Intron A (Interferon alfa-2b)



Interferon alfa-2b

Biological Response Modifier

Action And Clinical Pharmacology: Interferon alfa-2b has exhibited antiproliferative effects in preclinical studies employing both cell culture systems and human tumor xenografts in animals, and has demonstrated significant immunomodulatory activity in vitro. Interferon alfa-2b also inhibits viral replication in vitro and in vivo.

Interferons exert their cellular activities by binding to specific membrane receptors on the cell surface. The results of several studies suggest that, once bound to the cell membrane, interferon initiates a complex sequence of intracellular events that include the induction of certain enzymes. It is thought that this process, at least in part, is responsible for the various cellular responses to interferon, including inhibition of virus replication in virus-infected cells, suppression of cell proliferation and such immunomodulation activities as enhancement of the phagocytic activity of macrophages and augmentation of the specific cytotoxicity of lymphocytes for target cells. All of these activities possibly contribute to interferon’s therapeutic effects.

Pharmacokinetics: The pharmacokinetics of interferon alfa-2b injection were studied in 12 healthy male volunteers following single doses of 5 million IU/madministered i.m., s.c. and as a 30-minute i.v. infusion in a cross-over design. Interferon concentrations were determined using a radioimmunoassay (RIA) with a detection limit equal to 10 IU/mL. The mean serum interferon concentrations following i.m. and s.c. 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-lives of interferon following both i.m. and s.c. injections were approximately 2 to 3 hours. Serum levels were below the detection limit 16 hours post-injection. After i.v. administration, serum interferon levels peaked (135 to 273 IU/mL) by the end of the infusion, then declined at a slightly more rapid rate than after s.c. or i.m. drug administration, becoming undetectable 4 hours after the infusion. The elimination half-life was approximately 2 hours. Urine levels of interferon following a single dose (5 million IU/m were below the detection limit following each of the 3 routes of administration.

In another study, the pharmacokinetics of interferon alfa-2b were studied in 12 healthy male volunteers following single 10 million IU doses administered s.c., i.m. and as a 30-minute i.v. infusion. The mean serum level profiles of interferon following s.c. and i.m. injections were comparable. The maximum serum levels obtained at 6 to 8 hours after injection were approximately 150 to 180 IU/mL. The elimination half-lives of interferon following both s.c. and i.m. injections were approximately 6 to 7 hours. Serum levels were below the detection limit of 25 IU/mL, 24 hours after the injections. Serum levels of interferon after i.v. administration peaked (546 IU/mL) by the end of the infusion, then declined rapidly with time, becoming undetectable 4 hours after the infusion. Urine levels of interferon were below the detection limit following each of the 3 routes of administration.

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

Indications And Clinical Uses: Chronic Hepatitis Non-A, Non-B/C: For the treatment of chronic hepatitis Non-A, Non-B/C (NANB/C) in patients 18 years or older with compensated liver disease who have a history of blood or blood product exposure and/or are HCV antibody positive. Studies in these patients demonstrated that interferon alfa-2b can produce normalization of ALT, clearance of serum HCV RNA and improvement in liver histology.

Chronic Active Hepatitis B: For the treatment of chronic active hepatitis B in patients 18 years of age or older with compensated liver disease and who have evidence of viral replication. Patients must be serum HBsAg positive for at least 6 months and have HBV replication, as demonstrated by positive serum HBeAg, with elevated serum ALT.

Studies in these patients demonstrated that interferon alfa-2b therapy can produce virologic remission of this disease (loss of serum HBeAg and HBV-DNA) and normalization of serum aminotransferases. Interferon alfa-2b therapy resulted in the loss of serum HBsAg in some responding patients.

Interferon alfa-2b is not indicated for the treatment of patients who are chronic carriers of hepatitis B surface antigen (HBsAg) but lack evidence of viral replication (serum HBeAg negative).

Chronic Myelogenous Leukemia: For the treatment of patients with chronic myelogenous leukemia (CML). Studies have demonstrated a greater likelihood of response to interferon alfa-2b therapy in patients who are in the chronic phase of the disease.

Thrombocytosis Associated with CML: Thrombocytosis is frequently associated with CML. During the clinical experience accumulated to date, approximately one-quarter (26%) of the patients diagnosed with CML had concomitant thrombocytosis, with a baseline platelet count of greater than 500´10L. Platelet control was achieved in all patients within 2 months of treatment.
Multiple Myeloma: Interferon alfa-2b maintenance is a therapeutic option for multiple myeloma patients who achieved objective remission on induction therapy (i.e., melphalan and prednisone). In the relatively older patient poplulation, the potential interferon-mediated benefit of prolonged remission duration must be weighed against the toxicity associated with interferon therapy. The approach to these patients should be individualized.

Non-Hodgkin’s Lymphoma: As adjuvant treatment of high tumor burden follicular lymphoma (Stage 3 or 4) in combination with appropriate chemotherapy, such as a CHOP-like regimen.

Malignant Melanoma: As adjuvant to surgical treatment in patients 18 years of age or older with malignant melanoma who are free of disease but at high risk for systemic recurrence, within 56 days of surgery.

AIDS-Related Kaposi’s Sarcoma: For the treatment of select patients, above 18 years of age with AIDS-Related Kaposi’s Sarcoma. Studies have demonstrated a greater likelihood of response in patients who are without systemic symptoms, who have limited lymphadenopathy and who have a relatively intact immune system.

Hairy Cell Leukemia: For the treatment of patients with hairy cell leukemia either following or replacing splenectomy.

Basal Cell Carcinoma: Interferon alfa-2b, administered intralesionally, should be considered as an alternative treatment for patients with primary superficial and noduloulcerative basal cell carcinoma, where surgery or radiation are considered inappropriate. The basal cell lesion should be subtyped prior to initiation of treatment since no data exist for the use of interferon alfa-2b in the following conditions: 1) recurrent basal cell carcinoma; 2) genetic or nevoid basal cell carcinoma; 3) basal cell carcinoma with evidence of deep tissue involvement; 4) morphealike basal cell carcinoma.

Condylomata Acuminata: For intralesional treatment of selected patients with condylomata acuminata involving external surfaces of the genital and perianal areas.

In selecting patients for interferon alfa-2b treatment, the physician should consider the nature of the patient’s lesion and the patient’s past treatment history, in addition to the patient’s ability to comply with the treatment regimen. Interferon alfa-2b therapy offers an additional approach to treatment in condylomata and is particularly useful for those patients who do not respond satisfactorily to other treatment modalities (e.g., podophyllin resin, surgery, cryotherapy, chemotherapy, and laser therapy), or whose lesions are more readily treatable by interferon alfa-2b than by other treatments.

Contra-Indications: Hypersensitivity to interferon alfa-2b or any of its components.

Manufacturers’ Warnings In Clinical States: Variations in dosage, routes of administration, and adverse reactions exist among different brands of interferon. Therefore, do not use different brands of interferon in any single treatment regimen.

General: Pulmonary infiltrates, pneumonitis and pneumonia, including fatality, have been observed rarely in interferon-alfa treated patients. The etiology has not been defined. Any patient developing fever, cough, dyspnea or other respiratory symptoms should have a chest x-ray taken. If the chest x-ray shows pulmonary infiltrates or there is evidence of pulmonary function impairment, the patient should be monitored closely, and, if appropriate, interferon-alfa treatment should be discontinued. While this has been reported more often in patients with chronic hepatitis non-A, non-B/C treated with interferon-alfa, it has also been reported in patients with oncologic diseases treated with interferon-alfa. These symptoms have been reported more frequently when shosaikoto, a Chinese herbal medication, has been administered concomitantly with interferon-alfa.

Patients with a pre-existing psychiatric condition or a history of severe psychiatric disorder should not be treated with interferon alfa-2b. Therapy should be discontinued for any patient developing severe depression during treatment.

AIDS-Related Kaposi’s Sarcoma: Interferon alfa-2b should not be used for patients with rapidly progressive visceral disease. Patients receiving concomitant zidovudine (AZT) have had a higher incidence of neutropenia than that expected with zidovudine alone. Careful monitoring of the WBC counts is indicated in all patients who are myelosuppressed and in all patients receiving other myelosuppressive medications. The effects of interferon alfa-2b when administered in association with drugs used in the treatment of AIDS-related disease are unknown.

Chronic Hepatitis Non-A, Non-B/C and Chronic Active Hepatitis B: Patients with decompensated liver disease, autoimmune hepatitis, a history of autoimmune disease or immune suppressed transplant recipients should not be treated with interferon alfa-2b. There are reports of worsening liver disease, including jaundice, hepatic encephalopathy, hepatic failure and death following interferon alfa-2b therapy in patients with decompensated liver disease.

Patients with chronic hepatitis B with evidence of decreasing hepatic synthetic function, such as decreasing albumin levels or prolongation of prothrombin time, may be at increased risk of clinical decompensation if a flare of aminotransferases occurs. In considering these patients for interferon alfa-2b therapy, the potential risks must be evaluated against the potential benefits of treatment.

Pregnancy: Interferon alfa-2b has been shown to have abortifacient effects in Macaca mulatta (rhesus monkeys) at 90 and 180 times the i.m. or s.c. dose of 2 million IU/m Although abortion was observed in all dose groups (7.5 million, 15 million, and 30 million IU/kg), it was only statistically significant versus control at the mid- and high-dose groups (corresponding to 90 and 180 times the i.m. or s.c. dose of 2 million IU/m. There are no adequate and well-controlled studies in pregnant women. Interferon alfa-2b should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactation: It is not known whether the components of this drug are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from interferon alfa-2b in nursing infants, a decision to use or discontinue the drug should be based on a benefit to risk assessment.

Effect on Fertility: Interferon may impair fertility. In studies of interferon use in nonhuman primates, menstrual cycle abnormalities have been observed. Decreased serum estradiol and progesterone concentrations have been reported in women treated with human leukocyte interferon. Therefore, fertile women should not receive interferon alfa-2b injection unless they are using effective contraception during the treatment period. When interferon alfa-2b is used by fertile men, a possible effect on fertility should be considered.

Precautions: Patients should be cautioned not to change brands of interferon without medical consultation as a change in dosage may result.

Acute serious hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) have been observed rarely during interferon alfa-2b therapy. If such a reaction develops, the drug should be discontinued and appropriate medical therapy instituted immediately. Transient rashes do not necessitate interruption of treatment.

There have been reports of interferon exacerbating pre-existing conditions of psoriasis. Therefore, interferon alfa-2b should be used in these patients only if the potential benefit justifies the potential risk.

Hepatotoxicity, including fatality, has been observed rarely in interferon alfa-2b treated patients. Any patient developing liver function abnormalities during treatment should be monitored closely and if appropriate, treatment should be discontinued.

Because of the fever and other flu-like symptoms associated with interferon alfa-2b administration, it should be used cautiously in patients with debilitating medical conditions, such as those with a history of cardiovascular disease (e.g., unstable angina, uncontrolled congestive heart failure), pulmonary disease (e.g., chronic obstructive pulmonary disease) or diabetes mellitus prone to ketoacidosis.

While fever may be associated with interferon therapy, other causes of persistent fever should be ruled out. Caution should also be observed in patients with coagulation disorders (e.g., thrombophlebitis, pulmonary embolism) or severe myelosuppression.

Patients with a history of myocardial infarction and/or previous or current arrhythmic disorders, who require interferon alfa-2b therapy, should be closely monitored (see Laboratory Tests). Those patients who have pre-existing cardiac abnormalities and/or are in advanced stages of cancer, should have ECGs taken prior to and during the course of treatment. Cardiac arrhythmias (primarily supraventricular) usually respond to conventional therapy but may require dose modification or discontinuation of interferon alfa-2b therapy.

Transient reversible cardiomyopathy was reported in approximately 2% of the AIDS-Related Kaposi’s Sarcoma patients treated with interferon alfa-2b. Cardiomyopathy has also been reported in AIDS patients not receiving interferon alfa-2b therapy. Baseline chest x-rays are suggested and should be repeated if clinically indicated.

Adequate hydration should be maintained in patients undergoing inferferon alfa-2b therapy since hypotension related to fluid depletion has been seen in some patients during therapy and up to 2 days post-therapy. Fluid replacement may be necessary.

Retinal hemorrhages, cotton-wool spots, and retinal artery or vein obstruction have been observed rarely in patients treated with interferon alfa, including interferon alfa-2b. The etiologic explanation for these findings has not yet been established. These events appear to occur after use of the drug for several months, but also have been reported after shorter treatment periods. Diabetes mellitus or hypertension have been present in some patients. Any patient complaining of changes in visual acuity or visual fields, or reporting other ophthalmologic symptoms during treatment with interferon alfa-2b, should have an eye examination. Because the retinal events may have to be differentiated from those seen with diabetic or hypertensive retinopathy, a baseline ocular examination is recommended prior to treatment with interferon in patients with diabetes mellitus or hypertension.

CNS effects manifested by depression, confusion and other alterations of mental status have been observed in some interferon alfa-2b-treated patients, and suicidal ideation and attempted suicide have been observed rarely. These adverse effects have occurred in patients treated with recommended doses as well as in patients treated with higher interferon alfa-2b doses. More significant obtundation and coma have been observed in some patients, usually elderly, treated at higher doses. While these effects are generally reversible upon discontinuation of therapy, in a few patients full resolution took up to 3 weeks. Very rarely, seizures have occurred with high doses of interferon alfa-2b. Narcotics, hypnotics or sedatives should be administered with caution concomitantly with interferon alfa-2b.

Administration of interferon alfa-2b in combination with other chemotherapeutic agents may lead to increased risk of toxicity (severity and duration), which may be life-threatening or fatal as a result of the concomitantly administered drug. The most commonly reported potentially life-threatening or fatal adverse events include mucositis, diarrhea, neutropenia, renal impairment, and electrolyte disturbance. Because of the risk of increased toxicity, careful adjustments of doses are required for interferon alfa-2b and for the concomitant chemotherapeutic agents.

In the presence of thyroid dysfunction, interferon alfa-2b treatment may be initiated or continued only if TSH levels can be maintained in the normal range by medication. Discontinuation of interferon alfa-2b therapy has not reversed thyroid dysfunction occurring during treatment.

Children: Safety and effectiveness have not been established in patients below the age of 18 years.

Laboratory Tests: In addition to those tests normally required for monitoring patients, the following laboratory tests are recommended for all patients on interferon alfa-2b therapy prior to beginning treatment and then periodically thereafter: standard hematologic tests-including hemoglobin, complete and differential white blood cell counts and platelet count; blood chemistries-including electrolytes, calcium, liver enzyme tests and serum creatinine and TSH.

The hematologic parameters of the patients should be followed closely as part of the treatment, and also because a certain degree of myelodepression has been detected in some patients under treatment with interferon alfa-2b.

Mild to moderate leukopenia and elevated serum liver enzyme (AST) levels have been reported with intralesional administration of interferon alfa-2b; therefore, the monitoring of these laboratory parameters should be considered.

For specific laboratory testing recommendations on chronic hepatitis Non-A, Non-B/C and chronic active hepatitis B, see Dosage.

Adverse Reactions: Systemic Administration: The most commonly reported adverse effects were fever, fatigue, headache and myalgia (flu-like symptoms). Fever and fatigue were reversible within 72 hours of interruption or cessation of treatment and were dose related.

Common adverse effects include rigors, anorexia and nausea.

Less common adverse effects include vomiting, diarrhea, arthralgia, asthenia, somnolence, dizziness, dry mouth, alopecia, flu-like symptoms (unspecified), back pain, depression, malaise, pain, increased sweating, taste alteration, irritability, insomnia, confusion, impaired concentration and hypotension.

Rarely reported adverse reactions include abdominal pain, rash, nervousness, injection site disorders, paresthesia, herpes simplex, pruritus, eye pain, anxiety, epistaxis, coughing, pharyngitis, pulmonary infiltrates, pneumonitis and pneumonia, impaired consciousness, weight decrease, facial edema, dyspnea, dyspepsia, tachycardia, hypertension, increased appetite, decreased libido, hypoesthesia, taste alteration, loose stool, gingival bleeding, leg cramps, neuropathy, polyneuropathy, rhabdomyolysis (sometimes serious), hearing disorder, renal failure, renal insufficiency, nephrotic syndrome, and diabetes mellitus/hyperglycemia. Hyperthyroidism or hypothyroidism have also been observed rarely. Hepatotoxicity, including fatality, has been observed rarely (see Precautions).

Cardiovascular adverse reactions, particularly arrhythmia, appeared to be correlated mostly with pre-existing cardiovascular disease and prior cardiotoxic therapy. Transient reversible cardiomyopathy has been reported rarely in patients without prior evidence of cardiac disease. Very rarely reported adverse reactions include pancreatitis, cardiac ischemia and myocardial infarction.

Clinically significant laboratory abnormalities, most frequently occurring at doses greater than 10 million IU daily, include reduction in granulocyte and white blood cell counts; decreases in hemoglobin level and platelet count; increases in alkaline phosphatase, lactate dehydrogenase (LDH), serum creatinine, serum urea nitrogen, and TSH levels. Increase in serum ALT/AST levels have been noted as an abnormality in some non-hepatitis subjects and also in some patients with chronic hepatitis B coincident with clearance of viral DNAp.

There were no new or unusual toxicities associated with the use of interferon alfa-2b for the treatment of malignant melanoma. The most commonly reported adverse reactions were gastrointestinal events, hematologic events, hepatic toxicity, neurologic toxicity, vomiting, chills, fatigue, fever and myalgia. In the surgical adjuvant trial involving 280 patients, 100% of patients treated with interferon alfa-2b experienced at least 1 adverse event compared to 43% for the observation patients. Severe adverse events occurred in 78% of interferon alfa-2b treated patients versus 6% of observation patients. Sixty-five percent of patients had at least 1 dose modification due to toxicity. Twenty-four percent of patients discontinued interferon alfa-2b treatment due to adverse events.

The following adverse reactions were reported to be possibly or probably treatment-related in the trial involving 143 interferon alfa-2b treated patients. The most commonly reported adverse reactions were fatigue, fever, myalgia, anorexia, nausea, headache and chills. Less common adverse reactions were depression, diarrhea, alopecia, taste alteration, dizziness, rash, pain (unspecified), dyspnea, paresthesia, influenza-like symptoms, confusion, bleeding, coughing, increased sweating, arthralgia, malaise and insomnia.

Intralesional Administration: Most reported adverse reactions were mild to moderate, transient and rapidly reversible. The incidence of reported adverse reactions in the patients treated for condylomata acuminata appears to increase in proportion to the number of lesions treated and consequently, is dose related.

The most common adverse reactions are flu-like symptoms, (rigors/chills, fever, headache, myalgia and malaise). Other commonly reported side effects include nausea, fatigue, dizziness, arthralgia, back pain and injection site reactions (burning, itching, pain and injection site bleeding). In patients treated for condylomata acuminata injection site reactions appear to be due to manipulation of the lesion rather than the interferon alfa-2b therapy.

Rarely reported side effects include diarrhea, somnolence, depression, pain, dyspepsia, increased sweating, unspecified flu-like symptoms, confusion, weakness, vomiting, flushing, leg cramps, asthenia, taste perversion, dermatitis and pruritus.

Low white blood cell counts, elevated serum liver enzyme (AST) levels and low platelet counts have been reported in some patients with intralesional administration of interferon alfa-2b. Most of these laboratory findings were transient, rapidly reversible and mild to moderate in severity.

Reported adverse reactions and abnormal laboratory test values observed in patients who were re-treated for condylomata acuminata with interferon alfa-2b were qualitatively and quantitatively similar to those reported above.

The following adverse events have been reported very rarely after administration of interferon alfa-2b: Blood Disorders: hemolytic anemia, granulocytopenia, leukopenia, increased gamma globulins, coagulation disorder.

Body as a Whole: dehydration, hypercalcemia, cachexia, peripheral edema, lymphadenopathy, periorbital edema, malignant hyperpyrexia, transplant rejection, acidosis, ascites.

Cardiovascular: palpitations, postural hypotension, chest pain, chest pain substernal, bradycardia, cardiac failure, cardiomyopathy, atrial fibrillation, arrhythmia, extrasystole, angina pectoris, thrombophlebitis, peripheral ischemia.

Central and Peripheral Nervous System: amnesia, stupor, convulsions, hypertonia, hyperesthesia, hot flashes, migraine, encephalopathy, tremor, coma, extrapyramidal disorder, paresis, speech disorder, dysphonia, syncope, tinnitus, vertigo, abnormal coordination, ataxia, aphasia, CNS dysfunction, abnormal gait, hyperkinesia, dystonia, paralysis, hyperparesthesia.

Endocrine: gynecomastia, virilism, aggravation of diabetes mellitus, hyperglycemia, adrenal hypercorticism.

Gastrointestinal: eructation, stomatitis, stomatitis ulcerative, constipation, tenesmus, ileus, thirst, melena, increased saliva, esophagitis, rectal bleeding after stool, dysphagia, gastrointestinal hemorrhage, gastric ulcer, gingivitis, gum hyperplasia, rectal hemorrhage, oral leukoplakia, gastrointestinal mucosal discoloration, abdominal distention, flatulence, tongue discoloration, glossitis, taste loss, discolored feces.

Liver and Biliary: abnormal hepatic function tests, bilirubinemia, jaundice, right upper quadrant pain, hepatosplenomegaly, splenomegaly, hepatic encephalopathy.

Musculoskeletal: bone pain, muscle weakness, arthritis, arthrosis, myopathy.

Psychiatric Disorders: agitation, emotional lability, personality disorder, abnormal thinking, abnormal dreaming, sleep disorder, dysphonia, flushing, hypokinesia, suicide attempt, paroniria, apathy, aggravated depression, neurosis, aggressive reaction, feeling of ebriety, hallucination, dementia, paranoid reactions.

Reproduction: impotence, leukorrhea, menorrhagia, uterine bleeding, vaginal hemorrhage, amenorrhea.

Resistance Mechanism Disorders (i.e., altered resistance to infection): stye, conjunctivitis, viral and fungal infections, moniliasis, sepsis.

Respiratory: hypoxia, stridor, nasal congestion, pneumonia, sinusitis, rhinitis, rhinorrhea, bronchospasm, cyanosis, wheezing, pleural pain, sneezing, nonproductive coughing, pulmonary embolism, pulmonary edema, laryngitis, cold.

Skin and Appendages: urticaria, acne, nail disorders, hypertrichosis, purpura, peripheral ischemia, furunculosis, nonherpetic cold sores, epidermal necrolysis, lacrimal gland disorder, cyanosis of the hand, photosensitivity, skin discoloration, chloasma, abnormal hair texture, increased hair growth, skin depigmentation, dermatitis lichenoides, melanosis, vitiligo, dry skin, dermatitis, erythema, maculopapular rash, pustular rash, clammy skin, injection site reaction.

Urinary: micturition disorder, nocturia, polyuria, hematuria, micturition frequency, cystitis, oliguria, nephrosis, urinary incontinence, hyperuricemia.

Visual and Auditory Disorders: photophobia, blurred vision, abnormal vision, diplopia, dry eyes, oculomotor nerve paralysis, retinal disorder, retinal hemorrhage, night blindness, twitching, earache, deafness, hyperacusis.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Distinction between the therapeutic dose of interferon alfa-2b and overdose has not been clearly defined. Symptoms of overdose may include amplification of the adverse effects, notably flu-like symptoms, leukopenia or thrombocytopenia and increased serum liver enzyme levels. The severity of the adverse reactions can be ameliorated by adjusting the dose level and schedule, or in some cases termination of interferon alfa-2b therapy. Cardiovascular side effects such as hypotension and arrhythmia may require supportive therapy.

Dosage And Administration: Interferon alfa-2b injection may be administered using either sterilized glass or plastic disposable syringes.

In general, the dosage may be adjusted according to the patient’s tolerance to the medication. If severe adverse reactions develop, the dosage should be modified (50% reduction) or therapy should be temporarily discontinued until the adverse reactions abate. If persistent or recurrent intolerance develops following adequate dosage adjustment, or if the disease progresses rapidly, treatment with interferon alfa-2b should be discontinued.

For maintenance dosage regimens administered s.c. or i.m., the patient may self-administer the dose at the discretion of the physician.

Laboratory Tests: Standard hematologic tests and blood chemistries (complete blood count and differential, platelet count, electrolytes, liver enzymes, including serum ALT, serum bilirubin, and albumin, serum protein, and serum creatinine) should be conducted in all patients prior to and periodically during treatment with interferon alfa-2b. Thyroid stimulating hormone (TSH) levels must be within normal limits prior to initiation of interferon alfa-2b therapy. Any patient developing symptoms consistent with possible thyroid dysfunction during interferon alfa-2b therapy should have an evaluation of thyroid function.

In patients treated for hepatitis, the recommended testing schedule is at weeks 1, 2, 4, 8, 12, 16, and every other month, thereafter, throughout treatment. If ALT flares (³ 2 times baseline) during interferon alfa-2b therapy, interferon alfa-2b may be continued unless signs or symptoms of liver failure are observed. During ALT flare, liver function tests for prothrombin time, ALT, alkaline phosphatase, albumin and bilirubin levels should be performed at 2 week intervals.

Chronic Hepatitis Non-A, Non-B/C: The recommended dosage of interferon alfa-2b is 3 million IU administered s.c. or i.m. 3 times/week for up to 18 months. Most patients who respond demonstrate improvement in ALT levels within 12 weeks. Some patients who fail to respond to 3 million IU may benefit from higher doses of up to 10 million IU 3 times/week.

Current clinical experience in patients who remain on interferon alfa-2b for 12 to 18 months indicates that a higher proportion of patients demonstrated a sustained response after longer durations of therapy than those who discontinued therapy after 6 months.

Patients who relapse following therapy may be retreated with the same dosage regimen to which they had previously responded.

A liver biopsy should be performed to establish the diagnosis of chronic hepatitis. Patients should be tested for the presence of antibody to HCV and other causes of chronic hepatitis, including autoimmune hepatitis should be excluded. Prior to initiation of interferon alfa-2b therapy, the physician should establish that the patient has compensated liver disease with no evidence of hepatic failure. Serum bilirubin, serum albumin, and serum creatinine should be within normal limits.

Prior to initiation of interferon alfa-2b therapy, CBC and platelet counts should be evaluated in order to establish baselines for monitoring potential toxicity. During treatment with interferon alfa-2b, these tests should be evaluated at weeks 1 and 2, and monthly thereafter. ALT levels should be evaluated after 2, 12 and 24 weeks of therapy to assess response to treatment.

Thyroid stimulating hormone (TSH) must be within normal limits upon initiation of interferon alfa-2b treatment. Patients with pre-existing thyroid abnormalities may be treated if TSH levels can be maintained in the normal range by medication.

Chronic Active Hepatitis B: The recommended dosage of interferon alfa-2b is 30 to 35 million IU/week, administered s.c. or i.m. either as 5 million IU daily or 10 million IU 3 times/week, for 16 weeks.

Prior to initiation of therapy, a liver biopsy may be useful in establishing a diagnosis of chronic hepatitis. The physician should establish that the patient has compensated liver disease. The following patient entrance criteria for compensated liver disease were used in the clinical studies:

No history of hepatic encephalopathy, variceal bleeding, ascites, or other clinical signs of decompensation; bilirubin: normal; albumin: stable and within normal limits; prothrombin time:
Patients with other causes of chronic hepatitis should be excluded. CBC and platelet counts should be evaluated prior to initiation of interferon alfa-2b therapy in order to establish baselines for monitoring potential toxicity. These tests should be repeated at treatment weeks 1, 2, 4 and monthly thereafter. Liver function tests, including serum ALT, albumin and bilirubin, should be evaluated after 1, 2, 4, 8, 12 and 16 weeks of therapy. HBeAg, HBsAg, and ALT should be evaluated at the end of therapy, as well as at 3 and 6 months post-therapy, since patients may become virologic responders during the 6-month period following the end of treatment.

For patients with decreases in granulocyte or platelet counts, the following guidelines for dose modifications were used in the clinical trials: See Table I.

Interferon alfa-2b therapy was resumed at 50% or increased to 100% of the initial dose when granulocytes and/or platelets increased above the appropriate values.

A transient increase in ALT ³2 times baseline value (flare) can occur during interferon alfa-2b therapy for chronic active hepatitis B. In clinical trials, this flare generally occurred 8 to 12 weeks after initiation of therapy and was more frequent in responders (63%, 24/38) than in nonresponders (27%, 13/48). However, coincident elevation in bilirubin ³3 mg/dL occurred infrequently (2%, 2/85). When ALT flare occurs, in general interferon alfa-2b therapy should be continued unless signs and symptoms of liver failure are observed. During ALT flare, clinical symptomatology and liver function tests including ALT, albumin and bilirubin, should be monitored at approximately 2-week intervals.

Chronic Myelogenous Leukemia: The recommended dosage of interferon alfa-2b is 4 to 5 million IU/madministered daily s.c. Dosages as little as 0.5 million IU/mor as high as 10 million IU/mmay be necessary to achieve or maintain control of the white blood cell count. When the white blood cell count is controlled, the dosage may be administered 3 times/week (every other day). The dosage may be adjusted according to the patient’s tolerance to the medication.

Treatment should be initiated as early as possible after diagnosis, and continued until complete hematological response is achieved or for a maximum of 18 months. Responding patients generally show a hematologic response within 2 to 3 months of treatment. These patients should continue to be treated until a complete hematologic response is obtained, as defined by a white blood cell (WBC) count of 3 to 4 x 10L. All patients with a complete hematological response should further continue treatment in order to achieve a cytogenetic response which in some patients may not occur until 2 years after treatment initiation.

In patients, who at the time of initiation of therapy with interferon alfa-2b, present with extremely high white blood cell counts leading to possible life-threatening complications, consideration should be given to concomitant interventions such as leukapheresis in order to quickly lower the white blood cell count. Once the immediate risk to the patient has been reduced, interferon alfa-2b therapy should be initiated.

Thrombocytosis Associated with CML: The recommended dosage for the control of thrombocytosis in CML is the same as that recommended above for the treatment of CML. Dose adjustments made for the control of the white blood cell counts should also be appropriate to control platelet counts.

Multiple Myeloma: In patients who are in the plateau phase following inductive chemotherapy, interferon alfa-2b may be administered as monotherapy, s.c., at a dose of 3 million IU/m 3 times a week (every other day).

Treatment should continue unless clear disease progresses or severe intolerance occurs.

Non-Hodgkin’s Lymphoma: When used adjunctively with chemotherapy, the recommended dosage of interferon alfa-2b is 5 million IU 3 times/week on alternate days administered s.c. for a duration of 18 months.

The standard chemotherapeutic treatment for patients with high tumor burden follicular lymphomas is the administration of a combination chemotherapy regimen. Most of these regimens are related to the well-known CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone] regimen such as the CHVP regimen of doxorubicin, cyclophosphamide, teniposide and prednisolone.

At diagnosis, most follicular lymphoma patients have a disseminated disease, stage III or stage IV. Despite this advanced disease, many patients have an indolent course and survive several years after diagnosis. A wait and watch approach may be appropriate for these patients, especially if their tumor burden is low. Treatment is frequently initiated without delay for patients with high-tumor burden such as bulky lymphadenopathy, major organ obstruction or compression syndromes, malignant effusions, bone marrow failure, or rapidly enlarging tumors.

Malignant Melanoma: The recommended interferon alfa-2b treatment regimen includes an induction treatment of 5 consecutive days/week for 4 weeks as an i.v. infusion at a dose of 20 million IU/m followed by a maintenance treatment of 3 times/week for 48 weeks as a s.c. injection, at a dose of 10 million IU/m Therapy should be administered for a total of 1 year unless the disease progresses.

Induction therapy is administered as a 20-minute i.v. infusion of interferon alfa-2b in 100 mL of normal saline.

If severe adverse reactions develop during interferon alfa-2b treatment, particularly if granulocytes decrease to 5´upper limit of normal, treatment should be temporarily discontinued until the adverse reaction abates. Interferon alfa-2b treatment should be restarted at 50% of the previous dose. If intolerance persists after dose adjustment or if granulocytes decrease to 10´upper limit of normal, interferon alfa-2b therapy should be discontinued. In the clinical trial, patients were able to maintain clinical benefit in conjunction with appropriate dose modifications.

For patients treated for malignant melanoma, liver function and white blood cell and differential counts should be monitored weekly during the induction phase of therapy and monthly during the maintenance phase of therapy.

AIDS-Related Kaposi’s Sarcoma: The recommended dosage of interferon alfa-2b is 30 million IU/m3 times/week administered s.c. or i.m.

When patients initiate therapy at 30 million IU/m3 times/week, the average dose tolerated at the end of 12 weeks of therapy is approximately 75% of the weekly dose and 50% of the weekly dose at the end of 24 weeks of therapy.

Lesion measurements and blood counts should be performed prior to initiation of therapy and should be monitored periodically during treatment to determine whether response to treatment or disease stabilization has occurred.

When disease stabilization or a response to treatment occurs, treatment should continue until there is no further evidence of tumor or until discontinuation is required by evidence of a severe opportunistic infection or adverse effect.

Hairy Cell Leukemia: The recommended dosage of interferon alfa-2b is 2 million IU/madministered s.c. 3 times/week (every other day).

Prior to initiation of therapy, tests should be performed to quantitate peripheral blood hemoglobin, platelets, granulocytes and hairy cells and bone marrow hairy cells. These parameters should be monitored periodically during treatment to determine whether response to treatment has occurred. The normalization of one or more hematologic variables usually begins within 2 months of initiation of therapy. Improvement in all 3 hematologic variables (granulocyte count, platelet count and hemoglobin level) may require 6 months or more of therapy.

If a patient does not respond within 6 months, treatment should be discontinued. If a response to treatment does occur, treatment usually should be continued until no further improvement is observed and the laboratory parameters have been stable for about 3 months. It is not known whether continued treatment after that point is beneficial.

Basal Cell Carcinoma: The lesion to be injected should be cleaned first with a sterile alcohol pad. The intralesional injection should be made into the base and substance of the lesion using a fine needle (30 gauge) and a 1 mL syringe. Care should be taken not to go too deeply beneath the lesion. S.C. injection should be avoided. For lesions with an initial area below 2 cm inject 0.15 mL of reconstituted solution containing 1.5 million IU interferon alfa-2b (see Reconstitution) into the lesion 3 times/week on alternate days, for 3 weeks. The cumulative dose administered per lesion should be 13.5 million IU. As many as 3 lesions can be treated at one time.

Large superficial and noduloulcerative basal cell lesions (lesions with an area between 2 and 10 cm should be treated 3 times/week for 3 weeks with 0.5 million IU/cmof the lesion’s initial size (the minimum dose being 1.5 million IU and the maximum dose being 5.0 million IU). Only one large lesion should be treated at a time.

The improvement in clinical status (appearance, size, erythema, etc.) of the treated lesion is a reliable predictor of biopsy-proven cures. Therefore, the clinical status should be monitored periodically after treatment end. Improvement in disease signs usually begins at approximately 8 weeks after treatment initiation. If no clinical improvement on the lesion is observed after 8 to 12 weeks, excision should be reconsidered.

Condylomata Acuminata: Inject 1 million IU of interferon alfa-2b (0.1 mL of reconstituted interferon alfa-2b solution) into each lesion 3 times/week on alternate days, for 3 weeks. Only the 10 million IU vial of interferon alfa-2b when reconstituted with 1 mL of designated diluent results in an isotonic solution at the desired concentration of 1 million IU/0.1 mL. 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 (approximating 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; s.c. 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. As many as 5 lesions can be treated at one time. To reduce side effects, interferon alfa-2b injections may be administered in the evening, when possible. Additionally, acetaminophen may be administered at the time of injection to alleviate some of the potential side effects.

The maximum response usually occurs 4 to 8 weeks after initiation of the first treatment course. If results at 12 to 16 weeks after the initial treatment course has concluded are not satisfactory, a second course of treatment using the above dosage schedule may be instituted providing that clinical symptoms and signs, or changes in laboratory parameters (liver function tests, WBC and platelets) do not preclude such a course of action.

Patients with 6 to 10 condylomata may receive a second (sequential) course of treatment at the above dosage schedule, to treat up to 5 additional condylomata per course of treatment. Patients with greater than 10 condylomata may receive additional sequences depending on how large a number of condylomata are present.

Concomitant Therapy: Acetaminophen has been used successfully to alleviate the symptoms of fever and headache which can occur with interferon alfa-2b therapy. The recommended acetaminophen dosage is 500 mg to 1 g given 30 minutes before administration of interferon alfa-2b. The maximum dosage of acetaminophen to be given is 1 g 4 times daily. In order to properly assess the source of fever, adjunctive acetaminophen should be limited to a maximum of 5 consecutive days unless otherwise specified by the prescribing physician.

A synergistic adverse effect on the white blood cell count may occur when interferon alfa-2b is administered concomitantly with zidovudine. Patients receiving the two agents concomitantly have had a dose-dependent higher incidence of neutropenia than expected when zidovudine is administered alone.

Interactions between interferon alfa-2b and other drugs have not been fully evaluated. Caution should be exercised when administering interferon alfa-2b in combination with other potentially myelosuppressive agents.

Reconstitution: Interferon alfa-2b lyophilized powder should be reconstituted with accompanying Bacteriostatic Water for Injection USP (preserved with benzyl alcohol, 0.9%), as diluent. If the patient is allergic to benzyl alcohol or if it is preferred by the physician, Sterile Water for Injection may be used.

S.C. or I.M. Administration: Using a sterile syringe and needle, inject 1 mL of Bacteriostatic Water for Injection USP (preserved with benzyl alcohol, 0.9%), supplied, or Sterile Water for Injection into the vial. Agitate gently to hasten complete dissolution of the powder. The appropriate dose should then be withdrawn with a sterile syringe and injected slowly s.c. or i.m.

Intralesional Administration: An isotonic solution of interferon alfa-2b is recommended for the treatment of basal cell carcinoma. Only the 10 million IU vial of Intron A when reconstituted with 1 mL of designated diluent results in an isotonic solution at the desired concentration of 1 million IU/0.1 mL. Reconstitution of other vial sizes to prepare the dilution required for intralesional use will result in a hypertonic solution.

I.V. Administration: The lyophilized powder form of interferon alfa-2b should be reconstituted by adding 1 mL of the provided diluent to the vial. The calculated amount of interferon for the appropriate dose then should be withdrawn from the vial(s), added to 100 mL of Sterile Normal Saline solution, and administered over 20 minutes. No other drug can be infused concomitantly with Intron A.

Intron A ready-to-use solution is not recommended for i.v. administration unless it is pre-filtered prior to use. A 0.2-micron filter can be used.

Compatibility with Other I.V. Fluids: In addition to i.v. normal saline solution, Intron A, at final concentrations of 50 000 to 1 million IU/mL is stable and compatible in the following mixtures for up to 24 hours at refrigerated or at room temperature in glass bottles: Ringers Injection, Amino Acid Injections, Lactate Ringers Injection, 5% Sodium Bicarbonate Injection.

The admixtures remained stable for the 6-hour infusion period through an administration set.

Stability and Storage: Store lyophilized powder and ready-to-use solution between 2 and 8°C.

Reconstituted Lyophilized Intron A: Diluted with Bacteriostatic Water for Injection USP (preserved with benzyl alcohol, 0.9%) – supplied with Intron A: If stored between 2 and 8°C, use within 30 days. If stored between 15 and 30°C, use within 14 days. Diluted with Sterile Water for Injection: Store at 2 to 30°C; use within 24 hours.

The reconstituted solution is clear and colorless to light yellow in color. The reconstituted material, as for all parenteral drug products, should be inspected visually for particulate matter and discoloration prior to administration.

Availability And Storage: Lyophilized Powder with Diluent: Each vial contains: 3, 5, 10 or 18´10IU of interferon alfa-2b, aminoacetic acid, sodium phosphate dibasic anhydrous, sodium phosphate monobasic monohydrate and human albumin and 1 vial of 1 mL Bacteriostatic Water for Injection USP (preserved with benzyl alcohol, 0.9%). Store between 2 and 8°C.

Ready-to-Use Solution: Each mL contains: 5´10IU of interferon alfa-2b, sodium phosphate dibasic anhydrous, sodium phosphate monobasic monohydrate, glycine, human albumin, methylparaben, propylparaben, q.s. water for injection to make 1 mL. Vials of 2 and 5 mL. Store between 2 and 8°C.

INTRON A® Schering Interferon alfa-2b Biological Response Modifier

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