NOVARTIS EXHIBIT 2148
`Par v Novartis, IPR 2016-00084
`Page 1 of 8
`
`

`
`NOVARTIS EXHIBIT 2148
`Par v Novartis, IPR 2016-00084
`Page 2 of 8
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`

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`Consult 1992 Supplements for revisions
`
`5. Breathe in slowly through the mouthpiece. If you hear a
`whistling sound, breathe slower until no sound can be
`heard.
`
`Physicians' Desk Reference®
`INTRON® A I£
`Interferon alfa-2b
`recombinant
`For Injection
`
`DESCRIPTION
`INTRON A Interferon alfa-2b, recombinant for intramuscu-
`lar, subcutaneous or intralesional Injection is a purified ster-
`ile, lyophilized recombinant interferon formulation. The
`3 million, 5 million, 25 million and 50 million IU packages
`are for use by intramuscular or subcutaneous injection. The
`10 million IU package is for intramuscular, subcutaneous, or
`intralesional injection. (See WARNINGS and PRECAU-
`TIONS.)
`Interferon alfa-2b, recombinant is a water soluble protein
`with a molecular weight of 19,271 daltons produced by re-
`combinant DNA techniques. It is obtained from the bacterial
`fermentation of a strain of Escherichia coli bearing a geneti-
`cally engineered plasmid containing an interferon alfa-2b
`gene from human leukocytes. The fermentation is carried
`out in a defined nutrient medium containing the antibiotic
`tetracycline hydrochloride at a concentration of 5 to 10 mg/
`L; the presence of this antibiotic is not detectable in the final
`product. The specific activity of Interferon alfa-2b, recombi-
`nant is approximately 2 X 108 IU/mg protein.
`The content of Interferon alfa-2b, recombinant is expressed
`in terms of International Units (IU). International Units are
`determined by comparison of the antiviral activity of the
`interferon alfa-2b, recombinant with the activity of the inter-
`national reference preparation of human leukocyte inter-
`feron established by the World Health Organization (WHO).
`Each vial of INTRON A contains either 3 million, 5 million,
`10 million, 25 million or 50 million IU of interferon alfa-2b,
`recombinant, 20 mg glycine, 2.3 mg sodium phosphate diba-
`sic, 0.55 mg sodium phosphate monobasic, and 1.0 mg human
`albumin are also present. Based on the specific activity of
`INTRON A as approximately 2 X 108 IU/mg protein, the
`corresponding mg quantities of interferon alfa-2b, recombi-
`nant in the vials described above are approximately 0.015
`mg, 0.025 mg, 0.05 mg, 0.125 mg, and 0.25 mg protein, respec-
`tively. Prior to administration, the lyophilized powder is to
`be reconstituted with the provided Diluent for INTRON A
`Interferon alfa-2b, recombinant (bacteriostatic water for
`injection) containing 0.9% benzyl alcohol as a preservative.
`(See DOSAGE AND ADMINISTRATION.)
`Lyophilized INTRON A is a white to cream colored powder.
`CLINICAL PHARMACOLOGY
`General The interferons are a family of naturally occur-
`ring, small protein molecules with molecular weights of ap-
`proximately 15,000 to 21,000 daltons. They are produced and
`secreted by cells in response to viral infections or to various
`synthetic and biological inducers. Three major classes of
`interferons have been identified: alpha, beta, and gamma.
`These three classes are not homogenous, and each may con-
`tain several different molecular species of interferon. As an
`example, at least 14 genetically distinct human alpha inter-
`ferons have been identified thus far. INTRON A has been
`classified as an alpha interferon.
`Interferons exert their cellular activities by binding to spe-
`cific membrane receptors on the cell surface. Preliminary
`studies to characterize these membrane receptors and to
`determine the subsequent fate of the human interferon-re-
`ceptor complex have been carried out using 12BI-labeled in-
`terferon alfa-2b, recombinant. Human interferon receptors,
`as isolated from human lymphoblastoid (Daudi) cells, appear
`to be highly asymmetric membrane proteins. They exhibit
`selectivity for human but not murine interferons, suggesting
`speciefrspecificity. Studies with other interferons have dem-
`onstrated varying degrees of species-specificity.
`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 im-
`munomodulating activities as enhancement of the phagc-
`cytic activity of macrophages and augmentation of the
`specific cytotoxicity of lymphocytes for target cells. Any of
`these activities might contribute to interferon's therapeutic
`effects.
`Preclinical Pharmacology INTRON A Interferon alfa-2b,
`recombinant for Injection has exhibited antiproliferative
`effects in preclinical studies employing both cell culture sys-
`tems and human tumor xenografts in animals, and has dem-
`onstrated significant immunomodulatory activity in vitro.
`The clinical significance of these findings is unknown.
`The antiproliferative activity of INTRON A was evaluated in
`vitro using mouse and human leukemia cell lines, and hu-
`man osteosarcoma, melanoma, and normal amnion cells. No
`activity was seen in mouse leukemia cells, which again sug-
`gests species-specificity.
`The immunomodulating activity of INTRON A was demon-
`strated in vitro by its augmentation of the spontaneous "nat-
`
`6. Breathe in the entire contents of the bag. You will know
`to stop when the bag collapses and you cannot breathe in
`anymore.
`7. Hold his or her breath while slowly counting to five.
`8. Breathe out slowly into the bag.
`
`9 Repeat the inhale/exhale cycle (steps 5 through 8) a sec-
`ond time, keeping lips tightly closed around the mouth-
`piece.'
`
`IMPORTANT NOTE: Repeat steps 2 through 9 for each dose
`of medication prescribed by your doctor.
`10. Remove the mouthpiece from mouth. Take drug canister
`off the reservoir bag. Unlock mouthpiece from the bag
`and store all components in carrying case.
`
`IMPORTANT CLEANING INSTRUCTIONS
`Your patients should:
`1. Clean only the mouthpiece thoroughly with warm (not
`hot) running water at least once a day. InspirEase® is not
`dishwasher safe. Always clean by hand.
`2. The clear plastic reed section of the mouthpiece should not
`be touched due to potential breakage. We recommend a
`visual inspection of the reed section for signs of breakage
`prior to each use. If reed breakage occurs, replace mouth-
`piece immediately; otherwise replace mouthpiece as
`needed every six months.
`3. After cleaning, wait until mouthpiece is completely dry
`before storing in carrying case. Do not place near artificial
`heat such as dishwasher or oven.
`4. We recommend that the reservoir bag be replaced every
`two to three weeks or as needed. However, if there is a hole
`or tear in it, replace immediately.
`
`NOTE: You will need a doctor's prescription for replace-
`ment bags or a new starter kit.
`InspirEase is designed for use with, most "spray inhaler"
`(metered dose inhaler) containers currently available; for
`single-patient use and single-dose use.
`The usual caution should be exercised in dosing medications
`and evaluating patient response.
`The prescribing information for the marketed MDIs varies
`with respect to dosing, administration, etc. We recommend
`that these be followed when using InspirEase.
`
`CAUTION: Federal law restricts this device to sale by or on
`the order of a physician.
`
`Rev. 3/89
`
`REFERENCES
`1. Sackner MA, Brown LK, Kim CS: Chest 80 (suppl):
`915-918,1981.2. Tobin MJ, Jenouri G, Danta I, et al: Am Rev
`Respir Dis 126:670-675, 1982. 3. Saundere KB:Br Med J
`1:1037-1038, 1965. 4. Gayrard P, Orehek J: Respiration
`40:47-52, 1980. 5. Shim C, Williams MH Jr: Am J Med
`69:891-894, 1980.
`Distributed by: Schering Corporation, Kenilworth, NJ 07033
`USA
`Copyright© 1987, 1989 Schering Corporation, USA
`All rights reserved.
`
`2097
`
`ural killer" activity of human lymphocytes, its enhancement
`of the tumoricidal activity of human monocytes against hu-
`man tumor cells, and its induction of Class I histocompatibil-
`lty antigens on the surface of a number of cell types. These
`effects appear to be dose-dependent.
`In vivo studies of INTRON A showed inhibition of tumor
`growth. INTRON A injected intralesionally (0.2 million or
`0.8 million IU once daily for 7 days) delayed the development
`and reduced the volume of human osteosarcoma implants in
`athymic mice. The effect was dose-related. Additionally,
`subcutaneous administration of INTRON A at a dose of 0.2
`million IU/day inhibited the growth of implanted human
`breast tumor xenografts in athymic mice by about 50% after
`23 days. INTRON A has not been shown to be effective in the
`treatment of osteosarcoma or carcinoma of the breast in
`humans.
`Pharmacokinetux The pharmacokinetics of INTRON A
`were studied in 12 healthy male volunteers following single
`doses of 5 million IU/m2 administered intramuscularly, sub-
`cutaneously and as a 30-minute intravenous infusion in a
`cross-over design. INTRON A concentrations were deter-
`mined using a radioimmunoassay (RIA) with a detection
`limit equal to 10 IU/mL.
`The mean serum concentration of INTRON A following in-
`tramuscular 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-lives
`of INTRON A following both intramuscular and subcutane-
`ous injections were approximately two to three hours.
`Serum concentrations were below the detection limit by 16
`hours after the injections.
`After intravenous administration, serum concentrations of
`INTRON A peaked (135 to 273 IU/mL) by the end of the infu-
`sion, then declined at a slightly more rapid rate than after
`intramuscular or subcutaneous drug administration, becom-
`ing undetectable four hours after the infusion. The elimina-
`tion half-life was approximately two hours.
`Urine concentrations of INTRON A following a single dose
`(5 million IU/m2) were not detectable after any of the paren-
`teral routes of administration. This result was expected since
`preliminary studies with isolated and perfused rabbit kid-
`neys have shown that the kidney may be the main site of
`interferon catabolism.
`There is no pharmacokinetic data available for the intrale-
`sional route of administration.
`Hairy Cell Leukemia In clinical trials in patients with hairy
`cell leukemia, there was depression of circulating red blood
`cells, white blood cells and platelets during the first one to
`two months of treatment with INTRON A. Subsequently,
`both splenectomized and non-splenectomized patients with
`hairy cell leukemia, treated with INTRON A achieved sub-
`stantial and sustained improvements in granulocytes, plate-
`lets, and hemoglobin levels in 75% of treated patients and at
`least some improvement (minor responses) occurred in 90%.
`For the entire study group median platelet counts were
`within the normal range after 2 months, median hemoglobin
`levels were in the normal range after 4 months and median
`granulocyte counts were in the normal range after 5 months
`of treatment. Responses of blood cell elements were similar
`in splenectomized and non-splenectomized patients except
`that median platelet counts after maximum response was to
`a level of 100,000/mm3 in the latter group.
`Treatment with INTRON A Interferon alfa-2b, recombinant
`for Injection resulted in a decrease in bone marrow hypercel-
`lularity 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 pa-
`tients. The percentage of patients with such an HCI de-
`creased to 25% after six months and to 14% after one year.
`These results indicate that even though hematologic im-
`provement had occurred earlier, prolonged treatment with
`INTRON A 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 with INTRON A. Addition-
`ally, the percentage of patients with confirmed and serious
`infections declined during treatment with INTRON A as
`granulocyte counts improved.
`The responses observed in non-splenectomized patients in-
`cluded reversal of splenomegaly and of abnormalities in
`blood cell counts attributable to hypersplenism. In some
`cases there was reversal of clinically significant hypersplen-
`ism that may have resulted in need for splenectomy.
`Reduced risk of major complications of hairy cell leukemia
`(serious infections, bleeding diatheses, transfusion require-
`ments) were apparent within 3 months of initiation of treat-
`
`Continued on next page
`
`Information on Schering products appearing on these pages
`is effective as of August 15, 1991.
`
`NPC02233820
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`NOVARTIS EXHIBIT 2148
`Par v Novartis, IPR 2016-00084
`Page 3 of 8
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`

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`2098
`
`Sobering—Cont.
`
`ment in comparisons of INTRON A treated patients to a con-
`trol group. No deaths occurred in patients treated with
`INTRON A during the subsequent 9 months of treatment
`and follow-up, while the mortality rate in the control group
`was 20% in the same time interval based on probability of
`survival analysis.
`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%.
`During the initial 3 months of treatment, there may be inter-
`feron-mediated suppression of hematopoiesis.
`Serum Neutralizing Antibodies In a multicenter controlled
`clinical trial involving 145 hairy cell leukemia patients, no
`serum neutralizing antibodies were detected in the 90 pa-
`tients evaluated.
`In AIDS-Related Kaposi's Sarcoma patients treated with
`INTRON A, one out of 24 patients have developed detectable
`serum neutralizing antibodies.
`Serum neutralizing antibodies have been detected in less
`than 3% of patients treated with higher doses of INTRON A
`in malignancies other than hairy cell leukemia or AIDS-
`Related Kaposi's Sarcoma. The clinical significance of these
`findings is unknown.
`Condylomata Acuminata Condylomata acuminate (vene-
`real or genital warts) are associated with infections of the
`human papilloma virus (HPV), especially HPV type-6 and
`possibly type-11. Given the antiviral and antiproliferative
`activities of interferons and the viral etiology of condylo-
`mata, placebo-controlled clinical trials were conducted to
`evaluate the efficacy and safety of intralesional injections of
`INTRON A in the treatment of condylomata acuminata
`In the three controlled double-blind clinical trials conducted
`to determine the efficacy of INTRON A in condyloma, a total
`of 192 patients were evaluable for efficacy (a total of 224
`were evaluable for safety). These patients were injected in-
`tralesionally with 1 million IU of INTRON A per lesion. Up
`to five lesions per patient were treated three times a week for
`three weeks, and the patients were then observed for up to 16
`weeks after the full treatment course. These studies snowed
`that INTRON A was significantly more effective than pla-
`cebo in the treatment of condylomata, as measured by disap-
`pearance of lesions, decreases in lesion size, and by an overall
`change in disease status. In the 192 patients evaluated, 42%
`experienced clearing of all treated lesions, while 24% experi-
`enced marked (>75% to <100%) and 18% experienced
`moderate (>50% to <75%) reduction in lesion size, and
`10% of patients had a slight reduction (< 50%) in lesion size.
`Therefore, in these studies, 84% of patients experienced ei-
`ther lesion clearing or marked to moderate reduction in le-
`sion size. INTRON A was effective in treating lesions of all
`sizes.
`In one of these studies involving 125 patients in whom multi-
`ple (up to three) lesions were treated, a significant number of
`patients whose lesions were treated with INTRON A (54
`patients out of 125 or 43%) experienced complete clearing of
`all treated lesions at one time or another during the course of
`the study. Of these 54 patients, 81% remained cleared of all
`treated lesions 16 weeks after treatment was initiated.
`In this study, the percentage of patients who had one, two or
`three lesions treated and had all respective treated lesions
`cleared after one course of therapy ranged from 31 to 56%.
`Those 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. Overall
`percentage of patients who had all their treated lesions clear
`after two courses of treatment ranged from 57 to 85%.
`Also from the above study, the INTRON A Interferon alfa-
`2b, recombinant for Injection treated lesions showed im-
`provement within two to four weeks after the start of treat-
`ment. In 64% (68 patients out of 107) of those patients who
`experienced lesion clearing, or marked (£ 75% to < 100%)
`or moderate (> 50% to < 75%) reduction in lesion size, the
`maximal response to INTRON A therapy was noted four to
`eight weeks after initiation of treatment. Additionally, a
`greater number of placebo-treated patients experienced ex-
`acerbations of their lesions during the posttreatment period,
`than did patients treated with INTRON A.
`There was no significant difference in the clearing of lesions
`between those patients who had received other prior thera-
`pies for condylomata and those who had not. However, pa-
`tients having condylomata for a shorter duration had better
`responses to treatment with INTRON A than those with
`lesions of a longer duration There was no difference in re-
`sponse to treatment of penile, vulvar or perianal condylo-
`mata or of condylomata appearing in heavily or lightly
`keratinized areas.
`Serum neutralizing activity was detected in 0.8% of patients
`(2 out of 260) evaluated who received INTRON A intralesion-
`ally. The significance of the appearance of serum neutraliz-
`ing activity is not known.
`
`Physicians' Desk Reference®
`AIDS-Related Kaposi's Sarcoma Kaposi's Sarcoma (KS) is a
`common manifestation of the Acquired Immune Deficiency
`Syndrome (AIDS). Kaposi's Sarcoma lesions are usually cu-
`taneous but may also occur throughout the gastrointestinal
`tract and occasionally affect visceral organs. They fre-
`quently are very numerous and may be painful and dis-
`figuring.
`INTRON A was administered to AIDS-Related Kaposi's Sar-
`coma patients in three separate clinical trials to evaluate
`efficacy and safety. A total of 144 patients were treated in
`these studies
`The first clinical trial was a randomized study comparing the
`efficacy and safety of subcutaneous low dose (1 million IU/
`m INTRON A) versus intravenous high dose (50 million
`IU/m2 INTRON A) therapy. Both treatments were adminis-
`tered daily for 5 days every other week. Preliminary results
`showed objective responses in both regimens, but a shorter
`time to response and a higher response rate occurred with
`the 50 million IU/m2 regimen. This study showed signifi-
`cantly greater activity in patients who were asymptomatic
`(afebrile and without weight loss) than in those with sys-
`temic symptoms (57% vs. 23%).
`In the second clinical study patients with AIDS-Related KS
`received 30 million IU/m5 of INTRON A, subcutaneously
`three times per week (TTW). Doses were adjusted for patient
`tolerance. In this study the average weekly dose delivered in
`the first four weeks was 150 million IU; at the end of twelve
`weeks this averaged 110 million IU/week; and by twenty-
`four weeks averaged 75 million IU/week. A response rate of
`44% was obtained in asymptomatic patients versus 7% in
`symptomatic patients. The median time to response was
`approximately 2 months and the median duration of re-
`sponse was approximately three months for the asymptom-
`atic patients. For the symptomatic patients, the median time
`to response was one month and median duration of response
`was also one month. Baseline T4/T8 ratios were 0.46 for re-
`sponders vs. 0.33 for non-responders.
`In a third study INTRON A was administered daily as a sub-
`cutaneous injection of 35 million IU/d for 12 weeks. Mainte-
`nance treatment, with every other day dosing, was continued
`for up to one year in patients achieving antitumor and anti-
`viral responses. The median time to response was 2 months
`and median duration of response 5 months in the asymptom-
`atic patients.
`In all studies, the likelihood of response has been greatest in
`patients with relatively intact immune systems as assessed
`by baseline T4 counts (interchangeable with CD4) or T4/T8
`ratios. Results at doses of 30 million IU/m2 TTW and 35 mil-
`lion IU/daily, subcutaneously were similar and are provided
`together in Tables 1 and 2 below. These tables demonstrate
`the relationship of response to baseline T4 count or T4/T8
`ratio in both asymptomatic (subtype A) and symptomatic
`(subtype B) patients in the 30 million IU/m2 TTW dose and
`the 35 million IU/d dose.
`TABLE 1
`RESPONSE BY BASELINE T4 COUNT*
`30 million IU/m*
`TIW, SC and 35 million IU Daily, SC
`Asymptomatic Symptomatic
`T4<200 4/14(29%) 0/19(0%)
`200<T4<400 6/12(50%) ) 0/5 (0%)
`} 58%
`T4>400 5/7 (71%) J 0/0 (0%)
`TABI F 2
`RESPONSE BY T4/T8 RATIOS*
`30 million IU/m2
`TTW, SC and 35 million IU Daily, SC
`Asymptomatic Symptomatic
`T4/T8<0.25 1/13 (8%) 0/21 (0%)
`0.25 <T4/T8< 0.50 13/21(62%) | 3/14(21%)
`} 60%
`0.50<T4/T8 11/19(58%) J 0/3 (0%)
`* Data for T4, T4/T8, and asymptomatic and symptomatic
`classification was not available for all patients.
`In the 30 million IU study group, there were 7% (5/72) of
`patients who 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) of the patients were partial responders.
`For patients who received 30 million IU, TIW, the median
`survival time is longer in patients with T4 greater than 200
`(30.7 months) than in patients with T4 less than or equal to
`200 (8.9 months). Among responders, the median survival
`time was 22.6 months versus 9.7 months in non-responders.
`Chronic Hepatitis Non-A, Non-B/C (NANB/C) The safety and
`efficacy of INTRON A Interferon alfa-2b, recombinant for
`Injection in the treatment of chronic hepatitis NANB/C was
`evaluated in four randomized controlled clinical studies in
`which INTRON A was administered subcutaneously at doses
`of 1,2, or 3 million IU three times a week (TTW) for 6 months
`(23 or 24 weeks). All patients studied were 18 years of age or
`older and had compensated liver disease. Of the 332 patients
`evaluable for efficacy in these trials, 81% had a history of
`blood or blood product exposure, 8% had a history of intrave-
`nous drug abuse, 2% had a history of surgery without blood
`
`Consult 1992 Supplements for revisions
`products, and the remainder had other exposure. Retrospec-
`tively, 86% (172/199) of the patients with blood or blood
`product exposure who were tested were found to be positive
`for antibody to hepatitis C virus (HCV).
`In each of these four clinical studies, INTRON A was shown
`to produce a statistically significant improvement in serum
`alanine aminotransferase (ALT) levels. Three of the four
`studies used the 3 million IU dose of INTRON A, and gave
`the following results:
`ALT RESPONSES!
`IN CHRONIC HEPATITIS NANB/C PATIENTS
`Treatment Group
`Number of Patients (%)
`INTRON A
`Study
`3 million IU Controls _ Value
`
`Number
`(9%) <0.001
`P- 29/55
`(53%)
`5/55
`(12%) 0.02
`(43%)
`3/25
`2 10/23
`(18%) 0.005
`3/17
`3 12/17
`(71%)
`
`All Studies 61/96 (54%) 11/97 (11%) -C0.001
`} Includes reduction in ALT level to:
`normal,
`near normal (< 1.5 times the upper limit of normal), or
`partial response (> 50% decrease in ALT level).
`* Untreated or Placebo
`t INTRON A 3 million IU, TTW, 6 months versus control.
`Of the 54% of patients responding to INTRON A at a dose of
`3 million IU, 70% achieved reductions in ALT levels to nor-
`mal, 18% achieved reductions to near normal levels, and
`12% achieved partial responses.
`Histological improvement was evaluated by comparison of
`pre- and posttreatment liver biopsies using a pathologist's
`Global Assessment and the semi-quantitative Knodell His-
`tology Activity Index (HAI).2
`In one of the three studies there was a statistically signifi-
`cant histological improvement, as assessed by both methods,
`for patients treated with 3 million IU INTRON A Interferon
`alfa-2b, recombinant for Injection, compared to controls. A
`similar trend was observed in the two other studies; however
`the improvement was not statistically significant.
`HISTOLOGICAL IMPROVEMENT
`IN CHRONIC HEPATITIS NANB/C PATIENTS
`A. Global Assessment
`Treatment Group
`Number of Patients (%)
`Study INTRON A
`Number 3 million IU Controls*
`1 23/45 (51%) 12/36 (33%)
`2 11/18 (61%) 10/18 (56%)
`3 14/16 (88%) 7/16 (44%)
`
`All Studies 48/79 (61%) 29/70 (41%) 0.01
`* Untreated or Placebo
`t INTRON A 3 million IU, TTW, 6 months compared to con-
`trol for improvement versus no improvement.
`B. Knodell Histology Activity Index!
`Treatment Group
`Number of Patients (%)
`Study INTRON A Pf
`Number 3 million IU Controls* Value
`1 29/45 (64%) 18/36 (50%) 0.26
`2 12/19 (63%) 10/18 (56%) 0.75
`3 14/16 (88%) 8/15 (53%) 0.054
`
`All Studies 65/80 (69%) 36/69 (62%) 0.04
`X Includes the following:
`Category I— Periportal necrosis
`Category II— Intralobular degeneration and necrosis
`Category HI— Portal inflammation
`Category IV— Fibrosis
`* Untreated or Placebo
`t INTRON A 3 million IU, TIW, 6 months compared to con-
`trol for improvement versus no improvement.
`Subsequent combined analysis of results for three studies,
`showed a statistically significant histological improvement
`in patients treated with INTRON A 3 million IU, compared
`to controls for both Global Assessment and the Knodell HAI.
`The improvement was due primarily to decreases in severity
`of necrosis and degeneration in the lobular and periportal
`regions (Knodell HAI Categories I + II), which were ob-
`served in 65% (52/80) of patients treated with 3 million IU
`INTRON A, compared to 46% (32/70) of controls. Diminu-
`tion of disease activity in these regions of the liver was ac-
`companied by a reduction or normalization of serum ALT
`level in many patients. Disease activity increased in these
`regions in only 3% of all patients treated with INTRON A at
`3 million IU, whereas an increase was observed in 16% of the
`controls. No patient achieving an ALT response with 3 mil-
`lion IU INTRON A therapy showed increased periportal or
`lobular necrosis and degeneration.
`Patients were followed for six months after the end of
`INTRON A therapy. During this period the ALT response
`was maintained in 51% (26/51) of patients who responded at
`the 3 million IU TTW dose. Of patients who relapsed during
`
`NPC02233821
`
`NOVARTIS EXHIBIT 2148
`Par v Novartis, IPR 2016-00084
`Page 4 of 8
`
`

`
`Consult 1992 Supplements for revisions
`
`the follow-up period and were retreated at this dose, 83%
`(15/18) responded to retreatment.
`Serum Neutralizing Antibodies Serum anti-interferon neu-
`tralizing antibodies were detected in 15% (7/46) of the pa-
`tients who received INTRON A for chronic hepatitis
`NANB/C at 3 million IU TIW for 6 months and were tested
`for antibody activity. The titers were low and the signifi-
`cance of the appearance of serum anti-interferon neutraliz-
`ing activity is not known.
`INDICATIONS AND USAGE
`General INTRON A is indicated for the treatment of hairy
`cell leukemia, selected cases of condylomata acuminate in-
`volving external surfaces of the genital and perianal areas,
`AIDS-Related Kaposi's Sarcoma in select patients 18 years
`or older, and chronic hepatitis Non-A, Non-B/C (NANB/C)
`in patients 18 years of older with compensated liver disease
`who have a history of blood or blood product exposure and/or
`are HCV antibody positive.
`Hairy Cell Leukemia INTRON A for Injection is indicated
`for the treatment of patientB 18 years of age or older with
`hairy cell leukemia. Studies have shown that INTRON A can
`produce clinically meaningful regression or stabilization of
`this disease, both in previously splenectomized and non-
`splenectomized patients.
`Prior to initiation of therapy, tests should be performed to
`quantitate peripheral blood hemoglobin, platelets, granulc-
`cytes and hairy cells and bone marrow hairy cells. These
`parameters should be monitored periodically during treat-
`ment to determine whether response to treatment has oc-
`curred. If a patient does not respond within 6 months, treat-
`ment should be discontinued. If a response to treatment does
`occur, treatment usually should be continued until no fur-
`ther improvement is observed and these laboratory parame-
`ters have been stable for about 3 months (see DOSAGE
`AND ADMINISTRATION). It is not known whether con-
`tinued treatment after that time point is beneficial. Studies
`are in progress to evaluate this question.
`The 50 million IU strength is not to be used for the treatment
`of hairy cell leukemia.
`Condylomata Acuminata INTRON A Interferon alfa-2b,
`recombinant for Injection is indicated also for intralesional
`treatment of selected cases of condylomata acuminata in-
`volving external surfaces of the genital and perianal areas
`(see DOSAGE AND ADMINISTRATION). The 3 million, 5
`million, and 25 million IU strengths are not to be used for the
`intralesional treatment of condylomata since the dilution
`required for intralesional use would result in a hypertonic
`solution. The 50 million IU strength is not to be used for the
`treatment of condylomata.
`In selecting patients for treatment with INTRON A, the phy-
`sician should consider the nature of the patient's lesion and
`the patient's past treatment history, in addition to the pa-
`tient's ability to comply with the treatment regimen.
`INTRON A offers an additional approach to treatment in
`condyloma and is particularly useful for those patients who
`do not respond satisfactorily to other treatment modalities
`(e.g., podophyllin resin, surgery, cryotherapy, chemother-
`apy, and laser therapy), or whose lesions are more readily
`treatable by INTRON A than by other treatments.
`The use of this product in adolescents has not been studied.
`Interferon alpha has been shown to affect the menstrual
`cycle and decrease serum estradiol and progesterone levels
`in females. Consideration should be given as to whether the
`adolescent patient should be treated.
`AIDS-Related Kaposi's Sarcoma INTRON A is also indi-
`cated for the treatment of select patients, above 18 years of
`age with AIDS-Related Kaposi's Sarcoma. Studies have dem-
`onstrated a greater likelihood of response to INTRON A
`therapy in patients who are without systemic symptoms,
`who have limited lymphadenopathy and who have a rela-
`tively intact immune system.
`Lesion measurements and blood counts should be performed
`prior to initiation of therapy and should be monitored period-
`ically during treatment to determine whether response to
`treatment or disease stabilization has occurred.
`When disease stabilization or a response to treatment occurs,
`treatment Bhould continue until there is no further evidence
`of tumor or until discontinuation is required by evidence of a
`severe opportunistic infection or adverse effect.
`Chronic Hepatitis Non-A, Non-B/C (NANB/C) INTRON A is
`indicated for the treatment of chronic hepatitis Non-A, Non-
`B/C (NANB/C) in patients 18 years or older with compen-
`sated liver disease who have a history of blood or blood prod-
`uct exposure and/or are HCV antibody positive. Studies in
`these patients demonstrated that INTRON A can produce
`clinically meaningful effects on this disease, manifested by
`normalization of serum alanine aminotransferase (ALT)
`level and reduction in liver necrosis and degeneration.
`A liver biopsy should be performed to establish the diagnosis
`of chronic hepatitis. Patients should be tested for the pres-
`ence of antibody to HCV. Patients with other causes of
`chronic hepatitis, including a