NOVARTIS EXHIBIT 2146
`Par v Novartis, IPR 2016-00084
`Page 1 of 7
`
`

`
`NOVARTIS EXHIBIT 2146
`Par v Novartis, IPR 2016-00084
`Page 2 of 7
`
`

`
`874
`
`Cetus—Cont.
`
`tant congestive heart failure. Treatment consists of vigorous
`management of congestive heart failure with digitalis prepa-
`rations and diuretics. The use of peripheral vasodilators has
`been recommended.
`DOSAGE AND ADMINISTRATION
`Care in the administration of doxorubicin hydrochloride will
`reduce the chance of perivenous infiltration. It may also de-
`crease the chance of local reactions such as urticaria and
`erythematous streaking. On intravenous administration of
`doxorubicin, extravasation may occur with or without any
`accompanying stinging or burning sensation and even if
`blood returns well on aspiration of the infusion needle. If any
`signs or symptoms of extravasation have occurred, the injec-
`tion or infusion should be immediately terminated and re-
`started in another vein If it is known or suspected that sub-
`cutaneous extravasation has occurred, local infiltration with
`an injectable corticosteroid and flooding the site with nor-
`mal saline has been reported to lessen the local reaction.
`Because of the progressive nature of extravasation reactions,
`the area of injection should be frequently examined and
`plastic surgery consultation obtained If ulceration begins,
`early wide excision of the involved areas should be consid-
`ered '
`The most commonly used dosage schedule is 60-75 mg/m2 as
`a single intravenous injection administered at 21-day inter-
`vals. The lower dose should be given to patients with inade-
`quate marrow reserves due to old age, or prior therapy, or
`neoplastic marrow infiltration. An alternative dose schedule
`is weekly doses of 20 mg/m2 which has been reported to pro-
`duce a lower incidence of congestive heart failure Thirty
`mg/m2 on each of three successive days repeated every four
`weeks has also been used. Doxorubicin dosage must be re-
`duced if the bihrubin is elevated as follows: Serum bilirubin
`1.2 to 3.0 mg/dL—give V2 normal dose, > 3 mg/dL—give
`V4 normal dose.
`It is recommended that doxorubicin be slowly administered
`into a tubing of a freely running intravenous infusion of So-
`dium Chloride Injection, USP or 5% Dextrose Injection,
`USP The tubing should be attached to a Butterfly® needle
`inserted preferably into a large vein. If possible, avoid veins
`over joints or in extremities with compromised venous or
`lymphatic drainage. The rate of administration is dependent
`on the size of the vein and the dosage. However, the dose
`should be administered in not less than 3 to 5 minutes. Local
`erythematous streaking along the vein as well as facial
`flushing may be indicative of too rapid an administration A
`burning or stinging sensation may be indicative of perive-
`nous infiltration and the infusion should be immediately
`terminated and restarted in another vein. Perivenous infil-
`tration may occur painlessly.
`Doxorubicin should not be mixed with heparin or 5-fluoro-
`uracil since it has been reported that these drugs are incom-
`patible to the extent that a precipitate may form. Until spe-
`cific compatibility data are available, it is not recommended
`that doxorubicin be mixed with other drugs.
`Doxorubicin has been used concurrently with other ap-
`proved chemotherapeutic agents. Evidence is available
`that in some types of neoplastic disease combination chemo-
`therapy is superior to single agents. The benefits and risks of
`such therapy continue to be elucidated.
`Handling and Disposal: Skin reactions associated with dox-
`orubicin have been reported. Caution in the handling of solu-
`tion must be exercised and the use of gloves is recommended.
`If doxorubicin contacts the skin or mucosae, immediately
`wash thoroughly with soap and water.
`Procedures for proper handling and disposal of anti-cancer
`drugs should be considered Several guidelines on this sub-
`ject have been published 2_7 There is no general agreement
`that all of the procedures recommended in the guidelines are
`necessary or appropriate.
`HOW SUPPLIED
`Doxorubicin Hydrochloride Injection. USP.
`Sterile, single use only, contains no preservative.
`NDC 53905-235-10 10 mg vial; 2 mg/mL, 5 mL, 10 vial packs.
`NDC 53905-236-06 20 mg vial; 2 mg/mL, 10 mL, 6 vial packs.
`NDC 53905-237-01 50 mgvial; 2 mg/mL, 25 mL, single vial
`packs.
`Store under refrigeration, 2"-8"C (36M6T), protect from
`light and retain in carton until time of use. Discard unused
`portion.
`CAUTION: Federal law prohibits dispensing without pre-
`scription.
`REFERENCES
`1. Rudolph R et al: Skin Ulcers Due to Adriamycin Cancer
`38.1087-1094, Sept. 1976
`2 Recommendations for the Safe Handling of Parenteral
`Antineoplastic Drugs. NIH Publication No 83-2621. For
`sale by the Superintendent of Documents, U.S. Govern-
`ment Printing Office, Washington, D.C. 20402.
`3. AMA Council Report. Guidelines for Handling Parenteral
`AntineopJastics. JAMA, March 15, 1985.
`
`Physicians' Desk Reference®
`4. National Study Commission on Cytotoxic Exposure-Rec-
`ommendations for Handling Cytotoxic Agents Available
`from Louis P Jeffrey, Sc.D., Director of Pharmacy Ser-
`vices, Rhode Island Hospital, 593 Eddy Street, Providence,
`Rhode Island 02902.
`5. Clinical Oncological Society of Australia. Guidlines and
`recommendations for safe handling of antieoplastic
`agents. Med J Australia J.-426--428, 1983.
`6. Jones RB, et al Safe handling of chemotherapeutic agents:
`A report from the Mount Sinai Medical Center. CA-A Can-
`cer Journal for Clinicians Sept/Oct, 258-263, 1983.
`7 American Society of Hospital Pharmacists technical assis-
`tance bulletin on handling cytotoxic drugs in hospitals.
`Am J Hosp Pharm 42.131-137, 1985.
`MANUFACTURED BY:
`Farmitalia Carlo Erba
`Milan, Italy
`DISTRIBUTED BY:
`Cetus Oncology Corporation
`4650 Horton Street
`Emeryville, CA 94608-2997
`Revised February 1, 1991 057200291
`NO-P-03
`
`LEUCOVORIN Calcium for Injection
`
`5
`
`HOW SUPPLIED
`Leucovorin Calcium for Injection is supplied in packs of ten
`individually-boxed vials.
`50 mg vial: NDC 53905-051-10 Each vial contains 50 mg
`leucovorin as the calcium salt and 45 mg sodium chloride.
`100 mg vial: NDC 53905-052-10. Each vial contains 100 mg
`leucovorin as the calcium salt and 90 mg sodium chloride.
`Caution: Federal law prohibits dispensing without pre-
`scription.
`Revised April, 1991 DD-P-02
`
`METOCLOPRAMIDE INJECTION, USP
`
`5
`
`HOW SUPPLIED
`Metoclopramide Injection, USP is supplied as a Pharmacy
`Bulk Package containing 5 mg metoclopramide (present as
`the hydrochloride) per mL in the following package
`strengths:
`NDC 53905-195-01 250 mg in 50 mL
`NDC 53905-196-01 500 mg in 100 mL
`Store at controlled room temperature, 15" to 3G*C (59" to
`86"F). Do not permit to freeze. Contains no preservative.
`PROTECT FROM LIGHT. Retain in carton until time of use.
`Discard unused portion no later than 4 hours after initial
`entry.
`Dilutions may be stored unprotected from light under nor-
`mal light conditions up to 24 hours after preparation.
`Metoclopramide Injection, USP is also supplied as a 30 mL
`single-dose non-Pharmacy Bulk Package containing 5 mg
`metoclopramide (present as the hydrochloride) per mL in a
`carton of six flip-top vials
`NDC 53905-194-06 150 mg in 30 mL
`Refer to the full prescribing information enclosed with this
`product for dosage and administration directions.
`
`Container
`
`30 mL
`(single-dose vial)
`
`50 mL Pharmacy
`Bulk Package
`
`100 mL Pharmacy
`Bulk Package
`
`Total Concen-
`Contents* tration Administration
`
`150 mg 5 mg/mL For IV infusion
`Only—Dilute
`Before Using
`250 mg 5 mg/mL For IV infusion
`Only—Dilute
`Before Using
`500 mg 5 mg/mL For IV infusion
`Only—Dilute
`Before Using
`
`•Metoclopramide (present as the hydrochloride)
`CAUTION: Federal law prohibits dispensing without pre-
`scription.
`Revised June, 1992
`
`JB-P-04
`
`PROLEUKIN®
`[pro lu '-Am ]
`Aldesleukin
`For Injection
`
`5
`
`WARNINGS
`PROLEUKIN® (aldesleukin for injection) should be
`administered only in a hospital setting under the super-
`vision of a qualified physician experienced in the use of
`anti-cancer agents. An intensive care facility and spe-
`
`Consult 1993 Supplements for revisions
`
`cialists skilled in cardiopulmonary or intensive care
`medicine must be available.
`Proleukin administration has been associated with cap-
`illary leak syndrome (CLS). CLS results in hypotension
`and reduced organ perfusion which may be severe and
`can result in death.
`Therapy with Proleukin should be restricted to patients
`with normal cardiac and pulmonary functions as de-
`fined by thallium stress testing and formal pulmonary
`function testing. Extreme caution should be used in
`patients with normal thallium stress tests and pulmo-
`nary function tests who have a history of prior cardiac
`or pulmonary disease.
`Proleukin administration should be held in patients
`developing moderate to severe lethargy or somnolence;
`continued administration may result in coma.
`
`DESCRIPTION
`PROLEUKIN® (aldesleukin), a human recombinant inter-
`leukin-2 product, is a highly purified protein with a molecu-
`lar weight of approximately 15,300 daltons. The chemical
`name is des-alanyl-1, serine-125 human interleukin-2.
`Proleukin, a lymphokine, is produced by recombinant DNA
`technology using a genetically engineered E. coli strain con-
`taining an analog of the human interleukin-2 gene. Genetic
`engineering techniques were used to modify the human IL-2
`gene, and the resulting expression clone encodes a modified
`human interleukin-2. This recombinant form differs from
`native interleukin-2 in the following ways: a) Proleukin is
`not glycosylated because it is derived from E. coll. ; b) The
`molecule has no N-terminal alanine; the codon for this
`amino acid was deleted during the genetic engineering pro-
`cedure; c) The molecule has serine substituted for cysteine at
`amino acid position 125, this was accomplished by site spe-
`cific manipulation during the genetic engineering proce-
`dure; and d) the aggregation state of Proleukin is likely to be
`different from that of native interleukin-2.
`Biological activities tested in vitro for the native non-recom-
`binant molecule have been reproduced with Proleukin.1,2
`Proleukin for Injection is supplied as a sterile, white to off-
`white, lyophilized cake in single-use vials intended for intra-
`venous (IV) administration. When reconstituted with 1.2 mL
`Sterile Water for Injection, USP, each mL contains 18 mil-
`lion IU (1.1 mg) Proleukin, 50 mg mannitol, and 0 18 mg so-
`dium dodecyl sulfate, buffered with approximately 017 mg
`monobasic and 0.89 mg dibasic sodium phosphate to a pH of
`7.5 (range 7.2 to 7.8). The manufacturing process for Proleu-
`kin involves fermentation in a defined medium containing
`tetracycline hydrochloride. The presence of the antibiotic is
`not detectable in the final product Proleukin contains no
`preservatives in the final product
`Proleukin biological potency is determined by a lymphocyte
`proliferation bioassay and is expressed in International
`Units (IU) as established by the World Health Organization
`1ST International Standard for interleukin 2 (human). The
`relationship between potency and protein mass is as follows:
`18 million (18 X 10*) HJ Proleukin® = 1.1 mg protein
`CLINICAL PHARMACOLOGY
`Proleukin® has been shown to possess the biological activity
`of human native interleukin-2.''2. In vitro studies performed
`on human cell lines demonstrate the immunoregulatory
`properties of Proleukin, including: a) enhancement of lym-
`phocyte mitogenesis and stimulation of long-term growth of
`human interleukin-2 dependent cell lines; b) enhancement of
`lymphocyte cytotoxicity; c) induction of killer cell [lympho-
`kine-activated (LAK) and natural (NK)] activity; and d) in-
`duction of interferon-gamma production.
`The in vivo administration of Proleukin in select murine
`tumor models and in the clinic produces multiple iromuno-
`logical effects in a dose dependent manner. These effects
`include activation of cellular immunity with profound lym-
`phocytosis, eosinophilia, and thrombocytopenia, and the
`production of cytokines including tumor necrosis factor, IL-1
`and gamma interferon.3 In vivo experiments in murine tu-
`mor models have shown inhibition of tumor growth.4 The
`exact mechanism by which Proleukin mediates its antitu-
`mor activity in animals and humans is unknown.
`Pharmacokinetics: Proleukin exists as biologically active,
`non-covalently bound microaggregates with an average size
`of 27 recombinant interleukin-2 molecules. The solubilizing
`agent, sodium dodecyl sulfate, may have an effect on the
`kinetic properties of this product. The pharmacokinetic pro-
`file of Proleukin is characterized by high plasma concentra-
`tions following a short IV infusion, rapid distribution to ex-
`travascular, extracellular space and elimination from the
`body by metabolism in the kidneys with little or no bioactive
`protein excreted in the urine.
`Studies of IV Proleukin in sheep and humans indicated that
`approximately 30% of the administered dose initially dis-
`tributes to the plasma.
`This is consistent with studies in rats that demonstrate a
`rapid (< 1 minute) and preferential uptake of approximately
`70% of an administered dose into the liver, kidney and lung.
`
`NPC02233826
`
`NOVARTIS EXHIBIT 2146
`Par v Novartis, IPR 2016-00084
`Page 3 of 7
`
`

`
`Consult 1993 Supplements for revisions
`
`Physicians' Desk Reference®
`
`875
`
`The serum half-life (T V2) curves of Proleukin remaining in
`the plasma are derived from studies done in 52 cancer pa-
`tients following a 5 minute IV infusion.5 These patients were
`shown to have a distribution and elimination T \ of 13 and
`85 minutes, respectively
`The relatively rapid clearance rate of Proleukin has led to
`dosage schedules characterized by frequent, short infusions.
`Observed serum levels are proportional to the dose of Proleu-
`kin.
`Following the initial rapid organ distribution described
`above, the primary route of clearance of circulating Proleu-
`kin is the kidney. In humans and animals, Proleukin is
`cleared from the circulation by both glomerular filtration
`and peritubular extraction in the kidney.*""9 This dual mech-
`anism for delivery of Proleukin to the proximal tubule may
`account for the preservation of clearance in patients with
`rising serum creatinine values. Greater than 80% of the
`amount of Proleukin distributed to plasma, cleared from the
`circulation and presented to the kidney is metabolized to
`amino acids in the cells lining the proximal convoluted
`tubules. In humans, the mean clearance rate in cancer pa-
`tients is 268 mL/mm.9
`Immunogenicity: Fifty-eight of 76 renal cancer patients
`(76%) treated with the every 8 hour Proleukin regimen de-
`veloped low titers of non-neutralizing anti-interleukin-2
`antibodies. Neutralizing antibodies were not detected in this
`group of patients, but have been detected in 1/106 (< 1%)
`patients with IV Proleukin using a wide variety of schedules
`and doses. The clinical significance of anti-interleukin-2
`antibodies is unknown.
`Clinical Experience: Two hundred and fifty-five patients
`with metastatic renal cell cancer were treated with single
`agent Proleukin. Treatment was given by the every 8 hour
`regimen in 7 clinical studies conducted at 21 institutions. To
`be eligible for study, patients were required to have bidimen-
`sionally measurable disease; Eastern Cooperative Oncology
`Group (ECOG) Performance Status (PS) of 0 or 1 (see Table I);
`and normal organ function, including normal cardiac stress
`test and pulmonary function tests. Patients with brain me-
`tastases, active infections,' organ allografts and diseases re-
`quiring steroid treatment were excluded. In addition, it was
`noted that 218 of the 225 (85%) patients had undergone ne-
`phrectomy prior to treatment with Proleukin.
`Proleukin was given by 15 minute IV infusion every 8 hours
`for up to 5 days (maximum of 14 doses). No treatment was
`given on days 6 to 14 and then dosing was repeated for up to
`5 days on days 15 to 19 (maximum of 14 doses). These 2 cycles
`constituted 1 course of therapy. All patients were treated
`with 28 doses or until dose-limiting toxicity occurred requir-
`ing ICU-level support. Patients received a median of 20 of 28
`scheduled doses of Proleukin. Doses were held for specific
`toxicities (See "DOSAGE AND ADMINISTRATION"
`Section, "Dose Modification" Subsection). A variety of seri-
`ous adverse events were encountered including: hypoten-
`sion; oliguria/anuria; mental status changes including coma;
`pulmonary congestion and dyspnea; GI bleeding; respiratory
`failure leading to intubation; ventricular arrhythmias; myo-
`cardial ischemia and/or infarction; ileus or intestinal perfo-
`ration, renal failure requiring dialysis; gangrene; seizures;
`sepsis and death (See "ADVERSE REACTIONS" Section).
`Due to the toxicities encountered during the clinical trials,
`investigators used the following concomitant medications.
`Acetaminophen and indomethacin were started immedi-
`ately prior to Proleukin to reduce fever. Renal function was
`particularly monitored because indomethacin may cause
`synergistic nephrotoxicity. Meperidine was added to control
`the rigors associated with fever. Ranitidine or cimetidine
`were given for prophylaxis of gastrointestinal irritation and
`bleeding. Antiemetics and antidiarrheals were used as
`needed to treat other gastrointestinal side effects. These
`medications were discontinued 12 hours after the last dose of
`Proleukin. Hydroxyzine or diphenhydramine used to control
`symptoms from pruritic rashes and continued until resolu-
`tion of pruritus. NOTE: Prior to the use of any product men-
`tioned in this paragraph, the physician should refer to the
`package insert for the respective product.
`For the 255 patients in the Proleukin database, objective
`response was seen in 15% or 37 patients with nine (4%) com-
`plete and 28 (11%) partial responders. The 95% confidence
`interval for response was 11 to 20%. Onset of tumor regres-
`sion has been observed as early as 4 weeks after completion
`of the first course of treatment and tumor regression may
`continue for up to 12 months after the start of treatment.
`Durable responses were achieved with a median duration of
`objective (partial or complete) response by Kaplan-Meier
`projection at 23 2 months (1 to 50 months). The median dura-
`tion of objective partial response was 18.8 months. The pro-
`portion of responding patients who will have response dura-
`tions of 12 months or greater is projected to be 85% for all
`responders and 79% for patients with partial responses
`(Kaplan-Meier).
`Median
`Complete Partial Response Onset of
`Duration
`Responders Responders Rate Response
`of Response
`9 (4%) 28 (11%) 15% 1 to
`23.2 months
`12 mos.
`(range 1-50)
`
`Performance Status Equivalent
`
`ECOG'
`0
`1
`2
`
`Karnofsky
`100
`80-90
`60-70
`
`3
`
`4
`
`40-50
`
`20-30
`
`TABLE 1
`PERFORMANCE STATUS SCALE
`
`Performance Status Definitions
`
`Asymptomatic
`Symptomatic fully ambulatory
`Symptomatic; in bed less than 50% of
`day
`Symptomatic, in bed more than 50% of
`day
`Bedridden
`
`Zubrod, CG, et al J Chron Dis 11:7-33, 1960
`
`Pre-Treatment
`ECOG PS
`
`0
`r
`£2
`
`TABLE II
`PROLEUKIN RESPONSE ANALYZED BY ECOG' PERFORMANCE STATUS (PS)
`No of Patients Response % of Patients
`Treated (n=255) CR PR Responding
`
`166
`
`21
`7
`0
`
`18%
`9%
`0%
`
`On-Study
`Death Rate
`
`4%
`6%
`
`* Eastern Cooperative Oncology Group
`Response was observed in both lung and non-lung sites (e.g.
`liver, lymph node, renal bed recurrences, soft tissue). Pa-
`tients with individual bulky lesions (> 5 X 5 cm) as well as
`large cumulative tumor burden (>25 cm2 tumor area)
`achieved durable responses.
`An analysis of prognostic factors showed that performance
`status as defined by the ECOG (see Table I) was a significant
`predictor of response. PS 0 patients had an 18% overall rate
`of objective response, which included all 9 complete response
`patients and 21 of 28 partial response patients. PS 1 patients
`had a lower rate of response (9%), all of which were partial
`responses. In this group it was notable that 6 of the 7 re-
`sponders had resolution of tumor related symptoms and im-
`proved performance status to PS 0. All seven patients were
`fully functional and 4 of the 7 returned to work, suggesting
`that responses among the PS 1 patients were clinically
`meaningful as well (see Table II).
`In addition, the frequency of toxicity was related to the per-
`formance status. As a group, PS 0 patients, when compared
`with PS 1 patients, had lower rates of adverse events with
`fewer on-study deaths (4% vs. 6%), less frequent intubations
`(8% vs. 25%), gangrene (OK vs. 6%), coma (IK vs. 6%). GI
`bleeding (4% vs. 8%), and sepsis (6K vs. 18K). These differ-
`ences in toxicity are reflected in the shorter mean time to
`hospital discharge for PS 0 patients (2 vs. 3 days) as well as
`the smaller percentage of PS 0 patients experiencing a
`delayed (> 7 days) discharge from the hospital (8 K vs. 19K).
`[See Table I and Table II above.]
`
`INDICATIONS AND USAGE
`Proleukin (aldesleukin) is indicated for the treatment of
`adults ("i. 18 years of age) with metastatic renal cell carci-
`noma.
`Careful patient selection is mandatory prior to the adminis-
`tration of Proleukin. See "CONTRAINDICATIONS",
`"WARNINGS" and "PRECAUTIONS" Sections regarding
`patient screening, including recommended cardiac and pul-
`monary function tests and laboratory tests.
`Evaluation of clinical studies to date reveals that patients
`with more favorable ECOG performance status (ECOG PS 0)
`at treatment initiation respond better to Proleukin, with a
`higher response rate and lower toxicity (See "CLINICAL
`PHARMACOLOGY" Section, "Clinical Experience" Sub-
`section). Therefore, selection of patients for treatment
`should include assessment of performance status, as de-
`scribed in Table I.
`Experience in patients with PS > 1 is extremely limited.
`CONTRAINDICATIONS
`Proleukin (aldesleukin) is contramdicated in patients with a
`known history of hypersensitivity to interleukin-2 or any
`component of the Proleukin formulation.
`Patients with an abnormal thallium stress test or pulmonary
`function tests are excluded from treatment with Proleukin.
`Patients with organ allografts should be excluded as well In
`addition, retreatment with Proleukin is contramdicated in
`patients who experienced the following toxicities while re-
`ceiving an earlier course of therapy:
`• Sustained ventricular tachycardia (> 5 beats)
`• Cardiac rhythm disturbances not controlled or unrespon-
`sive to management
`• Recurrent chest pain with ECG changes, consistent with
`angina or myocardial infarction
`• Intubation required > 72 hours
`• Pericardial tamponade
`• Renal dysfunction requiring dialysis > 72 hours
`• Coma or toxic psychosis lasting > 48 hours
`• Repetitive or difficult to control seizures
`• Bowel ischemia/perforation
`• GI bleeding requiring surgery
`
`WARNINGS
`See boxed "WARNINGS"
`Proleukin (aldesleukin) administration has been associated
`with capillary leak syndrome (CLS) which results from ex-
`travasation of plasma proteins and fluid into the extravascu-
`lar space and loss of vascular tone. CLS results in hypoten-
`sion and reduced organ perfusion which may be severe and
`can result in death The CLS may be associated with cardiac
`arrhythmias (supraventricular and ventricular), angina,
`myocardial infarction, respiratory insufficiency requiring
`intubation, gastrointestinal bleeding or infarction, renal
`insufficiency, and mental status changes.
`Because of the severe adverse events which generally accom-
`pany Proleukin therapy at the recommended dosages, thor-
`ough clinical evaluation should be performed to exclude
`from treatment patients with significant cardiac, pulmo-
`nary, renal, hepatic or CNS impairment.
`Should adverse events occur, which require dose modifica-
`tion, dosage should be withheld rather than reduced (See
`"DOSAGE AND ADMINISTRATION" Section, "Dose
`Modification" Subsection).
`Proleukin may exacerbate disease symptoms in patients
`with clinically unrecognized or untreated CNS metastases.
`All patients should have thorough evaluation and treatment
`of CNS metastases prior to receiving Proleukin therapy
`They should be neurologically stable with a negative CT
`scan In addition, extreme caution should be exercised in
`treating patients with a history of seizure disorder because
`Proleukin may cause seizures
`Intensive Proleukin treatment is associated with impaired
`neutrophil function (reduced chemotaxis) and with an in-
`creased risk of disseminated infection, including sepsis and
`bacterial endocarditis, in treated patients Consequently,
`pre-existing bacterial infections should be adequately
`treated prior to initiation of Proleukin therapy Addition-
`ally, all patients with indwelling central lines should receive
`antibiotic prophylaxis effective against S. aureus 10~ 12 Anti-
`biotic prophylaxis which has been associated with a reduced
`incidence of staphylococcal infections in Proleukin studies
`includes the use of: oxacillin, nafcilhn, ciprofloxacin, or van-
`comycin. Disseminated infections acquired in the course of
`Proleukin treatment are a major contributor to treatment
`morbidity and use of antibiotic prophylaxis and aggressive
`treatment of suspected and documented infections may re-
`duce the morbidity of Proleukin treatment. NOTE: Prior to
`the use of any product mentioned in this paragraph, the phy-
`sician should refer to the package insert for the respective
`product.
`PRECAUTIONS
`General: Patients should have normal cardiac, pulmonary,
`hepatic and CNS function at the start of therapy. Patients
`who have had a nephrectomy are still eligible for treatment
`if they have serum creatinine levels < 1 5 mg/dL
`Adverse events are frequent, often serious, and sometimes
`fatal.'
`Capillary leak syndrome (CLS) begins immediately after
`Proleukin treatment starts and is marked by increased capil-
`lary permeability to protein and fluids and reduced vascular
`tone. In most patients, this results in a concomitant drop in
`mean arterial blood pressure within 2 to 12 hours after the
`start of treatment. With continued therapy, clinically signif-
`icant hypotension (defined as systolic blood pressure below
`90 mm Hg or a 20 mm Hg drop from baseline systolic pres-
`sure) and hypoperfusion will occur. In addition, extravasa-
`tion of protein and fluids into the extravascular space will
`lead to edema formation and creation of effusions
`Medical management of CLS begins with careful monitoring
`of the patient's fluid and organ perfusion status. This is
`Continued on next page
`
`NPC02233827
`
`NOVARTIS EXHIBIT 2146
`Par v Novartis, IPR 2016-00084
`Page 4 of 7
`
`

`
`876
`
`Cetus—Cont.
`
`achieved by frequent determination of blood pressure and
`pulse, and by monitoring organ function, which includes
`assessment of mental status and urine output. Hypovolemia
`is assessed by catheterization and central pressure monitor-,
`ing
`Flexibility in fluid and pressor management is essential for
`maintaining organ perfusion arid blood pressure. Conse-
`quently, extreme caution should be used in treating patients
`with fixed requirements for large volumes of fluid (e.g pa-
`tients with hypercalcemia).
`Patients with hypovolemia are managed by administering
`IV fluids, either colloids or crystalloids. IV fluids are usually
`given when the central venous pressure (CVP) is below 3 to 4
`mm H20. Correction of hypovolemia may require large
`volumes of IV fluids but caution is required because unre-
`strained fluid administration may exacerbate problems asso-
`ciated with edema formation or effusions.
`With extravascular fluid accumulation, edema is common
`and some patients may develop ascites or pleural effusions.
`Management of these events depends on a careful balancing
`of the effects of fluid shifts so that neither the consequences
`of hypovolemia (e.g. impaired organ perfusion) nor the conse-
`quences of fluid accumulations (e.g. pulmonary edema) ex-
`ceeds the patient's tolerance.
`Clinical experience has shown that early administration of
`dopamine (1 to 5 ug/kg/min) to patients manifesting capil-
`lary leak syndrome, before the onset of hypotension, can
`help to maintain organ perfusion particularly to the kidney
`and thus preserve urine output Weight and urine output
`should be carefully monitored. If organ perfusion and blood
`pressure are not sustained by dopamine therapy, clinical
`investigators have increased the dose of dopamine to 6 to 10
`Hg/kg/min or have added phenylephrine hydrochloride (1 to
`5 /ig/kg/min) to low dose dopamine. (See "CLINICAL
`PHARMACOLOGY" Section, "Clinical Experience" Sub-
`section). Prolonged use of pressors, either in combination or
`as individual agents, at relatively high doses, may be associ-
`ated with cardiac rhythm disturbances. NOTE: Prior to the
`use of any product mentioned in this paragraph, the physi-
`cian should refer to the package insert for the respective
`product.
`Failure to maintain organ perfusion, demonstrated by al-
`tered mental status, reduced urine output, a fall in the sys-
`tolic blood pressure below 90 mm Hg or onset of cardiac ar-
`rhythmias, should lead to holding the subsequent doses until
`recovery of organ perfusion and a return of systolic blood
`pressure above 90 mm Hg are observed. (See "DOSAGE
`AND ADMINISTRATION" Section, "Dose Modification"
`Subsection).
`Recovery from CLS begins soon after cessation of Proleukin
`therapy Usually, within a few hours, the blood pressure
`rises, organ perfusion is restored and resorption of extrava-
`sated fluid and protein begins. If there has been excessive
`weight gain or edema formation, particularly if associated
`with shortness of breath from pulmonary congestion, use of
`diuretics, once blood pressure has normalized, has been
`shown to hasten recovery.
`Oxygen is given to the patient if pulmonary function moni-
`toring confirms that P002 is decreased.
`Proleukin administration may cause anemia and/or throm-
`bocytopenia. Packed red blood cell transfusions have been
`given both for relief of anemia and to insure maximal oxygen
`carrying capacity. Platelet transfusions have been given to
`resolve absolute thrombocytopenia and to reduce the risk of
`GI bleeding. In addition, leukopenia and neutropenia are
`observed.
`Proleukin administration results in fever, chills, rigors, pru-
`ritus and gastrointestinal side effects in most patients
`treated at recommended doses. These side effects have been
`aggressively managed as described in the "CLINICAL
`PHARMACOLOGY" Section, "Clinical Experience" Sub-
`section
`Renal and hepatic function are impaired during Proleukin
`treatment. Use of concomitant medications known to be
`nephrotoxic or hepatotoxic may further increase toxicity to
`the kidney or liver. In addition, reduced kidney and liver
`function secondary to Proleukin treatment may delay elimi-
`nation of concomitant medications and increase the risk of
`adverse events from those drugs.
`Patients may experience mental status changes including
`irritability, confusion, or depression while receiving Proleu-
`kin These mental status changes may be indicators of bac-
`teremia or early bacterial sepsis. Mental status changes due
`solely to Proleukin are generally reversible when drug ad-
`ministration is discontinued. However, alterations in mental
`status may progress for several days before recovery begins.
`Impairment of thyroid function has been reported following
`Proleukin treatment. A small number of treated patients
`went on to require thyroid replacement therapy. This im-
`pairment of thyroid function may be a manifestation of auto-
`
`Physicians' Desk Reference®
`
`Consult 1993 Supplements for revisions
`
`Events by Body System
`
`TABLE III
`Incidence of Adverse Events
`% of Patients Events by Body System
`
`% of Patients
`
`85
`71
`70
`22
`8
`5
`3
`1
`7
`5
`4
`3
`2
`2
`1
`1
`1
`1
`1
`1
`1
`
`54
`52
`10
`
`9
`8
`7
`6
`1
`1
`1
`
`64 .
`56
`56
`11
`4
`1
`
`77
`' 64
`34
`10
`9
`6
`
`Cardiovascular
`Hypotension
`(requiring pressors)
`Sinus Tachycardia
`Arrhythmias
`Atrial
`Supra ventricular
`Ventricular
`Junctional
`Bradycardia
`Premature Ventricular Contractions
`Premature Atrial Contractions
`Myocardial Ischemia
`Myocardial Infarction
`Cardiac Arrest
`Congestive Heart Failure
`Myocarditis
`Stroke
`Gangrene
`Pericardial Effusion
`Endocarditis
`Thrombosis
`Pulmonary
`Pulmonary Congestion
`Dyspnea
`Pulmonary Edema
`Respiratory Failure
`(leading to intubatio