CENTER FOR DRUG EVALUATION. AND RESEARCH
`
`Application Number 2 ( -( Z, 0
`
`FINAL. PRINTED LABELING
`
`Petitioner TWi Pharms., Inc.
`EX1017, Page 1 of 35
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`

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`October 13. 2000
`
`Package Iosert
`
`.NOVANTRONE®
`
`mito:xantrooe
`
`for injection concentrate
`
`WARNING
`
`:tJOV ANTROJ\rE® (mitoxantrone for injection concentrate) should be
`
`administered under the supervision of a physician experienced in the use of cytotoxic
`
`chemotherapy agents.
`
`NOV ANTRONE should 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 if there is extravasation during administration.
`(See ADVERSE REACTIONS, General, Cutaneous)
`
`NOT FOR INTRA IllECAL USE. Severe injury with permanent sequelae can
`
`result from intrathecal administration. (See WARNINGS, General)
`
`Except for the treatment of acute nonlymphocytic leukemia, NOV ANIRONE
`therapy generally should not be given to patients with baseline neutrophil counts of less
`
`than 1500 cells/mm3• In order to monitor the occurrence of bone marrow suppression,
`primarily neutropenia, which may be severe and result in infection, it is recommended
`
`that fre~uent peripheral blood cell counts be performed on all patients receiving
`NOV ANTRONE.
`
`Myocardial toxic:ity, manifested in its most severe fonn by potentially fatal
`congestive heaxf failure (CHF), may occur either during therapy with NOV ANTRONE or
`months to years after termination of therapy'. Use of NOV ANTRONE has been
`associated with cardioto:ticity; this risk increases with cwnulative dose. In cancer
`patients, the risk of symptomatic congestive heart failure (CHF) was estimated to be
`
`1
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`EX1017, Page 2 of 35
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`NOVANTRONE PACKAGE INSERT
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`10-05-00
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`2.6% for patients receiving up to a cwnulative dose of 140 mg/m2
`patients should be monitored for evidence of cardiac toxicity and questioned about
`symptoms of heart failure prior to initiation oftreatnient. Patients with multiple sclerosis
`who reach a cumulative dose of ·100 mg/m2 should be monitored for evidence of cardiac
`
`• For this reason,
`
`toxicity prior to each subsequent dose. Ordinarily, patients with multiple sclerosis should
`not receive a cumulative dose greater than 140 mg/m2
`• Active or dormant cardiovascular
`disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous
`
`therapy with other anthracyclines or anthracenediones, or concomitant use of other
`
`cardiotoxic drugs may increase the risk of cardiac toxicity. Cardiac toxicity with
`
`NOV ANTRONE may occur at lower cumulative doses whether or not cardiac risk factors
`
`are present. For additional infonnation, see WARNINGS, Cardiac Effects, and
`
`DOSAGE AND ADMINISTRATION.
`
`Secondary acut~ myelogenous leukemia (AML) has been reported in cancer
`
`patients treated with anthracyclines. NOV ANTRONE is an anthracenedione, a related
`
`drug. The occurrence of refractory 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 bei~n escalated. Secondary le~emias have been reported in cancer
`patients treated with NOV ANTRONE in combination with other cytotoxic agents; the
`
`incidence of these events has not been quantified.
`
`DESCRIPTION
`
`..
`
`NOV ANTRONE (mitoxantrone hydrochloride) is a synthetic antineoplastic
`
`anthracenedione for intravenous use. The molecular formula is C22H2aN406•2HCl and
`
`the molecular weight is. 517.41. It is supplied as a concentrate that MUST BE DILUTED
`
`PRIOR TO INJECTION. The concentrate is 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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`EX1017, Page 3 of 35
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`NOVANTRONE PACKAGE INSERT
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`10-0S-00
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`0.14 mEq of sodium per mL. The product does not contain preservatives. The chemical
`name is l ,4-dihydroxy-5,8-bis([2-[(2-hydroxyethyl) amino ]ethyl]amino ]-9,l 0-
`
`anthracenedione dihydrcichJoride and the structural formula is:
`
`OH
`
`O
`
`2HCI
`
`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 ribonucleic acid (RNA) and is a potent inhibitor of topoisomcrase II,
`an enzyme responsible for WlCoiling and repairing damaged DNA. It has a cytocidal
`
`effect on both prolifera1ing and nonproliferating cultured human cells, suggesting lack of
`
`cell cycle phase specifo::ity.
`
`NOV ANTRONE has been shown in vitro to inhibit B cell, T cell, and
`
`macrophage proliferation and impair antigen presentatio~ as well as the secretion of
`interfqon gamma, lNFcx, and IL-2.1
`
`-4
`
`Pharm.acokinetics
`
`Pharmacqkinetics of mitoxantrone in patients following a single intravenous
`
`administration_ of NOV ANT RONE can be characterized by a three-compartment model.
`
`The mean alpha half-life of mitoxantrone is 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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`NOVANTRONE PACKAGE INSERT
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`(median approximately 75 hours). Phannacokinetic studies have not been performed in
`
`humans receiving multiple daily dosing. Distribution to tissues is extensive: steady-state
`volume of distribution exceeds 1000 Um2
`• Tissue concentrations of mitoxantrone appear
`to exceed those in the blood during the terminal elimination phase. In the healthy
`monkey, distribution to brain, spinal cord, eye, and spinal fluid is low.
`
`In patients administered 1-5-90 mg/m2 of NOV ANTRONE intravenously, there is
`a linear relationship between dose and the area under the concentration-time curve
`
`(AUC).
`
`Mitoxantrone is 78% bound to plasma proteins in the observed concentration
`range of 26-455 ng/mL. This binding is independent of concentration and is not affected
`by the presence of phenytoin, doxorubic~ methotrexate, prednisone, prednisolooe,
`
`heparin, or aspirin.
`
`Metabolism and Elimin:ition
`
`Mitoxantrone is excreted in urine and feces as either unchanged drug or as
`inactive metabolites. In human studies, 11 % and 25% of the dose were recovered in
`
`urine and feces, 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
`NOV ANfRONE have not been elucidated.
`
`4
`In vitro drug interaction studies have demonstrated that mitoxantrone did not
`inhibit CYP450 IA2, 2A6, 2C9, 2Cl9, 2D6, 2El, and 3A4 across a broad concentration
`range. The results of in vitro induction studies are inconclusive, but suggest that
`mitoxantrone is~ weak inducer ofCYP450 2El activity.
`
`Special Popula.tions
`
`Gender: The effect of gender on mitoxantrone phannacolcinetics is unknown.
`
`4
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`EX1017, Page 5 of 35
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`NOVANTRONE~ACKl,.GEINSERT
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`IO-OS-00
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`Geriatric: In elderly patients with breast cancer, the systemic mitoxantrone
`, compared with 28.3 L/hr/m2 and ~ 6.2 L/hr/m2 for non•
`clearance was 21.3 L/hr/m2
`elderly patients with nasopharyngeal carcinoma and malignant lymphoma, respectively.
`
`Pediatric: Mitoxantrone pharmacokinetics in the pediatric population are
`
`unknown.
`
`Race: The effo:;t of race on mitoxantrone pharmacokinetics is unknown.
`
`Renal Impairment: Mitoxantrone phamiacolcinetics in patients with renal
`
`impairment are unknown.
`
`Hepatic lmpainnent: Mitoxantrone clearance is reduced by hepatic impairment.
`
`Patients with severe hepatic dysfunction (bilirubin > 3.4 mg/dL) have an AUC more than
`
`three times greater tha.u1 that of patients with normal hepatic fi.mction receiving the same
`dose. Patients with multiple sclerosis who have hepatic impainnent should ordinarily not
`
`be treated with NOV Al-JTRONE. Other patients with hepatic impairment should be
`
`treated with caution and dosage adjustment may be required.
`
`Drug Interactions: Pharmacokinetic studies of the interaction of NOV ANTRONE
`with concomitantly administered medications have not been performed. The pathways
`leading to the metaboli:;m of NOVANTRONE have not been elucidated. To date, post(cid:173)
`
`marketing experience bas not revealed any significant drug interactions in patients who
`
`have received NOV ANTRONE for treatment of cancer. Information on drug interactions
`in patients with multipk~ sclerosis is limited.
`4
`
`CLINICAL TRIALS
`
`Multiple Sclero~is
`
`The safety and efficacy ofNOVANTRONE in multiple sclerosis were assessed in
`two randomized, multicenter clinical studies.
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`EX1017, Page 6 of 35
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`NOVANTRONE PACKAGE. INSERT
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`10-05-00
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`One randomized, (;ontrolled study (Study l) was conducted in patients with
`
`second.al)' progressive or progressive relapsing multiple sclerosis. Patients in this study
`
`demonstrated significant neurological disability based on the Kurtzke Expanded
`
`Disability Status Scale (E.DSS). The EDSS is an ordinal scale with 0.5 point increments
`
`ranging from 0.0 to 10.0 (increasing score indicates worsening} and based largely on
`
`ambulatory impairment i.f1 its middle range (EDSS 4.5 to 7.5 points). Patients in this
`
`study had experienced a mean deterioration in EDSS of about 1.6 points over the
`
`18 months prior to enrollment
`
`Patients were ran.domized to receive placebo. 5 mg/m2 NOV ANTRONE, or
`12 mg/m2 NOV ANTRONE administered 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 and the decision to treat relapses with steroids were made by
`unblinded treating physicians. A multivariate analrsis of five clinical variables (EDSS,
`
`Ambulation_Index [AI), nwnber of relapses requiring treatment with steroids, months to
`
`first relapse needing treatment with steroids, an~ Standard Neurological Status [SNS])
`was used to determine primary efficacy. The AI is an ordinal scale ranging from Oto 9 in
`one point increments to define progressive ambulatory impairment. The SNS provides an
`
`ovens! measure ofneurologic impairment and disability, with scores ranging from 0
`
`(normal neurologic examination) to 99 (worst possible score).
`
`Results of Study 1 are summarized in Table 1.
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`EX1017, Page 7 of 35
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`Table 1
`Efficacy Results at Month 24
`Study 1
`
`Primary Endpoints
`
`Primary efficac)' multivariate ane,lysis•
`Primary clinical vurilables analyzed:
`EDSS change .. (mean)
`Ambulation Index change .. (mean)
`Mean number ofrdnpscs per patient requiring
`corticosteroid treatment (adju!;tcd for discontinuation)
`Monlhs to f"U'Sl relapse requiring cortico.s1eroid treatment
`(median fl 11 quartile})
`Standard Neurological Status ch:111gc .. (mean)
`
`MRI
`
`Treatment Groups
`N0VANTRONE
`12 mg/m1
`S mg/mz
`(N c64)
`(N=60)
`
`Placebo
`(N=64)'
`
`p-value
`FbctbOVI
`12 mg/rn1
`NOVANTR.ONE
`
`0.23
`0.77
`1.20
`
`-0.23
`0.41
`0.73
`
`-0.13
`0.30
`0.40
`
`14.2 [6.7)
`
`NR. [6.9) NR (20.4)
`
`0.77
`
`-0.38
`
`-1.07
`
`<0.0001
`
`0.0194
`0.0306
`0.0002
`
`0.0004
`
`0.0269
`
`No. of patients wilh new Gd-cnliam:ing lesions
`S/32 (16%)
`Change in number ofT2-wcight:::d lesions, mean (n)u
`1.94 (32)
`NR .. not reached wiihi'.n 2A monUu; I\.GU "' magnetic reR>llMCC lmag\i;g_
`• Wei-l.achin trst.
`•• Month 24 value mi.Dus baseline.
`l A subset of l l O plllii:nl:s W8S selected for MRI analysis. MRI results were not available for all patients at all time points.
`
`0.022
`0.027
`
`4137 (11%)
`0.68 (34)
`
`0/31
`0.29 (28)
`
`A second randomized, controlled study (Study 2) evaluated NOV ANTRONE in
`combination with methylprednisolo_ne (MP) and was conducted in patients with
`secondary progressive c,r worsening relapsing-remitting multiple sclerosis who had
`
`residual neurological de:ficit between relapses. Alf patients had 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 I g of IV MP and
`under,.,-ent monthly MR.I scans. Only patients who developed at least one new Gd(cid:173)
`enhancing 1vlR.I lesion during the 2-montb screening period were eligible for
`
`randomization. A total of 42 evaluable patients received monthly treatments of 1 g of IV
`MP alone (n = 21) or~ 12 mg/m2 of IV NOV ANTRONE plus I g of IV MP (n =a 21)
`(NOV + MP) fof 6 months. Patients we.re evaluated monthly, and stµdy outcome was
`determined after 6 moo.tbs. The primary measure of effectiveness in this study was a
`comparison of the proportion of patients in each treatment group who developed no new
`Gd-enhancing MRI lesions at 6 months; these MRis were assessed by a blinded panel.
`
`7
`
`.
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`.JMl"I-C....J C..UV-
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`~ - ~ -
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`NOVANTRONE PACKAC:E INSERT
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`10--05-00
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`Additional outcomes we:re measured, including EDSS and number of relapses, but all
`
`clinical measures in this trial were assessed by an wiblinded treating physician. Five
`
`patients, all in the MP alone arm~ failed to complete the study due to lack of efficacy.
`
`The results of th.is trial are displayed in Table 2.
`
`Table2
`Efficacy Results
`Study2
`MP alone
`(N •21)
`
`Primary Endpoint
`Patients (%) without new Gd-enhaneii\g lesions on
`MR.ls (primary endpoint)°
`
`NOV+l\lP
`(N"" 21)
`
`S (31%)
`
`19 (90%}
`
`Secondary Endpoints
`-1.1
`-0.1
`EDSS change (Month 6 minus baseline}" (mean}
`0.7
`3.0
`Annualized relapse rate (mean per patient)
`14 (67%}
`7 (33%)
`Patients(%) without relapses
`• MP = mclhylprednisolone; N + MP= NOV ANfRONE plus methylprednisolone.
`• Results at Month 6, not induding data for 5 withdrawals in the MP alone group.
`
`p--value
`
`0.001
`
`0.013
`0.003
`0.031
`
`Advanced Hormone-Refractory Prostate Cancer
`
`A multi center Phase 2 trial of NOV ANTRONE and low-dose prednisone (N + P)
`was conducted in 27 symptomatic patients with honnone-refracto:ry prostate cancer.
`Using NPCP (National .Prostate Cancer Project) criteria for disease response, there was
`
`one partial responder an1d 12 patients with stable disease. However, nine patients or 33%
`achieved a palliative response defined on the basis of reduction in analgesic use or pain
`intemity.
`
`These findings led to the initiation of a randomized multicenter trial (CCI(cid:173)
`NOV22) comparing the effectiveness of (N + P) to low-dose prednisone alone (P).
`Eligible patients were required to have metastatic or locally advanced disease that had
`-
`•;·
`progressed on ~tandard hormonal therapy, a.castrate serum testosterone level, and at least
`mild pain at study entry. NOV ANTRONE was a.dptlnistered at a dose of 12 mg/m2 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
`
`8
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`NOVANTRONE PACKAGE INSERT
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`10-05-00
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`arm if they progressed ,:,r if they were not improved after a mini.mum of 6 weeks of
`
`therapy with prednisom:: alone.
`
`A total of 161 patients were randomized, 80 to the N + P ann and 81 to the P arm.
`The median NOV ANT RONE dose administered was 12 mg/m2 per cycle. The median
`cwnulative NOV ANTitONE dose administered was 73 mg/m2 (range of 12 to
`212 mg/m2
`).
`
`A primary palliative response (defined as a 2-point decrease in pain intensity in a
`6-point pain scale, assc,ciated with stable analgesic use, and lasting a minimum of
`6 weeks) was achieved in 29% of patients randomized to N + P compared to 12% of
`patients randomized to Palone (p :::= 0.011). Two responders left the study after meeting
`
`primary response crite1ion for two consecutive cycles. For the purposes ofthis analysis,
`
`these two patients were assigned a response dwation· of 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 secondary_responses) was achieved in 38% of patients
`randomized to N + P compared to 21% of patients 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 of overall palliative response for patients randomized
`to N + P was 5.6 months compared to 1.9 months for patients randomized to Palone
`..
`(p = 0.0004) .
`
`Time to progression was defined as a l~point increase in pain intensity, or a
`
`> 25% increase in analgesic use, or evidence of disease progression on radiographic
`
`studies, or requirement for radiotherapy. The median time to progression for all patients
`randomized to N + P was 4.4 months compared to 2.3 months for all patients randomized
`to P alone (p = 0.0001 ). Median time to death was 11.3 months for all patients on the
`N + P ann compared t•o 10.8 months for all patients on Palone (p = 0.2324).
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`Forty-eight patients on the Parm crossed over to receive N + P. Of these. 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). Time trends for pain intensity prior to
`
`crossover were significautly worse for patients who crossed over than for those who
`remained on Palone (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.
`
`l)le clinical significance of a fall in prostate-specific antigen (PSA)
`
`concentrations after chemotherapy is unclear. On the CCI-NOV22 trial, a PSA fall of
`
`50% or greater for two c:ons~cutive follow-up assessments after baseline was reported in
`33% of all patients randomized to the N + P arm and 9% of all patients randomized to the
`Parm. These findings should be interpreted with caution since PSA responses were not
`
`defined prospectively. A nwnber 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 endpoint ofthi!1 study. For example. among the 26 evaluable patients
`randomized to the N + P arm who bad a~ 50% reduction in PSA, only 13 had a primary
`palliative response. Als.o, among 42 evaluable patients on this arm who did not have this
`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 NOV ANTRONE plus hydrocortisone (N + H) versus hydrocortisone
`alone (fl) 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.
`NOV ANTRONE was administered intravenously at a dose of 14 mg!m2 e-ve-ry 21 days
`and hydrocortisone was administered orally at a daily dose of 40 mg. A total of 242
`subjects were randomized, 119 to the N + H ann and 123 to the H arm. There were no
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`NOVANTRONEPACKAG~E~lN~S~E~R~T _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ~l=O-O-=c..~--"-"'0
`
`differences in survival between the two arms, with a median of 11.1 months in the N + H
`arm, and 12 months in lhe Hann (p = 0.3298).
`
`Using NPCP criteria for response, partial responses were achieved in 10 patients
`
`(8.4%) randomized to the N +Harm compared with 2 patients (1.6%) randomized to the
`Harm (p = 0.018). Th(: median time to progression, defined by NPCP criteria, for
`patients randomized to the N + H ann 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 +Harm, compared 'v\ilh + 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 not statistically 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 avajlable data on the N +Harm, compared with +8% for 38 patients
`on H alone (p = 0.057). A time trend analysis for pain intensity in individual patients
`showed no difference between treatment arms.
`
`Acute Nonlympbocytic Leukemia
`
`Jn two large randomized multicenter trials, remission induction therapy for acute
`nonlymphocytic leukemia (ANLL) with NOV ANfRONE 12 mg/m2 daily for 3 days as a
`10-minute intravenous infusion and cytarabine 100 mg/m2 for 7 days given as a
`
`continuous 24-hour infusion was compared with daunorubicin 45 mg/ol- daily by
`intravenous ~ion foir 3 days plus the same dose and schedule of cytarabine used with
`
`NOV ANTRONE. Patients who had an incomplete antileu.kemic response received a
`
`second induction course in which NOV ANTRONE or daunorubici.n was administered for
`
`2 days and cytarabine for 5 days using the same daily dosage schedule. Response rates
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`!'JOVANUlONE .PACKAGE INSERT
`
`-
`
`10-05--00
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`and median survival iafonnation for both the U.S. and international multicenter trials are
`
`given in Table 3:
`
`Trial
`
`Table3
`Response Rat~ Time to Respoose, and Survival
`in U.S. aad Iaternatiooal Trials
`% Complete
`Response (CR)
`QMlli
`NOV
`63 (62198)
`53 (S4/102)
`U.S.
`50 (56/l 12)
`SI (62/123)
`lotcroational
`NOV-= NOV ANTRONEIP + cytarabioe
`DAUN ~ dauoorubicio + cytanibinc
`
`Median Time
`to CR (days)
`J2A1lli
`NOV
`3S
`42
`36
`42
`
`Survival (days)
`QMlN
`NOV-
`312
`237
`192
`230
`
`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 S days of cytarabine and 2 days of
`NOV ANTRONE or daunorubicin were given. The first consolidation course was
`administered 6 weeks after the start of the final induction course if the patient achieved a
`complete remission. Tot! second consolidation course was generally administered
`4 weeks later. FuH hematologic recovery was necessary for patients to receive
`consolidation therapy. For the U.S. trial, medi~ granulocyte nadirs for patients receiving
`NOV ANTRONE + cytarabine for consolidation cow-ses 1 and 2 were 10/mm3 for both
`courses, and for those patients receiving daunorubicin + cytarabine nadirs were 170/mrn.3
`and 260/mm3
`, respectively. Median platelet nadirs for patients who received
`NOV ANTRONE + cytarabine for consolidation courses l and 2 were 17 >OOO/nun3 and
`14,000/mm!, respectively, and were 33,000/mm3 and 22,000/mm3 in courses 1 and 2 for
`those patients who received dawiorubicin + cytarabine. The benefit of consolidation
`
`therapy in ANLL patients who achieve a complete remission remains controversial.
`-
`However, in the only well-coutrolled prospective, randomized multicenter trials with
`NOV ANTRO~ in ANLL, consolidation therapy was given to all patients who achieved
`a complete remission. During consolidation in the U.S. study, two myelo~uppression(cid:173)
`related deaths occurred on the NOV ANTRONE ann and one on the daunorubicin arm.
`
`However, in the international study there were eight deaths on the NOV ANTRONE ann
`
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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
`
`NOV ANTRONE is indicated for reducing neurologic disability-and/or the
`frequency of clinical relapses in patients with secondary (chronic) progressive,
`
`progressive relapsing, or worsening relapsing-remitting multiple sclerosis (i.e., patients
`
`whose neurologic status is significantly abnormal between relapses). NOV ANTRONE is
`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 superimposed clinical relapses, and
`worsening relapsing-remitting disease was characterized by clinical relapses resulting in a
`
`step-wise worsening of disability.
`
`NOV ANTRONE in combination with corticosteroids is indicated as initial
`chemotherapy for the treatment of patients with pain reiated to advanced hormone(cid:173)
`
`refractory prostate cancer.
`
`NOV ANTRONE in combination with other approved drug(s) is indicated in the
`
`initial therapy of acute nonlymphocytic leukemia (ANLL) in adults. lbis category
`includes myelogenous, promyelocytic, monocytic, and erythroid acute leukemias .
`
`..
`
`CONTRA.INDICATIONS
`
`NOV ANTRONE is contraindicated in patients who have demonstrated prior
`hypersensitivity to it.
`
`WARNINGS
`
`WHEN NOV ANTRONE IS USED IN IBGH DOSES (> 14 mg/m2/d x 3 days)
`
`SUCH AS INDICATED FOR THE TREATMENTOF I:ElJKEMIA, SEVERE
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`MYELOSUPPRESSION WILL OCCUR TIIEREFORE, IT IS RECOMMENDED
`
`TiiA T NOV ANTRONE BE ADMINISTERED ONLY BY PHYSICIANS
`
`EXPERIENCED IN THE CHEMOTIIERAPY OP THIS DISEASE. LABORATORY
`
`AND SUPPORTIVE SERVICES MUST BE AVAILABLE FOR HEMATOLOGIC
`
`AND CHEMISTRY MONITORING AND ADruNCTIVE THERAPIES, INCLUDING
`
`ANTIBIOTICS. BLOOD AND BLOOD PRODUCTS MUST BE AVAILABLE TO
`
`SUPPORT PATIENTS DURING TIIB EXPECTED PERIOD OF MEDULLARY
`HYPOPLASIA AND SEVERE MYELOSUPPRESSION. PARTICULAR CARE
`
`SHOULD BE GIVEN TO ASSURING FULL HEMATOLOGIC RECOVERY BEFORE
`UNDERTAKING CONSOLIDATION THERAPY (IF nns TREA TMENf 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 NOY ANTRONE unless it is felt that the possible benefit from such
`
`treatment warrants the risk of further medullary suppression.
`
`The safety of NOV ANTRONE (mitoxantrone for iajection concentrate) in
`patients with hepatic insufficiency is not established (see CLINICAL
`PHARMACOLOGY).
`
`"5afety for use by routes other than intravenous administration has not been
`
`established.
`
`NOV ANTRONE is not indicated for subcutaneous, intramuscular, or intra-arterial
`injection. There.,have been reports of local/regional neuropathy, some irreversible,
`.
`-
`following intra-arterial injection.
`
`N_OV ANTRONE must not be given by intrathecal. 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.
`
`Topoisomerase II inhibitors, including NOV ANTRONE, in combination with
`other antineoplastic agents, have been associated \\ith the development of acute
`
`leukemia.
`
`Cardiac Effects
`
`_Because of the possible danger of cardiac effects in patients p~cviously treated
`
`with daunorubicin or doxorubicin, the .benefit-to•risk ratio of NOV ANTRONE therapy in
`
`such patients should be determined before starting therapy.
`
`_.
`
`Fwictional cardiac changes including decreases in left ventricular ejection fraction
`(L VEF) and irreversible congestive heart failure can occur with NOV ANTRONE.
`Cardiac toxicity may be more common in patients with prior treatment with
`anthracyclines, prior mediastinal radiotherapy, or with preexisting cardiovascular disease.
`Such patients should have regular c~diac monitoring of L VEF from the initiation of
`therapy. Cancer patients who received cumulative doses of 140 mg/m2 either alone or in
`combination with other chemotherapeutic agents had a cwnulative 2.6% probability of
`clinical congestive heart failw-e. In comparative oncology trials, the overall cumulative
`probability rate of moderate or severe decreases in LVEF at this dose was 13%.
`
`Multin,le Sclerosis: Functional cardiac changes may occur in patients with
`multiple.aclerosis treated with NOVANTRONE. In one controlled trial (Study 1. see
`CLINICAL TRIALS, Multiple Sclerosis), two patients (2%) of 127 receiving
`NOVANTRONE, one receiving a 5 mg/m2 dose and the other receiving the 12 mg/m2
`dose. had L VEF values th~t decreased to below 50%. An additional pa~ent receiving
`12 mg/m2
`• who 4id not have L VEF measured, had a decrease in another
`echocardiographic measurement of ventricular function (fractional shortening) that led to
`discontinuation from the trial (see ADVERSE REACTIONS, Multiple Sclerosis).
`
`There were no reports of congestive heart failure in either controlled trial.
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`Evaluation of L VEF (by echocardiogram or MUGA) is recommended prior to
`
`administration of the initial dose of NOV ANTRONE. Ordinarily, patients with a
`baseline L VEF of <50% should not be treated with NOV ANTRONE. Subsequent LVEF
`
`evaluations are recommended if signs or symptoms of congestive heart failure develop,
`
`and prior to alI doses administered to patients who have received a cumulative dose of::::
`l 00 mr}m2• NOV ANTRONE should not ordinarily be administered to multiple sclerosis
`patients who have received a cumulative lifetime dose of?:: 140 mg/m2
`either L VEF of< 50% or a clinically significant reduction in L VEF.
`
`, or those with
`
`Leukemia: Acute congestive heart failure may occasionally occur in patients
`treated with NOV ANTRONE for ANLL. In first-line comparative trials of
`NOV ANTRONE + 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 hemorrhage that often accompany the W1derlying
`
`disease.
`
`Hormone-Refractory Prostate Ca