(cid:11)(cid:14)(cid:31)(cid:35)(cid:56)(cid:17)(cid:32)(cid:35)(cid:56)(cid:13)(cid:36)(cid:40)(cid:18)(cid:56)(cid:15)(cid:42)(cid:8)(cid:24)(cid:41)(cid:8)(cid:39)(cid:21)(cid:33)(cid:27)(cid:4)(cid:56)(cid:9)(cid:29)(cid:56)(cid:35)(cid:15)(cid:38)(cid:16)(cid:8)(cid:35)(cid:12)(cid:20)(cid:56)
`
`
`
`(cid:8)(cid:52)(cid:52)(cid:48)(cid:46)(cid:44)(cid:54)(cid:51)(cid:50)(cid:56)(cid:28)(cid:55)(cid:49)(cid:45)(cid:47)(cid:53)(cid:56) (cid:7)(cid:56)(cid:1)(cid:56)(cid:3) (cid:2)(cid:56)(cid:43)(cid:56)(cid:6)(cid:56)
`
`(cid:17)(cid:23)(cid:8)(cid:25)(cid:5)(cid:56)(cid:34)(cid:37)(cid:30)(cid:14)(cid:13)(cid:56)(cid:24)(cid:8)(cid:10)(cid:15)(cid:26)(cid:22)(cid:27)(cid:19)(cid:56)
`
`(cid:38)(cid:40)(cid:47)(cid:42)(cid:40)(cid:49)(cid:40)(cid:3)(cid:21)(cid:20)(cid:22)(cid:28)
`CELGENE 2139
`(cid:36)(cid:51)(cid:50)(cid:55)(cid:40)(cid:59)(cid:3)(cid:89)(cid:17)(cid:3)(cid:38)(cid:40)(cid:47)(cid:42)(cid:40)(cid:49)(cid:40)
`APOTEX v. CELGENE
`(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:21)(cid:22)(cid:16)(cid:19)(cid:19)(cid:24)(cid:20)(cid:21)
`IPR2023-00512
`
`

`

`October 13, 2000
`
`Package Insert
`
`‘NOVANTRONE®
`
`mitoxantrone
`
`for injection concentrate
`
`WARNING
`NOVANTRONE® (mitoxantronefor injection concentrate) should be
`administered under the supervision of a physician experienced in the use of cytotoxic
`
`chemotherapy agents.
`
`NOVANTRONEshould be given slowly into a freely flowing intravenous
`infusion. It must never be given subcutaneously, intramuscularly, or intra-arterially.
`Severe local tissue damage may occur ifthere is extravasation during administration.
`(See ADVERSE REACTIONS, General, Cutaneous)
`
`NOT FOR INTRATHECAL USE.Severe injury with permanent sequelae can
`result from intrathecal administration. (See WARNINGS, General)
`
`Exceptfor the treatmentof acute nonlymphocytic leukemia,NOVANTRONE
`therapy generally should not be given to patients with baseline neutrophil counts ofless
`than 1500 cells/mm’.
`Inorder to monitor the occurrence ofbone marrow suppression,
`primarily neutropenia, which may be severe andresult in infection, it is recommended
`that frefluent peripheral bloodceil counts be performed onall patients receiving
`NOVANTRONE.
`
`Myocardial toxicity, manifested in its most severe form bypotentially fatal
`congestive heartfailure (CHF), may occur either during therapy with NOVANTRONE or
`months to years after termination oftherapy. Use of NOVANTRONE has been
`associated with cardiotoxicity; this risk increases with cumulative dose. In cancer
`patients, the risk of symptomatic congestive heart failure (CHF) was estimated to be
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`NOVANTRONE PACKAGE INSERT 10-05-00
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`2.6% for patients receiving up to a cumulative dose of 140 mg/m’. Forthis reason,
`patients should be monitored for evidence ofcardiac toxicity and questioned about
`symptoms ofheart failure priorto initiation of treatment. Patients with multiple sclerosis
`who reach a cumulative dose of 100 mg/m’ should be monitored for evidence of cardiac
`toxicity prior to each subsequent dose. Ordinarily, patients with multiple sclerosis should
`not receive a cumulative dose greater than 140 mg/m’. Active or dormant cardiovascular
`disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous
`therapy with other anthracyclines or anthracenediones, or concomitantuse of other
`cardiotoxic drugs mayincreasethe risk ofcardiac toxicity. Cardiac toxicity with
`NOVANTRONE mayoccur at lower cumulative doses whether or not cardiac risk factors
`are present. For additional information, see WARNINGS, Cardiac Effects, and
`DOSAGE AND ADMINISTRATION.
`
`Secondary acute myelogenous leukemia (AML) has been reported in cancer
`patients treated with anthracyclines. NOVANTRONE is an anthracenedione,a related
`
`drug. The occurrenceofrefractory secondary leukemia is more common when
`anthracyclines are given in combination with DNA-damaging antineoplastic agents, when
`
`patients have been heavily pretreated with cytotoxic drugs, or when doses of
`
`anthracyclines have been escalated. Secondary leukemias have been reported in cancer
`
`patients treated with NOVANTRONEin combination with other cytotoxic agents; the
`
`incidence of these events has not been quantified.
`
`
`DESCRIPTION
`
`*NOVANTRONE (mitoxantrone hydrochloride) is a synthetic antineoplastic
`anthracenedione for intravenous use. The molecular formula is Cz»HzsN«O¢e2HCland
`the molecular weight is 517.41. Itis supplied as a concentrate that MUST BE DILUTED
`PRIOR TO INJECTION.The concentrateis a sterile, nonpyrogenic,dark blue aqueous
`solution containing mitoxantrone hydrochloride equivalent to 2 mg/mL mitoxantrone free
`base, with sodium chloride (0.80% w/v), sodium acetate (0.005% w/v), and acetic acid
`(0.046% w/v) as inactive ingredients. The solution has a pH of 3.0 to 4.5 and contains
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`
`
`NOVANTRONE PACKAGEINSERT.1005-00
`
`0.14 mEq of sodium per mL. The product does not contain preservatives. The chemical
`nameis 1 ,4-dihydroxy-5,8-bis[(2-[(2-hydroxyethyl) aminoJethy!Jamino]-9,10-
`anthracenedione dihydrochloride and the structural formulais:
`
`OH
`
`oO
`
`NHCH 2CH2NHCH 2CH20H
`
`C) oe
`
`-
`
`2HCI
`
`CH NHCH 2CH;NHCH 2CHZ0H
`
`CLINICAL PHARMACOLOGY
`
`Mechanism of Action
`
`Mitoxantrone, a DNA-reactive agent that intercalates into deoxyribonucleic acid
`
`(DNA)through hydrogen bonding,causes crosslinks and strand breaks. Mitoxantrone
`
`also interferes with nbcnucleic acid (RNA) andis a potent inhibitor of topoisomeraseII,
`
`an enzymeresponsible for uncoiling and repairing damaged DNA.It has a cytocidal
`
`effect on both proliferating and nonproliferating cultured human cells, suggesting lack of
`
`cell cycle phase specificity.
`
`NOVANTRONEhas been shown in vitro to inhibit B cell, T cell, and
`macrophageproliferation and impair antigen presentation, as well as the secretion of
`interfegon gamma, TNFa,and IL-2.'*
`
`Pharmacokinetics
`Pharmacokinetics ofmitoxantronein patients following a single intravenous
`administration ofNOVANTRONE can be characterized by a three-compartment model.
`The mean alpha half-life of mitoxantroneis 6 to 12 minutes, the mean beta half-life is 1.1
`
`to 3.1 hours and the mean gamma(terminal or elimination) half-life is 23 to 215 hours
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`(median approximately 75 hours). Pharmacokinetic studies have not been performedin
`
`humans receiving multiple daily dosing. Distributionto tissues is extensive: steady-state
`volume ofdistribution exceeds 1000 L/m’. Tissue concentrations of mitoxantrone appear
`to exceed thosein the blood during the terminal elimination phase. In the healthy
`
`monkey, distribution tobrain, spinal cord, eye, and spinal fluid is low.
`
`In patients administered 15-90 mg/m” ofNOVANTRONE intravenously, there is
`a linear relationship between dose and the area under the concentration-time curve
`
`(AUC).
`
`Mitoxantroneis 78% bound to plasmaproteins in the observed concentration
`range of 26-455 ng/mL. This bindingis independent of concentration and is not affected
`by the presence of phenytoin, doxorubicin, methotrexate, prednisone, prednisolone,
`heparin, or aspirin.
`
`Metabolism and Elimination
`
`Mitoxantroneis excreted in urine and feces as either unchanged drugor as
`inactive metabolites. In human studies, 11% and 25% of the dose were recovered in
`urine andfeces, respectively, as either parent drug or metabolite during the 5-day period
`following drug administration, Of the material recovered in urine, 65% was unchanged
`drug. The remaining 35% was composed ofmonocarboxylic and dicarboxylic acid
`derivatives and their glucuronide conjugates. The pathways leading to the metabolism of
`NOVANTRONEhave not been elucidated.
`
`‘In vitro drug interaction studies have demonstrated that mitoxantrone did not
`inhibit CYP450 1A2, 246, 2C9, 2C19, 2D6, 2E1, and 3A4 across a broad concentration
`range. Theresults of in vitro induction studies are inconclusive, but suggest that
`mitoxantrone isa weak inducer of CYP450 2E1 activity.
`
`Special Populations
`
`
`Gender: Theeffect of gender on mitoxantrone pharmacokinetics is unknown.
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`Geriatric: In elderly patients with breast cancer, the systemic mitoxantrone
`clearance was 21.3 L/hr/m’, compared with 28.3 L/r/m’ and 16.2 L/hr/m?for non-
`elderly patients with nasopharyngeal carcinoma and malignant lymphoma, respectively.
`
`Pediatric: Mitoxantrone pharmacokinetics in the pediatric population are
`
`unknown.
`
`-
`
`Race: The effect of race on mitoxantrone pharmacokinetics is unknown.
`
`Renal Irapairment: Mitoxantrone pharmacokinetics in patients with renal
`impairment are unknown.
`
`Hepatic Impairment: Mitoxantrone clearance is reduced by hepatic impairment.
`Patients with severe hepatic dysfunction (bilirubin > 3.4 mg/dL) have an AUC morethan
`three times greater thanthat of patients with normal hepatic function receiving the same
`dose. Patients with multiple sclerosis who have hepatic impairment should ordinarily not
`be treated with NOVANTRONE.Other patients with hepatic impairmentshould be
`treated with caution and dosage adjustment may be required.
`
`Drug Interactions: Pharmacokinetic studies ofthe interaction ofNOVANTRONE
`with concomitantly administered medications have not been performed. The pathways
`Jeading to the metabolism of NOVANTRONE havenot been elucidated. To date, post-
`marketing experience has not revealed any significant drug interactions in patients who
`have received NOVANTRONE fortreatment of cancer. Information on drug interactions
`in patients with multiple sclerosisis limited.
`4
`
`CLINICAL TRIALS
`
`Multiple Sclerosis
`The safetyand efficacy ofNOVANTRONEinmultiple sclerosiswere assessed in
`
`two randomized, multicenter clinical studies.
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`One randomized,controlled study (Study 1) was conducted in patients with
`secondary progressive or propressive relapsing multiple sclerosis. Patients in this study
`demonstrated significant neurological disability based on the Kurtzke Expanded
`Disability Status Scale (EDSS). The EDSSis an ordinal scale with 0.5 point increments
`ranging from 0.0 to 10.0 (increasing score indicates worsening) and based largely on
`ambulatory impairmentinits middle range (EDSS4.5 to 7.5 points). Patients in this
`" study had experienced a mean deterioration in EDSSof about 1.6 points over the
`18 months prior to enrollment.
`
`Patients were randomized to receive placebo,5 mg/m? NOVANTRONE,or
`12 mg/m? NOVANTRONEadministered IV every 3 months for 2 years. High-dose
`methylprednisolone was administered to treat relapses. The intent-to-treat analysis
`cohort consisted of 188 patients; 149 completed the 2-year study. Patients were
`evaluated every 3 months, and clinical outcome was determined after 24 months. In
`addition, a subset of patients was assessed with magnetic resonance imaging (MRI) at
`baseline, Month 12, and Month 24. Neurologic assessments and MRI reviews were
`
`performed by evaluators blinded to study drug and clinical outcome, although the
`diagnosis of relapse andthe decisionto treat relapses with steroids were made by
`unblinded treating physicians. A multivariate analysis of five clinical variables (EDSS,
`AmbulationIndex [AI], numberof relapses requiring treatment with steroids, months to
`
`first relapse needing treatment with steroids, and Standard Neurological Status [SNS])
`was used to determine primary efficacy. The Al is an ordinal scale ranging from 0 to 9 in
`one point increments to define progressive arabulatory impairment. The SNS provides an
`overafl measure of neurologic impairment and disability, with scores ranging from 0
`(nonnal neurologic examination) to 99 (worst possible score).
`
`Results of Study | are summarized in Table 1.
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`Table 1
`Efficacy Results at Mouth 24
`Stady1
`
`p-value
`Treatment Groups
`Placebo vs
`NOVANTRONE
`12 we/n*
`Smeg/m*
`12 mg/m”
`NOVANTRONE
`(N=64)
`(N=60)
`-
`_ < 0.0001
`
`Placebo
`(N=)
`-
`
`0.23
`0.77
`1.20
`
`;
`— 0.23
`0.41
`0.73
`
`~0.13
`0.30
`0.40
`
`0.0194
`0.0306
`0.0002
`
`0.0004
`
`Primary Endpoints
`Primary efficacy multivariate analysis®
`Primary clinical variables analyzed:
`EDSSchangé®® (mean)
`Ambulation Index change®* (mean)
`Mcan number of relapses per paticnt requiring
`corticosteroid treatment (adjusted for discontinuation)
`Months to first relapsc requiring corticosteroid treatment
`(median {17 quartile])
`Standard Nevrological Status change** (mean)
`0.77
`— 0.38
`—1.07
`0.0269
`
`
`14.2 [6.7]
`
`NR [6.9] NR [20.4]
`
`MRI
`
`5/32 (16%) 4/37(11%)
`No.ofpatients with new Gd-cnhancing lesions
` 1.94(32)
`0.68 (34)
`Change in number of T2-weighted lesions, mean(n)**
`NR = notreached within 24 months; Mn = magnetic resonance imaging.
`© Wei-Lachin test.
`°* Month 24 value minus basclinc.
`t A subset of 110 patients wag selected for MRI analysis. MRI results were not available for all patients at all time points.
`
`0/31
`(0.29 (28)
`
`0.022
`0.027
`
`A second randomized, controlled study (Study 2) evaluated NOVANTRONE in
`combination with methylprednisolone (MP) and was conducted in patients with
`secondary progressive or worsening relapsing-remitting multiple sclerosis who had
`residual neurological deficit between relapses. Allpatients bad experienced at least two
`relapses with sequelae or neurological deterioration within the previous 12 months. The
`average deterioration in EDSS was 2.2 points during the previous 12 months. During the
`screening period, patients were treated with two monthly doses of 1 g of IV MP and
`underyent monthly MEI scans. Only patients who developed at Icast one new Gd-
`enhancing MRI lesion during the 2-month screening period were elipible for
`randomization. A total of 42 evaluable patients received monthly treatments of1 g of IV
`MP alone (n = 21) or ~12 mg/m” ofIV NOVANTRONE plus 1 g ofIV MP (n= 21)
`(NOV + MP) for 6 months. Patients were evaluated monthly, and study outcome was
`determined after 6 months. The primary measureofeffectivenessin this study was a
`comparisonofthe proportion ofpatients in each treatment group who developed no new
`Gd-enhancing MRI lesionsat 6 months; these MRIs were assessed by a blinded panel.
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`Additional outcomes were measured, including EDSS and numberof relapses, butall
`
`clinical measuresin this trial were assessed by an unblinded treating physician. Five
`
`patients, all in the MP alone arm,failed to complete the study due to lack of efficacy.
`
`The results of this trial are displayed in Table2.
`
`Table 2
`Efficacy Results
`Study 2
`
`Primary Endpoint
`Patients (%) without new Gd-enhancing lesions on
`MRIs(primary endpoint)”
`
`MP alone NOV + MP
`(N=21)
`(N=21)
`5 (31%)
`19 (90%)
`
`Secondary Endpolats
`-hl
`-0.1
`EDSS change (Month 6 minus baseline)(mean)
`0.7
`3.0
`Annualized relapse rate (mean perpatient)
`14 (67%)
`7 B3%)
`Patients (%) without relapses
`' MP = methylprednisolone; N + MP = NOVANTRONE plus methyiprednisolone.
`* Results at Month 6, not including data for $ withdrawals in the MP alone group.
`
`p-value
`0.001
`
`0.013
`0.003
`0.031
`
`Advanced Hormone-Refractory Prostate Cancer
`
`A multicenter Phase 2 trial ofNOVANTRONE and low-dose prednisone (N + P)
`was conducted in 27 symptomatic patients with honnone-refractory prostate cancer.
`Using NPCP (National Prostate Cancer Project) criteria for disease response, there was
`one partial responder and 12 patients with stable disease. However, nine patients or 33%
`achieveda palliative response defined on the basis ofreduction in analgesic use or pain
`intensity.
`
`These findingsled to the initiation of a randomized multicenter trial (CCI-
`NOV22) comparing theeffectiveness of (N + P) to low-dose prednisone alone (P).
`Eligible patientswere required to have metastatic or locally advanced disease that had
`progressed on standard hormonal therapy, acastrate serum testosterone level, and at least
`mild pain at study entry. NOVANTRONE was administered at a dose of 12 mg/m” by
`short IV infusion every 3 weeks. Prednisone was administered orally at a dose of 5 mg
`twice a day. Patients randomized to the prednisone arm were crossed over to the N + P
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`arm if they progressed or if they were not improved after a minimum of 6 weeks of
`
`therapy with prednisonealone.
`
`A total of 161 patients were randomized, 80 to the N + P arm and 81 to the P arm.
`The median NOVANTRONEdoseadministered was 12 mg/m’per cycle. The median
`cumulative NOVANTRONE dose administered was 73 mg/m? (rangeof 12 to
`212 mg/m’).
`
`A primary palliative response (defined as a 2-point decrease in pain intensity in a
`
`6-point pain scale, asscciated with stable analgesic use, and Jasting a minimum of
`
`6 weeks) was achieved in 29% ofpatients randomized to N + P compared to 12% of
`
`patients randomized to P alone (p = 0.011). Two responders left the study after meeting
`
`primary responsecriterion for two consecutive cycles. For the purposes ofthis analysis,
`these two patients wereassigned a response durationof zero days. A secondary palliative
`response was defined as a 50% or greater decrease in analgesic use, associated with
`stable pain intensity, and lasting a minimum of 6 weeks. An overall palliative response ,
`(defined as primary plus secondaryresponses) was achieved in 38% ofpatients
`randomized to N + P compared to 21% ofpatients randomized to P (p = 0.025).
`
`The median duration of primary palliative response‘for patients randomized to
`N + P was 7.6 months compared to 2.1 months for patients randomized to P alone
`(p = 0.0009). The median duration ofoverall palliative response for patients randomized
`to N + P was 5.6 months compared to 1.9 months for patients randomized to P alone
`(p= 0.0004).
`
`Timeto progression was defined as a I-point increasein pain intensity, or a
`> 25% increase in analgesic use, or evidence of disease progression on radiographic
`Studies, or requirementfor radiotherapy. The median time to progression for all patients
`randomized to N + P was 4.4 months compared to 2.3 months forall patients randomized
`to P alone (p = 0.0001). Median timeto death was 11.3 months for all patients on the
`N + P arm compared to 10.8 monthsforall patients on P alone (p = 0.2324).
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`Forty-eight patients on the P arm crossed over to receive N + P. Ofthese,thirty
`patients had progressed on P, while 18 had stable disease on P. The median cycle of
`crossover was 5 cycles (range of 2 to 16 cycles). Timetrendsfor pain intensity priorto
`crossover were significantly worse for patients who crossed over than for those who
`remained on P alone (p = 0.012). Nine patients (19%) demonstrated a palliative response
`
`on N + P after crossover. The median time to death for patients who crossed over to
`
`N + P was 12.7 months.
`
`The clinical significance of a fall in prostate-specific antigen (PSA)
`concentrations after chemotherapyis unclear. On the CCI-NOV22trial, a PSAfall of
`50% or greater for two consecutive follow-up assessments after baseline was reported in
`33% ofall patients randomized to the N + P arm and 9% ofall patients randomized to the
`P arm. Thesefindings should be interpreted with caution since PSA responses were not
`defined prospectively. A number of patients were inevaluable for response, and there
`was an imbalance between treatment arms in the numbers of evaluable patients. In
`addition, PSA reduction did not correlate precisely with palliative response, the primary
`efficacy endpointof this study. For example, amongthe 26 evaluable patients
`randomized to the N + P arm who had a 2 50% reduction in PSA, only 13 had a primary
`palliative response. Also, among 42 evaluablepatients on this arm whodid not havethis
`
`reduction in PSA,8 nonetheless had a primary palliative response.
`
`Investigators at Cancer and Leukemia Group B (CALGB) conducted a Phase 3
`comparative trial of NOVANTRONE plus hydrocortisone (N + H) versus hydrocortisone
`alone @) in patients with hormone-refractory prostate cancer (CALGB 9182). Eligible
`patients were required to have metastatic disease that had progressed despite at least one
`hormonal therapy. Progression at study entry was defined on the basis of progressive
`symptoms, increases in measurable or osseous disease, or rising PSA levels.
`NOVANTRONE was administered intravenously at a dose of 14 mg/m? every 21 days
`and hydrocortisone was administered orally at a daily dose of 40 mg. A total of242
`subjects were randomized, 119 to the N + H arm and 123 to the H arm. There were no
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`differences in survival between the two arms, with a median of 11.1 months in the N + H
`
`arm, and 12 monthsin the H arm (p = 0.3298).
`
`Using NPCPcriteria for response, partial responses were achieved in 10 patients
`
`(8.4%) randomized to the N + H arm compared with 2 patients (1.6%) randomized to the
`H arm (p= 0.018). The median timeto progression, defined by NPCPcriteria, for
`patients randomized to the N + H arm was 7.3 months compared to 4.1 months for
`patients randomized to H alone (p = 0.0654).
`
`Approximately 60% of patients on each arm required analgesics at baseline.
`Analgesic use was measured in this study using a 5-point scale. The best percent change
`from baseline in mean analgesic use was -17% for 61 patients with available data on the
`N + Hamm, compared with +17% for 61 patients on H alone (p = 0.014). A time trend
`analysis for analgesic use in individual patients also showed a trend favoring the N + H
`
`arm over H alone but was notstatistically significant.
`
`Pain intensity was measured using the Symptom Distress Scale (SDS) Pain Item 2
`(a 5-point scale). The best percent change from baseline in mean pain intensity was -14%
`for 37 patients with available data on the N + H arm, compared with +8% for 38 patients
`on H alone(p = 0.057). A timetrend analysis for pain intensity in individual patients
`showed no difference between treatment amns.
`
`Acute Nonlymphocytic Leukemia
`
`gn two large randomized multicenter trials, remission induction therapy for acute
`nonlymphocytic leukemia (ANLL) with NOVANTRONE 12 mg/m? daily for 3 days asa
`10-minute intravenous infusion and cytarabine 100 mg/m” for 7 days given as a
`continuous 24-hour infusion was compared with daunorubicin 45 mg/m” daily by
`intravenous infusion for 3 days plus the same dose and schedule ofcytarabine used with
`NOVANTRONE.Patients whohad an incomplete antileukemic response received a
`second induction course in which NOVANTRONE or daunorubicin was administered for
`2 days andcytarabinefor 5 days using the same daily dosage schedule. Response rates
`
`11
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`—
`
`and median survival information for both the U.S. and international multicenter tals are
`given in Table 3:
`
`_
`Table 3
`Response Rates, Time to Respouse, snd Survival
`in U.S. and International Trials
`
`
`
`Median Time
`% Complete
`Survival (days)
`to CR (days)
`Response (CR)
`NOV.
`DAUN
`NOV
`DAUN
`NOV
`DAUN
`312
`237
`35
`42
`63 (62/98)
`53 (54/102)
`US.
`
`
`International 50 (S6/L12)—$t (62/123) 36 42 192 230
`
`
`
`NOV = NOVANTRONE® + cytarabine
`DAUN = daunombicio + cytarabine
`
`Trial
`
`In these studies, two consolidation courses were administered to complete
`responders on each arm. Consolidation therapy consisted of the same drug and daily
`dosage used for remission induction, but only 5 days ofcytarabine and 2 days of
`NOVANTRONE or daunorubicin were given. The first consolidation course was
`
`administered 6 weeks after the start ofthe final induction courseif the patient achieved a
`complete remission. The second consolidation course was generally administered
`4 weeks later. Full hematologic recovery was necessary for patients to receive
`consolidation therapy. For the U.S.trial, median granulocyte nadirs for patients receiving
`NOVANTRONE + cytarabine for consolidation courses } and 2 were 10/mum’ for both
`courses, andfor those patients receiving daunorubicin + cytarabine nadirs were 170/mm?
`and 260/mm’, respectively. Median platelet nadirs for patients who received
`NOVANTRONE + cytarabine for consolidation courses 1 and 2 were 17,000/aun? and
`14,000/mm,, respectively, and were 33,000/mm’ and 22,000/mmn’in courses 1 and 2 for
`those patients who received daunorubicin + cytarabine. The benefit ofconsolidation
`
`therapy in ANLLpatients who achieve a complete remission remains controversial.
`However,in the only well-controlled prospective, randomized multicenter trials with
`NOVANTRONE in ANLL,consolidation therapy was given to all patients who achieved
`a complete remission. During consolidation in the U.S. study, two myelosuppression-
`related deaths occurred on the NOVANTRONEarm and one on the daunorubicin arm.
`
`However, in the intemational study there were eight deaths on the NOVANTRONE arm
`
`y
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`during consolidation which were related to the myelosuppression and none on the
`daunorubicin arm where less myelosuppression occurred.
`
`INDICATIONS AND USAGE
`
`NOVANTRONE isindicated for reducing neurologic disabilityand/or the
`
`frequency of clinical relapses in patients with secondary (chronic) progressive,
`propressive relapsing, or worsening relapsing-remitting multiple sclerosis (i.c., patients
`whose neurologic status is significantly abnormal between relapses). NOVANTRONEis
`not indicated in the treatment of patients with primary progressive multiple sclerosis.
`
`The clinical patterns of multiple sclerosis in the studies were characterized as
`
`follows: secondary progressive and progressive relapsing disease were characterized by
`
`gradual increasing disability with or without superimposedclinical relapses, and
`
`worsening relapsing-remitting disease was characterized by clinical relapses resulting in a
`
`step-wise worsening ofdisability.
`
`NOVANTRONE in combination with corticosteroids is indicated as initial
`chemotherapy forthe treatmentofpatients with pain related to advanced hormone-
`refractory prostate cancer.
`
`NOVANTRONE in combination with other approved drug(s) is indicated in the
`initial therapy of acute nonlymphocytic leukemia (ANLL)in adults. This category
`includes myelogenous, promyelocytic, monocytic, and erythroid acute leukemias.
`
`4
`
`CONTRAINDICATIONS
`
`NOVANTRONE is contraindicated in patients who have demonstrated prior
`hypersensitivity to it.
`
`WARNINGS
`
`WHEN NOVANTRONE IS USED IN HIGH DOSES(> 14 mg/m?/d x 3 days)
`SUCH AS INDICATED FOR THE TREATMENTOFLEUKEMIA, SEVERE
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`MYELOSUPPRESSION WILL OCCUR. THEREFORE, IT IS RECOMMENDED
`
`THAT NOVANTRONEBE ADMINISTERED ONLY BY PHYSICIANS
`
`EXPERIENCED IN THE CHEMOTHERAPY OF THIS DISEASE. LABORATORY
`
`AND SUPPORTIVE SERVICES MUST BE AVAILABLE FOR HEMATOLOGIC
`
`AND CHEMISTRY MONITORING AND ADJUNCTIVE THERAPIES, INCLUDING
`ANTIBIOTICS. BLOOD AND BLOOD PRODUCTS MUST BE AVAILABLE TO
`
`SUPPORT PATIENTS DURING THE EXPECTED PERIOD OF MEDULLARY
`
`HYPOPLASIA AND SEVERE MYELOSUPPRESSION. PARTICULAR CARE
`
`SHOULDBE GIVEN TO ASSURING FULL HEMATOLOGIC RECOVERY BEFORE
`UNDERTAKING CONSOLIDATION THERAPY(IF THIS TREATMENT IS USED)
`
`AND PATIENTS SHOULD BE MONITORED CLOSELY DURING THIS PHASE.
`
`NOVANTRONE ADMINISTERED AT ANY DOSE CAN CAUSE
`
`MYELOSUPPRESSION.
`
`General
`
`Patients with preexisting myelosuppression as the result of prior drug therapy
`should not receive NOVANTRONEunless itis felt that the possible benefit from such
`treatment warrants therisk of further medullary suppression.
`
`The safety of NOVANTRONE (mitoxantronefor injection concentrate) in
`patients with hepatic insufficiency is not established (see CLINICAL
`
`PHARMACOLOGY).
`
`Safety for use by routes other than intravenous administration has not been
`
`established.
`
`NOVANTRONE isnot indicated for subcutaneous,intramuscular, or intra-arterial
`injection. There,have been reports of local/regional neuropathy, someirreversible,
`following intra-arterial injection.
`
`NOVANTRONEmust not be given byintrathecal injection. There have been
`reports of neuropathy and neurotoxicity, both central and peripheral, following intrathecal
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`injection. These reports have included seizures leading to coma and severe neurologic
`sequelae, and paralysis with bowel and bladder dysfunction.
`
`TopoisomeraseII inhibitors, including NOVANTRONE, in combination with
`otherantineoplastic agents, have been associated with the development ofacute
`
`leukemia.
`
`Cardiac Effects
`
`Becauseof the possible danger of cardiac effects in patients previously treated
`with daunorubicin or doxorubicin, the benefit-to-risk ratio of NOVANTRONE therapyin
`
`such patients should be determined before starting therapy.
`
`.
`
`Functional cardiac changes including decreasesin left ventricular ejection fraction
`
`(LVEF)andirreversible congestive heart failure can occur with NOVANTRONE.
`
`Cardiac toxicity may be more commonin patients with prior treatment with
`anthracyclines, prior mediastinal radiotherapy, or with preexisting cardiovascular disease.
`Suchpatients should have regular cardiac monitoring of LVEF from the initiation of
`therapy. Cancer patients who received cumulative doses of 140 mg/m’either aloneorin
`combination with other chemotherapeutic agents had a cumulative 2.6% probability of
`clinical congestive heart failure. In comparative oncology trials, the overall cumulative
`probability rate of moderate or severe decreases in LVEFat this dose was 13%.
`
`Multiple Sclerosis: Functional cardiac changes may occur in patients with
`multiple gclerosis treated with NOVANTRONE.In onecontrolled trial (Study 1, see
`CLINICAL TRIALS, Multiple Sclerosis), two patients (2%) of 127 receiving
`NOVANTRONE,onereceiving a 5 mg/m” dose andthe other receiving the 12 mg/m?
`dose, had LVEF values that decreased to below 50%. An additional patient receiving
`12 mg/m’, who did not have LVEF measured, had a decrease in another
`echocardiographic measurementofventricular function (fractional shortening) that led to
`discontinuation from thetrial (see ADVERSE REACTIONS,Multiple Sclerosis).
`There were no reports of congestive heart failure in either controlled trial.
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`Evaluation of LVEF (by echocardiogram or MUGA)is recommended prior to
`administration ofthe initial dose of NOVANTRONE.Ordinarily, patients with a
`baseline LVEF of <50% should not be treated with NOVANTRONE. Subsequent LVEF
`evaluations are recommended if signs or symptomsof congestive heart failure develop,
`and priorto all doses administered to patients who have received a cumulative dose of>
`100 mp/m?. NOVANTRONE shouldnot ordinarily be administered to multiple sclerosis
`patients who have received a cumulative lifetime dose of> 140 mg/m’,or those with
`either LVEF of < 50% or a clinically significant reduction in LVEF.
`
`Leukemia: Acute congestive heart failure may occasionally occur in patients
`treated with NOVANTRONE for ANLL. In first-line comparativetrials of
`
`NOVANTRONE+ cytarabine vs daunorubicin + cytarabine in adult patients with
`previously untreated ANLL,therapy was associated with congestive heart failure in 6.5%
`of patients on each arm. A causal relationship between drug therapy and cardiac effects
`is difficult to establish in this setting since myocardial function is frequently depressed by
`
`the anemia, fever and infection, and hemorrhagethat often accompanythe underlying
`
`disease.
`
`Hormone-Refractory Prostate Cancer: Functional cardiac changes such as
`decreases in LVEFand congestive heart failure may occur in patients with hormone-
`refractory prostate cancer treated with NOVANTRONE.Ina randomized comparative
`
`trial of NOVANTRONE plus low-dose prednisone vs low-dose prednisone, 7 of 128
`patients (5.5 %) treated with NOVANTRONE had a cardiac event defined as any
`decreasé in LVEF belowthe nonmnal range, congestive heart failure (n = 3), or myocardial
`ischemia. Twopatients had a priorhistory of cardiac disease. The total NOVANTRONE
`dose administered to patients with cardiac effects ranged from > 48 to 212 mg/m’.
`
`Among112 patients evaluable for safety on the NOVANTRONE +
`
`hydrocortisone arm of the CALGB mal, 18 patients (19%) had a reduction in cardiac
`
`function, 5 patients (5%) had cardiac ischemia, and 2 patients (2%) experienced
`pulmonary edema. The range of total NOVANTRONEdoses administer