NOVANTRONE
`
`mitoXANTRONE for injection concentrate
`
`WARNING
`
`NOVANTRONE (mitoxantrone for injection concentrate) should be administered under
`the supervision of a physician experienced in the use of cytotoxic chemotherapy agents.
`
`NOVANTRONE 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 and DOSAGE AND
`ADMINISTRATION, Preparation and Administration Precautions).
`
`NOT FOR INTRATHECAL USE. Severe injury with permanent sequelae can result
`from intrathecal administration. (See WARNINGS, General)
`
`Except for the treatment of acute nonlymphocytic leukemia, NOVANTRONE therapy
`generally should not be given to patients with baseline neutrophil counts of less than
`1,500 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 frequent peripheral blood cell counts be performed on all patients receiving
`NOVANTRONE .
`
`Cardiotoxicity:
`Congestive heart failure (CHF), potentially fatal, may occur either during therapy with
`NOVANTRONE or months to years after termination of therapy. Cardiotoxicity risk
`increases with cumulative NOVANTRONE dose and may occur whether or not cardiac
`risk factors are present. Presence or history of cardiovascular disease, radiotherapy to the
`mediastinal/pericardial area, previous therapy with other anthracyclines or
`anthracenediones, or use of other cardiotoxic drugs may increase this risk. In cancer
`patients, the risk of symptomatic CHF was estimated to be 2.6% for patients receiving up
`to a cumulative dose of 140 mg/m2. To mitigate the cardiotoxicity risk with
`NOVANTRONE, prescribers should consider the following:
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`AVENTIS EXHIBIT 2111
`Mylan v. Aventis, IPR2016-00712
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`All Patients:
`- All patients should be assessed for cardiac signs and symptoms by history, physical
`examination, and ECG prior to start of NOVANTRONE therapy.
`- All patients should have baseline quantitative evaluation of left ventricular ejection
`fraction (LVEF) using appropriate methodology (ex. Echocardiogram, multi-gated
`radionuclide angiography (MUGA), MRI, etc.).
`Multiple Sclerosis Patients:
`- MS patients with a baseline LVEF below the lower limit of normal should not be treated
`with NOVANTRONE .
`- MS patients should be assessed for cardiac signs and symptoms by history, physical
`examination and ECG prior to each dose.
`- MS patients should undergo quantitative reevaluation of LVEF prior to each dose using
`the same methodology that was used to assess baseline LVEF. Additional doses of
`NOVANTRONE should not be administered to multiple sclerosis patients who have
`experienced either a drop in LVEF to below the lower limit of normal or a clinically
`significant reduction in LVEF during NOVANTRONE therapy.
`- MS patients should not receive a cumulative NOVANTRONE dose greater than
`140 mg/m2.
`- MS patients should undergo yearly quantitative LVEF evaluation after stopping
`NOVANTRONE to monitor for late occurring cardiotoxicity.
`
`For additional information, see WARNINGS, Cardiac Effects, and DOSAGE AND
`ADMINISTRATION.
`
`Secondary acute myelogenous leukemia (AML) has been reported in multiple sclerosis
`and cancer patients treated with mitoxantrone. In a cohort of mitoxantrone treated MS
`patients followed for varying periods of time, an elevated leukemia risk of 0.25% (2/802)
`has been observed. Postmarketing cases of secondary AML have also been reported. In
`1774 patients with breast cancer who received NOVANTRONE concomitantly with
`other cytotoxic agents and radiotherapy, the cumulative risk of developing treatment-
`related AML, was estimated as 1.1% and 1.6% at 5 and 10 years, respectively (see
`WARNINGS section). Secondary acute myelogenous leukemia (AML) has been
`reported in cancer patients treated with anthracyclines. NOVANTRONE is an
`anthracenedione, a related drug.
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`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 been
`escalated.
`
`DESCRIPTION
`NOVANTRONE (mitoxantrone hydrochloride) is a synthetic antineoplastic
`anthracenedione for intravenous use. The molecular formula is C22H28N4O6 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
`0.14 mEq of sodium per mL. The product does not contain preservatives. The chemical
`name is 1,4-dihydroxy-5,8-bis[[2-[(2-hydroxyethyl) amino]ethyl]amino]-9,10-
`anthracenedione dihydrochloride and the structural formula is:
`
`OH
`
`O
`
`NHCH 2CH2NHCH 2CH2OH
`
`.
`
`2HCl
`
`OH
`
`O
`
`NHCH 2CH2NHCH 2CH2OH
`
`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
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`interferes with ribonucleic acid (RNA) and is a potent inhibitor of topoisomerase II, an
`enzyme responsible 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.
`
`NOVANTRONE has been shown in vitro to inhibit B cell, T cell, and macrophage
`proliferation and impair antigen presentation, as well as the secretion of interferon
`gamma, TNF , and IL-2.
`Pharmacokinetics
`
`Pharmacokinetics of mitoxantrone in patients following a single intravenous
`administration of NOVANTRONE 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
`(median approximately 75 hours). Pharmacokinetic studies have not been performed in
`humans receiving multiple daily dosing. Distribution to tissues is extensive: steady-state
`volume of distribution exceeds 1,000 L/m2. 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 15-90 mg/m2 of NOVANTRONE 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, doxorubicin, methotrexate, prednisone, prednisolone, heparin, or
`aspirin.
`
`Metabolism and Elimination
`
`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
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`remaining 35% was composed of monocarboxylic and dicarboxylic acid derivatives and
`their glucuronide conjugates. The pathways leading to the metabolism of
`NOVANTRONE have not been elucidated.
`
`Special Populations
`
`Gender
`The effect of gender on mitoxantrone pharmacokinetics is unknown.
`
`Geriatric
`In elderly patients with breast cancer, the systemic mitoxantrone clearance was 21.3
`L/hr/m2, compared with 28.3 L/hr/m2 and 16.2 L/hr/m2 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 Impairment
`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 more than three times greater than that
`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 impairment should be treated with caution
`and dosage adjustment may be required.
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`Drug Interactions: In vitro drug interaction studies have demonstrated that
`mitoxantrone did not inhibit CYP450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 across a
`broad concentration range. The results of in vitro induction studies are inconclusive, but
`suggest that mitoxantrone may be a weak inducer of CYP450 2E1 activity.
`
`Pharmacokinetic studies of the interaction of NOVANTRONE with concomitantly
`administered medications in humans have not been performed. The pathways leading to
`the metabolism of NOVANTRONE have not been elucidated. To date, post-marketing
`experience has not revealed any significant drug interactions in patients who have
`received NOVANTRONE for treatment of cancer. Information on drug interactions in
`patients with multiple sclerosis is limited.
`
`CLINICAL TRIALS
`Multiple Sclerosis
`
`The safety and efficacy of NOVANTRONE in multiple sclerosis were assessed in two
`randomized, multicenter clinical studies.
`
`One randomized, controlled study (Study 1) was conducted in patients with secondary
`progressive or progressive relapsing multiple sclerosis. Patients in this study
`demonstrated significant neurological disability based on the Kurtzke Expanded
`Disability Status Scale (EDSS). 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 in 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 randomized to receive placebo, 5 mg/m2 NOVANTRONE, or 12 mg/m2
`NOVANTRONE 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
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`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 analysis of five clinical variables (EDSS,
`Ambulation Index [AI], number of 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 AI is an ordinal scale ranging from 0 to 9 in
`one point increments to define progressive ambulatory impairment. The SNS provides an
`overall measure of neurologic 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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`Table 1
`Efficacy Results at Month 24
`Study 1
`
`Treatment Groups
`NOVANTRONE
`5 mg/m2
`12 mg/m2
`(N = 64)
`(N = 60)
`-
`-
`
`Placebo
`(N = 64)
`-
`
`Primary Endpoints
`Primary efficacy multivariate analysis*
`Primary clinical variables analyzed:
`EDSS change** (mean)
`Ambulation Index change** (mean)
`Mean number of relapses per patient requiring
`corticosteroid treatment (adjusted for discontinuation)
`Months to first relapse requiring corticosteroid treatment
`(median [1st quartile])
`Standard Neurological Status change** (mean)
`
`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
`
`p-value
`Placebo vs
`12 mg/m2
`NOVANTRONE
`
`< 0.0001
`
`0.0194
`0.0306
`0.0002
`
`0.0004
`
`0.0269
`
`MRI‡
`5/32 (16%) 4/37 (11%)
`No. of patients with new Gd-enhancing lesions
`1.94 (32)
`0.68 (34)
`Change in number of T2-weighted lesions, mean (n)**
`NR = not reached within 24 months; MRI = magnetic resonance imaging.
`* Wei-Lachin test.
`** Month 24 value minus baseline.
`‡ A subset of 110 patients was 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. All 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 1 g of IV MP and
`underwent monthly MRI scans. Only patients who developed at least one new Gd-
`enhancing MRI lesion during the 2-month 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 NOVANTRONE plus 1 g of IV MP (n = 21)
`(NOV + MP) for 6 months. Patients were evaluated monthly, and study outcome was
`determined after 6 months. The primary measure of effectiveness in this study was a
`comparison of the proportion of patients in each treatment group who developed no new
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`Gd-enhancing MRI lesions at 6 months; these MRIs were assessed by a blinded panel.
`Additional outcomes were measured, including EDSS and number of relapses, but all
`clinical measures in 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 Table 2.
`
`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 Endpoints
`EDSS change (Month 6 minus baseline)* (mean)
`-1.1
`-0.1
`0.7
`3.0
`Annualized relapse rate (mean per patient)
`14 (67%)
`7 (33%)
`Patients (%) without relapses
`MP = methylprednisolone; NOV + MP = NOVANTRONE plus methylprednisolone.
`* Results at Month 6, not including 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 multicenter Phase 2 trial of NOVANTRONE and low-dose prednisone (N + P) was
`conducted in 27 symptomatic patients with hormone-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%
`achieved a palliative response defined on the basis of reduction in analgesic use or pain
`intensity.
`
`These findings led to the initiation of a randomized multicenter trial (CCI-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 standard hormonal therapy, a castrate serum testosterone level, and at least mild pain
`at study entry. NOVANTRONE was administered 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 arm if
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`they progressed or if they were not improved after a minimum of 6 weeks of therapy with
`prednisone alone.
`
`A total of 161 patients were randomized, 80 to the N + P arm and 81 to the P arm. The
`median NOVANTRONE dose administered was 12 mg/m2 per cycle. The median
`cumulative NOVANTRONE 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, associated 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 P alone (p = 0.011). Two responders left the study after meeting primary
`response criterion for two consecutive cycles. For the purposes of this analysis, these two
`patients were assigned a response duration 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 P alone (p = 0.0004).
`
`Time to progression was defined as a 1-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 arm compared to 10.8 months for all patients on P alone (p = 0.2324).
`
`Forty-eight patients on the P arm 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
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`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
`chemotherapy is unclear. On the CCI-NOV22 trial, a PSA fall of 50% or greater for two
`consecutive 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 P arm. These
`findings 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
`endpoint of this study. For example, among the 26 evaluable patients randomized to the
`N + P arm who had a
`50% reduction in PSA, only 13 had a primary palliative response.
`Also, 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 NOVANTRONE plus hydrocortisone (N + H) versus hydrocortisone
`alone (H) 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/m2 every 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 arm and 123 to the H arm. There were no
`differences in survival between the two arms, with a median of 11.1 months in the N + H
`arm and 12 months in the H arm (p = 0.3298).
`
`Using NPCP criteria 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
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`(p = 0.018). The median time to progression, defined by NPCP criteria, 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 + H
`arm, 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 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 available data on the N + H arm, 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 Nonlymphocytic Leukemia
`
`In two large randomized multicenter trials, remission induction therapy for acute
`nonlymphocytic leukemia (ANLL) with NOVANTRONE 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/m2 daily by
`intravenous infusion for 3 days plus the same dose and schedule of cytarabine used with
`NOVANTRONE. Patients who had an incomplete antileukemic response received a
`second induction course in which NOVANTRONE or daunorubicin was administered for
`2 days and cytarabine for 5 days using the same daily dosage schedule. Response rates
`and median survival information for both the U.S. and international multicenter trials are
`given in Table 3:
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`Trial
`
`Table 3
`Response Rates, Time to Response, and Survival
`in U.S. and International Trials
`% Complete
`Median Time
`Response (CR)
`to CR (days)
`NOV
`DAUN
`NOV
`DAUN
`63 (62/98)
`53 (54/102)
`35
`42
`U.S.
`50 (56/112)
`51 (62/123)
`36
`42
`International
`NOV = NOVANTRONE + cytarabine
`DAUN = daunorubicin + cytarabine
`
`Survival (days)
`NOV
`DAUN
`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 5 days of cytarabine and 2 days of NOVANTRONE 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. 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 1 and 2 were 10/mm3 for both courses, and for those patients
`receiving daunorubicin + cytarabine nadirs were 170/mm3 and 260/mm3, respectively.
`Median platelet nadirs for patients who received NOVANTRONE + cytarabine for
`consolidation courses 1 and 2 were 17,000/mm3 and 14,000/mm3, respectively, and were
`33,000/mm3 and 22,000/mm3 in courses 1 and 2 for those patients who received
`daunorubicin + cytarabine. The benefit of consolidation therapy in ANLL patients 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 NOVANTRONE arm and one on the daunorubicin arm. However, in the
`international study there were eight deaths on the NOVANTRONE arm during
`consolidation which were related to the myelosuppression and none on the daunorubicin
`arm where less myelosuppression occurred.
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`INDICATIONS AND USAGE
`NOVANTRONE 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). NOVANTRONE 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.
`
`NOVANTRONE in combination with corticosteroids is indicated as initial chemotherapy
`for the treatment of patients 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.
`
`CONTRAINDICATIONS
`NOVANTRONE is contraindicated in patients who have demonstrated prior
`hypersensitivity to it.
`
`WARNINGS
`WHEN NOVANTRONE IS USED IN HIGH DOSES (> 14 mg/m2/d x 3 days) SUCH
`AS INDICATED FOR THE TREATMENT OF LEUKEMIA, SEVERE
`MYELOSUPPRESSION WILL OCCUR. THEREFORE, IT IS RECOMMENDED
`THAT NOVANTRONE BE 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
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`ANTIBIOTICS. BLOOD AND BLOOD PRODUCTS MUST BE AVAILABLE TO
`SUPPORT PATIENTS DURING THE EXPECTED PERIOD OF MEDULLARY
`HYPOPLASIA AND SEVERE MYELOSUPPRESSION. PARTICULAR CARE
`SHOULD BE 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 NOVANTRONE unless it is felt that the possible benefit from such treatment
`warrants the risk of further medullary suppression.
`
`The safety of NOVANTRONE (mitoxantrone for 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 is not indicated for subcutaneous, intramuscular, or intra-arterial
`injection. There have been reports of local/regional neuropathy, some irreversible,
`following intra-arterial injection.
`
`NOVANTRONE must not be given by intrathecal injection. There have been reports of
`neuropathy and neurotoxicity, both central and peripheral, following intrathecal injection.
`These reports have included seizures leading to coma and severe neurologic sequelae,
`and paralysis with bowel and bladder dysfunction.
`
`Topoisomerase II inhibitors, including NOVANTRONE, have been associated with the
`development of secondary AML and myelosuppression.
`
`Cardiac Effects
`
`Because of the possible danger of cardiac effects in patients previously treated with
`daunorubicin or doxorubicin, the benefit-to-risk ratio of NOVANTRONE therapy in such
`patients should be determined before starting therapy.
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`Functional cardiac changes including decreases in left ventricular ejection fraction
`(LVEF) and irreversible congestive heart failure can occur with NOVANTRONE.
`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 cardiac monitoring of LVEF 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 cumulative 2.6% probability of
`clinical congestive heart failure. In comparative oncology trials, the overall cumulative
`probability rate of moderate or severe decreases in LVEF at this dose was 13%.
`
`Multiple Sclerosis
`Changes in cardiac function may occur in patients with multiple sclerosis 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 LVEF values that decreased to
`below 50%. An additional patient receiving 12 mg/m2, who did not have LVEF
`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.
`
`MS patients should be assessed for cardiac signs and symptoms by history, physical
`examination, ECG, and quantitative LVEF evaluation using appropriate methodology
`(ex. Echocardiogram, MUGA, MRI, etc.) prior to the start of NOVANTRONE therapy.
`MS patients with a baseline LVEF below the lower limit of normal should not be treated
`with NOVANTRONE. Subsequent LVEF and ECG evaluations are recommended if
`signs or symptoms of congestive heart failure develop and prior to every dose
`administered to MS patients. NOVANTRONE should not be administered to MS
`patients who experience a reduction in LVEF to below the lower limit of normal, to those
`who experience a clinically significant reduction in LVEF, or to those who have received
`a cumulative lifetime dose of 140 mg/m2. MS patients should have yearly quantitative
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`LVEF evaluation after stopping NOVANTRONE to monitor for late-occurring
`cardiotoxicity.
`
`Leukemia
`Acute congestive heart failure may occasionally occur in patients treated with
`NOVANTRONE for ANLL. In first-line comparative trials 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 hemorrhage that often accompany the underlying disease.
`
`Hormone-Refractory Prostate Cancer
`Functional cardiac changes such as decreases in LVEF and congestive heart failure may
`occur in patients with hormone-refractory prostate cancer treated with NOVANTRONE.
`In a 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 decrease in LVEF below the normal range, congestive heart failure
`(n = 3), or myocardial ischemia. Two patients had a prior history of cardiac disease. The
`total NOVANTRONE dose administered to patients with cardiac effects ranged from >
`48 to 212 mg/m2.
`
`Among 112 patients evaluable for safety on the NOVANTRONE + hydrocortisone arm
`of the CALGB trial, 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 NOVANTRONE doses administered to these patients is not available.
`
`Pregnancy
`
`NOVANTRONE may cause fetal harm when administered to a pregnant woman.
`Women of chil