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Intron A

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Intron A

SIDE EFFECTS

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

  MALIGNANT MELANOMA FOLLICULAR LYMPHOMA HAIRY CELL LEUKEMIA CONDYLOMATA ACUMINATA AIDS- RELATED KAPOSI’S SARCOMA CHRONIC HEPATITIS C|| CHRONIC HEPATITIS B
Adults Pediatrics
20 MIU/m² Induction (IV) 10 MIU/m² Maintenance (SC) 5 MIU TIW/SC 2 MIU/m² TIW/SC 1MIU/lesion 30 MIU/m² TIW/S C 35 MIUQD/SC 3MIU TIW 5MIU QD 10MIU TIW 6MIU/m²TIW
ADVERSE EXPERIENCE N=143 N=135 N=145 N=352 N=74 N=29 N=183 N=101 N=78 N=116
Aoolication-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 32 6 2 11 14 8 7 10 27
  constipation 1 14 < 1 -- 1 10 4 5 -- 2
  gingivitis 2‡ 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 Svstem 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 § 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” 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
* Dash (--) indicates not reported
† Vomiting was reported with nausea as a single term
‡ Includes stomatitis/mucositis
§ Amnesia was reported with confusion as a single term
||Percentages based upon a summary of all adverse events during 18 to 24 months of treatment
¶ Predominantly lethargy
* Dash (--) indicates not reported
† Vomiting was reported with nausea as a single term
‡ Includes stomatitis/mucositis
§ Amnesia was reported with confusion as a single term
||Percentages based upon a summary of all adverse events during 18 to 24 months of treatment
¶ Predominantly lethargy

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/m² 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/m² 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/m² 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 “flulike” 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 MlU/m² Induction (IV) 10 MlU/m² Maintenance (SC) 5 MIU TIW/SC 2 MIU/m² TIW/SC 1 MIU/lesion 30 MIU/m² TIW/SC 35 MIU QD/SC 3 MIU TIW 5 MIU QD 10 MIU TIW 6 MIU/m² 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
Hemoglobin 22 8 NA -- 1 15 26¶ 32* 23* 17**
White Blood Cell Count 1 -- NA 17 10 22 26† 68† 34† 9†
Platelet Count 15 13 NA -- 0 8 15‡ 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§ 75§ 61§ 70§
  1000- < 1500/mm³ 66 -- -- -- -- -- 32 30 32 43
   750- < 1000/mm³ -- 21 -- -- -- -- 10 24 18 18
   500- < 750/mm³ 25 -- -- -- -- -- 1 17 9 7
   < 500/mm³ 1 13 -- -- -- -- 2 4 2 2
NA — Not Applicable — Patients' initial hematologic laboratory test values were abnormal due to their condition.
* Decrease of ≥ 2 g/dL
** Decrease of ≥ 2 g/dL; 14% 2- < 3 g/dL; 3% ≥ 3 g/dL
† Decrease to < 3000/mm³
‡ Decrease to < 70,000/mm³
§ Neutrophils plus bands
|| White Blood Cell Count was reported as neutropenia
¶ Decrease of ≥ 2 g/dL; 20% 2- < 3 g/dL; 6% ≥ 3 g/dL

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

Skin and Subcutaneous Tissue Disorders

injection site necrosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, urticaria

Read the Intron A (interferon alfa-2b, recombinant for injection) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Interactions between INTRON A and other drugs have not been fully evaluated. Caution should be exercised when administering INTRON A therapy in combination with other potentially myelosuppressive agents such as zidovudine. Concomitant use of alpha interferon and theophylline decreases theophylline clearance, resulting in a 100% increase in serum theophylline levels.

Read the Intron A Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 9/25/2014
This monograph has been modified to include the generic and brand name in many instances.

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