DESCRIPTION

Roferon-A (Interferon alfa-2a, recombinant) is asterile protein product for use by injection. Roferon-A is manufacturedby recombinant DNA technology that employs a genetically engineered Escherichia coli bacterium containingDNA that codes for the human protein. Interferon alfa-2a, recombinantis a highly purified protein containing 165 amino acids, and it hasan approximate molecular weight of 19,000 daltons. Fermentation iscarried out in a defined nutrient medium containing the antibiotictetracycline hydrochloride, 5 mg/L. However, the presence of the antibioticis not detectable in the final product. Roferon-A is supplied in prefilledsyringes. Each glass syringe barrel contains 0.5 mL of product. Inaddition, there is a needle, which is ½ inch in length.

Single Use Prefilled Syringes

3 million IU (11.1 mcg/0.5mL) Roferon-A per syringe — The solution is colorlessand each 0.5 mL contains 3 MIU of Interferon alfa-2a, recombinant,3.605 mg sodium chloride, 0.1 mg polysorbate 80, 5 mg benzyl alcoholas a preservative and 0.385 mg ammonium acetate.

6 million IU (22.2 mcg/0.5 mL) Roferon-Aper syringe — The solution is colorless and each0.5 mL contains 6 MIU of Interferon alfa-2a, recombinant, 3.605 mgsodium chloride, 0.1 mg polysorbate 80, 5 mg benzyl alcohol as a preservativeand 0.385 mg ammonium acetate.

9 million IU (33.3 mcg/0.5 mL) Roferon-A per syringe — The solution is colorless and each 0.5 mL contains 9 MIUof Interferon alfa-2a, recombinant, 3.605 mg sodium chloride, 0.1mg polysorbate 80, 5 mg benzyl alcohol as a preservative and 0.385mg ammonium acetate.

The route of administrationis by subcutaneous injection.

CLINICAL PHARMACOLOGY

The mechanism by which Interferon alfa-2a, recombinant,or any other interferon, exerts antitumor or antiviral activity isnot clearly understood. However, it is believed that direct antiproliferativeaction against tumor cells, inhibition of virus replication and modulationof the host immune response play important roles in antitumor andantiviral activity.

The biological activitiesof Interferon alfa-2a, recombinant are species-restricted, i.e., theyare expressed in a very limited number of species other than humans.As a consequence, preclinical eva luation of Interferon alfa-2a, recombinanthas involved in vitro experiments with human cells and some in vivoexperiments.1 Using human cells in culture, Interferonalfa-2a, recombinant has been shown to have antiproliferative andimmunomodulatory activities that are very similar to those of themixture of interferon alfa subtypes produced by human leukocytes.In vivo, Interferon alfa-2a, recombinant has been shown to inhibitthe growth of several human tumors growing in immunocompromised (nude)mice. Because of its species-restricted activity, it has not beenpossible to demonstrate antitumor activity in immunologically intactsyngeneic tumor model systems, where effects on the host immune systemwould be observable. However, such antitumor activity has been repeatedlydemonstrated with, for example, mouse interferon-alfa in transplantablemouse tumor systems. The clinical significance of these findings isunknown.

The metabolism of Interferon alfa-2a,recombinant is consistent with that of alpha-interferons in general.Alpha-interferons are totally filtered through the glomeruli and undergorapid proteolytic degradation during tubular reabsorption, renderinga negligible reappearance of intact alfa interferon in the systemiccirculation. Small amounts of radiolabeled Interferon alfa-2a, recombinantappear in the urine of isolated rat kidneys, suggesting near completereabsorption of Interferon alfa-2a, recombinant catabolites. Livermetabolism and subsequent biliary excretion are considered minor pathwaysof elimination for alfa interferons.

The serumconcentrations of Interferon alfa-2a, recombinant reflected a largeintersubject variation in both healthy volunteers and patients withdisseminated cancer.

In healthy people, Interferonalfa-2a, recombinant exhibited an elimination half-life of 3.7 to8.5 hours (mean 5.1 hours), volume of distribution at steady-stateof 0.223 to 0.748 L/kg (mean 0.400 L/kg) and a total body clearanceof 2.14 to 3.62 mL/min/kg (mean 2.79 mL/min/kg) after a 36 MIU (2.2×108pg) intravenous infusion. After intramuscular and subcutaneousadministrations of 36 MIU, peak serum concentrations ranged from 1500to 2580 pg/mL (mean 2020 pg/mL) at a mean time to peak of 3.8 hoursand from 1250 to 2320 pg/mL (mean 1730 pg/mL) at a mean time to peakof 7.3 hours, respectively. The apparent fraction of the dose absorbedafter intramuscular injection was greater than 80%.

The pharmacokinetics of Interferon alfa-2a, recombinant after singleintramuscular doses to patients with disseminated cancer were similarto those found in healthy volunteers. Dose proportional increasesin serum concentrations were observed after single doses up to 198MIU. There were no changes in the distribution or elimination of Interferonalfa-2a, recombinant during twice daily (0.5 to 36 MIU), once daily(1 to 54 MIU), or three times weekly (1 to 136 MIU) dosing regimensup to 28 days of dosing. Multiple intramuscular doses of Interferonalfa-2a, recombinant resulted in an accumulation of two to four timesthe single dose serum concentrations. There is no pharmacokineticinformation in patients with chronic hepatitis C, hairy cell leukemia,and chronic myelogenous leukemia.

Serum neutralizingactivity, determined by a highly sensitive enzyme immunoassay, anda neutralization bioassay, was detected in approximately 25% of allpatients who received Roferon-A.2 Antibodies to human leukocyteinterferon may occur spontaneously in certain clinical conditions(cancer, systemic lupus erythematosus, herpes zoster) in patientswho have never received exogenous interferon.3 The significanceof the appearance of serum neutralizing activity is not known.

Clinical Studies

Studies have shown that Roferon-A can normalize serumALT, improve liver histology and reduce viral load in patients withchronic hepatitis C. Other studies have shown that Roferon-A can produceclinically meaningful tumor regression or disease stabilization inpatients with hairy cell leukemia.4,5 In Ph-positive ChronicMyelogenous Leukemia, Roferon-A supplemented with intermittent chemotherapyhas been shown to prolong overall survival and to delay disease progressioncompared to patients treated with chemotherapy alone.6 Inaddition, Roferon-A has been shown to produce sustained complete cytogeneticresponses in a small subset of patients with CML in chronic phase.The activity of Roferon-A in Ph-negative CML has not been determined.

Effects On Chronic HepatitisC

The safety and efficacy of Roferon-A was eva luatedin multiple clinical trials involving over 2000 patients 18 yearsof age or older with hepatitis, with or without cirrhosis, who hadelevated serum alanine aminotransferase (ALT) levels and tested positivefor antibody to hepatitis C. Roferon-A was given three times a week(tiw) by subcutaneous (SC) or intramuscular (IM) injection in a varietyof dosing regimens, including dose escalation and de-escalation regimens.Normalization of serum ALT was defined in all studies as two consecutivenormal serum ALT values at least 21 days apart. A sustained response(SR) was defined as normalization of ALT both at the end of treatmentand at the end of at least 6 months of treatment-free follow-up.

In trials in which Roferon-A was administered for 6 months,6 MIU, 3 MIU, and 1 MIU were directly compared. Six MIU was associatedwith higher SR rates but greater toxicity (see ADVERSE REACTIONS). In studies in which the same dose of Roferon-A was administeredfor 6 or 12 months, the longer duration was associated with higherSR rates and adverse events were no more severe or frequent in thesecond 6 months than in the first 6 months. Based on these data, therecommended regimens are 3 MIU for 12 months or 6 MIU for the first3 months followed by 3 MIU for the next 9 months (see Table 1 and DOSAGE AND ADMINISTRATION). There are no direct comparisons of these two regimens.

Younger patients (e.g., less than 35 years of age) andpatients without cirrhosis on liver biopsy were more likely to respondcompletely to Roferon-A than those patients greater than 35 yearsof age or patients with cirrhosis on liver biopsy.

In the two studies in which Roferon-A was administered subcutaneouslythree times weekly for 12 months, 20/173 (12%) patients experienceda sustained response to therapy (see Table1). Of these patients, 15/173 (9%) maintained this sustainedresponse during continuous follow-up for up to four years. Patientswho have ALT normalization but who fail to have a sustained responsefollowing an initial course of therapy may benefit from retreatmentwith higher doses of Roferon-A (see DOSAGE AND ADMINISTRATION).

A subset of patients had liverbiopsies performed both before and after treatment with Roferon-A.An improvement in liver histology as assessed by Knodell HistologyActivity Index was generally observed.

A retrospectivesubgroup analysis of 317 patients from two studies suggested a correlationbetween improvement in liver histology, durable serum ALT responserates, and decreased viral load as measured by the polymerase chainreaction (PCR).

Effects on Ph-Positive ChronicMyelogenous Leukemia (CML)

Roferon-A was eva luated in two trials of patientswith chronic phase CML. Study DM84-38 was a single center phase IIstudy conducted at the MD Anderson Cancer Center, which enrolled 91patients, 81% were previously treated, 82% were Ph positive, and 63%received Roferon-A within 1 year of diagnosis. Study MI400 was a multicenterrandomized phase III study conducted in Italy by the Italian CooperativeStudy Group on CML in 335 patients; 226 Roferon-A and 109 chemotherapy.Patients with Ph-positive, newly diagnosed or minimally treated CMLwere randomized (ratio 2:1) to either Roferon-A or conventional chemotherapywith either hydroxyurea or busulfan. In study DM84-38, patients startedRoferon-A at 9 MIU/day, whereas in study MI400, it was progressivelyescalated from 3 to 9 MIU/day over the first month. In both trials,dose escalation for insufficient hematologic response, and dose attenuationor interruption for toxicity was permitted. No formal guidelines fordose attenuation were given in the chemotherapy arm of study MI400.In addition, in the Roferon-A arm, the MI400 protocol allowed theaddition of intermittent single agent chemotherapy for insufficienthematologic response to Roferon-A alone. In this trial, 44% of theRoferon-A treated patients also received intermittent single agentchemotherapy at some time during the study.

The two studies were analyzed according to uniform response criteria.For hematologic response: complete response (WBC <9×109/L, normalization of the differential with no immature formsin the peripheral blood, disappearance of splenomegaly), partial response(>50% decrease from baseline of WBC to <20%×109/L). For cytogenetic response: complete response (0% Ph-positivemetaphases), partial response (1% to 34% Ph-positive metaphases).

In study DM84-38, the median survival from initiationof Roferon-A was 47 months. In study MI400, the median survival forthe patients on the interferon arm was 69 months, which was significantlybetter than the 55 months seen in the chemotherapy control group (48patients in study MI400 proceeded to BMT and in study DM84-38, 15patients proceeded to BMT). Roferon-A treatment significantly delayeddisease progression to blastic phase as evidenced by a median timeto disease progression of 69 months to 46 months with chemotherapy.

By multivariate analysis of prognostic factors associatedwith all 335 patients entered into the randomized study, treatmentwith Roferon-A (with or without intermittent additional chemotherapy;p=0.006), Sokal index7 (p=0.006) and WBC (p=0.023) werethe three variables associated with an improved survival, independentof other baseline characteristics (Karnofsky performance status andhemoglobin being the other factors entered into the model).

In study MI400, overall hematologic responses, [completeresponses (CR) and partial responses (PR)], were observed in approximately60% of patients treated with Roferon-A (40% CR, 20% PR), comparedto 70% with chemotherapy (30% CR, 40% PR). The median time to reacha complete hematologic response was 5 months in the Roferon-A armand 4 months in the chemotherapy arm. The overall cytogenetic responserate (CR+PR), in patients receiving Roferon-A, was 10% and 12% instudies MI400 and DM84-38, respectively, according to the intent-to-treatprinciple. In contrast, only 2% of the patients in the chemotherapyarm of study MI400 achieved a cytogenetic response (with no completeresponses). Cytogenetic responses were observed only in patients whohad complete hematologic responses. In study DM84-38, hematologicand cytogenetic response rates were higher in the subset of patientstreated with Roferon-A within 1 year of diagnosis (76% and 17%, respectively)compared to the subset initiating Roferon-A therapy more than 1 yearfrom diagnosis (29% and 4%, respectively). In an exploratory analysis,patients who achieved a cytogenetic response lived longer than thosewho did not.

Severe adverse events were observedin 66% and 31% of patients on study DM84-38 and MI400, respectively.Dose reduction and temporary cessation of therapy was required frequently.Permanent cessation of Roferon-A, due to intolerable side effects,was required in 15% and 23% of patients on studies DM84-38 and MI400,respectively (see ADVERSE REACTIONS).

Limited data are available on the use of Roferon-A inchildren with Ph-positive, adult-type CML. A published report on 15children with CML suggests a safety profile similar to that seen inadult CML; clinical responses were also observed8 (see DOSAGEAND ADMINISTRATION).

Effects on Hairy Cell Leukemia

A multicenter US phase II study (N2752) enrolled218 patients; 75 were eva luable for efficacy in a preliminary analysis;218 patients were eva luable for safety. Patients were to receive astarting dose of Roferon-A up to 6 MIU/m2/day, for an inductionperiod of 4 to 6 months. Responding patients were to receive 12 monthsmaintenance therapy.

During the first 1 to 2months of treatment of patients with hairy cell leukemia, significantdepression of hematopoiesis was likely to occur. Subsequently, therewas improvement in circulating blood cell counts. Of the 75 patientswho were eva luable for efficacy following at least 16 weeks of therapy,46 (61%) achieved complete or partial response. Twenty-one patients(28%) had a minor remission, 8 (11%) remained stable, and none hadworsening of disease. All patients who achieved either a completeor partial response had complete or partial normalization of all peripheralblood elements including hemoglobin level, white blood cell, neutrophil,monocyte and platelet counts with a concomitant decrease in peripheralblood and bone marrow hairy cells. Responding patients also exhibiteda marked reduction in red blood cell and platelet transfusion requirements,a decrease in infectious episodes and improvement in performance status.The probability of survival for 2 years in patients receiving Roferon-A(94%) was statistically increased compared to a historical controlgroup (75%).

INDICATIONS AND USAGE

Roferon-A is indicated for the treatment of chronichepatitis C and hairy cell leukemia in patients 18 years of age orolder. In addition, it is indicated for chronic phase, Philadelphiachromosome (Ph) positive chronic myelogenous leukemia (CML) patientswho are minimally pretreated (within 1 year of diagnosis).

For Patients With ChronicHepatitis C

Roferon-A is indicated for use in patients with chronichepatitis C diagnosed by HCV antibody and/or a history of exposureto hepatitis C who have compensated liver disease and are 18 yearsof age or older. A liver biopsy and a serum test for the presenceof antibody to HCV should be performed to establish the diagnosisof chronic hepatitis C. Other causes of hepatitis, including hepatitisB, should be excluded prior to therapy with Roferon-A.

CONTRAINDICATIONS

Roferon-A is contraindicated in patients with:

• Hypersensitivity to Roferon-A or any of its components
• Autoimmune hepatitis
• Hepatic decompensation (Child-Pugh class B and C) before orduring treatment

Roferon-A is contraindicated in neonates and infantsbecause it contains benzyl alcohol. Benzyl alcohol is associatedwith an increased incidence of neurologic and other complicationsin neonates and infants, which are sometimes fatal.

WARNINGS

Roferon-A should be administered under the guidanceof a qualified physician (see DOSAGE AND ADMINISTRATION). Appropriate management of the therapy and its complicationsis possible only when adequate facilities are readily available.

Neuropsychiatric Disorders

DEPRESSION AND SUICIDAL BEHAVIOR INCLUDING SUICIDALIDEATION, SUICIDAL ATTEMPTS AND SUICIDES HAVE BEEN REPORTED IN ASSOCIATIONWITH TREATMENT WITH ALFA INTERFERONS, INCLUDING ROFERON-A, IN PATIENTSWITH AND WITHOUT PREVIOUS PSYCHIATRIC ILLNESS. Roferon-A should beused with extreme caution in patients who report a history of depression.Patients should be informed that depression and suicidal ideationmay be side effects of treatment and should be advised to report theseside effects immediately to the prescribing physician. Patients receivingRoferon-A therapy should receive close monitoring for the occurrenceof depressive symptomatology. Psychiatric intervention and/or cessationof treatment should be considered for patients experiencing depression.Although dose reduction or treatment cessation may lead to resolutionof the depressive symptomatology, depression may persist and suicideshave occurred after withdrawing therapy (see PRECAUTIONS and ADVERSE REACTIONS).

Central nervous system adversereactions have been reported in a number of patients. These reactionsincluded decreased mental status, dizziness, impaired memory, agitation,manic behavior and psychotic reactions. More severe obtundation andcoma have been rarely observed. Most of these abnormalities were mildand reversible within a few days to 3 weeks upon dose reduction ordiscontinuation of Roferon-A therapy. Careful periodic neuropsychiatricmonitoring of all patients is recommended. Roferon-A should be usedwith caution in patients with seizure disorders and/or compromisedcentral nervous system function.

Cardiovascular Disorders

Roferon-A should be administered with caution topatients with cardiac disease or with any history of cardiac illness.Acute, self-limited toxicities (i.e., fever, chills) frequently associatedwith Roferon-A administration may exacerbate preexisting cardiac conditions.Rarely, myocardial infarction has occurred in patients receiving Roferon-A.Cases of cardiomyopathy have been observed on rare occasions in patientstreated with alpha interferons.

Cerebrovascular Disorders

Ischemic and hemorrhagic cerebrovascular events havebeen observed in patients treated with interferon alfa-based therapies,including Roferon-A. Events occurred in patients with few or no reportedrisk factors for stroke, including patients less than 45 years ofage. Because these are spontaneous reports, estimates of frequencycannot be made and a causal relationship between interferon alfa-basedtherapies and these events is difficult to establish.

Hypersensitivity

Serious, acute hypersensitivity reactions (e.g.,urticaria, angioedema, bronchoconstriction and anaphylaxis), as wellas skin rashes have been rarely observed during alpha-interferon therapy,including interferon alfa-2a. If a serious reaction develops duringtreatment with Roferon-A, discontinue treatment and institute appropriatemedical therapy immediately. Transient rashes do not necessitate interruptionof treatment.

Hepatic Disorders

In chronic hepatitis C, initiation of alfa-interferontherapy, including Roferon-A, has been reported to cause transientliver abnormalities, which in patients with poorly compensated liverdisease can result in increased ascites, hepatic failure or death.

Gastrointestinal Disorders

Infrequently, severe or fatal gastrointestinal hemorrhagehas been reported in association with alpha-interferon therapy.

Ulcerative, and hemorrhagic/ischemic colitis, sometimesfatal, have been observed within 12 weeks of starting alpha interferontreatment. Abdominal pain, bloody diarrhea, and fever are the typicalmanifestations of colitis. Roferon-A should be discontinued immediatelyif these symptoms develop. The colitis usually resolves within 1 to3 weeks of discontinuation of alpha interferon.

Infections

While fever may be associated with the flu-like syndromereported commonly during interferon therapy, other causes of highor persistent fever must be ruled out, particularly in patients withneutropenia. Serious and severe infections (bacterial, viral, fungal),some fatal, have been reported during treatment with alpha interferonsincluding Roferon-A. Appropriate anti-infective therapy should bestarted immediately and discontinuation of therapy should be considered.

Bone Marrow Toxicity

Alpha-interferons suppress bone marrow function andmay result in severe cytopenias and anemia including very rare eventsof aplastic anemia. Cytopenias (e.g., leukopenia, thrombocytopenia)can lead to an increased risk of infections or hemorrhage. It is advisedthat complete blood counts (CBC) be obtained pretreatment and monitoredroutinely during therapy. Alpha interferon therapy should be discontinuedin patients who develop severe decreases in neutrophil (<0.5 ×109/L) or platelet counts (<25 × 109/L).

Caution should be exercised when administeringRoferon-A to patients with myelosuppression or when Roferon-A is usedin combination with other agents that are known to cause myelosuppression.Synergistic toxicity has been observed when Roferon-A is administeredin combination with zidovudine (AZT).9

Endocrine Disorders

Roferon-A causes or aggravates hypothyroidism andhyperthyroidism. Hyperglycemia has been observed in patients treatedwith Roferon-A. Symptomatic patients should have their blood glucosemeasured and followed-up accordingly. Patients with diabetes mellitusmay require adjustment of their anti-diabetic regimen.

Pulmonary Disorders

Dyspnea, pulmonary infiltrates, pneumonia, bronchiolitisobliterans, interstitial pneumonitis and sarcoidosis, some resultingin respiratory failure and/or patient deaths, may be induced or aggravatedby alpha interferon therapy. Patients who develop persistent or unexplainedpulmonary infiltrates or pulmonary function impairment should discontinuetreatment with Roferon-A.

Ophthalmologic Disorders

Decrease or loss of vision, retinopathy includingmacular edema, retinal artery or vein thrombosis, retinal hemorrhagesand cotton wool spots, optic neuritis, and papilledema are inducedor aggravated by treatment with Interferon alfa-2a or other alphainterferons. All patients should receive an eye examination at baseline.Patients with preexisting ophthalmologic disorders (e.g., diabeticor hypertensive retinopathy) should receive periodic ophthalmologicexams during interferon alpha treatment. Any patient who developsocular symptoms should receive a prompt and complete eye examination.Interferon alfa-2a treatment should be discontinued in patients whodevelop new or worsening ophthalmologic disorders.

Pancreatitis

Pancreatitis has been observed in patients receivingalpha interferon treatment, including those who developed marked triglycerideelevations. In some cases, fatalities have been observed. Althougha causal relationship to Roferon-A has not been established, markedtriglyceride elevation is a risk factor for development of pancreatitis.Roferon-A should be suspended if symptoms or signs suggestive of pancreatitisare observed. In patients diagnosed with pancreatitis, discontinuationof therapy with Roferon-A should be considered.

PRECAUTIONS

General

In all instances where the use of Roferon-A is consideredfor chemotherapy, the physician must eva luate the need and usefulnessof the drug against the risk of adverse reactions. Most adverse reactionsare reversible if detected early. If severe reactions occur, the drugshould be reduced in dosage or discontinued and appropriate correctivemeasures should be taken according to the clinical judgment of thephysician. Reinstitution of Roferon-A therapy should be carried outwith caution and with adequate consideration of the further need forthe drug and, alertness to possible recurrence of toxicity. The minimumeffective doses of Roferon-A for treatment of hairy cell leukemiaand chronic myelogenous leukemia have not been established.

Variations in dosage and adverse reactions exist amongdifferent brands of Interferon. Therefore, do not use different brandsof Interferon in a single treatment regimen.

The safety and efficacy of Roferon-A have not been established inorgan transplant recipients.

Renal Impairment

Dose-limiting renal toxicities were unusual. Infrequently,severe renal toxicities, sometimes requiring renal dialysis, havebeen reported with alpha-interferon therapy alone or in combinationwith IL-2. In patients with impaired renal function, signs and symptomsof interferon toxicity should be closely monitored. Roferon-A shouldbe used with caution in patients with creatinine clearance <50mL/min.

Autoimmune Disease

Development or exacerbation of autoimmune diseasesincluding idiopathic thrombocytopenic purpura, vasculitis, Raynaud'sphenomenon, rheumatoid arthritis, psoriasis, interstitial nephritis,thyroiditis, lupus erythematosus, hepatitis, myositis and rhabdomyolysishave been observed in patients treated with alpha-interferons. Anypatient developing an autoimmune disorder during treatment shouldbe closely monitored and, if appropriate, treatment should be discontinued.

Information for Patients

Patients should be cautioned not to change brandsof Interferon without medical consultation, as a change in dosagemay result. Patients should be informed regarding the potential benefitsand risks attendant to the use of Roferon-A. If home use is determinedto be desirable by the physician, instructions on appropriate useshould be given, including review of the contents of the enclosed Medication Guide. Patients shouldbe well hydrated, especially during the initial stages of treatment.

Patients should be thoroughly instructed in the importanceof proper disposal procedures and cautioned against reusing syringesand needles. If home use is prescribed, a puncture-resistant containerfor the disposal of used syringes and needles should be supplied tothe patient. The full container should be disposed of according todirections provided by the physician (see Medication Guide).

Patients should be advised that laboratoryeva luations are required before starting therapy and periodicallythereafter (see Laboratory Tests).

Patients receiving high-dose alpha-interferon should becautioned against performing tasks that require complete mental alertnesssuch as operating machinery or driving a motor vehicle. Patients tobe treated with Roferon-A should be informed that depression and suicidalideation may be side effects of treatment and should be advised toreport these side effects immediately to the prescribing physician.

Laboratory Tests

Leukopenia and elevation of hepatic enzymes occurredfrequently but were rarely dose-limiting. Thrombocytopenia occurredless frequently. Proteinuria and increased cells in urinary sedimentwere also seen infrequently.

Complete bloodcounts with differential platelet counts and clinical chemistry testsshould be performed before initiation of Roferon-A therapy and atappropriate periods during therapy. Patients with neutrophil count<1500/mm3, platelet count <75,000/mm3,hemoglobin <10 g/dL and creatinine >1.5 mg/dL were excluded fromseveral major chronic hepatitis C studies; patients with these laboratoryabnormalities should be carefully monitored if treated with Roferon-A.Since responses of hairy cell leukemia, chronic hepatitis C and chronicmyelogenous leukemia are not generally observed for 1 to 3 monthsafter initiation of treatment, very careful monitoring for severedepression of blood cell counts is warranted during the initial phaseof treatment.

Those patients who have preexistingcardiac abnormalities and/or are in advanced stages of cancer shouldhave electrocardiograms taken before and during the course of treatment.

Liver Function

For patients being treated for chronic hepatitisC, serum ALT should be eva luated before therapy to establish baselinesand repeated at week 2 and monthly thereafter following initiationof therapy for monitoring clinical response. Patients developing liverfunction abnormalities during Roferon-A treatment should be closelymonitored and if necessary treatment should be discontinued. Use ofalpha-interferons has been rarely associated with severe hepatic dysfunctionand liver failure.

Thyroid Function

Patients with preexisting thyroid abnormalities maybe treated if normal thyroid stimulating hormone (TSH) levels canbe maintained by medication. Testing of TSH levels in these patientsis recommended at baseline and every 3 months following initiationof therapy.

Triglycerides

Elevated triglyceride levels have been observed inpatients treated with interferons including Roferon-A therapy. Triglyceridelevels should be monitored periodically during treatment and elevatedlevels should be managed as clinically appropriate. Hypertriglyceridemiamay result in pancreatitis. Discontinuation of Roferon-A therapy shouldbe considered for patients with persistently elevated triglycerides(e.g., triglycerides >1000 mg/dL) associated with symptoms of potentialpancreatitis, such as abdominal pain, nausea, or vomiting.

Drug Interactions

Roferon-A has been reported to reduce the clearanceof theophylline.10,11 The clinical relevance of this interactionis presently unknown. Caution should be exercised when administeringRoferon-A in combination with other potentially myelosuppressive agents.Synergistic toxicity has been observed when Roferon-A is administeredin combination with zidovudine (AZT) (see WARNINGS: Bone Marrow Toxicity).

In transplant recipients, therapeuticimmunosuppression may be weakened because interferons also exert animmunostimulatory action.

Alpha-interferonsmay affect the oxidative metabolic process by reducing the activityof hepatic microsomal cytochrome enzymes in the P450 group. Althoughthe clinical relevance is still unclear, this should be taken intoaccount when prescribing concomitant therapy with drugs metabolizedby this route.

The neurotoxic, hematotoxic orcardiotoxic effects of previously or concurrently administered drugsmay be increased by interferons. Interactions could occur followingconcurrent administration of centrally acting drugs. Use of Roferon-Ain conjunction with interleukin-2 may potentiate risks of renal failure.

Carcinogenesis, Mutagenesis,Impairment of Fertility

Carcinogenesis

Roferon-A has not been tested for its carcinogenicpotential.

Mutagenesis

A. Internal Studies — Ames tests using sixdifferent tester strains, with and without metabolic activation, wereperformed with Roferon-A up to a concentration of 1920 µg/plate.There was no evidence of mutagenicity.

Humanlymphocyte cultures were treated in vitro with Roferon-A at noncytotoxicconcentrations. No increase in the incidence of chromosomal damagewas noted.

B. Published Studies — Thereare no published studies on the mutagenic potential of Roferon-A.However, a number of studies on the genotoxicity of human leukocyteinterferon have been reported.

A chromosomaldefect following the addition of human leukocyte interferon to lymphocytecultures from a patient suffering from a lymphoproliferative disorderhas been reported.

In contrast, other studieshave failed to detect chromosomal abnormalities following treatmentof lymphocyte cultures from healthy volunteers with human leukocyteinterferon.

It has also been shown that humanleukocyte interferon protects primary chick embryo fibroblasts fromchromosomal aberrations produced by gamma rays.

Impairment of Fertility

Roferon-A has been studied for its effect on fertilityin Macaca mulatta (rhesus monkeys). Nonpregnant rhesus females treatedwith Roferon-A at doses of 5 and 25 MIU/kg/day have shown menstrualcycle irregularities, including prolonged or shortened menstrual periodsand erratic bleeding; these cycles were considered to be anovulatoryon the basis that reduced progesterone levels were noted and thatexpected increases in preovulatory estrogen and luteinizing hormoneswere not observed. These monkeys returned to a normal menstrual rhythmfollowing discontinuation of treatment.

Pregnancy

Pregnancy Category C

Roferon-A has been associated with statisticallysignificant, dose-related increases in abortions in pregnant rhesusmonkeys treated with 1, 5, or 25 MIU/kg/day (approximately 20 to 500times the human weekly dose, when scaled by body surface area) duringthe early to midfetal period of organogenesis (gestation day 22 to70). Abortifacient activity was also observed in 2/6 pregnant rhesusmonkeys treated with 25 MIU/kg/day Roferon-A (500 times the humandose) during the period of late fetal development (days 79 to 100of gestation). No teratogenic effects were seen in either study. However,the validity of extrapolating doses used in animal studies to humandoses is not established. Therefore, no direct comparison of the dosesthat induced fetal death in monkeys to dose levels of Roferon-A usedclinically can be made. There are no adequate and well-controlledstudies of Roferon-A in pregnant women. Roferon-A is to be used duringpregnancy only if the potential benefit to the woman justifies thepotential risk to the fetus. Roferon-A is recommended for use in womenof childbearing potential and in men only when they are using effectivecontraception during therapy.

The injectablesolution contains benzyl alcohol. The excipient benzyl alcohol canbe transmitted via the placenta. The possibility of toxicity shouldbe taken into account in premature infants after the administrationof Roferon-A solution for injection immediately prior to birth orCesarean section.

Male fertility and teratologiceva luations have yielded no significant adverse effects to date.

Nursing Mothers

It is not known whether this drug is excreted inhuman milk. Because many drugs are excreted in human milk and becauseof the potential for serious adverse reactions in nursing infantsfrom Roferon-A, a decision should be made whether to discontinue nursingor to discontinue the drug, taking into account the importance ofthe drug to the mother.

Pediatric Use

Use of Roferon-A in children with Ph-positive adult-typeCML is supported by evidence from adequate and well-controlled studiesof Roferon-A in adults with additional data from the literature onthe use of alfa interferon in children with CML. A published reporton 15 children with Ph-positive adult-type CML suggests a safety profilesimilar to that seen in adult CML; clinical responses were als