Intron A

Mechanism of Action

Inhibits HBV replication; immunomodulatory actions; may induce gene transcription; interferes with oncogene expression, may change cell surface antigen expressoin; cytotoxic activity of macrophages increases

Suppresses cell proliferation

Pharmacokinetics

Half-Life: 2-3 hr (IM/SC); 2 hr (IV)

Peak Plasma Time: 3-12 hr (IM/SC); 30 min (IV)

Pharmacogenomics

Polymorphic cytokine genes (encoding IL-10, a Th2 cytokine); Th2 responses are associated with production of large amounts of antibodies

Patients with chronic hepatitis C are 5 times more likely to have a favorable response to interferon alfa if they carried the IL-10 genetic polymorphism that results in low expression of IL-10 than if they did not

Get emergency medical help if you have signs of an allergic reaction: hives, skin rash with blistering and peeling; anxiety, chest pain, difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• vision changes;
• severe stomach pain with bloody diarrhea;
• pale skin, easy bruising or bleeding (nosebleeds, bleeding gums);
• sudden chest pain or discomfort, wheezing, dry cough, feeling short of breath;
• depression, irritability, confusion, thoughts about hurting yourself or others, or falling back into a previous pattern of drug addiction;
• heart attack symptoms--chest pain or pressure, pain spreading to your jaw or shoulder, nausea, sweating;
• signs of a stroke--sudden numbness or weakness (especially on one side of the body), sudden severe headache, slurred speech, problems with balance;
• new or worsened autoimmune disorders--skin problems, joint pain or swelling, cold feeling or pale appearance in your fingers or toes;
• signs of infection--fever, chills, body aches, cough with yellow or pink mucus, pain or burning when you urinate;
• liver problems--stomach pain or swelling, loss of appetite, severe drowsiness, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);
• pancreas problems--severe pain in your upper stomach spreading to your back, vomiting;
• thyroid problems--weight changes, skin changes, feeling hot or cold all the time; or
• high blood sugar--increased thirst or urination, hunger, fruity breath odor, tiredness, weight loss.

Your cancer treatments may be delayed or permanently discontinued if you have certain side effects.

Common side effects may include:

• flu-like symptoms, feeling tired;
• nausea, loss of appetite, weight loss;
• thinning hair; or
• swelling, redness, or itching where an injection was given.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Intron A is part of the drug class:

• interferon

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Intron A and certain other medicines may affect each other and cause side effects.

Especially tell your healthcare provider if you take:

• the anti-hepatitis B medicine telbivudine (Tyzeka)
• the anti-HIV medicine zidovudine (Retrovir)
• theophylline (Theo-24, Elixophyllin, Uniphyl, Theolair). Your healthcare provider may need to monitor the amount of theophylline in your body and make changes to your theophylline dose.

Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.

Intron A Solution for Injection and Intron A Solution for Injection in the Multidose Pens:

• Store in the refrigerator between 36°F to 46°F (2°C to 8°C).
• Intron A Solution for Injection in Multidose vials for injection and Intron A Solution for Injection in the Multidose Pens may be used to give more than 1 injection of medicine.
• Do not freeze.
• Throw away any unused Intron A Multidose Pen remaining after 4 weeks.
• Throw away any unused Intron A Solution for Injection remaining in the vial after one month.

Intron A Powder for Injection:

Before mixing, store in the refrigerator between 36°F to 46°F (2°C to 8°C).

• After mixing the Intron A Powder for Injection, use the solution right away or store the solution in the refrigerator for up to 24 hours between 36°F to 46°F (2°C to 8°C).
• Throw away any medicine left in the vial after you withdraw 1 dose.
• Do not freeze.

Keep Intron A and all medicines out of the reach of children.

Tell your doctor about all your current medicines and any you start or stop using, especially:

• telbivudine;

• theophylline; or

• zidovudine.

This list is not complete. Other drugs may interact with interferon alfa-2b, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of interferon alfa-2b injection in children 1 to 17 years of age with hepatitis B or children 3 to 16 years of age with hepatitis C.

Appropriate studies have not been performed on the relationship of age to the effects of interferon alfa-2b injection in children with lymphoma, malignant melanoma, genital warts, hairy cell leukemia, and Kaposi sarcoma. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of interferon alfa-2b injection in the elderly. However, elderly patients are more likely to have age-related liver, kidney, bone marrow, or heart problems, which may require caution and an adjustment in the dose for patients receiving interferon alfa-2b injection.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Pirfenidone

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Ribavirin

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Autoimmune disorders (eg, psoriasis, Raynaud disease, rhabdomyolysis, rheumatoid arthritis, sarcoidosis, systemic lupus erythematosus, or vasculitis) or
• Blood clotting problems (eg, pulmonary embolism, thrombophlebitis) or
• Bone marrow problems or
• Bowel problems (eg, colitis) or
• Depression or mental illness, history of or
• Diabetes or
• Diabetic retinopathy (diabetic eye problem) or
• Eye or vision problems (eg, retinopathy, optic neuritis) or
• Heart attack, history of or
• Heart or blood vessel disease, history of or
• Heart rhythm problems (eg, arrhythmia) or
• Hypertensive retinopathy (eye problem caused by high blood pressure) or
• Hypertriglyceridemia (high triglycerides in the blood) or
• Hypotension (low blood pressure) or
• Liver disease (including cirrhosis), severe or
• Lung disease or other breathing problems (eg, COPD), history of or
• Stroke, history of or
• Thyroid problems—Use with caution. May make these conditions worse.

• Autoimmune hepatitis (liver inflammation) or
• Human immunodeficiency virus (HIV) infection or
• Kidney disease, severe or
• Liver or other organ transplant or
• Sickle cell anemia (red blood cell disorder) or
• Thalassemia major (genetic blood disorder) or
• Weakened immune system—Should not be used in patients with these conditions.

• Kidney disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly. Blood tests may be needed to check for unwanted effects.

Using interferon alfa-2b injection together with ribavirin while you are pregnant can harm your unborn baby. These medicines may also cause birth defects if the father is using it when his sexual partner becomes pregnant. If a pregnancy occurs while you are using these medicines, tell your doctor right away.

A negative pregnancy test is required for women who are of childbearing age before starting combination therapy with interferon alfa-2b injection and ribavirin. Female patients and female partners of male patients must use 2 forms of birth control during therapy and for 6 months after therapy ends. Female patients must have regular pregnancy tests during combination therapy.

This medicine may cause serious types of allergic reactions, including anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Call your doctor right away if you have itching, hives, hoarseness, trouble breathing, trouble swallowing, or any swelling of your hands, face, mouth, or throat.

Interferon alfa-2b injection can temporarily lower the number of white blood cells in your blood, increasing the chance of getting an infection. It can also lower the number of platelets, which are necessary for proper blood clotting. If this occurs, there are certain precautions you can take, especially when your blood count is low, to reduce the risk of infection or bleeding:

• If you can, avoid people with infections. Check with your doctor immediately if you think you are getting an infection or if you get a fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination.
• Check with your doctor immediately if you notice any unusual bleeding or bruising, black, tarry stools, blood in the urine or stools, or pinpoint red spots on your skin.
• Be careful when using a regular toothbrush, dental floss, or toothpick. Your medical doctor, dentist, or nurse may recommend other ways to clean your teeth and gums. Check with your medical doctor before having any dental work done.
• Do not touch your eyes or the inside of your nose unless you have just washed your hands and have not touched anything else in the meantime.
• Be careful not to cut yourself when you are using sharp objects such as a safety razor or fingernail or toenail cutters.
• Avoid contact sports or other situations where bruising or injury could occur.

This medicine can increase thoughts of suicide in people with or without a history of a mental illness. This medicine may also cause relapse in people with a history of substance abuse. Tell your doctor right away if you start to feel more depressed or exhibit aggressive behavior. Also tell your doctor right away if you have thoughts of hurting yourself or others. Report any unusual thoughts or behaviors that trouble you, especially if they are new or get worse quickly. Make sure your caregiver knows if you have trouble sleeping, get upset easily, have a big increase in energy, or start to act reckless. Also tell your doctor if you have sudden or strong feelings, such as feeling nervous, angry, restless, violent, or scared. If you, your child, or your caregiver notice any of these side effects during treatment and up to 6 months after treatment, tell your doctor right away.

The powder form of this medicine contains albumin, which comes from human blood. Some human blood products have transmitted certain viruses to people who have received them, although the risk is low. Human donors and donated blood are both tested for viruses to keep the transmission risk low. Talk with your doctor about this risk if you have questions.

Check with your doctor if blurred vision, decreased vision, or any other change in vision occurs during your treatment. Your doctor may want you to have your eyes checked by an ophthalmologist (eye doctor).

Check with your doctor right away if you have pain or tenderness in the upper stomach, pale stools, dark urine, loss of appetite, nausea, unusual tiredness or weakness, or yellow eyes or skin. These could be symptoms of a serious liver problem.

This medicine may make you tired or unable to concentrate. Do not drive or do anything else that could be dangerous until you know how this medicine affects you.

Interferon alfa-2b injection and ribavirin combination may cause a dry mouth. For temporary relief of mouth dryness, use sugarless candy or gum, melt bits of ice in your mouth, or use a saliva substitute. However, if your mouth continues to feel dry for more than 2 weeks, check with your medical doctor or dentist. Continuing dryness of the mouth may increase the chance of dental disease, including tooth decay, gum disease, and fungus infections.

Some patients who have used this medicine with ribavirin have had vomiting. If you vomit during or after your treatment, rinse your mouth out with water. This may also help prevent damage to your teeth and gums.

Children who use interferon alfa-2b and ribavirin combination may have weight loss and slowed growth. Most children have a growth spurt and gain weight after therapy ends. If you have questions about this, talk to your doctor.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

General

The interferons are a family of naturally occurring small proteins and glycoproteins with molecular weights of approximately 15,000 to 27,600 daltons produced and secreted by cells in response to viral infections and to synthetic or biological inducers.

Interferons exert their cellular activities by binding to specific membrane receptors on the cell surface. Once bound to the cell membrane, interferons initiate a complex sequence of intracellular events. In vitro studies demonstrated that these include the induction of certain enzymes, suppression of cell proliferation, immunomodulating activities such as enhancement of the phagocytic activity of macrophages and augmentation of the specific cytotoxicity of lymphocytes for target cells, and inhibition of virus replication in virus-infected cells.

In a study using human hepatoblastoma cell line HB 611, the in vitro antiviral activity of alpha interferon was demonstrated by its inhibition of hepatitis B virus (HBV) replication.

The correlation between these in vitro data and the clinical results is unknown. Any of these activities might contribute to interferon's therapeutic effects.

The pharmacokinetics of INTRON® A were studied in 12 healthy male volunteers following single doses of 5 million IU/m2 administered intramuscularly, subcutaneously, and as a 30-minute intravenous infusion in a crossover design.

The mean serum Intron A concentrations following intramuscular and subcutaneous injections were comparable. The maximum serum concentrations obtained via these routes were approximately 18 to 116 IU/mL and occurred 3 to 12 hours after administration. The elimination half-life of Intron A following both intramuscular and subcutaneous injections was approximately 2 to 3 hours. Serum concentrations were undetectable by 16 hours after the injections.

After intravenous administration, serum Intron A concentrations peaked (135-273 IU/mL) by the end of the 30-minute infusion, then declined at a slightly more rapid rate than after intramuscular or subcutaneous drug administration, becoming undetectable 4 hours after the infusion. The elimination half-life was approximately 2 hours.

Urine Intron A concentrations following a single dose (5 million IU/m2) were not detectable after any of the parenteral routes of administration. This result was expected since preliminary studies with isolated and perfused rabbit kidneys have shown that the kidney may be the main site of interferon catabolism.

There are no pharmacokinetic data available for the intralesional route of administration.

In Intron A-treated patients tested for antibody activity in clinical trials, serum anti-interferon neutralizing antibodies were detected in 0% (0/90) of patients with hairy cell leukemia, 0.8% (2/260) of patients treated intralesionally for condylomata acuminata, and 4% (1/24) of patients with AIDS-Related Kaposi's Sarcoma. Serum neutralizing antibodies have been detected in less than 3% of patients treated with higher Intron A doses in malignancies other than hairy cell leukemia or AIDS-Related Kaposi's Sarcoma. The clinical significance of the appearance of serum anti-interferon neutralizing activity in these indications is not known.

Serum anti-interferon neutralizing antibodies were detected in 7% (12/168) of patients either during treatment or after completing 12 to 48 weeks of treatment with 3 million IU TIW of Intron A therapy for chronic hepatitis C and in 13% (6/48) of patients who received Intron A therapy for chronic hepatitis B at 5 million IU QD for 4 months, and in 3% (1/33) of patients treated at 10 million IU TIW. Serum anti-interferon neutralizing antibodies were detected in 9% (5/53) of pediatric patients who received Intron A therapy for chronic hepatitis B at 6 million IU/m2 TIW. Among all chronic hepatitis B or C patients, pediatrics and adults with detectable serum neutralizing antibodies, the titers detected were low (22/24 with titers less than or equal to 1:40 and 2/24 with titers less than or equal to 1:160). The appearance of serum anti-interferon neutralizing activity did not appear to affect safety or efficacy.

Hairy Cell Leukemia

In clinical trials in patients with hairy cell leukemia, there was depression of hematopoiesis during the first 1 to 2 months of Intron A treatment, resulting in reduced numbers of circulating red and white blood cells, and platelets. Subsequently, both splenectomized and nonsplenectomized patients achieved substantial and sustained improvements in granulocytes, platelets, and hemoglobin levels in 75% of treated patients and at least some improvement (minor responses) occurred in 90%. Intron A treatment resulted in a decrease in bone marrow hypercellularity and hairy cell infiltrates. The hairy cell index (HCI), which represents the percent of bone marrow cellularity times the percent of hairy cell infiltrate, was greater than or equal to 50% at the beginning of the study in 87% of patients. The percentage of patients with such an HCI decreased to 25% after 6 months and to 14% after 1 year. These results indicate that even though hematologic improvement had occurred earlier, prolonged Intron A treatment may be required to obtain maximal reduction in tumor cell infiltrates in the bone marrow.

The percentage of patients with hairy cell leukemia who required red blood cell or platelet transfusions decreased significantly during treatment and the percentage of patients with confirmed and serious infections declined as granulocyte counts improved. Reversal of splenomegaly and of clinically significant hypersplenism was demonstrated in some patients.

A study was conducted to assess the effects of extended Intron A treatment on duration of response for patients who responded to initial therapy. In this study, 126 responding patients were randomized to receive additional Intron A treatment for 6 months or observation for a comparable period, after 12 months of initial Intron A therapy. During this 6-month period, 3% (2/66) of Intron A-treated patients relapsed compared with 18% (11/60) who were not treated. This represents a significant difference in time to relapse in favor of continued Intron A treatment (P=0.006/0.01, Log Rank/Wilcoxon). Since a small proportion of the total population had relapsed, median time to relapse could not be estimated in either group. A similar pattern in relapses was seen when all randomized treatment, including that beyond 6 months, and available follow-up data were assessed. The 15% (10/66) relapses among Intron A patients occurred over a significantly longer period of time than the 40% (24/60) with observation (P=0.0002/0.0001, Log Rank/Wilcoxon). Median time to relapse was estimated, using the Kaplan-Meier method, to be 6.8 months in the observation group but could not be estimated in the Intron A group.

Subsequent follow-up with a median time of approximately 40 months demonstrated an overall survival of 87.8%. In a comparable historical control group followed for 24 months, overall median survival was approximately 40%.

Malignant Melanoma

The safety and efficacy of Intron A was evaluated as adjuvant to surgical treatment in patients with melanoma who were free of disease (post surgery) but at high risk for systemic recurrence. These included patients with lesions of Breslow thickness greater than 4 mm, or patients with lesions of any Breslow thickness with primary or recurrent nodal involvement. In a randomized, controlled trial in 280 patients, 143 patients received Intron A therapy at 20 million IU/m2 intravenously five times per week for 4 weeks (induction phase) followed by 10 million IU/m2 subcutaneously three times per week for 48 weeks (maintenance phase). In the clinical trial, the median daily Intron A dose administered to patients was 19.1 million IU/m2 during the induction phase and 9.1 million IU/m2 during the maintenance phase. Intron A therapy was begun less than or equal to 56 days after surgical resection. The remaining 137 patients were observed.

Intron A therapy produced a significant increase in relapse-free and overall survival. Median time to relapse for the Intron A-treated patients versus observation patients was 1.72 years versus 0.98 years (P<0.01, stratified Log Rank). The estimated 5-year relapse-free survival rate, using the Kaplan-Meier method, was 37% for Intron A-treated patients versus 26% for observation patients. Median overall survival time for Intron A-treated patients versus observation patients was 3.82 years versus 2.78 years (P=0.047, stratified Log Rank). The estimated 5-year overall survival rate, using the Kaplan-Meier method, was 46% for Intron A-treated patients versus 37% for observation patients.

In a second study of 642 resected high-risk melanoma patients, subjects were randomized equally to one of three groups: high-dose Intron A therapy for 1 year (same schedule as above), low-dose Intron A therapy for 2 years (3 MU/d TIW SC), and observation. Consistent with the earlier trial, high-dose Intron A therapy demonstrated an improvement in relapse-free survival (3-year estimated RFS 48% versus 41%; median RFS 2.4 versus 1.6 years, P=not significant). Relapse-free survival in the low-dose Intron A arm was similar to that seen in the observation arm. Neither high-dose nor low-dose Intron A therapy showed a benefit in overall survival as compared to observation in this study.

Follicular Lymphoma

The safety and efficacy of Intron A in conjunction with CHVP, a combination chemotherapy regimen, was evaluated as initial treatment in patients with clinically aggressive, large tumor burden, Stage III/IV follicular Non-Hodgkin's Lymphoma. Large tumor burden was defined by the presence of any one of the following: a nodal or extranodal tumor mass with a diameter of greater than 7 cm; involvement of at least three nodal sites (each with a diameter of greater than 3 cm); systemic symptoms; splenomegaly; serous effusion, orbital or epidural involvement; ureteral compression; or leukemia.

In a randomized, controlled trial, 130 patients received CHVP therapy and 135 patients received CHVP therapy plus Intron A therapy at 5 million IU subcutaneously three times weekly for the duration of 18 months. CHVP chemotherapy consisted of cyclophosphamide 600 mg/m2, doxorubicin 25 mg/m2, and teniposide (VM-26) 60 mg/m2, administered intravenously on Day 1 and prednisone at a daily dose of 40 mg/m2 given orally on Days 1 to 5. Treatment consisted of six CHVP cycles administered monthly, followed by an additional six cycles administered every 2 months for 1 year. Patients in both treatment groups received a total of 12 CHVP cycles over 18 months.

The group receiving the combination of Intron A therapy plus CHVP had a significantly longer progression-free survival (2.9 years versus 1.5 years, P=0.0001, Log Rank test). After a median follow-up of 6.1 years, the median survival for patients treated with CHVP alone was 5.5 years while median survival for patients treated with CHVP plus Intron A therapy had not been reached (P=0.004, Log Rank test). In three additional published, randomized, controlled studies of the addition of interferon alpha to anthracycline-containing combination chemotherapy regimens,1-3 the addition of interferon alpha was associated with significantly prolonged progression-free survival. Differences in overall survival were not consistently observed.

Condylomata Acuminata

Condylomata acuminata (venereal or genital warts) are associated with infections of the human papilloma virus (HPV). The safety and efficacy of Intron A in the treatment of condylomata acuminata were evaluated in three controlled double-blind clinical trials. In these studies, Intron A doses of 1 million IU per lesion were administered intralesionally three times a week (TIW), in less than or equal to 5 lesions per patient for 3 weeks. The patients were observed for up to 16 weeks after completion of the full treatment course.

Intron A treatment of condylomata was significantly more effective than placebo, as measured by disappearance of lesions, decreases in lesion size, and by an overall change in disease status. Of 192 Intron A-treated patients and 206 placebo-treated patients who were evaluable for efficacy at the time of best response during the course of the study, 42% of Intron A patients versus 17% of placebo patients experienced clearing of all treated lesions. Likewise, 24% of Intron A patients versus 8% of placebo patients experienced marked (75% to less than 100%) reduction in lesion size, 18% versus 9% experienced moderate (50% to 75%) reduction in lesion size, 10% versus 42% had a slight (less than 50%) reduction in lesion size, 5% versus 24% had no change in lesion size, and 0% versus 1% experienced exacerbation (P<0.001).

In one of these studies, 43% (54/125) of patients in whom multiple (less than or equal to 3) lesions were treated experienced complete clearing of all treated lesions during the course of the study. Of these patients, 81% remained cleared 16 weeks after treatment was initiated.

Patients who did not achieve total clearing of all their treated lesions had these same lesions treated with a second course of therapy. During this second course of treatment, 38% to 67% of patients had clearing of all treated lesions. The overall percentage of patients who had cleared all their treated lesions after two courses of treatment ranged from 57% to 85%.

Intron A-treated lesions showed improvement within 2 to 4 weeks after the start of treatment in the above study; maximal response to Intron A therapy was noted 4 to 8 weeks after initiation of treatment.

The response to Intron A therapy was better in patients who had condylomata for shorter durations than in patients with lesions for a longer duration.

Another study involved 97 patients in whom three lesions were treated with either an intralesional injection of 1.5 million IU of Intron A per lesion followed by a topical application of 25% podophyllin, or a topical application of 25% podophyllin alone. Treatment was given once a week for 3 weeks. The combined treatment of Intron A and podophyllin was shown to be significantly more effective than podophyllin alone, as determined by the number of patients whose lesions cleared. This significant difference in response was evident after the second treatment (Week 3) and continued through 8 weeks post-treatment. At the time of the patient's best response, 67% (33/49) of the Intron A- and podophyllin-treated patients had all three treated lesions clear while 42% (20/48) of the podophyllin-treated patients had all three clear (P=0.003).

AIDS-Related Kaposi's Sarcoma

The safety and efficacy of Intron A in the treatment of Kaposi's Sarcoma (KS), a common manifestation of the Acquired Immune Deficiency Syndrome (AIDS), were evaluated in clinical trials in 144 patients.

In one study, Intron A doses of 30 million IU/m2 were administered subcutaneously three times per week (TIW) to patients with AIDS-Related KS. Doses were adjusted for patient tolerance. The average weekly dose delivered in the first 4 weeks was 150 million IU; at the end of 12 weeks this averaged 110 million IU/week; and by 24 weeks averaged 75 million IU/week.

Forty-four percent of asymptomatic patients responded versus 7% of symptomatic patients. The median time to response was approximately 2 months and 1 month, respectively, for asymptomatic and symptomatic patients. The median duration of response was approximately 3 months and 1 month, respectively, for the asymptomatic and symptomatic patients. Baseline T4/T8 ratios were 0.46 for responders versus 0.33 for nonresponders.

In another study, Intron A doses of 35 million IU were administered subcutaneously, daily (QD), for 12 weeks. Maintenance treatment, with every other day dosing (QOD), was continued for up to 1 year in patients achieving antitumor and antiviral responses. The median time to response was 2 months and the median duration of response was 5 months in the asymptomatic patients.

In all studies, the likelihood of response was greatest in patients with relatively intact immune systems as assessed by baseline CD4 counts (interchangeable with T4 counts). Results at doses of 30 million IU/m2 TIW and 35 million IU/QD were subcutaneously similar and are provided together in TABLE 1. This table demonstrates the relationship of response to baseline CD4 count in both asymptomatic and symptomatic patients in the 30 million IU/m2 TIW and the 35 million IU/QD treatment groups.

In the 30 million IU study group, 7% (5/72) of patients were complete responders and 22% (16/72) of the patients were partial responders. The 35 million IU study had 13% (3/23 patients) complete responders and 17% (4/23) partial responders.

For patients who received 30 million IU TIW, the median survival time was longer in patients with CD4 greater than 200 (30.7 months) than in patients with CD4 less than or equal to 200 (8.9 months). Among responders, the median survival time was 22.6 months versus 9.7 months in nonresponders.

Chronic Hepatitis C

The safety and efficacy of Intron A in the treatment of chronic hepatitis C was evaluated in 5 randomized clinical studies in which an Intron A dose of 3 million IU three times a week (TIW) was assessed. The initial three studies were placebo-controlled trials that evaluated a 6-month (24-week) course of therapy. In each of the three studies, Intron A therapy resulted in a reduction in serum alanine aminotransferase (ALT) in a greater proportion of patients versus control patients at the end of 6 months of dosing. During the 6 months of follow-up, approximately 50% of the patients who responded maintained their ALT response. A combined analysis comparing pretreatment and post-treatment liver biopsies revealed histological improvement in a statistically significantly greater proportion of Intron A-treated patients compared to controls.

Two additional studies have investigated longer treatment durations (up to 24 months).5,6 Patients in the two studies to evaluate longer duration of treatment had hepatitis with or without cirrhosis in the absence of decompensated liver disease. Complete response to treatment was defined as normalization of the final two serum ALT levels during the treatment period. A sustained response was defined as a complete response at the end of the treatment period, with sustained normal ALT values lasting at least 6 months following discontinuation of therapy.

In Study 1, all patients were initially treated with Intron A 3 million IU TIW subcutaneously for 24 weeks (run-in-period). Patients who completed the initial 24-week treatment period were then randomly assigned to receive no further treatment, or to receive 3 million IU TIW for an additional 48 weeks. In Study 2, patients who met the entry criteria were randomly assigned to receive Intron A 3 million IU TIW subcutaneously for 24 weeks or to receive Intron A 3 million IU TIW subcutaneously for 96 weeks. In both studies, patient follow-up was variable and some data collection was retrospective.

Results show that longer durations of Intron A therapy improved the sustained response rate (see TABLE 2). In patients with complete responses (CR) to Intron A therapy after 6 months of treatment (149/352 [42%]), responses were less often sustained if drug was discontinued (21/70 [30%]) than if it was continued for 18 to 24 months (44/79 [56%]). Of all patients randomized, the sustained response rate in the patients receiving 18 or 24 months of therapy was 22% and 26%, respectively, in the two trials. In patients who did not have a CR by 6 months, additional therapy did not result in significantly more responses, since almost all patients who responded to therapy did so within the first 16 weeks of treatment.

A subset (less than 50%) of patients from the combined extended dosing studies had liver biopsies performed both before and after Intron A treatment. Improvement in necroinflammatory activity as assessed retrospectively by the Knodell (Study 1) and Scheuer (Study 2) Histology Activity Indices was observed in both studies. A higher number of patients (58%, 45/78) improved with extended therapy than with shorter (6 months) therapy (38%, 34/89) in this subset.

Combination treatment with Intron A and REBETOL® (ribavirin USP) provided a significant reduction in virologic load and improved histologic response in adult patients with compensated liver disease who were treatment-naïve or had relapsed following therapy with alpha interferon alone; pediatric patients previously untreated with alpha interferon experienced a sustained virologic response. See REBETOL prescribing information for additional information.

Chronic Hepatitis B

The safety and efficacy of Intron A in the treatment of chronic hepatitis B were evaluated in three clinical trials in which Intron A doses of 30 to 35 million IU per week were administered subcutaneously (SC), as either 5 million IU daily (QD), or 10 million IU three times a week (TIW) for 16 weeks versus no treatment. All patients were 18 years of age or older with compensated liver disease, and had chronic hepatitis B virus (HBV) infection (serum HBsAg positive for at least 6 months) and HBV replication (serum HBeAg positive). Patients were also serum HBV-DNA positive, an additional indicator of HBV replication, as measured by a research assay.7,8 All patients had elevated serum alanine aminotransferase (ALT) and liver biopsy findings compatible with the diagnosis of chronic hepatitis. Patients with the presence of antibody to human immunodeficiency virus (anti-HIV) or antibody to hepatitis delta virus (anti-HDV) in the serum were excluded from the studies.

Virologic response to treatment was defined in these studies as a loss of serum markers of HBV replication (HBeAg and HBV DNA). Secondary parameters of response included loss of serum HBsAg, decreases in serum ALT, and improvement in liver histology.

In each of two randomized controlled studies, a significantly greater proportion of Intron A-treated patients exhibited a virologic response compared with untreated control patients (see TABLE 3). In a third study without a concurrent control group, a similar response rate to Intron A therapy was observed. Pretreatment with prednisone, evaluated in two of the studies, did not improve the response rate and provided no additional benefit.

The response to Intron A therapy was durable. No patient responding to Intron A therapy at a dose of 5 million IU QD or 10 million IU TIW relapsed during the follow-up period, which ranged from 2 to 6 months after treatment ended. The loss of serum HBeAg and HBV DNA was maintained in 100% of 19 responding patients followed for 3.5 to 36 months after the end of therapy.

In a proportion of responding patients, loss of HBeAg was followed by the loss of HBsAg. HBsAg was lost in 27% (4/15) of patients who responded to Intron A therapy at a dose of 5 million IU QD, and 35% (8/23) of patients who responded to 10 million IU TIW. No untreated control patient lost HBsAg in these studies.

In an ongoing study to assess the long-term durability of virologic response, 64 patients responding to Intron A therapy have been followed for 1.1 to 6.6 years after treatment; 95% (61/64) remain serum HBeAg negative, and 49% (30/61) lost serum HBsAg.

Intron A therapy resulted in normalization of serum ALT in a significantly greater proportion of treated patients compared to untreated patients in each of two controlled studies (see TABLE 4). In a third study without a concurrent control group, normalization of serum ALT was observed in 50% (12/24) of patients receiving Intron A therapy.

Virologic response was associated with a reduction in serum ALT to normal or near normal (less than or equal to 1.5 × the upper limit of normal) in 87% (13/15) of patients responding to Intron A therapy at 5 million IU QD, and 100% (23/23) of patients responding to 10 million IU TIW.

Improvement in liver histology was evaluated in Studies 1 and 3 by comparison of pretreatment and 6-month post-treatment liver biopsies using the semiquantitative Knodell Histology Activity Index.9 No statistically significant difference in liver histology was observed in treated patients compared to control patients in Study 1. Although statistically significant histological improvement from baseline was observed in treated patients in Study 3 (P≤0.01), there was no control group for comparison. Of those patients exhibiting a virologic response following treatment with 5 million IU QD or 10 million IU TIW, histological improvement was observed in 85% (17/20) compared to 36% (9/25) of patients who were not virologic responders. The histological improvement was due primarily to decreases in severity of necrosis, degeneration, and inflammation in the periportal, lobular, and portal regions of the liver (Knodell Categories I + II + III). Continued histological improvement was observed in four responding patients who lost serum HBsAg and were followed 2 to 4 years after the end of Intron A therapy.10

The safety and efficacy of Intron A in the treatment of chronic hepatitis B was evaluated in one randomized controlled trial of 149 patients ranging from 1 year to 17 years of age. Seventy-two patients were treated with 3 million IU/m2 of Intron A therapy administered subcutaneously three times a week (TIW) for 1 week; the dose was then escalated to 6 million IU/m2 TIW for a minimum of 16 weeks up to 24 weeks. The maximum weekly dosage was 10 million IU TIW. Seventy-seven patients were untreated controls. Study entry and response criteria were identical to those described in the adult patient population.

Patients treated with Intron A therapy had a better response (loss of HBV DNA and HBeAg at 24 weeks of follow-up) compared to the untreated controls (24% [17/72] versus 10% [8/77] P=0.05). Sixteen of the 17 responders treated with Intron A therapy remained HBV DNA and HBeAg negative and had a normal serum ALT 12 to 24 months after completion of treatment. Serum HBsAg became negative in 7 out of 17 patients who responded to Intron A therapy. None of the control patients who had an HBV DNA and HBeAg response became HBsAg negative. At 24 weeks of follow-up, normalization of serum ALT was similar in patients treated with Intron A therapy (17%, 12/72) and in untreated control patients (16%, 12/77). Patients with a baseline HBV DNA less than 100 pg/mL were more likely to respond to Intron A therapy than were patients with a baseline HBV DNA greater than 100 pg/mL (35% versus 9%, respectively). Patients who contracted hepatitis B through maternal vertical transmission had lower response rates than those who contracted the disease by other means (5% versus 31%, respectively). There was no evidence that the effects on HBV DNA and HBeAg were limited to specific subpopulations based on age, gender, or race.

General

IMPORTANT: INTRON® A is supplied as 1) Powder for Injection/Reconstitution; 2) Solution for Injection in Vials. Not all dosage forms and strengths are appropriate for some indications. It is important that you carefully read the instructions below for the indication you are treating to ensure you are using an appropriate dosage form and strength.

To enhance the tolerability of Intron A, injections should be administered in the evening when possible.

To reduce the incidence of certain adverse reactions, acetaminophen may be administered at the time of injection.

The solution should be allowed to come to room temperature before using.

Hairy Cell Leukemia

(see DOSAGE AND ADMINISTRATION, General)

The recommended dose for the treatment of hairy cell leukemia is 2 million IU/m2 administered intramuscularly or subcutaneously 3 times a week for up to 6 months. Patients with platelet counts of less than 50,000/mm3 should not be administered Intron A intramuscularly, but instead by subcutaneous administration. Patients who are responding to therapy may benefit from continued treatment.

NOTE: Intron A Powder for Injection does not contain a preservative. The vial must be discarded after reconstitution and withdrawal of a single dose.

• If severe adverse reactions develop, the dosage should be modified (50% reduction) or therapy should be temporarily withheld until the adverse reactions abate and then resume at 50% (1 MIU/m2 TIW).
• If severe adverse reactions persist or recur following dosage adjustment, Intron A should be permanently discontinued.
• Intron A should be discontinued for progressive disease or failure to respond after six months of treatment.

Malignant Melanoma

(see DOSAGE AND ADMINISTRATION, General)

Intron A adjuvant treatment of malignant melanoma is given in two phases, induction and maintenance.

The recommended daily dose of Intron A in induction is 20 million IU/m2 as an intravenous infusion, over 20 minutes, 5 consecutive days per week, for 4 weeks (see Dose Adjustment below).

NOTE: Intron A Solution for Injection in vials is NOT recommended for intravenous administration and should not be used for the induction phase of malignant melanoma.

NOTE: Intron A Powder for Injection does not contain a preservative. The vial must be discarded after reconstitution and withdrawal of a single dose.

NOTE: Regular laboratory testing should be performed to monitor laboratory abnormalities for the purpose of dose modifications (see PRECAUTIONS, Laboratory Tests).

• Intron A should be withheld for severe adverse reactions, including granulocyte counts greater than 250/mm3 but less than 500/mm3 or SGPT/SGOT greater than 5-10× upper limit of normal, until adverse reactions abate. Intron A treatment should be restarted at 50% of the previous dose.
• Intron A should be permanently discontinued for:
  • Toxicity that does not abate after withholding Intron A
  • Severe adverse reactions which recur in patients receiving reduced doses of Intron A
  • Granulocyte count less than 250/mm3 or SGPT/SGOT of greater than 10× upper limit of normal

The recommended dose of Intron A for maintenance is 10 million IU/m2 as a subcutaneous injection three times per week for 48 weeks (see Dose Adjustment below).

NOTE: Intron A Powder for Injection does not contain a preservative. The vial must be discarded after reconstitution and withdrawal of a single dose.

NOTE: Regular laboratory testing should be performed to monitor laboratory abnormalities for the purpose of dose modifications (see PRECAUTIONS, Laboratory Tests).

• Intron A should be withheld for severe adverse reactions, including granulocyte counts greater than 250/mm3 but less than 500/mm3 or SGPT/SGOT greater than 5-10× upper limit of normal, until adverse reactions abate. Intron A treatment should be restarted at 50% of the previous dose.
• Intron A should be permanently discontinued for:
  • Toxicity that does not abate after withholding Intron A
  • Severe adverse reactions which recur in patients receiving reduced doses of Intron A
  • Granulocyte count less than 250/mm3 or SGPT/SGOT of greater than 10× upper limit of normal

Follicular Lymphoma

(see DOSAGE AND ADMINISTRATION, General)

The recommended dose of Intron A for the treatment of follicular lymphoma is 5 million IU subcutaneously three times per week for up to 18 months in conjunction with anthracycline-containing chemotherapy regimen and following completion of the chemotherapy regimen.

NOTE: Intron A Powder for Injection does not contain a preservative. The vial must be discarded after reconstitution and withdrawal of a single dose.

• Doses of myelosuppressive drugs were reduced by 25% from a full-dose CHOP regimen, and cycle length increased by 33% (e.g., from 21 to 28 days) when alpha interferon was added to the regimen.
• Delay chemotherapy cycle if neutrophil count was less than 1500/mm3 or platelet count was less than 75,000/mm3.
• Intron A should be permanently discontinued if SGOT exceeds greater than 5× the upper limit of normal or serum creatinine greater than 2.0 mg/dL (see WARNINGS).
• Administration of Intron A therapy should be withheld for a neutrophil count less than 1000/mm3, or a platelet count less than 50,000/mm3.
• Intron A dose should be reduced by 50% (2.5 MIU TIW) for a neutrophil count greater than 1000/mm3, but less than 1500/mm3. The Intron A dose may be re-escalated to the starting dose (5 million IU TIW) after resolution of hematologic toxicity (ANC greater than 1500/mm3).

Condylomata Acuminata

(see DOSAGE AND ADMINISTRATION, General)

The recommended dose is 1.0 million IU per lesion in a maximum of 5 lesions in a single course. The lesions should be injected three times weekly on alternate days for 3 weeks. An additional course may be administered at 12 to 16 weeks.

NOTE: Intron A Powder for Injection does not contain a preservative. The vial must be discarded after reconstitution and withdrawal of a single dose.

NOTE: Do not use the following formulations for this indication:

• the 18 million or 50 million IU Powder for Injection
• the 18 million IU multidose Intron A Solution for Injection

None

The injection should be administered intralesionally using a Tuberculin or similar syringe and a 25- to 30-gauge needle. The needle should be directed at the center of the base of the wart and at an angle almost parallel to the plane of the skin (approximately that in the commonly used PPD test). This will deliver the interferon to the dermal core of the lesion, infiltrating the lesion and causing a small wheal. Care should be taken not to go beneath the lesion too deeply; subcutaneous injection should be avoided, since this area is below the base of the lesion. Do not inject too superficially since this will result in possible leakage, infiltrating only the keratinized layer and not the dermal core.

AIDS-Related Kaposi's Sarcoma

(see DOSAGE AND ADMINISTRATION, General)

The recommended dose of Intron A for Kaposi's Sarcoma is 30 million IU/m2/dose administered subcutaneously or intramuscularly three times a week until disease progression or maximal response has been achieved after 16 weeks of treatment. Dose reduction is frequently required (see Dose Adjustment below).

NOTE: Intron A Solution for Injection in vials should NOT be used for AIDS-Related Kaposi's Sarcoma.

NOTE: Intron A Powder for Injection does not contain a preservative. The vial must be discarded after reconstitution and withdrawal of a single dose.

• Intron A dose should be reduced by 50% or withheld for severe adverse reactions.
• Intron A may be resumed at a reduced dose if severe adverse reactions abate with interruption of dosing.
• Intron A should be permanently discontinued if severe adverse reactions persist or if they recur in patients receiving a reduced dose.

Chronic Hepatitis C

(see DOSAGE AND ADMINISTRATION, General)

The recommended dose of Intron A for the treatment of chronic hepatitis C is 3 million IU three times a week (TIW) administered subcutaneously or intramuscularly. In patients tolerating therapy with normalization of ALT at 16 weeks of treatment, Intron A therapy should be extended to 18 to 24 months (72 to 96 weeks) at 3 million IU TIW to improve the sustained response rate (see CLINICAL PHARMACOLOGY, Chronic Hepatitis C). Patients who do not normalize their ALTs or have persistently high levels of HCV RNA after 16 weeks of therapy rarely achieve a sustained response with extension of treatment. Consideration should be given to discontinuing these patients from therapy.

When Intron A is administered in combination with REBETOL®, patients with impaired renal function and/or those over the age of 50 should be carefully monitored with respect to the development of anemia. See REBETOL prescribing information for dosing when used in combination with REBETOL for adults and pediatric patients.

If severe adverse reactions develop during Intron A treatment, the dose should be modified (50% reduction) or therapy should be temporarily discontinued until the adverse reactions abate. If intolerance persists after dose adjustment, Intron A therapy should be discontinued.

Chronic Hepatitis B Adults

(see DOSAGE AND ADMINISTRATION, General)

The recommended dose of Intron A for the treatment of chronic hepatitis B is 30 to 35 million IU per week, administered subcutaneously or intramuscularly, either as 5 million IU daily (QD) or as 10 million IU three times a week (TIW) for 16 weeks.

NOTE: Intron A Powder for Injection does not contain a preservative. The vial must be discarded after reconstitution and withdrawal of a single dose.

The safety and efficacy of Intron A alone or in combination with boceprevir or ribavirin for the treatment of chronic hepatitis C genotype 1 infection in patients co-infected with hepatitis B virus (HBV) and HCV have not been studied.

Chronic Hepatitis B Pediatrics

(see DOSAGE AND ADMINISTRATION, General)

The recommended dose of Intron A for the treatment of chronic hepatitis B is 3 million IU/m2 three times a week (TIW) for the first week of therapy followed by dose escalation to 6 million IU/m2 TIW (maximum of 10 million IU TIW) administered subcutaneously for a total duration of 16 to 24 weeks.

NOTE: Intron A Powder for Injection does not contain a preservative. The vial must be discarded after reconstitution and withdrawal of a single dose.

If severe adverse reactions or laboratory abnormalities develop during Intron A therapy, the dose should be modified (50% reduction) or discontinued if appropriate, until the adverse reactions abate. If intolerance persists after dose adjustment, Intron A therapy should be discontinued.

For patients with decreases in white blood cell, granulocyte or platelet counts, the following guidelines for dose modification should be followed:

Intron A therapy was resumed at up to 100% of the initial dose when white blood cell, granulocyte, and/or platelet counts returned to normal or baseline values.

INTRON® A Powder for Injection

Intron A Powder for Injection, 10 million IU per vial and Diluent for Intron A (Sterile Water for Injection USP) 5 mL per vial; boxes containing 1 Intron A vial and 1 vial of Intron A Diluent (NDC 0085-4350-01).

Intron A Powder for Injection, 18 million IU per vial and Diluent for Intron A (Sterile Water for Injection USP) 5 mL per vial; boxes containing 1 vial of Intron A and 1 vial of Intron A Diluent (NDC 0085-4351-01).

Intron A Powder for Injection, 50 million IU per vial and Diluent for Intron A (Sterile Water for Injection USP) 5 mL per vial; boxes containing 1 Intron A vial and 1 vial of Intron A Diluent (NDC 0085-4352-01).

Intron A Solution for Injection in Vials

Intron A Solution for Injection, 18 million IU multidose vial (22.8 million IU per 3.8 mL per vial); boxes containing 1 vial of Intron A Solution for Injection (NDC 0085-1168-01).

Intron A Solution for Injection, 25 million IU multidose vial (32 million IU per 3.2 mL per vial); boxes containing 1 vial of Intron A Solution for Injection (NDC 0085-1133-01).

Storage

• Intron A Powder for Injection/Reconstitution
  Intron A Powder for Injection should be stored in the refrigerator at 2° to 8°C (36°-46°F). After reconstitution, the solution should be used immediately, but may be stored up to 24 hours at 2° to 8°C (36°-46°F). Throw away any medicine left in the vial after you withdraw 1 dose.
• Intron A Solution for Injection in Vials
  Intron A Solution for Injection in vials should be stored in the refrigerator at 2° to 8°C (36°-46°F).
  Intron A Solution for Injection should not be frozen and should be kept away from heat. Throw away any unused Intron A Solution for Injection remaining in the vial after one month.

Applies to interferon alfa-2b: injectable kit, injectable powder for injection, injectable solution

General

Clinical trials were conducted for various indications using a wide range of doses (from 6 million international units/m2/week in hairy cell leukemia up to 100 million international units/m2/week in melanoma). Most side effects reported during clinical trials were mild to moderate in severity and manageable. Some side effects were transient and most diminished with continued therapy. Influenza-like symptoms (mainly fever, headache, rigors/chills, myalgia, malaise, and fatigue) were reported most often; these side effects were reversible within 72 hours after interrupting or stopping therapy. Side effects were dose-related. In general, more severe toxicities were observed at higher doses; hematologic, hepatic, cardiovascular, and neurologic toxicities were more common with higher doses.

The manufacturer product information for ribavirin should be consulted, if applicable.[Ref]

Other

Very common (10% or more): Fatigue (up to 96%), pyrexia (up to 94%), influenza-like symptoms (up to 79%), asthenia (up to 63%), chills (up to 54%), rigors (up to 42%), chest pain (up to 28%), irritability (up to 22%), unspecified pain (up to 18%), moniliasis (up to 17%), malaise (up to 14%), decreased weight (up to 13%), viral infection
Common (1% to 10%): Facial edema, nonspecific infection, peripheral edema, herpes simplex resistance, thirst, flushing, breast pain
Uncommon (0.1% to 1%): Bacterial infection
Rare (0.01% to 0.1%): Sepsis, resistance mechanism disorders (e.g., altered resistance to infection [rarely life-threatening or fatal]), weakness
Very rare (less than 0.01%): Cachexia, earache, hot flashes/flushes, fungal infection, malignant hyperpyrexia
Frequency not reported: Hernia, edema, hypothermia, nonspecific inflammation, mastitis, increased weight, substernal chest pain, hyperthermia, abscess, Haemophilus, infection, parasitic infection, otitis media, Trichomonas
Postmarketing reports: Asthenic conditions (including asthenia, malaise, fatigue)[Ref]

Hematologic

Very common (10% or more): Decreased granulocyte count (up to 92%), neutropenia (up to 92%), decreased WBC count (up to 68%), decreased hemoglobin (up to 32%), anemia (up to 27%), decreased platelet count (up to 15%), leukopenia
Common (1% to 10%): Thrombocytopenia, bleeding, lymphadenopathy, lymphopenia
Very rare (less than 0.01%): Aplastic anemia, pure red cell aplasia, hemolytic anemia, coagulation disorder, splenomegaly
Frequency not reported: Hypochromic anemia, granulocytopenia, lymphadenitis, lymphocytosis, thrombocytopenia purpura
Postmarketing reports: Pancytopenia (concurrent anemia, leukopenia, thrombocytopenia), idiopathic thrombocytopenia purpura, thrombotic thrombocytopenic purpura[Ref]

Aplastic anemia and pure red cell aplasia have also been reported during postmarketing experience.[Ref]

Musculoskeletal

Myositis has also been reported during postmarketing experience.[Ref]

Very common (10% or more): Myalgia (up to 75%), musculoskeletal pain (up to 21%), arthralgia (up to 19%), back pain (up to 19%)
Common (1% to 10%): Arthritis
Rare (0.01% to 0.1%): Rhabdomyolysis (sometimes serious), myositis, leg cramps
Very rare (less than 0.01%): Arthrosis, bone pain, muscle weakness, myopathy
Frequency not reported: Arthritis aggravated, bone disorder, carpal tunnel syndrome, muscle atrophy, tendinitis, rheumatoid arthritis (new or aggravated), spondylitis, twitching[Ref]

Metabolic

Very common (10% or more): Anorexia (up to 69%), increased alkaline phosphatase (up to 13%)
Common (1% to 10%): Hypocalcemia, dehydration, hyperuricemia
Uncommon (0.1% to 1%): Increased LDH
Rare (0.01% to 0.1%): Diabetes mellitus, hyperglycemia, increased appetite
Very rare (less than 0.01%): Acidosis, aggravation of diabetes mellitus, hypercalcemia, hypertriglyceridemia
Frequency not reported: Alcohol intolerance[Ref]

Gastrointestinal

Very common (10% or more): Nausea (up to 66%), diarrhea (up to 45%), vomiting (up to 32%), dry mouth (up to 28%), abdominal pain (up to 23%), right upper quadrant pain (up to 15%), constipation (up to 14%), gingivitis (up to 14%), stomatitis, dyspepsia
Common (1% to 10%): Loose stools, gastrointestinal (GI) disorder, ulcerative stomatitis, glossitis
Rare (0.01% to 0.1%): Gingival bleeding
Very rare (less than 0.01%): Abdominal distension, colitis, dysphagia, eructation, esophagitis, flatulence, gastric ulcer, GI hemorrhage, GI mucosal discoloration, gum hyperplasia, ileus, increased saliva, ischemic colitis, melena, oral leukoplakia, pancreatitis, rectal bleeding after stool, rectal hemorrhage, tenesmus, tongue disorder, ulcerative colitis
Frequency not reported: Abdominal ascites, gallstones, gastritis, gastroenteritis, halitosis, hemorrhoids, intestinal disorder, mouth ulceration, mucositis, oral hemorrhage, tooth disorder, periodontal disorder (not otherwise specified), dental disorder (not otherwise specified)[Ref]

Pancreatitis has also been reported during postmarketing experience.[Ref]

Hepatic

Worsening liver disease, including jaundice, hepatic encephalopathy, hepatic failure, and death have been reported after use of this drug in patients with decompensated liver disease, autoimmune hepatitis, or history of autoimmune disease, and in immunosuppressed transplant recipients.[Ref]

Very common (10% or more): Elevated AST (up to 63%), elevated ALT (up to 15%)
Common (1% to 10%): Hepatomegaly
Rare (0.01% to 0.1%): Hepatotoxicity (including fatality)
Very rare (less than 0.01%): Abnormal hepatic function tests, bilirubinemia, hepatic encephalopathy, hepatic failure, hepatosplenomegaly, jaundice
Frequency not reported: Biliary pain, hepatitis, increased transaminases (AST/ALT), worsening liver disease[Ref]

Nervous system

Impaired consciousness included cases of encephalopathy.

Frontal subcortical dysfunction and choreic movements of the limbs appeared in a 68-year-old woman almost 2 years after the start of interferon alfa-2b (the active ingredient contained in Intron A) (3 x 10[6] units/day) for chronic myeloid leukemia. She had no history of psychiatric disorders and no hereditary neurodegenerative disease with long-term recombinant interferon therapy. Symptoms of personality changes, short memory loss, and choreic movements progressively worsened over a 4 month period until she became bedridden. One month after this drug was discontinued, patient's cognitive performance had improved and choreic movements had disappeared. Clinical examination of her cognitive performances at six and 12 months later were normal.

Peripheral neuropathy and hearing loss have also been reported during postmarketing experience.[Ref]

Very common (10% or more): Headache (up to 62%), somnolence (up to 33%), dizziness (up to 24%), altered taste/taste perversion (up to 24%), paresthesia (up to 21%), impaired concentration (up to 14%), amnesia (up to 14%)
Common (1% to 10%): Hypoesthesia, vertigo, tremor, migraine, tinnitus
Uncommon (0.1% to 1%): Peripheral neuropathy
Rare (0.01% to 0.1%): Impaired consciousness, neuropathy, polyneuropathy, seizure
Very rare (less than 0.01%): Abnormal coordination, abnormal gait, aphasia, ataxia, central nervous system dysfunction, cerebrovascular hemorrhage, cerebrovascular ischemia, coma, convulsions, deafness, dementia, dystonia, encephalopathy, extrapyramidal disorder, hearing disorder, hearing loss, hyperacusis, hyperesthesia, hyperkinesia, hypertonia, oculomotor nerve paralysis, paralysis, paresis, speech disorder, stupor, syncope, taste loss
Frequency not reported: Bell's palsy, hearing impairment, hypokinesia, hyporeflexia, labyrinthine disorder, loss of consciousness, mononeuropathies, neuralgia, neuritis, parosmia, stroke, frontal subcortical dementia, choreic movements mimicking Huntington's disease[Ref]

Psychiatric

Psychosis (including hallucinations) has also been reported during postmarketing experience.[Ref]

Very common (10% or more): Depression (up to 40%), confusion (up to 12%), insomnia (up to 12%), anxiety, emotional lability, nervousness, agitation
Common (1% to 10%): Decreased libido, sleep disorder
Uncommon (0.1% to 1%): Suicidal ideation, suicide attempt, suicide
Rare (0.01% to 0.1%): Aggressive behavior (sometimes directed against others), psychosis (including hallucinations)
Very rare (less than 0.01%): Abnormal thinking, apathy, depression aggravated, feeling of ebriety, neurosis, paroniria, personality disorder
Frequency not reported: Abnormal dreaming, delirium, manic depression, mania, psychosis, mental status change, bipolar disorders
Postmarketing reports: Homicidal ideation[Ref]

Dermatologic

Case reports of aseptic necrosis of the skin and ulceration have been described in patients with Kaposi's sarcoma associated with HIV infection treated with this drug.

Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and urticaria have also been reported during postmarketing experience.[Ref]

Very common (10% or more): Alopecia (up to 38%), rash (up to 25%), increased sweating (up to 21%), pruritus (up to 11%), dry skin
Common (1% to 10%): Dermatitis, purpura, herpes simplex, psoriasis (new or aggravated), maculopapular rash, erythematous rash, eczema, erythema, skin disorder
Very rare (less than 0.01%): Abnormal hair texture, acne, chloasma, dermatitis lichenoides, epidermal necrolysis, erythema multiforme, furunculosis, increased hair growth, melanosis, nail disorders, nonherpetic cold sores, photosensitivity, skin depigmentation, skin discoloration, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria, vitiligo
Frequency not reported: Cellulitis, cold and clammy skin, erythema nodosum, folliculitis, herpes zoster, lipoma, pallor, sebaceous cyst, skin nodule, urticaria, hair discoloration, trichomegaly, radiation recall dermatitis (manifested as erythematous macular rash in region of irradiation), aseptic necrosis of the skin and ulceration, lipoatrophy, cutaneous vasculitides[Ref]

Respiratory

Pulmonary arterial hypertension (PAH) has been reported with alpha interferons, particularly in patients with risk factors for PAH (e.g., portal hypertension, HIV infection, cirrhosis). Such events occurred at various time points normally several months after starting interferon alfa therapy.

Severe asthma developed in 2 patients as soon as 8 weeks after the start of this drug in patients diagnosed with chronic hepatitis C and mild asthma.

Pulmonary fibrosis has also been reported during postmarketing experience.[Ref]

Very common (10% or more): Dyspnea (up to 34%), coughing (up to 31%), pharyngitis (up to 31%), sinusitis (up to 21%), nonproductive cough (up to 14%)
Common (1% to 10%): Nasal congestion, bronchitis, rhinitis, epistaxis, respiratory disorder, rhinorrhea
Rare (0.01% to 0.1%): Pneumonia, pulmonary infiltrates, pneumonitis
Very rare (less than 0.01%): Bronchospasm, hypoxia, laryngitis, pleural pain, pulmonary edema, pulmonary embolism, pulmonary fibrosis, sneezing, stridor, wheezing
Frequency not reported: Asthma, dysphonia, hemoptysis, hypoventilation, pleural effusion, orthopnea, pneumothorax, pulmonary arterial hypertension, rales, respiratory insufficiency, tonsillitis, tracheitis, upper respiratory tract infection, severe asthma
Postmarketing reports: Pulmonary hypertension[Ref]

Local

Injection site necrosis has also been reported during postmarketing experience.[Ref]

Very common (10% or more): Injection site inflammation (up to 20%), injection site reaction
Common (1% to 10%): Injection site pain
Rare (0.01% to 0.1%): Injection site disorders
Very rare (less than 0.01%): Injection site necrosis
Frequency not reported: Burning, injection site bleeding, itching[Ref]

Renal

Very common (10% or more): Increased serum urea nitrogen levels (up to 12%)
Common (1% to 10%): Increased serum creatinine
Rare (0.01% to 0.1%): Renal failure, renal insufficiency
Very rare (less than 0.01%): Nephrotic syndrome, nephrosis

Nephrotic syndrome, renal failure, and renal insufficiency have also been reported during postmarketing experience.

Genitourinary

Very common (10% or more): Amenorrhea (up to 12%)
Common (1% to 10%): Polyuria, urinary tract infection, micturition frequency, dysmenorrhea, menorrhagia, menstrual disorder, vaginal disorder
Very rare (less than 0.01%): Cystitis, hematuria, impotence, leukorrhea, micturition disorder, nocturia, oliguria, urinary incontinence, uterine bleeding, vaginal hemorrhage
Frequency not reported: Albumin/protein in urine, dysuria, genital pruritus, incontinence, menstrual irregularity, pelvic pain, penis disorder, scrotal/penile edema, sexual dysfunction, vaginal dryness[Ref]

Ocular

Serous retinal detachment has also been reported during postmarketing experience.[Ref]

Very common (10% or more): Blurred vision
Common (1% to 10%): Conjunctivitis, abnormal vision, eye pain, lacrimal gland disorder
Rare (0.01% to 0.1%): Retinal hemorrhage, retinopathies (including macular edema), retinal artery or vein obstruction, optic neuritis, papilledema, loss of visual acuity or visual field, cotton wool spots
Very rare (less than 0.01%): Diplopia, dry eyes, night blindness, periorbital edema, photophobia, retinal disorder, serous retinal detachment, stye
Frequency not reported: Lacrimation, nystagmus
Postmarketing reports: Vogt-Koyanagi-Harada syndrome[Ref]

Cardiovascular

Cardiovascular side effects (especially arrhythmia) appeared to be associated with preexisting cardiovascular disease and prior use of cardiotoxic agents.[Ref]

Common (1% to 10%): Hypertension, palpitations, tachycardia
Uncommon (0.1% to 1%): Hypotension
Rare (0.01% to 0.1%): Cardiomyopathy, peripheral ischemia
Very rare (less than 0.01%): Angina pectoris, arrhythmia, atrial fibrillation, bradycardia, cardiac failure, cardiac ischemia, cyanosis, extrasystoles, myocardial infarction, postural hypotension, thrombophlebitis
Frequency not reported: Arteritis, cardiomegaly, coronary artery disorder, cyanosis of the hand, heart valve disorder, hematoma, phlebitis, poor peripheral circulation, polyarteritis nodosa, Raynaud's disease, superficial phlebitis, thrombosis, varicose vein, vasculitis, congestive heart failure, pericardial effusion[Ref]

Endocrine

Common (1% to 10%): Hypothyroidism, hyperthyroidism
Very rare (less than 0.01%): Gynecomastia, virilism
Frequency not reported: Goiter, increased thyroid-stimulating hormone levels
Postmarketing reports: Hypopituitarism[Ref]

Immunologic

Very rare (less than 0.01%): Sarcoidosis, exacerbation of sarcoidosis, increased gamma globulins, transplant rejection
Frequency not reported: Autoimmune disorders, immune-mediated disorders
Postmarketing reports: Systemic lupus erythematosus[Ref]

A broad range of autoimmune and immune-mediated disorders have been reported with alpha interferons including thyroid disorders, systemic lupus erythematosus, rheumatoid arthritis (new or aggravated), idiopathic and thrombotic thrombocytopenic purpura, vasculitis, neuropathies (including mononeuropathies), and Vogt-Koyanagi-Harada syndrome.

Sarcoidosis and exacerbation of sarcoidosis have also been reported during postmarketing experience.[Ref]

Hypersensitivity

Frequency not reported: Allergic reaction
Postmarketing reports: Acute hypersensitivity reactions (including anaphylaxis, angioedema, urticaria, bronchoconstriction)

Some side effects of Intron A may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.