriate treatment instituted. Therapy should be discontinued for patients developing thyroid abnormalities during treatment whose thyroid function cannot be normalized by medication. Discontinuation of INTRON A therapy has not always reversed thyroid dysfunction occurring during treatment. Diabetes mellitus has been observed in patients treated with alpha interferons. Patients with these conditions who cannot be effectively treated by medication should not begin INTRON A therapy. Patients who develop these conditions during treatment and cannot be controlled with medication should not continue INTRON A therapy. Gastrointestinal Disorders Hepatotoxicity, including fatality, has been observed in interferon alpha-treated patients, including those treated with INTRON A. INTRON A increases the risk of hepatic decompensation and death in patients with cirrhosis. Any patient developing liver function abnormalities during treatment should be monitored closely and if appropriate, treatment should be discontinued. Pulmonary Disorders Dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension, and sarcoidosis, some resulting in respiratory failure and/or patient deaths, may be induced or aggravated by INTRON A or other alpha interferons. Recurrence of respiratory failure has been observed with interferon rechallenge. The etiologic explanation for these pulmonary findings has yet to be established. Any patient developing fever, cough, dyspnea, or other respiratory symptoms should have a chest X-ray taken. If the chest X-ray shows pulmonary infiltrates or there is evidence of pulmonary function impairment, the patient should be closely monitored, and, if appropriate, interferon alpha treatment should be discontinued. While this has been reported more often in patients with chronic hepatitis C treated with interferon alpha, it has also been reported in patients with oncologic diseases treated with interferon alpha. Autoimmune Disorders Rare cases of autoimmune diseases including thrombocytopenia, vasculitis, Raynaud's phenomenon, rheumatoid arthritis, lupus erythematosus, and rhabdomyolysis have been observed in patients treated with alpha interferons, including patients treated with INTRON A. In very rare cases the event resulted in fatality. The mechanism by which these events developed and their relationship to interferon alpha therapy is not clear. Any patient developing an autoimmune disorder during treatment should be closely monitored and, if appropriate, treatment should be discontinued. Human Albumin The powder formulations of this product contain albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin. AIDS-Related Kaposi's Sarcoma INTRON A therapy should not be used for patients with rapidly progressive visceral disease (see CLINICAL PHARMACOLOGY ). Also of note, there may be synergistic adverse effects between INTRON A and zidovudine. Patients receiving concomitant zidovudine have had a higher incidence of neutropenia than that expected with zidovudine alone. Careful monitoring of the WBC count is indicated in all patients who are myelosuppressed and in all patients receiving other myelosuppressive medications. The effects of INTRON A when combined with other drugs used in the treatment of AIDS-related disease are unknown. Chronic Hepatitis C and Chronic Hepatitis B Patients with decompensated liver disease, autoimmune hepatitis or a history of autoimmune disease, and patients who are immunosuppressed transplant recipients should not be treated with INTRON A. There are reports of worsening liver disease, including jaundice, hepatic encephalopathy, hepatic failure, and death following INTRON A therapy in such patients. Therapy should be discontinued for any patient developing signs and symptoms of liver failure. Chronic hepatitis B patients with evidence of decreasing hepatic synthetic functions, such as decreasing albumin levels or prolongation of prothrombin time, who nevertheless meet the entry criteria to start therapy, may be at increased risk of clinical decompensation if a flare of aminotransferases occurs during INTRON A treatment. In such patients, if increases in ALT occur during INTRON A therapy for chronic hepatitis B, they should be followed carefully, including close monitoring of clinical symptomatology and liver function tests including ALT, prothrombin time, alkaline phosphatase, albumin, and bilirubin. In considering these patients for INTRON A therapy, the potential risks must be evaluated against the potential benefits of treatment. Peripheral Neuropathy Peripheral neuropathy has been reported when alpha interferons were given in combination with telbivudine. In one clinical trial, an increased risk and severity of peripheral neuropathy was observed with the combination use of telbivudine and pegylated interferon alfa-2a as compared to telbivudine alone. The safety and efficacy of telbivudine in combination with interferons for the treatment of chronic hepatitis B has not been demonstrated. Use with Ribavirin (See also REBETOL ® prescribing information) REBETOL may cause birth defects and/or death of the unborn child. REBETOL therapy should not be started until a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy. Patients should use at least two forms of contraception and have monthly pregnancy tests (see CONTRAINDICATIONS and PRECAUTIONS, Information for Patients ). Combination treatment with INTRON A and REBETOL was associated with hemolytic anemia. Hemoglobin less than 10 g/dL was observed in approximately 10% of adult and pediatric patients in clinical trials. Anemia occurred within 1 to 2 weeks of initiation of ribavirin therapy. Combination treatment with INTRON A and REBETOL should not be used in patients with creatinine clearance less than 50 mL/min. See REBETOL prescribing information for additional information.

ADVERSE REACTIONS General The adverse experiences listed below were reported to be possibly or probably related to INTRON ® A therapy during clinical trials. Most of these adverse reactions were mild to moderate in severity and were manageable. Some were transient and most diminished with continued therapy. The most frequently reported adverse reactions were "flu-like" symptoms, particularly fever, headache, chills, myalgia, and fatigue. More severe toxicities are observed generally at higher doses and may be difficult for patients to tolerate. TREATMENT-RELATED ADVERSE EXPERIENCES BY INDICATION Dosing Regimens Percentage (%) of Patients Dash (--) indicates not reported MALIGNANT MELANOMA FOLLICULAR LYMPHOMA HAIRY CELL LEUKEMIA CONDYLOMATA ACUMINATA AIDS-RELATED KAPOSI'S SARCOMA CHRONIC HEPATITIS C Percentages based upon a summary of all adverse events during 18 to 24 months of treatment CHRONIC HEPATITIS B Adults Pediatrics 20 MIU/m 2 Induction (IV) 10 MIU/m 2 Maintenance (SC) 5 MIU TIW/SC 2 MIU/m 2 TIW/SC 1 MIU/lesion 30 MIU/m 2 TIW/SC 35 MIU QD/SC 3 MIU TIW 5 MIU QD 10 MIU TIW 6 MIU/m 2 TIW ADVERSE EXPERIENCE N=143 N=135 N=145 N=352 N=74 N=29 N=183 N=101 N=78 N=116 Application-Site Disorders 20 injection site inflammation -- 1 -- -- -- -- 5 3 -- -- other (≤5%) burning, injection site bleeding, injection site pain, injection site reaction (5% in chronic hepatitis B pediatrics), itching Blood Disorders (<5%) anemia, anemia hypochromic, granulocytopenia, hemolytic anemia, leukopenia, lymphocytosis, neutropenia (9% in chronic hepatitis C, 14% in chronic hepatitis B pediatrics), thrombocytopenia (10% in chronic hepatitis C) (bleeding 8% in malignant melanoma), thrombocytopenia purpura Body as a Whole facial edema -- 1 -- <1 -- 10 <1 3 1 <1 weight decrease 3 13 <1 <1 5 3 10 2 5 3 other (≤5%) allergic reaction, cachexia, dehydration, earache, hernia, edema, hypercalcemia, hyperglycemia, hypothermia, inflammation nonspecific, lymphadenitis, lymphadenopathy, mastitis, periorbital edema, poor peripheral circulation, peripheral edema (6% in follicular lymphoma), phlebitis superficial, scrotal/penile edema, thirst, weakness, weight increase Cardiovascular System Disorders (<5%) angina, arrhythmia, atrial fibrillation, bradycardia, cardiac failure, cardiomegaly, cardiomyopathy, coronary artery disorder, extrasystoles, heart valve disorder, hematoma, hypertension (9% in chronic hepatitis C), hypotension, palpitations, phlebitis, postural hypotension, pulmonary embolism, Raynaud's disease, tachycardia, thrombosis, varicose vein Endocrine System Disorders (<5%) aggravation of diabetes mellitus, goiter, gynecomastia, hyperglycemia, hyperthyroidism, hypertriglyceridemia, hypothyroidism, virilism Flu-like Symptoms fever 81 56 68 56 47 55 34 66 86 94 headache 62 21 39 47 36 21 43 61 44 57 chills 54 -- 46 45 -- -- -- -- -- -- myalgia 75 16 39 44 34 28 43 59 40 27 fatigue 96 8 61 18 84 48 23 75 69 71 increased sweating 6 13 8 2 4 21 4 1 1 3 asthenia -- 63 7 -- 11 -- 40 5 15 5 rigors 2 7 -- -- 30 14 16 38 42 30 arthralgia 6 8 8 9 -- 3 16 19 8 15 dizziness 23 -- 12 9 7 24 9 13 10 8 influenza-like symptoms 10 18 37 -- 45 79 26 5 -- <1 back pain -- 15 19 6 1 3 -- -- -- -- dry mouth 1 2 19 -- 22 28 5 6 5 -- chest pain 2 8 <1 <1 1 28 4 4 -- -- malaise 6 -- -- 14 5 -- 13 9 6 3 pain (unspecified) 15 9 18 3 3 3 -- -- -- -- other (<5%) chest pain substernal, hyperthermia, rhinitis, rhinorrhea Gastrointestinal System Disorders diarrhea 35 19 18 2 18 45 13 19 8 12 anorexia 69 21 19 1 38 41 14 43 53 43 nausea 66 24 21 17 28 21 19 50 33 18 taste alteration 24 2 13 <1 5 7 2 10 -- -- abdominal pain 2 20 <5 1 5 21 16 5 4 23 loose stools -- 1 -- <1 -- 10 2 2 -- 2 vomiting Vomiting was reported with nausea as a single term 32 6 2 11 14 8 7 10 27 constipation 1 14 <1 -- 1 10 4 5 -- 2 gingivitis 2 Includes stomatitis/mucositis 7 -- -- -- 14 -- 1 -- -- dyspepsia -- 2 -- 2 4 -- 7 3 8 3 other (<5%) abdominal ascites, abdominal distension, colitis, dysphagia, eructation, esophagitis, flatulence, gallstones, gastric ulcer, gastritis, gastroenteritis, gastrointestinal disorder (7% in follicular lymphoma), gastrointestinal hemorrhage, gastrointestinal mucosal discoloration, gingival bleeding, gum hyperplasia, halitosis, hemorrhoids, increased appetite, increased saliva, intestinal disorder, melena, mouth ulceration, mucositis, oral hemorrhage, oral leukoplakia, rectal bleeding after stool, rectal hemorrhage, stomatitis, stomatitis ulcerative, taste loss, tongue disorder, tooth disorder Liver and Biliary System Disorders (<5%) abnormal hepatic function tests, biliary pain, bilirubinemia, hepatitis, increased lactate dehydrogenase, increased transaminases (SGOT/SGPT) (elevated SGOT 63% in malignant melanoma and 24% in follicular lymphoma), jaundice, right upper quadrant pain (15% in chronic hepatitis C), and very rarely, hepatic encephalopathy, hepatic failure, and death Musculoskeletal System Disorders musculoskeletal pain -- 18 -- -- -- -- 21 9 1 10 other (<5%) arteritis, arthritis, arthritis aggravated, arthrosis, bone disorder, bone pain, carpal tunnel syndrome, hyporeflexia, leg cramps, muscle atrophy, muscle weakness, polyarteritis nodosa, tendinitis, rheumatoid arthritis, spondylitis Nervous System and Psychiatric Disorders depression 40 9 6 3 9 28 19 17 6 4 paresthesia 13 13 6 1 3 21 5 6 3 <1 impaired concentration -- 1 -- <1 3 14 3 8 5 3 amnesia Amnesia was reported with confusion as a single term 1 <5 -- -- 14 -- -- -- -- confusion 8 2 <5 4 12 10 1 -- -- 2 hypoesthesia -- 1 <5 1 -- 10 -- -- -- -- irritability 1 1 -- -- -- -- 13 16 12 22 somnolence 1 2 <5 3 3 -- 33 Predominantly lethargy 14 9 5 anxiety 1 9 5 <1 1 3 5 2 -- 3 insomnia 5 4 -- <1 3 3 12 11 6 8 nervousness 1 1 -- 1 -- 3 2 3 -- 3 decreased libido 1 1 <5 -- -- -- 1 5 1 -- other (<5%) abnormal coordination, abnormal dreaming, abnormal gait, abnormal thinking, aggravated depression, aggressive reaction, agitation (7% in chronic hepatitis B pediatrics), alcohol intolerance, apathy, aphasia, ataxia, Bell's palsy, CNS dysfunction, coma, convulsions, delirium, dysphonia, emotional lability, extrapyramidal disorder, feeling of ebriety, flushing, hearing disorder, hearing impairment, hot flashes, hyperesthesia, hyperkinesia, hypertonia, hypokinesia, impaired consciousness, labyrinthine disorder, loss of consciousness, manic depression, manic reaction, migraine, neuralgia, neuritis, neuropathy, neurosis, paresis, paroniria, parosmia, personality disorder, polyneuropathy, psychosis, speech disorder, stroke, suicidal ideation, suicide attempt, syncope, tinnitus, tremor, twitching, vertigo (8% in follicular lymphoma) Reproduction System Disorders (<5%) amenorrhea (12% in follicular lymphoma), dysmenorrhea, impotence, leukorrhea, menorrhagia, menstrual irregularity, pelvic pain, penis disorder, sexual dysfunction, uterine bleeding, vaginal dryness Resistance Mechanism Disorders moniliasis -- 1 -- <1 -- 17 -- -- -- -- herpes simplex 1 2 -- 1 -- 3 1 5 -- -- other (<5%) abscess, conjunctivitis, fungal infection, hemophilus, herpes zoster, infection, infection bacterial, infection nonspecific (7% in follicular lymphoma), infection parasitic, otitis media, sepsis, stye, trichomonas, upper respiratory tract infection, viral infection (7% in chronic hepatitis C) Respiratory System Disorders dyspnea 15 14 <1 -- 1 34 3 5 -- -- coughing 6 13 <1 -- -- 31 1 4 -- 5 pharyngitis 2 8 <5 1 1 31 3 7 1 7 sinusitis 1 4 -- -- -- 21 2 -- -- -- nonproductive coughing 2 7 -- -- -- 14 0 1 -- -- nasal congestion 1 7 -- 1 -- 10 <1 4 -- -- other (≤5%) asthma, bronchitis (10% in follicular lymphoma), bronchospasm, cyanosis, epistaxis (7% in chronic hepatitis B pediatrics), hemoptysis, hypoventilation, laryngitis, lung fibrosis, pleural effusion, orthopnea, pleural pain, pneumonia, pneumonitis, pneumothorax, rales, respiratory disorder, respiratory insufficiency, sneezing, tonsillitis, tracheitis, wheezing Skin and Appendages Disorders dermatitis 1 -- 8 -- -- -- 2 1 -- -- alopecia 29 23 8 -- 12 31 28 26 38 17 pruritus -- 10 11 1 7 -- 9 6 4 3 rash 19 13 25 -- 9 10 5 8 1 5 dry skin 1 3 9 -- 9 10 4 3 -- <1 other (<5%) abnormal hair texture, acne, cellulitis, cyanosis of the hand, cold and clammy skin, dermatitis lichenoides, eczema, epidermal necrolysis, erythema, erythema nodosum, folliculitis, furunculosis, increased hair growth, lacrimal gland disorder, lacrimation, lipoma, maculopapular rash, melanosis, nail disorders, nonherpetic cold sores, pallor, peripheral ischemia, photosensitivity, pruritus genital, psoriasis, psoriasis aggravated, purpura (5% in chronic hepatitis C), rash erythematous, sebaceous cyst, skin depigmentation, skin discoloration, skin nodule, urticaria, vitiligo Urinary System Disorders (<5%) albumin/protein in urine, cystitis, dysuria, hematuria, incontinence, increased BUN, micturition disorder, micturition frequency, nocturia, polyuria (10% in follicular lymphoma), renal insufficiency, urinary tract infection (5% in chronic hepatitis C) Vision Disorders (<5%) abnormal vision, blurred vision, diplopia, dry eyes, eye pain, nystagmus, photophobia Hairy Cell Leukemia The adverse reactions most frequently reported during clinical trials in 145 patients with hairy cell leukemia were the "flu-like" symptoms of fever (68%), fatigue (61%), and chills (46%). Malignant Melanoma The INTRON A dose was modified because of adverse events in 65% (n=93) of the patients. INTRON A therapy was discontinued because of adverse events in 8% of the patients during induction and 18% of the patients during maintenance. The most frequently reported adverse reaction was fatigue, which was observed in 96% of patients. Other adverse reactions that were recorded in greater than 20% of INTRON A-treated patients included neutropenia (92%), fever (81%), myalgia (75%), anorexia (69%), vomiting/nausea (66%), increased SGOT (63%), headache (62%), chills (54%), depression (40%), diarrhea (35%), alopecia (29%), altered taste sensation (24%), dizziness/vertigo (23%), and anemia (22%). Adverse reactions classified as severe or life threatening (ECOG Toxicity Criteria grade 3 or 4) were recorded in 66% and 14% of INTRON A-treated patients, respectively. Severe adverse reactions recorded in greater than 10% of INTRON A-treated patients included neutropenia/leukopenia (26%), fatigue (23%), fever (18%), myalgia (17%), headache (17%), chills (16%), and increased SGOT (14%). Grade 4 fatigue was recorded in 4% and grade 4 depression was recorded in 2% of INTRON A-treated patients. No other grade 4 AE was reported in more than 2 INTRON A-treated patients. Lethal hepatotoxicity occurred in 2 INTRON A-treated patients early in the clinical trial. No subsequent lethal hepatotoxicities were observed with adequate monitoring of liver function tests (see PRECAUTIONS, Laboratory Tests ). Follicular Lymphoma Ninety-six percent of patients treated with CHVP plus INTRON A therapy and 91% of patients treated with CHVP alone reported an adverse event of any severity. Asthenia, fever, neutropenia, increased hepatic enzymes, alopecia, headache, anorexia, "flu-like" symptoms, myalgia, dyspnea, thrombocytopenia, paresthesia, and polyuria occurred more frequently in the CHVP plus INTRON A-treated patients than in patients treated with CHVP alone. Adverse reactions classified as severe or life threatening (World Health Organization grade 3 or 4) recorded in greater than 5% of CHVP plus INTRON A-treated patients included neutropenia (34%), asthenia (10%), and vomiting (10%). The incidence of neutropenic infection was 6% in CHVP plus INTRON A versus 2% in CHVP alone. One patient in each treatment group required hospitalization. Twenty-eight percent of CHVP plus INTRON A-treated patients had a temporary modification/interruption of their INTRON A therapy, but only 13 patients (10%) permanently stopped INTRON A therapy because of toxicity. There were four deaths on study; two patients committed suicide in the CHVP plus INTRON A arm and two patients in the CHVP arm had unwitnessed sudden death. Three patients with hepatitis B (one of whom also had alcoholic cirrhosis) developed hepatotoxicity leading to discontinuation of INTRON A. Other reasons for discontinuation included intolerable asthenia (5/135), severe flu symptoms (2/135), and one patient each with exacerbation of ankylosing spondylitis, psychosis, and decreased ejection fraction. Condylomata Acuminata Eighty-eight percent (311/352) of patients treated with INTRON A for condylomata acuminata who were evaluable for safety reported an adverse reaction during treatment. The incidence of the adverse reactions reported increased when the number of treated lesions increased from one to five. All 40 patients who had five warts treated reported some type of adverse reaction during treatment. Adverse reactions and abnormal laboratory test values reported by patients who were re-treated were qualitatively and quantitatively similar to those reported during the initial INTRON A treatment period. AIDS-Related Kaposi's Sarcoma In patients with AIDS-Related Kaposi's Sarcoma, some type of adverse reaction occurred in 100% of the 74 patients treated with 30 million IU/m 2 three times a week and in 97% of the 29 patients treated with 35 million IU per day. Of these adverse reactions, those classified as severe (World Health Organization grade 3 or 4) were reported in 27% to 55% of patients. Severe adverse reactions in the 30 million IU/m 2 TIW study included: fatigue (20%), influenza-like symptoms (15%), anorexia (12%), dry mouth (4%), headache (4%), confusion (3%), fever (3%), myalgia (3%), and nausea and vomiting (1% each). Severe adverse reactions for patients who received the 35 million IU QD included: fever (24%), fatigue (17%), influenza-like symptoms (14%), dyspnea (14%), headache (10%), pharyngitis (7%), and ataxia, confusion, dysphagia, GI hemorrhage, abnormal hepatic function, increased SGOT, myalgia, cardiomyopathy, face edema, depression, emotional lability, suicide attempt, chest pain, and coughing (1 patient each). Overall, the incidence of severe toxicity was higher among patients who received the 35 million IU per day dose. Chronic Hepatitis C Adults Two studies of extended treatment (18–24 months) with INTRON A show that approximately 95% of all patients treated experience some type of adverse event and that patients treated for extended duration continue to experience adverse events throughout treatment. Most adverse events reported are mild to moderate in severity. However, 29/152 (19%) of patients treated for 18 to 24 months experienced a serious adverse event compared to 11/163 (7%) of those treated for 6 months. Adverse events which occur or persist during extended treatment are similar in type and severity to those occurring during short-course therapy. Of the patients achieving a complete response after 6 months of therapy, 12/79 (15%) subsequently discontinued INTRON A treatment during extended therapy because of adverse events, and 23/79 (29%) experienced severe adverse events (WHO grade 3 or 4) during extended therapy. In patients using combination treatment with INTRON A and REBETOL, the primary toxicity observed was hemolytic anemia. Reductions in hemoglobin levels occurred within the first 1 to 2 weeks of therapy. Cardiac and pulmonary events associated with anemia occurred in approximately 10% of patients treated with INTRON A/REBETOL therapy. See REBETOL prescribing information for additional information. Chronic Hepatitis C Pediatrics In pediatric patients with chronic hepatitis C treated with INTRON A 3 MIU/m 2 three times weekly and REBETOL 15 mg/kg per day, all subjects (n=118) had at least one adverse event during 24-48 weeks of treatment, of which 80% were considered to be mild or moderate in severity. Six percent discontinued therapy due to adverse reactions and dose modifications were required in 30% of subjects, most commonly for anemia and neutropenia. Adverse events occurring in more than 50% of subjects included headache, fever, fatigue and anorexia. Adverse events occurring in 20-50% of subjects included influenza-like symptoms, abdominal pain, vomiting, nausea, myalgia, pharyngitis, diarrhea, viral infection, rigors, weight decrease, musculoskeletal pain, alopecia and dizziness. The most common laboratory test abnormalities were neutropenia (34%) and anemia (27%). Depression was reported in 13% (n=15) of children. Three of these subjects had suicidal ideation, and one attempted suicide. Weight loss and slowed growth are common in pediatric patients during combination therapy with INTRON A and REBETOL. Following treatment, rebound growth and weight gain occurred in most subjects. Long-term follow-up data in pediatric subjects, however, indicates that INTRON A in combination with REBETOL may induce a growth inhibition that results in reduced adult height in some patients (see PRECAUTIONS, Pediatric Use ). Chronic Hepatitis B Adults In patients with chronic hepatitis B, some type of adverse reaction occurred in 98% of the 101 patients treated at 5 million IU QD and 90% of the 78 patients treated at 10 million IU TIW. Most of these adverse reactions were mild to moderate in severity, were manageable, and were reversible following the end of therapy. Adverse reactions classified as severe (causing a significant interference with normal daily activities or clinical state) were reported in 21% to 44% of patients. The severe adverse reactions reported most frequently were the "flu-like" symptoms of fever (28%), fatigue (15%), headache (5%), myalgia (4%), rigors (4%), and other severe "flu-like" symptoms, which occurred in 1% to 3% of patients. Other severe adverse reactions occurring in more than one patient were alopecia (8%), anorexia (6%), depression (3%), nausea (3%), and vomiting (2%). To manage side effects, the dose was reduced, or INTRON A therapy was interrupted in 25% to 38% of patients. Five percent of patients discontinued treatment due to adverse experiences. Chronic Hepatitis B Pediatrics In pediatric patients with chronic hepatitis B (n=72) during 16-24 weeks of treatment, the most frequently reported adverse events were those commonly associated with interferon treatment: flu-like symptoms (100%), gastrointestinal system disorders (46%), and nausea and vomiting (40%). Neutropenia (13%) and thrombocytopenia (3%) were also reported. None of the adverse events was life threatening and most were moderate to severe and resolved upon dose reduction or drug discontinuation. ABNORMAL LABORATORY TEST VALUES BY INDICATION Dosing Regimens Percentage (%) of Patients MALIGNANT MELANOMA FOLLICULAR LYMPHOMA HAIRY CELL LEUKEMIA CONDYLOMATA ACUMINATA AIDS-RELATED KAPOSI'S SARCOMA CHRONIC HEPATITIS C CHRONIC HEPATITIS B Adults Pediatrics 20 MIU/m 2 Induction (IV) 10 MIU/m 2 Maintenance (SC) 5 MIU TIW/SC 2 MIU/m 2 TIW/SC 1 MIU/lesion 30 MIU/m 2 TIW/SC 35 MIU QD/SC 3 MIU TIW 5 MIU QD 10 MIU TIW 6 MIU/m 2 TIW Laboratory Tests N=143 N=135 N=145 N=352 N=69–73 N=26–28 N=140–171 N=96–101 N=75–103 N=113–115 NA - Not Applicable- Patients' initial hematologic laboratory test values were abnormal due to their condition. Hemoglobin 22 8 NA -- 1 15 26 Decrease of ≥2 g/dL; 20% 2–<3 g/dL; 6% ≥3 g/dL 32 Decrease of ≥2 g/dL 23 17 Decrease of ≥2 g/dL; 14% 2–<3 g/dL; 3% ≥3 g/dL White Blood Cell Count White Blood Cell Count was reported as neutropenia -- NA 17 10 22 26 Decrease to <3000/mm 3 68 34 9 Platelet Count 15 13 NA -- 0 8 15 Decrease to <70,000/mm 3 12 5 1 Serum Creatinine 3 2 0 -- -- -- 6 3 0 3 Alkaline Phosphatase 13 -- 4 -- -- -- -- 8 4 0 Lactate Dehydrogenase 1 -- 0 -- -- -- -- -- -- -- Serum Urea Nitrogen 12 4 0 -- -- -- -- 2 0 2 SGOT 63 24 4 12 11 41 -- -- -- -- SGPT 2 -- 13 -- 10 15 -- -- -- -- Granulocyte Count Total 92 36 NA -- 31 39 45 Neutrophils plus bands 75 61 70 1000–<1500/mm 3 66 -- -- -- -- -- 32 30 32 43 750–<1000/mm 3 -- 21 -- -- -- -- 10 24 18 18 500–<750/mm 3 25 -- -- -- -- -- 1 17 9 7 <500/mm 3 1 13 -- -- -- -- 2 4 2 2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of INTRON A alone or in combination with REBETOL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders pancytopenia (concurrent anemia, leukopenia, thrombocytopenia), aplastic anemia, pure red cell aplasia, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura Ear and Labyrinth Disorders hearing loss Endocrine Disorders hypopituitarism Eye Disorders Vogt-Koyanagi-Harada syndrome, serous retinal detachment Gastrointestinal Disorders pancreatitis General Disorders and Administration Site Conditions asthenic conditions (including asthenia, malaise, fatigue) Immune System Disorders cases of acute hypersensitivity reactions, including anaphylaxis and angioedema, systemic lupus erythematosus, sarcoidosis or exacerbation of sarcoidosis Musculoskeletal and Connective Tissue Disorders myositis Nervous System Disorders peripheral neuropathy Psychiatric Disorders homicidal ideation, psychosis including hallucinations Renal and Urinary Disorders renal failure, renal insufficiency, nephrotic syndrome Respiratory, Thoracic, and Mediastinal Disorders pulmonary hypertension, pulmonary fibrosis Skin and Subcutaneous Tissue Disorders injection site necrosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, urticaria

<table width="100%"> <caption>TREATMENT-RELATED ADVERSE EXPERIENCES BY INDICATION</caption> <col width="12%" align="left" valign="top"/> <col width="12%" align="center" valign="top"/> <col width="12%" align="center" valign="top"/> <col width="12%" align="center" valign="top"/> <col width="11%" align="center" valign="top"/> <col width="6%" align="center" valign="top"/> <col width="6%" align="center" valign="top"/> <col width="11%" align="center" valign="top"/> <col width="6%" align="center" valign="top"/> <col width="6%" align="center" valign="top"/> <col width="6%" align="center" valign="top"/> <thead> <tr styleCode="Botrule"> <th/> <th colspan="10">Dosing Regimens Percentage (%) of Patients<footnote ID="ft20">Dash (--) indicates not reported</footnote> </th> </tr> <tr styleCode="Botrule"> <th/> <th valign="middle">MALIGNANT MELANOMA</th> <th valign="middle">FOLLICULAR LYMPHOMA</th> <th valign="middle">HAIRY CELL LEUKEMIA</th> <th valign="middle">CONDYLOMATA ACUMINATA</th> <th colspan="2" valign="middle">AIDS-RELATED KAPOSI&apos;S SARCOMA</th> <th valign="middle">CHRONIC HEPATITIS C<footnote ID="ft21">Percentages based upon a summary of all adverse events during 18 to 24 months of treatment</footnote> </th> <th colspan="3">CHRONIC HEPATITIS B</th> </tr> <tr styleCode="Botrule"> <th/> <th/> <th/> <th/> <th/> <th/> <th/> <th/> <th colspan="2">Adults</th> <th>Pediatrics</th> </tr> <tr> <th/> <th styleCode="Botrule">20 MIU/m² Induction (IV) 10 MIU/m² Maintenance (SC)</th> <th styleCode="Botrule" valign="middle">5 MIU TIW/SC</th> <th styleCode="Botrule" valign="middle">2 MIU/m² TIW/SC</th> <th styleCode="Botrule" valign="middle">1 MIU/lesion</th> <th styleCode="Botrule" valign="middle">30 MIU/m² TIW/SC</th> <th styleCode="Botrule" valign="middle">35 MIU QD/SC</th> <th styleCode="Botrule" valign="middle">3 MIU TIW</th> <th styleCode="Botrule" valign="middle">5 MIU QD</th> <th styleCode="Botrule" valign="middle">10 MIU TIW</th> <th styleCode="Botrule" valign="middle">6 MIU/m²TIW</th> </tr> <tr styleCode="Botrule"> <th>ADVERSE EXPERIENCE</th> <th>N=143</th> <th>N=135</th> <th>N=145</th> <th>N=352</th> <th>N=74</th> <th>N=29</th> <th>N=183</th> <th>N=101</th> <th>N=78</th> <th>N=116</th> </tr> </thead> <tbody> <tr> <td> <content styleCode="bold underline italics">Application-Site Disorders</content> </td> <td/> <td/> <td>20</td> <td/> <td/> <td/> <td/> <td/> <td/> <td/> </tr> <tr> <td> injection site inflammation</td> <td>--</td> <td>1</td> <td>--</td> <td>--</td> <td>--</td> <td>--</td> <td>5</td> <td>3</td> <td>--</td> <td>--</td> </tr> <tr styleCode="Botrule"> <td> other (&#x2264;5%)</td> <td colspan="10" align="left">burning, injection site bleeding, injection site pain, injection site reaction (5% in chronic hepatitis B pediatrics), itching</td> </tr> <tr styleCode="Botrule"> <td> <content styleCode="bold italics">Blood Disorders (&lt;5%)</content> </td> <td colspan="10" align="left">anemia, anemia hypochromic, granulocytopenia, hemolytic anemia, leukopenia, lymphocytosis, neutropenia (9% in chronic hepatitis C, 14% in chronic hepatitis B pediatrics), thrombocytopenia (10% in chronic hepatitis C) (bleeding 8% in malignant melanoma), thrombocytopenia purpura</td> </tr> <tr> <td> <content styleCode="bold underline italics">Body as a Whole</content> </td> <td/> <td/> <td/> <td/> <td/> <td/> <td/> <td/> <td/> <td/> </tr> <tr> <td> facial edema</td> <td>--</td> <td>1</td> <td>--</td> <td>&lt;1</td> <td>--</td> <td>10</td> <td>&lt;1</td> <td>3</td> <td>1</td> <td>&lt;1</td> </tr> <tr> <td> weight decrease</td> <td>3</td> <td>13</td> <td>&lt;1</td> <td>&lt;1</td> <td>5</td> <td>3</td> <td>10</td> <td>2</td> <td>5</td> <td>3</td> </tr> <tr styleCode="Botrule"> <td valign="top"> other (&#x2264;5%)</td> <td colspan="10" align="left">allergic reaction, cachexia, dehydration, earache, hernia, edema, hypercalcemia, hyperglycemia, hypothermia, inflammation nonspecific, lymphadenitis, lymphadenopathy, mastitis, periorbital edema, poor peripheral circulation, peripheral edema (6% in follicular lymphoma), phlebitis superficial, scrotal/penile edema, thirst, weakness, weight increase</td> </tr> <tr styleCode="Botrule"> <td> <content styleCode="bold italics">Cardiovascular System Disorders (&lt;5%)</content> </td> <td colspan="10" align="left">angina, arrhythmia, atrial fibrillation, bradycardia, cardiac failure, cardiomegaly, cardiomyopathy, coronary artery disorder, extrasystoles, heart valve disorder, hematoma, hypertension (9% in chronic hepatitis C), hypotension, palpitations, phlebitis, postural hypotension, pulmonary embolism, Raynaud&apos;s disease, tachycardia, thrombosis, varicose vein</td> </tr> <tr styleCode="Botrule"> <td> <content styleCode="bold italics">Endocrine System Disorders (&lt;5%)</content> </td> <td colspan="10" align="left">aggravation of diabetes mellitus, goiter, gynecomastia, hyperglycemia, hyperthyroidism, hypertriglyceridemia, hypothyroidism, virilism</td> </tr> <tr> <td> <content styleCode="bold italics underline">Flu-like Symptoms</content> </td> <td/> <td/> <td/> <td/> <td/> <td/> <td/> <td/> <td/> <td/> </tr> <tr> <td> fever</td> <td>81</td> <td>56</td> <td>68</td> <td>56</td> <td>47</td> <td>55</td> <td>34</td> <td>66</td> <td>86</td> <td>94</td> </tr> <tr> <td> headache</td> <td>62</td> <td>21</td> <td>39</td> <td>47</td> <td>36</td> <td>21</td> <td>43</td> <td>61</td> <td>44</td> <td>57</td> </tr> <tr> <td> chills</td> <td>54</td> <td>--</td> <td>46</td> <td>45</td> <td>--</td> <td>--</td> <td>--</td> <td>--</td> <td>--</td> <td>--</td> </tr> <tr> <td> myalgia</td> <td>75</td> <td>16</td> <td>39</td> <td>44</td> <td>34</td> <td>28</td> <td>43</td> <td>59</td> <td>40</td> <td>27</td> </tr> <tr> <td> fatigue</td> <td>96</td> <td>8</td> <td>61</td> <td>18</td> <td>84</td> <td>48</td> <td>23</td> <td>75</td> <td>69</td> <td>71</td> </tr> <tr> <td> increased sweating</td> <td>6</td> <td>13</td> <td>8</td> <td>2</td> <td>4</td> <td>21</td> <td>4</td> <td>1</td> <td>1</td> <td>3</td> </tr> <tr> <td> asthenia</td> <td>--</td> <td>63</td> <td>7</td> <td>--</td> <td>11</td> <td>--</td> <td>40</td> <td>5</td> <td>15</td> <td>5</td> </tr> <tr> <td> rigors</td> <td>2</td> <td>7</td> <td>--</td> <td>--</td> <td>30</td> <td>14</td> <td>16</td> <td>38</td> <td>42</td> <td>30</td> </tr> <tr> <td> arthralgia</td> <td>6</td> <td>8</td> <td>8</td> <td>9</td> <td>--</td> <td>3</td> <td>16</td> <td>19</td> <td>8</td> <td>15</td> </tr> <tr> <td> dizziness</td> <td>23</td> <td>--</td> <td>12</td> <td>9</td> <td>7</td> <td>24</td> <td>9</td> <td>13</td> <td>10</td> <td>8</td> </tr> <tr> <td> influenza-like symptoms</td> <td>10</td> <td>18</td> <td>37</td> <td>--</td> <td>45</td> <td>79</td> <td>26</td> <td>5</td> <td>--</td> <td>&lt;1</td> </tr> <tr> <td> back pain</td> <td>--</td> <td>15</td> <td>19</td> <td>6</td> <td>1</td> <td>3</td> <td>--</td> <td>--</td> <td>--</td> <td>--</td> </tr> <tr> <td> dry mouth</td> <td>1</td> <td>2</td> <td>19</td> <td>--</td> <td>22</td> <td>28</td> <td>5</td> <td>6</td> <td>5</td> <td>--</td> </tr> <tr> <td> chest pain</td> <td>2</td> <td>8</td> <td>&lt;1</td> <td>&lt;1</td> <td>1</td> <td>28</td> <td>4</td> <td>4</td> <td>--</td> <td>--</td> </tr> <tr> <td> malaise</td> <td>6</td> <td>--</td> <td>--</td> <td>14</td> <td>5</td> <td>--</td> <td>13</td> <td>9</td> <td>6</td> <td>3</td> </tr> <tr> <td> pain (unspecified)</td> <td>15</td> <td>9</td> <td>18</td> <td>3</td> <td>3</td> <td>3</td> <td>--</td> <td>--</td> <td>--</td> <td>--</td> </tr> <tr styleCode="Botrule"> <td> other (&lt;5%)</td> <td colspan="10" align="left">chest pain substernal, hyperthermia, rhinitis, rhinorrhea</td> </tr> <tr> <td> <content styleCode="bold underline italics">Gastrointestinal System Disorders</content> </td> <td/> <td/> <td/> <td/> <td/> <td/> <td/> <td/> <td/> <td/> </tr> <tr> <td> diarrhea</td> <td>35</td> <td>19</td> <td>18</td> <td>2</td> <td>18</td> <td>45</td> <td>13</td> <td>19</td> <td>8</td> <td>12</td> </tr> <tr> <td> anorexia</td> <td>69</td> <td>21</td> <td>19</td> <td>1</td> <td>38</td> <td>41</td> <td>14</td> <td>43</td> <td>53</td> <td>43</td> </tr> <tr> <td> nausea</td> <td>66</td> <td>24</td> <td>21</td> <td>17</td> <td>28</td> <td>21</td> <td>19</td> <td>50</td> <td>33</td> <td>18</td> </tr> <tr> <td> taste alteration</td> <td>24</td> <td>2</td> <td>13</td> <td>&lt;1</td> <td>5</td> <td>7</td> <td>2</td> <td>10</td> <td>--</td> <td>--</td> </tr> <tr> <td> abdominal pain</td> <td>2</td> <td>20</td> <td>&lt;5</td> <td>1</td> <td>5</td> <td>21</td> <td>16</td> <td>5</td> <td>4</td> <td>23</td> </tr> <tr> <td> loose stools</td> <td>--</td> <td>1</td> <td>--</td> <td>&lt;1</td> <td>--</td> <td>10</td> <td>2</td> <td>2</td> <td>--</td> <td>2</td> </tr> <tr> <td> vomiting</td> <td> <footnote ID="ft22">Vomiting was reported with nausea as a single term</footnote> </td> <td>32</td> <td>6</td> <td>2</td> <td>11</td> <td>14</td> <td>8</td> <td>7</td> <td>10</td> <td>27</td> </tr> <tr> <td> constipation</td> <td>1</td> <td>14</td> <td>&lt;1</td> <td>--</td> <td>1</td> <td>10</td> <td>4</td> <td>5</td> <td>--</td> <td>2</td> </tr> <tr> <td> gingivitis</td> <td>2<footnote ID="ft23">Includes stomatitis/mucositis</footnote> </td> <td>7<footnoteRef IDREF="ft23"/> </td> <td>--</td> <td>--</td> <td>--</td> <td>14</td> <td>--</td> <td>1</td> <td>--</td> <td>--</td> </tr> <tr> <td> dyspepsia</td> <td>--</td> <td>2</td> <td>--</td> <td>2</td> <td>4</td> <td>--</td> <td>7</td> <td>3</td> <td>8</td> <td>3</td> </tr> <tr styleCode="Botrule"> <td> other (&lt;5%)</td> <td align="left" colspan="10">abdominal ascites, abdominal distension, colitis, dysphagia, eructation, esophagitis, flatulence, gallstones, gastric ulcer, gastritis, gastroenteritis, gastrointestinal disorder (7% in follicular lymphoma), gastrointestinal hemorrhage, gastrointestinal mucosal discoloration, gingival bleeding, gum hyperplasia, halitosis, hemorrhoids, increased appetite, increased saliva, intestinal disorder, melena, mouth ulceration, mucositis, oral hemorrhage, oral leukoplakia, rectal bleeding after stool, rectal hemorrhage, stomatitis, stomatitis ulcerative, taste loss, tongue disorder, tooth disorder</td> </tr> <tr styleCode="Botrule"> <td> <content styleCode="bold italics">Liver and Biliary System Disorders (&lt;5%)</content> </td> <td align="left" colspan="10">abnormal hepatic function tests, biliary pain, bilirubinemia, hepatitis, increased lactate dehydrogenase, increased transaminases (SGOT/SGPT) (elevated SGOT 63% in malignant melanoma and 24% in follicular lymphoma), jaundice, right upper quadrant pain (15% in chronic hepatitis C), and very rarely, hepatic encephalopathy, hepatic failure, and death</td> </tr> <tr> <td> <content styleCode="bold underline italics">Musculoskeletal System Disorders</content> </td> <td/> <td/> <td/> <td/> <td/> <td/> <td/> <td/> <td/> <td/> </tr> <tr> <td> musculoskeletal pain</td> <td>--</td> <td>18</td> <td>--</td> <td>--</td> <td>--</td> <td>--</td> <td>21</td> <td>9</td> <td>1</td> <td>10</td> </tr> <tr styleCode="Botrule"> <td> other (&lt;5%)</td> <td align="left" colspan="10">arteritis, arthritis, arthritis aggravated, arthrosis, bone disorder, bone pain, carpal tunnel syndrome, hyporeflexia, leg cramps, muscle atrophy, muscle weakness, polyarteritis nodosa, tendinitis, rheumatoid arthritis, spondylitis</td> </tr> <tr> <td> <content styleCode="bold underline italics">Nervous System and Psychiatric Disorders</content> </td> <td/> <td/> <td/> <td/> <td/> <td/> <td/> <td/> <td/> <td/> </tr> <tr> <td> depression</td> <td>40</td> <td>9</td> <td>6</td> <td>3</td> <td>9</td> <td>28</td> <td>19</td> <td>17</td> <td>6</td> <td>4</td> </tr> <tr> <td> paresthesia</td> <td>13</td> <td>13</td> <td>6</td> <td>1</td> <td>3</td> <td>21</td> <td>5</td> <td>6</td> <td>3</td> <td>&lt;1</td> </tr> <tr> <td> impaired concentration</td> <td>--</td> <td>1</td> <td>--</td> <td>&lt;1</td> <td>3</td> <td>14</td> <td>3</td> <td>8</td> <td>5</td> <td>3</td> </tr> <tr> <td> amnesia</td> <td> <footnote ID="ft24">Amnesia was reported with confusion as a single term</footnote> </td> <td>1</td> <td>&lt;5</td> <td>--</td> <td>--</td> <td>14</td> <td>--</td> <td>--</td> <td>--</td> <td>--</td> </tr> <tr> <td> confusion</td> <td>8</td> <td>2</td> <td>&lt;5</td> <td>4</td> <td>12</td> <td>10</td> <td>1</td> <td>--</td> <td>--</td> <td>2</td> </tr> <tr> <td> hypoesthesia</td> <td>--</td> <td>1</td> <td>&lt;5</td> <td>1</td> <td>--</td> <td>10</td> <td>--</td> <td>--</td> <td>--</td> <td>--</td> </tr> <tr> <td> irritability</td> <td>1</td> <td>1</td> <td>--</td> <td>--</td> <td>--</td> <td>--</td> <td>13</td> <td>16</td> <td>12</td> <td>22</td> </tr> <tr> <td> somnolence</td> <td>1</td> <td>2</td> <td>&lt;5</td> <td>3</td> <td>3</td> <td>--</td> <td>33<footnote ID="ft25">Predominantly lethargy</footnote> </td> <td>14</td> <td>9</td> <td>5</td> </tr> <tr> <td> anxiety</td> <td>1</td> <td>9</td> <td>5</td> <td>&lt;1</td> <td>1</td> <td>3</td> <td>5</td> <td>2</td> <td>--</td> <td>3</td> </tr> <tr> <td> insomnia</td> <td>5</td> <td>4</td> <td>--</td> <td>&lt;1</td> <td>3</td> <td>3</td> <td>12</td> <td>11</td> <td>6</td> <td>8</td> </tr> <tr> <td> nervousness</td> <td>1</td> <td>1</td> <td>--</td> <td>1</td> <td>--</td> <td>3</td> <td>2</td> <td>3</td> <td>--</td> <td>3</td> </tr> <tr> <td> decreased libido</td> <td>1</td> <td>1</td> <td>&lt;5</td> <td>--</td> <td>--</td> <td>--</td> <td>1</td> <td>5</td> <td>1</td> <td>--</td> </tr> <tr styleCode="Botrule"> <td> other (&lt;5%)</td> <td align="left" colspan="10">abnormal coordination, abnormal dreaming, abnormal gait, abnormal thinking, aggravated depression, aggressive reaction, agitation (7% in chronic hepatitis B pediatrics), alcohol intolerance, apathy, aphasia, ataxia, Bell&apos;s palsy, CNS dysfunction, coma, convulsions, delirium, dysphonia, emotional lability, extrapyramidal disorder, feeling of ebriety, flushing, hearing disorder, hearing impairment, hot flashes, hyperesthesia, hyperkinesia, hypertonia, hypokinesia, impaired consciousness, labyrinthine disorder, loss of consciousness, manic depression, manic reaction, migraine, neuralgia, neuritis, neuropathy, neurosis, paresis, paroniria, parosmia, personality disorder, polyneuropathy, psychosis, speech disorder, stroke, suicidal ideation, suicide attempt, syncope, tinnitus, tremor, twitching, vertigo (8% in follicular lymphoma)</td> </tr> <tr styleCode="Botrule"> <td> <content styleCode="bold italics">Reproduction System Disorders (&lt;5%)</content> </td> <td colspan="10" align="left">amenorrhea (12% in follicular lymphoma), dysmenorrhea, impotence, leukorrhea, menorrhagia, menstrual irregularity, pelvic pain, penis disorder, sexual dysfunction, uterine bleeding, vaginal dryness</td> </tr> <tr> <td> <content styleCode="bold underline italics">Resistance Mechanism Disorders</content> </td> <td/> <td/> <td/> <td/> <td/> <td/> <td/> <td/> <td/> <td/> </tr> <tr> <td> moniliasis</td> <td>--</td> <td>1</td> <td>--</td> <td>&lt;1</td> <td>--</td> <td>17</td> <td>--</td> <td>--</td> <td>--</td> <td>--</td> </tr> <tr> <td> herpes simplex</td> <td>1</td> <td>2</td> <td>--</td> <td>1</td> <td>--</td> <td>3</td> <td>1</td> <td>5</td> <td>--</td> <td>--</td> </tr> <tr styleCode="Botrule"> <td> other (&lt;5%)</td> <td colspan="10" align="left">abscess, conjunctivitis, fungal infection, hemophilus, herpes zoster, infection, infection bacterial, infection nonspecific (7% in follicular lymphoma), infection parasitic, otitis media, sepsis, stye, trichomonas, upper respiratory tract infection, viral infection (7% in chronic hepatitis C)</td> </tr> <tr> <td> <content styleCode="bold underline italics">Respiratory System Disorders</content> </td> <td/> <td/> <td/> <td/> <td/> <td/> <td/> <td/> <td/> <td/> </tr> <tr> <td> dyspnea</td> <td>15</td> <td>14</td> <td>&lt;1</td> <td>--</td> <td>1</td> <td>34</td> <td>3</td> <td>5</td> <td>--</td> <td>--</td> </tr> <tr> <td> coughing</td> <td>6</td> <td>13</td> <td>&lt;1</td> <td>--</td> <td>--</td> <td>31</td> <td>1</td> <td>4</td> <td>--</td> <td>5</td> </tr> <tr> <td> pharyngitis</td> <td>2</td> <td>8</td> <td>&lt;5</td> <td>1</td> <td>1</td> <td>31</td> <td>3</td> <td>7</td> <td>1</td> <td>7</td> </tr> <tr> <td> sinusitis</td> <td>1 </td> <td>4</td> <td>--</td> <td>--</td> <td>--</td> <td>21</td> <td>2</td> <td>--</td> <td>--</td> <td>--</td> </tr> <tr> <td> nonproductive coughing </td> <td>2</td> <td>7</td> <td>--</td> <td>--</td> <td>--</td> <td>14</td> <td>0</td> <td>1</td> <td>--</td> <td>--</td> </tr> <tr> <td> nasal congestion</td> <td>1</td> <td>7</td> <td>--</td> <td>1</td> <td>--</td> <td>10</td> <td>&lt;1</td> <td>4</td> <td>--</td> <td>--</td> </tr> <tr styleCode="Botrule"> <td> other (&#x2264;5%)</td> <td align="left" colspan="10">asthma, bronchitis (10% in follicular lymphoma), bronchospasm, cyanosis, epistaxis (7% in chronic hepatitis B pediatrics), hemoptysis, hypoventilation, laryngitis, lung fibrosis, pleural effusion, orthopnea, pleural pain, pneumonia, pneumonitis, pneumothorax, rales, respiratory disorder, respiratory insufficiency, sneezing, tonsillitis, tracheitis, wheezing</td> </tr> <tr> <td> <content styleCode="bold underline italics">Skin and Appendages Disorders</content> </td> <td/> <td/> <td/> <td/> <td/> <td/> <td/> <td/> <td/> <td/> </tr> <tr> <td> dermatitis</td> <td>1</td> <td>--</td> <td>8</td> <td>--</td> <td>--</td> <td>--</td> <td>2</td> <td>1</td> <td>-- </td> <td>--</td> </tr> <tr> <td> alopecia</td> <td>29</td> <td>23</td> <td>8</td> <td>--</td> <td>12</td> <td>31</td> <td>28</td> <td>26</td> <td>38</td> <td>17</td> </tr> <tr> <td> pruritus</td> <td>--</td> <td>10</td> <td>11</td> <td>1</td> <td>7</td> <td>--</td> <td>9</td> <td>6</td> <td>4</td> <td>3</td> </tr> <tr> <td> rash</td> <td>19</td> <td>13</td> <td>25</td> <td>--</td> <td>9</td> <td>10</td> <td>5</td> <td>8</td> <td>1</td> <td>5</td> </tr> <tr> <td> dry skin</td> <td>1</td> <td>3</td> <td>9</td> <td>--</td> <td>9</td> <td>10</td> <td>4</td> <td>3</td> <td>--</td> <td>&lt;1</td> </tr> <tr styleCode="Botrule"> <td> other (&lt;5%)</td> <td align="left" colspan="10">abnormal hair texture, acne, cellulitis, cyanosis of the hand, cold and clammy skin, dermatitis lichenoides, eczema, epidermal necrolysis, erythema, erythema nodosum, folliculitis, furunculosis, increased hair growth, lacrimal gland disorder, lacrimation, lipoma, maculopapular rash, melanosis, nail disorders, nonherpetic cold sores, pallor, peripheral ischemia, photosensitivity, pruritus genital, psoriasis, psoriasis aggravated, purpura (5% in chronic hepatitis C), rash erythematous, sebaceous cyst, skin depigmentation, skin discoloration, skin nodule, urticaria, vitiligo</td> </tr> <tr styleCode="Botrule"> <td> <content styleCode="bold italics">Urinary System Disorders (&lt;5%)</content> </td> <td align="left" colspan="10">albumin/protein in urine, cystitis, dysuria, hematuria, incontinence, increased BUN, micturition disorder, micturition frequency, nocturia, polyuria (10% in follicular lymphoma), renal insufficiency, urinary tract infection (5% in chronic hepatitis C)</td> </tr> <tr> <td> <content styleCode="bold italics">Vision Disorders (&lt;5%)</content> </td> <td align="left" colspan="10">abnormal vision, blurred vision, diplopia, dry eyes, eye pain, nystagmus, photophobia</td> </tr> </tbody> </table>

<table width="100%"> <caption>ABNORMAL LABORATORY TEST VALUES BY INDICATION</caption> <col width="12%" align="left" valign="top"/> <col width="12%" align="center" valign="top"/> <col width="12%" align="center" valign="top"/> <col width="12%" align="center" valign="top"/> <col width="11%" align="center" valign="top"/> <col width="6%" align="center" valign="top"/> <col width="6%" align="center" valign="top"/> <col width="11%" align="center" valign="top"/> <col width="6%" align="center" valign="top"/> <col width="6%" align="center" valign="top"/> <col width="6%" align="center" valign="top"/> <thead> <tr styleCode="Botrule"> <th/> <th colspan="10">Dosing Regimens Percentage (%) of Patients</th> </tr> <tr styleCode="Botrule"> <th/> <th valign="bottom">MALIGNANT MELANOMA</th> <th valign="bottom">FOLLICULAR LYMPHOMA</th> <th>HAIRY CELL LEUKEMIA</th> <th valign="bottom">CONDYLOMATA ACUMINATA</th> <th colspan="2" valign="bottom">AIDS-RELATED KAPOSI&apos;S SARCOMA</th> <th valign="bottom">CHRONIC HEPATITIS C</th> <th colspan="3" valign="bottom">CHRONIC HEPATITIS B</th> </tr> <tr styleCode="Botrule"> <th/> <th/> <th/> <th/> <th/> <th/> <th/> <th/> <th colspan="2">Adults</th> <th>Pediatrics</th> </tr> <tr> <th/> <th styleCode="Botrule">20 MIU/m² Induction (IV) 10 MIU/m² Maintenance (SC)</th> <th styleCode="Botrule" valign="middle">5 MIU TIW/SC</th> <th styleCode="Botrule" valign="middle">2 MIU/m² TIW/SC</th> <th styleCode="Botrule" valign="middle">1 MIU/lesion</th> <th styleCode="Botrule" valign="middle">30 MIU/m² TIW/SC</th> <th styleCode="Botrule" valign="middle">35 MIU QD/SC</th> <th styleCode="Botrule" valign="middle">3 MIU TIW</th> <th styleCode="Botrule" valign="middle">5 MIU QD</th> <th styleCode="Botrule" valign="middle">10 MIU TIW</th> <th styleCode="Botrule" valign="middle">6 MIU/m²TIW</th> </tr> <tr styleCode="Botrule"> <th>Laboratory Tests</th> <th>N=143</th> <th>N=135</th> <th>N=145</th> <th>N=352</th> <th>N=69&#x2013;73</th> <th>N=26&#x2013;28</th> <th>N=140&#x2013;171</th> <th>N=96&#x2013;101</th> <th>N=75&#x2013;103</th> <th>N=113&#x2013;115</th> </tr> </thead> <tfoot> <tr> <td colspan="11" align="left">NA - Not Applicable- Patients&apos; initial hematologic laboratory test values were abnormal due to their condition.</td> </tr> </tfoot> <tbody> <tr> <td>Hemoglobin</td> <td>22</td> <td>8</td> <td>NA</td> <td>--</td> <td>1</td> <td>15</td> <td>26<footnote ID="ft26">Decrease of &#x2265;2 g/dL; 20% 2&#x2013;&lt;3 g/dL; 6% &#x2265;3 g/dL </footnote> </td> <td>32<footnote ID="ft27">Decrease of &#x2265;2 g/dL</footnote> </td> <td>23<footnoteRef IDREF="ft27"/> </td> <td>17<footnote ID="ft28">Decrease of &#x2265;2 g/dL; 14% 2&#x2013;&lt;3 g/dL; 3% &#x2265;3 g/dL</footnote> </td> </tr> <tr> <td>White Blood Cell Count</td> <td> <footnote ID="ft29">White Blood Cell Count was reported as neutropenia</footnote> </td> <td>--</td> <td>NA</td> <td>17</td> <td>10</td> <td>22</td> <td>26<footnote ID="ft30">Decrease to &lt;3000/mm³ </footnote> </td> <td>68<footnoteRef IDREF="ft30"/> </td> <td>34<footnoteRef IDREF="ft30"/> </td> <td>9<footnoteRef IDREF="ft30"/> </td> </tr> <tr> <td>Platelet Count</td> <td>15</td> <td>13</td> <td>NA</td> <td>--</td> <td>0</td> <td>8</td> <td>15<footnote ID="ft31">Decrease to &lt;70,000/mm³ </footnote> </td> <td>12<footnoteRef IDREF="ft31"/> </td> <td>5<footnoteRef IDREF="ft31"/> </td> <td>1<footnoteRef IDREF="ft31"/> </td> </tr> <tr> <td>Serum Creatinine</td> <td>3</td> <td>2</td> <td>0</td> <td>--</td> <td>--</td> <td>--</td> <td>6</td> <td>3</td> <td>0</td> <td>3</td> </tr> <tr> <td>Alkaline Phosphatase</td> <td>13</td> <td>--</td> <td>4</td> <td>--</td> <td>--</td> <td>--</td> <td>--</td> <td>8</td> <td>4</td> <td>0</td> </tr> <tr> <td>Lactate Dehydrogenase</td> <td>1</td> <td>--</td> <td>0</td> <td>--</td> <td>--</td> <td>--</td> <td>--</td> <td>--</td> <td>--</td> <td>--</td> </tr> <tr> <td>Serum Urea Nitrogen</td> <td>12</td> <td>4</td> <td>0</td> <td>--</td> <td>--</td> <td>--</td> <td>--</td> <td>2</td> <td>0</td> <td>2</td> </tr> <tr> <td>SGOT</td> <td>63</td> <td>24</td> <td>4</td> <td>12</td> <td>11</td> <td>41</td> <td>--</td> <td>--</td> <td>--</td> <td>--</td> </tr> <tr> <td>SGPT</td> <td>2</td> <td>--</td> <td>13</td> <td>--</td> <td>10</td> <td>15</td> <td>--</td> <td>--</td> <td>--</td> <td>--</td> </tr> <tr> <td>Granulocyte Count</td> <td/> <td/> <td/> <td/> <td/> <td/> <td/> <td/> <td/> <td/> </tr> <tr> <td> <list listType="unordered"> <item>Total</item> </list> </td> <td>92</td> <td>36</td> <td>NA</td> <td>--</td> <td>31</td> <td>39</td> <td>45<footnote ID="ft32">Neutrophils plus bands</footnote> </td> <td>75<footnoteRef IDREF="ft32"/> </td> <td>61<footnoteRef IDREF="ft32"/> </td> <td>70<footnoteRef IDREF="ft32"/> </td> </tr> <tr> <td> <list listType="unordered"> <item>1000&#x2013;&lt;1500/mm³ </item> </list> </td> <td>66</td> <td>--</td> <td>--</td> <td>--</td> <td>--</td> <td>--</td> <td>32</td> <td>30</td> <td>32</td> <td>43</td> </tr> <tr> <td> <list listType="unordered"> <item>750&#x2013;&lt;1000/mm³ </item> </list> </td> <td>--</td> <td>21</td> <td>--</td> <td>--</td> <td>--</td> <td>--</td> <td>10</td> <td>24</td> <td>18</td> <td>18</td> </tr> <tr> <td> <list listType="unordered"> <item>500&#x2013;&lt;750/mm³ </item> </list> </td> <td>25</td> <td>--</td> <td>--</td> <td>--</td> <td>--</td> <td>--</td> <td>1</td> <td>17</td> <td>9</td> <td>7</td> </tr> <tr> <td> <list listType="unordered"> <item>&lt;500/mm³ </item> </list> </td> <td>1</td> <td>13</td> <td>--</td> <td>--</td> <td>--</td> <td>--</td> <td>2</td> <td>4</td> <td>2</td> <td>2</td> </tr> </tbody> </table>