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`5/20/2019
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`| Dosage
`§§
`Form/Route
`
`| Marketing
`Status
`
`TE
`|
`Code RLD R
`
`|
`
`INJECTABLE|INJECTION Discontinued
`
`— None
`
`Yes
`
`. Ne
`:
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`Active
`ingredients
`
`LEUSTATIN | CLADRIBINE
`
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`for safety or
`:
`| efficacy
`:
`reagone**
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`2 STANDARD |
`Type 1 - New
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`os/02/2012 SUPPL-34
`:
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`96/29/2006 2 SUPPL-30
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`Supplement
`Categories
`or Approval
`Type
`
`Letters, Reviews, Labels, Patient Package insert
`
`- Label (PDF)
`{hitps:/ww.aecessdata.ida.govidrugsatidadocefabel/201 2/020:
`| Letter (PDF)
`:
`(https:/Aweew.accessdata.fida.govidrugsatida_docs/appletier/2012)
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`|
`(https:/wurw.accessdata.kia.gowldrugsatida_docs/appletier/2006)
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`08/22/2002
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`_ SUPPL-21
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`or Approval
`Type
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`Letters, Reviews, Labels, Patient Package insert
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`-_ Letter (PDF)
`(hitps:/Avww.accessdata.fda.govidrugsatida_decs/appletter/2002)
`
`08/20/2002
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`| SUPPL-7
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`Letter (PDF)
`ihtips:/iwww.accessdata.fda.qovidrugsatida_docs/appletier/2002)
`
`98/20/2002 - SUPPL4
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`Letter (PDF)
`:
`ihtips:/iwew.accessdata.ida.gov/drugsatidadocs/appletien2002)
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`33
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`

`

`LEUSTATIN® (cladribine}
`injection
`For Intravenous Infusion Only
`
`WARNING
`
`
`
`LEUSTATIN(cladribine) Injection should be administered under the supervision of a
`qualified physician experienced in the use of antineoplastic therapy. Suppression of
`bone marrowfunction should be anticipated. This is usually reversible and appears to
`be dose dependent. Serious neurological toxicity (including ureversible paraparesis
`aod quadraparesis) has been reported in patients who received LEUSTATIN Injection
`by continuous infusion at high doses (4 to 9 times the recommended dose for Hairy
`Cell Leukemia). Neurologic toxicity appears to demonstrate a dose relationship;
`however, severe neurological toxicity has been reported rarely following treatment
`with standard cladribine dosing regimens.
`
`Acute nephrotoxicity has been observed with high doses of LEUSTATIN (4 to
`Stimes the recommended dose for Hairy Cell Leukemia), especially when given
`concomitantly with other nephrotoxic agents/therapies.
`
`DESCRIPTION
`
`LEUSTATIN (cladribine}) Injection (also commonly known as 2-chloro-2’-deoxy-
`B -D-aderiosine} is a synthetic antineoplastic agent
`for continuous intravenous
`infusion.
`Tt
`is
`a clear,
`colorless,
`sterile, preservative-free,
`isotonic
`solution.
`LEUSTATIN Injection is available in single-use vials containing 10 mg (1 mg/mL) of
`cladribine, a chlorinated purine nucleoside analog. Each milliliter of LEUSTATIN
`Injection contains 1 mg of the active ingredient and 9 mg (0.18 mEq) of sodium
`chloride as an inactive ingredient. The solution has a pH range of 5.5 to 8.0.
`Phosphoric acid and/or dibasic sodium phosphate may have been added to adjust the
`pH to 6.30.3.
`
`The chemical name for cladribine is 2-chloro-6-arnino-9-(2-deoxy-B-D-erythropento-
`furanosyl} purine and the structure is represented below:
`
`Reference ID: 3168717
`
`

`

`
`
`cladribine
`
`MW285.7
`
`CLINICAL PHARMACOLOGY
`
`Cellular Resistance and Sensitivity:
`The selective toxicity of 2-chloro-2'-deoxy-f$-D-adenosine towards certain normal
`and malignant
`lymphocyte and monocyte populations is based on the relative
`activities of deoxycytidine kinase and deoxynucleotidase. Cladribine passively
`crosses the cell membrane.
`In cells with a high ratio of deoxycytidine kinase to
`deoxynucieotidase,
`it
`is
`phosphorylated
`by
`deoxycytidine
`kinase
`te
`2-chioro-2’-deoxy-
`6
`-D-adenosine monophosphate
`(2-CdAMP).
`Since
`6
`2-chioro-2'-deoxy-
`-D-adenosine is
`resistant
`to deamination by adenosine
`deaminase and there is
`little deoxynucleotide deaminase in lymphocytes and
`monocytes, 2-CdAMP accumulates intracellularly and is subsequently converted into
`the
`active
`triphosphate deoxynucleotide,
`2-chloro-2’-deoxy-
`6
`-D-adenosine
`triphosphate (2-CdATP). It is postulated that cells with high deoxycytidine kinase and
`low deoxynucleotidase activities will be selectively killed by 2-chloro-2’-deoxy- 6
`-D-adenosine as toxic deoxynucleotides accumulate intracellularly.
`
`Cells containing high concentrations of deoxynucleotides are unable to properly
`repair single-strand DNA breaks. The broken ends of DNAactivate the enzyme poly
`(ADP-ribose) polymerase resulting in NAD and ATP depletion and disruption of
`cellular metabolism. There is evidence, also, that 2-CdATP is incorporated into the
`DNA of dividing cells,
`resulting in impairment of DNA synthesis. Thus,
`2-chioro-2'-deoxy- 8 -D-adenosine can be distinguished from other chemotherapeutic
`agents affecting purine metabolism in that it is cytotoxic to both actively dividing and
`quiescent lymphocytes and monocytes, inhibiting both DNAsynthesis and repair.
`
`Reference ID: 3168717
`
`

`

`Pharmacokinetics
`
`In a clinical investigation, 17 patients with Hairy Cell Leukemia and normal renal
`function were treated for 7 days with the recommended treatment regimen of
`LEUSTATIN Injection (0.09 mg/kg/day) by continuous intravenous infusion. The
`mean steady-state serum concentration was estimated to be 5.7 ng/mL with an
`estimated systemic clearance of 663.5 mL/h/kg when LEUSTATIN was given by
`continuous infusion over 7 days. In Hairy Cell Leukemia patients, there does not
`appear 10 be a relationship between serum concentrations and ultimate clinical
`outcome.
`
`In another study, 8 patients with hernatologic malignancies received a two (2) hour
`infusion of LEDSTATIN Injection (0.12 mg/kg). The mean end-of-infusion plasrna
`LEUSTATIN concentration was 48+19 ng/mL. For
`5 of these patients,
`the
`disappearance of LEUSTATIN could be described by either a biphasic or triphasic
`decline. For these patients with normal renal function, the mean terminal half-life was
`5.4 hours. Mean values for clearance and steady-state volume of distribution were
`9781422 mL/h/ke and 4542.8 L/kg, respectively.
`
`declines
`administration
`intravenous
`after
`concentration
`plasma
`Cladribine
`multi-exponentially with an average half-life of 6.7 +/- 2.5 hours. In general, the
`apparent volume ofdistribution of cladribine is approximately 9 L/kg, indicating an
`extensive distribution in badytissues.
`
`fluid) One
`cerebrospinal
`into
`penetrates
`Cladribine
`concentrations are approximately 25% of those in plasma.
`
`report
`
`indicates
`
`that
`
`LEUSTATIN is bound approximately 20%to plasmaproteins.
`
`Except for some understanding of the mechanism of cellular toxicity, no other
`information is available on the metabolism of LEUSTATIN in humans. An average
`of 18% of the administered dose has been reported to be excreted in urine ofpatients
`with
`solid
`tumors
`during
`a
`S-day
`continuous
`intravenous
`infusion
`of
`3.5-8.1 mg/m’/day of LEUSTATIN. The effect of renal and hepatic impairment on
`the elimination of cladribine has not been investigated in humans.
`
`GLINICAL STUDIES
`
`studies of LEUSTATIN (cladribine} have been
`Two single-center open label
`conducted in patients with Hairy Cell Leukemia with evidence of active disease
`requiring therapy.
`In the study conducted at
`the Scripps Clinic and Research
`Foundation (Study A), 89 patients were treated with a single course of LEUSTATIN
`Injection given by continuous intravenous infusion for 7 days at a dose of
`
`ad
`
`Reference ID: 3168717
`
`

`

`0.09 mg/kg/day. In the study conducted at the M.D. Anderson Cancer Center (Study
`B), 35 patients were treated with a 7-day continuous intravenous infusion of
`LEUSTATINInjection at a comparable dose of 3.6 mg/m’/day. A complete response
`(CR) required clearing of the peripheral blood and bone marrow of hairy cells and
`recovery of the hemoglobin to 12 g/dL, platelet count to 100 x 10°/L, and absolute
`neutrophil count to 1500 x 10°/L. A goodpartial response (GPR) required the same
`hematologic parameters as a cornplete response, and that fewer than 5% hairy cells
`remain in the bone marrow. A partial response (PR) required that hairy cells in the
`bone marrow be decreased by at least 50%from baseline and the same response for
`hematologic parameters as for complete response. A pathologic relapse was defined
`as an increase in bone marrowhairy cells to 25% of pretreatment levels. A clinical
`relapse was defined as the recurrence of cytopenias, specifically, decreases in
`hemoglobin > 2 9/dL, ANC = 25%orplatelet counts > 50,000. Patients who met the
`criteria for a cornplete response but subsequently were found to have evidence of
`bone marrowhairy cells (< 25% of pretreatment levels) were reclassified as partial
`responses and were not considered to be complete responses with relapse.
`
`Among patients evaluable for efficacy (N=106}, using the hematologic and bone
`marrow response criteria described above, the complete response rates in patients
`treated with LEUSTATIN Injection were 65% and 68% for Study A and StudyB,
`respectively, yielding a combined complete response rate of 66%. Overall response
`rates G.e., Complete plus Good Partial plus Partial Responses) were 89% and 86% in
`Study A and Study B, respectively, for a combined overall response rate of 88% in
`evaluable patients treated with LEUSTATINInjection.
`
`Using an intent-to-treat analysis (N=123) and further requiring no evidence of
`splenomegaly as a criterion for CR G.e., no palpable spleen on physical examination
`and < 13 cm on CT scan}, the complete response rates for Study A and Study B were
`54%and 53%, respectively, giving a combined CR rate of 54%. The overall response
`rates (CR + GPR + PR} were 90%and 85%, for Studies A and B, respectively,
`yielding a combined overall response rate of 89%.
`
`RESPONSE RATES TO LEUSTATEIN TREATMENTIN PATIENTS
`WITH HAIRY CELL LEUREMIA
`CR
`66%
`
`Overall
`88%
`
`Evatuable Patients
`N=106
`intent-to-treat Population
`
`N=123
`
`54%
`
`89%
`
`In these studics, 60% of the patients had not received prior chemotherapy for Hairy Cell
`Leukemia or had undergone splenectomy as the only prior treatment and were receiving
`4
`
`Reference ID: 3168717
`
`

`

`LEUSTATIN as a first-hne treatment. The remaming 40% of the patients received
`LEUSTATINas a second-line treatment, having been treated previously with other agents,
`including c-imterferon and/or deoxvcoformycin. The overall
`response rate for patients
`without prior chemotherapy was %2%, compared with 84% for previously treated pationts.
`LEUSTATIN ts active in previously treated patients; however, retrospective analysis suggests
`that the overall response rate is decreased in patients previouslytreated with splenectomyor
`deoxycoformycin and in pationts refractory to a-interferon,
`
`Aay Prior Chemotherapy
`
`Previous Splenectomy
`
`Previous interferon
`
`Interferon Refractory
`
`OVERALL RESPONSE RATES (CR + GPR + PR) TO LEUSTATIN TREATMENTIN
`PATIENTS WITH HAIRY CELL LEDKEMIA
`OVERALL RESPONSE
`NR + RELAPSE
`225)
`No Prior Chemotherapy
`68/74
`644
`92%
`14%
`4/49
`84+3
`84%
`22%
`32/41*
`9+]
`73%
`24%
`40/48
`&+3
`83%
`23%
`6/L1*
`S+2
`55%
`64%
`3/6*
`34+]
`50%
`66%
`—NR=NoResposse
`*¥P<0.05
`
`Previous Deoxycoformycin
`
`After a reversible decline, normalization of peripheral blood counts (Hemoglobin
`>12.0
`g/dL, Platelets >100
`x
`10°/L, Absolute Neutrophil Count
`(ANC)
`>1500 x LO°/L) was achieved by 92% of evaluable patients. The median time to
`normalization of peripheral counts was 9 weeks from the start of treatment (Range:
`2 to 72). The median time to normalization of Platelet Count was 2 weeks, the median
`time to normalization of ANC was 5 weeks and the median time to normalization of
`
`Hemoglobin was 8 weeks. With normalization of Platelet Count and Hermogiobin,
`requirements for platelet and RBC transfusions were abolished after Months 1 and 2,
`respectively,
`in those patients with complete response. Platelet recovery may be
`delayed in a minority of patients with severe baseline
`thrombocytopenia.
`Corresponding to normalization of ANC, a trend toward a reduced incidence of
`infection was seen after the third month, when compared to the months immediately
`preceding LEUSTATIN therapy.
`(see also WARNINGS, PRECAUTIONS and
`ADVERSE REACTIONS)
`
`Reference ID: 3168717
`
`

`

`LEUSTATIN TREATMENT IN PATIENTS WITH HAIRY CELL LEUKEMIA TIME TO
`NORMALIZATION OF PERIPHERAL BLOOD COURTS
`eeeAOEMedianTimetoNormalizationofCount®
`Platelet Count
`2 weeks
`Absolute Neutroplul Count
`5 weeks
`Hemogtobin
`8 wecks
`ANC, Hemoglobin and Platelet Count
`9 weeks
`* Day 1 = First day of rafasion
`
`For patients achieving a complete response, the median time to response (.¢., absence
`of hairy cells in bone marrow and peripheral blood together with normalization of
`peripheral blood parameters), measured from treatment start, was approximately
`4 months. Since bone marrow aspiration and biopsy were frequently not performed at
`the time of peripheral blood normalization, the median time ic complete response
`may actuaily be shorter than that which was recorded. At the time of data cut-off, the
`median duration of complete response was greater than 8 months and ranged to
`25+ months. Among 93 responding patients, seven had shown evidence of disease
`progression at the time of the data cut-off In four of these patients, disease was
`limited to the bone marrow without peripheral blood abnormalities (pathologic
`progression), while in three patients there were also peripheral blood abnormalities
`{clinical progression}. Seven patients who did not respond to a first course of
`LEUSTATIN received a second course of therapy. In the five patients who had
`adequate follow-up, additional courses did not appear to improve their overall
`
`response.
`
`INDICATIONS FOR USE
`
`LEUSTATIN Injection is indicated for the treatment of active Hairy Cell Leukemia
`as defined by clinically significant anemia, neutropenia,
`thrombocytopema or
`disease-related symptoms.
`
`CONTRAINDICATIONS
`
`LEUSTATINInjection is contraindicated in those patients who are hypersensitive to
`this drug or anyof its components.
`
`WARNINGS
`
`Due to increased risk of infection in the setting of immunosuppression with
`chemotherapy including LEUSTATIN,
`it is recommended not to administer live
`attenuated vaccines to patients receiving LEUSTATIN Injection.
`
`and
`anemia
`neutropenia,
`including
`bone marrow suppression,
`Severe
`treated with
`thrombocytopenia,
`has been commonly
`observed in patients
`LEUSTATIN, especially at high doses. At initiation of treatment, most patients in the
`clinical studies had hematologic impairment as a manifestation of active Hairy Cell
`6
`
`Reference ID: 3168717
`
`

`

`Leukemia. Following treatment with LEUSTATIN, further hematologic impairment
`occurred before recovery of peripheral blood counts began. During the first two
`weeks after
`treatment
`initiation, mean Platelet Count, ANC, and Hemoglobin
`concentration declined and subsequently increased with normalization of mean counts
`by Day 12, Week 5 and Week 8, respectively. The myelosuppressive effects of
`LEUSTATIN were most notable during the first month following treatment.
`Forty-four percent
`(44%) of patients
`received transfusions with RBCs
`and
`14% received transfusions with platelets during Month 1. Careful hematologic
`monitoring, especially during the first 4 to 8 weeks after treatment with LEUSTATIN
`Injection, is recommended (see PRECAUTIONS).
`
`Fever (T = 100°F) was associated with the use of LEUSTATIN in approximately
`two-thirds of patients (131/196) in the first month of therapy. Virtually all of these
`patients were treated empirically with parenteral antibiotics. Overall, 47% (93/196) of
`all patients bad fever in the setting of neutropenia (ANC < 1000),
`including
`62 patients (32%) with severe neutropenia (i.e, ANC < 500).
`
`In a Phase [ investigational study using LEUSTATIN in high doses (4 to 9 times the
`recommended dose for Hairy Cell Leukemia) as part of a bone marrow transplant
`conditioning regimen, which also included high dose cyclophosphamide and total
`body irradiation, acute nephrotoxicity and delayed onset neurotoxicity were observed.
`Thirty-one (31) poor-risk patients with drug-resistant acute leukemia in relapse
`(29 cases) or non-Hodgkins Lymphoma ( cases) received LEUSTATIN for 7 to
`14 days prior to bone marrowtransplantation. During infusion, 8 patients experienced
`gastrointestinal symptoms. While the bone marrow was inttially cleared of all
`hematopoietic elements, including tumor cells, leukemia eventually recurred in all
`treated patients. Within 7 to 13 days after starting treatment with LEUSTATIN,
`6 patients (19%) developed manifestations of renal dysfunction (e.g., acidosis, anuria,
`elevated serum creatinine, etc.) and 5 required dialysis. Several of these patients were
`also being treated with other medications having known nephrotoxic potential. Renal
`dysfunction was reversible in 2 of these patients.
`In the 4 patients whose renal
`function had not recovered at the time of death, autopsies were performed; in 2 of
`these, evidence of tubular damage was noted. Eleven (11) patients (35%) experienced
`delayed onset neurologic toxicity.
`In the majority,
`this was characterized by
`progressive ureversible motor weakness (paraparesis/quadriparesis) of the upper
`and/or lower extremities, first noted 35 to 84 days after starting high dose therapy
`with LEUSTATIN. Non-invasive testing (electromyography and nerve conduction
`studies} was consistent with demyelinating disease. Severe neurologic toxicity has
`also been noted with high doses of another drug inthis class.
`
`Reference ID: 3168717
`
`

`

`Axonal peripheral polyneuropathy was observed in a dose escalation study at the
`highest dose levels (approximately 4 times the recommended dose for Hairy Ceil
`Leukemia) in patients not recerving cyclophosphamide or total body irradiation.
`Severe neurological
`toxicity has been reported rarely following treatment with
`standard cladribine dosing regimens.
`
`In patients with Hairy Cell Leukemia treated with the recommended treatment
`regimen (0.09 mg/kg/day for 7 consecutive days}, there have been no reports of
`nephrologic toxicities.
`
`Serious (¢.g. respiratory infection, pneumonia and viral skin infections), including
`fatal infections (e.g. sepsis) were reported (seeADVERSE REACTIONS).
`
`Of the 196 Hairy Cell Leukemia patients entered in the two trials, there were 8 deaths
`following treatment. Of these, 6 were of infectious etiology, including 3 pneumonias,
`and 2 occurred in the first month following LEUSTATIN therapy. Of the 8 deaths,
`6 occurred in previouslytreated patients who were refractory to o interferon.
`
`is a constituent of the recommended diluent for the 7-day infusion
`Benzy! alcohol
`solution. Benzyl afcohol has been reported to be associated with a fatal “Gasping
`Syndrome" in premature infants. (see DOSAGE AND ADMINISTRATION)
`
`Pregnancy Category D:
`LEUSTATIN can cause fetal harm when administered to a pregnant woman.
`Although there is no evidence ofteratogenicity in humans due to LEUSTATIN,other
`drugs which inhibit DNA synthesis have been reported to be teratogenic in humans.
`Cladribine is teratogenic in animals. Advise females of reproductive potential to use
`highly effective contraception during treatment with LEUSTATIN.
`If LEOSTATIN
`is used during pregnancy, or if the patient becomes pregnant while taking this drug,
`the patient should be apprised of the potential hazard to the fetus.
`
`Cladribine is teratogenic in mice and rabbits and consequently has the potential to
`cause fetal harm when administered to a pregnant woman. Asignificant increase in
`fetal variations was observed in mice receiving 1.5 mg/kg/day (4.5 mg/m’) and
`increased resorptions, reduced litter size and increased fetal malformations were
`observed when mice received 3.0 me/ke/day (@ me/m’). Fetal death and
`malformations were observed in rabbits that received 3.0 ma/ke/day (33.0 mg/m’).
`No fetal effects were seen in mice at 0.5 mg/kg/day (1.5 mg/m’) or in rabbits at
`1.0 mg/kg/day (11.0 mg/m’).
`
`Reference ID: 3168717
`
`

`

`PRECAUTIONS
`
`General:
`
`LEUSTATIN Injection is a potent antineoplastic agent with potentially significant
`toxic side effects. It should be administered only under the supervision of a physician
`experienced with the use of cancer chemotherapeutic agents. Patients undergoing
`therapy should be closely chserved for signs of hematologic and non-hematologic
`toxicity. Periodic assessment of peripheral blood counts, particularly during the first
`4to 8 weeks post-treatment, is recommended to detect the development of anemia,
`neutropenia and thrombocytopenia and for early detection of any potential sequelae
`{e.g.,
`infection or bleeding) As with other potent chemotherapeutic agents,
`monitoring of renal and hepatic function is also recommended, especially in patients
`with underlying kidney or liver dysfunction (sce WARNINGS and ADVERSE
`REACTIONS).
`
`Fever was a frequently observed side effect during the first month on study. Since the
`majority of fevers occurred in neutropenic patients, patients should be closely
`monitored during the first month of treatment and empiric antibiotics should be
`initiated as clinically indicated. Although 69%of patients developed fevers, less than
`1/3 of febrile events were associated with documented infection. Given the known
`
`niyelasuppressive effects of LEUSTATIN,practitioners should carefully evaluate the
`risks and benefits of administering this drug to patients with active infections (see
`WARNINGS and ADVERSE REACTIONS).
`
`There are inadequate data on dosing of patients with renal or hepatic insufficiency.
`Development of acute renal insufficiency in some patients receiving high doses of
`LEUSTATIN has been described. Until more information is available, caution is
`advised when administering the drug to pattents with known or suspected renal or
`hepatic insufficiency (see WARNINGS).
`
`Rare cases of tumor lysis syndrome have been reported in patients treated with
`cladribine with other hematologic malignancies having a high tumor burden.
`
`LEUSTATIN Injection must be diluted in designated intravenous solutions prior to
`administration (see DOSAGE AND ADMINISTRATION}.
`
`Laboratory Tests:
`the patient's hematologic profile should be
`During and following treatment,
`monitored regularly to determine the degree of hematopoietic suppression. In the
`clinical studies, following reversible declines in all cell counts, the mean Platelet
`Count reached 100 x 10°/L by Day 12, the mean Absolute Neutrophil Count reached
`1500 x 10°/L by Week 5 and the mean Hemoglobin reached 12 g/dL. by Week 8.
`9
`
`Reference ID: 3168717
`
`

`

`After peripheral counts have normalized, bone marrowaspiration and biopsy should
`be performed to confirm response to treatment with LEUSTATIN. Febrile events
`should be investigated with appropriate laboratory and radiologic studies. Periodic
`assessment of renal function and hepatic function should be performed as clinically
`indicated.
`
`Drug interactions:
`There are no known drug interactions with LEUSTATIN Injection. Caution should be
`exercised if LEUSTATIN Injection is administered before, after, or in conjunction
`with other drugs known to cause imnmunosuppression or myelosuppression.
`(see
`WARNINGS)
`
`Carcinogenesis:
`No animal carcinogenicity studies have been conducted with cladribine. However, its
`carcinogenic potential cannot be excluded based on demonstrated genotoxicity of
`cladribine.
`
`Mutagenesis:
`the actions of cladribine yield DNA
`As expected for compounds in this class,
`damage. In mammalian cells in culture, cladribine caused the accumulation of DNA
`strand breaks. Cladribine was also incorporated into DNA of human lymphoblastic
`leukemia cells. Cladribine was not mutagenic in vitro (Ames and Chinese hamster
`ovary cell gene mutation tests} and did not induce unscheduled DNA synthesis in
`primary rat hepatocyte cultures. However, cladribine was clastogenic both im vitro
`{chromosome aberrations in Chinese hamster ovary cells) and in vivo (mouse bone
`marrow micronucleus test}.
`
`impairment of Fertility:
`The effect on human fertility is unknown. When administered intravenously to
`Cynomoleus monkeys, cladribine has been shown to cause suppression of rapidly
`generating cells, including testicular cells.
`
`Pregnancy:
`Pregnancy Category D: (see WARNINGS).
`
`Nursing Mothers:
`Tt is not known whether this drug is excreted in human milk. Because many drugs are
`excreted in human mulk and because of the potential for serious adverse reactions in
`nursing infants from cladribine, a decision should be made whether to discontinue
`nursing or discontinue the drug, taking into account the importance ofthe drug for the
`mother.
`
`13
`
`Reference ID: 3168717
`
`

`

`Pediatric Use:
`
`Safety and effectiveness in pediatric patients have not been established. In a Phase I
`study involving patients 1-21 years old with relapsed acute leukemia, LEUSTATIN
`was given by continuous
`intravenous
`infusion in doses
`ranging from 3.
`to
`10.7 me/m/day for 5 days (one-half to twice the dose recommended in Hairy Cell
`Leukemia). In this study, the dose-limiting toxicity was severe myelosuppression with
`profound neutropenia and thrombocytopenia. At the highest dose (10.7 mg/m’/day),
`3 of 7 patients developed irreversible myelosuppression and fatal systemic bacterial
`or
`fungal
`infections. No unique toxicities were noted in this
`study © {see
`WARNINGSand ADVERSE REACTIONS).
`
`Geriatric Use
`
`Clinical studies of LEUSTATIN did not include sufficient numbers of subjects aged
`65 and over to determine whether they respond differently from younger subjects.
`Other reported clinical experience has not identified differences in responses between
`the elderly and younger patients. In general, dose selection for an elderly patient
`should be cautious, reflecting the greater frequency of decreased hepatic, renal, or
`cardiac function, and of concomitant disease or other drug therapyin elderly patients.
`
`ADVERSE REACTIONS
`
`Clinical Trials Experience
`Adverse drug reactions reported by > 1% of LEUSTATIN-treated patients with HCL
`noted in the HCLclinical dataset (studies K90-091 and L91-048, n=$76) are shownin
`the table below.
`
`Adverse Drug Reactions in > 1%of Patients Treated With LEUSTATIN in HCL Cimical
`Trials
`
`Blood and Lymphatic System Disorder (sce ‘iso sections WARNINGS aa PRECAUTIONS)
`Anemia
`Febrie neutro} ena
`
`Cardiacpaniess
`
`System Grean Class
`Preferred Term
`
`LEUSTATIN (0376)
`%
`
`Headache
`
`1
`
`74
`
`Reference ID: 3168717
`
`

`

`eneNnceeceeeceeneceeceeneeeeeeneneeeeneneLeceeneeeneenneeteneteneeneenenetanteanteestitanetanteentetanetantentetatetantesntie
`Constipation
`Diarrhea
`
`eeneeecneeeeceeeeeneREcreereereereneeeeterenennennetnentnenteDresptsptseinstnstnstnstntunsinetnetneen
`Skin and Subcutaneous Tissue Disorders
`Ecchyraosis
`Hyperhidrosis
`
`Rash***
`
`Musculoskeletal, Connective Tissue, and Bone DisorderS$
`ArthralgiaeeInetnent
`
`i
`
`ooeecenceneeneAdministrationsitereactigree
`Asthena
`
`ooeeceneeneenePACerenceeceneneneaneaneeneerenennntnrmnrnnenbacscpeisiastasinsinstnsinsineneneen
`Malaise _
`
`i
`*t*
`
`Dyspneaine des dyspnea, dyspnea exertional, and wheesing
`Abdominal pain includes abdominal discomfort, abdominal pain, and abdominal! pain (ower and upper)
`Rash inchides erythema, rash, and rash (macular, macula~papular, papular, pruritic, pustular and
`erythematous)
`Pain inchides pain, back pain, chest pain, arthntis pain, bone pare, and pain in extremity
`*eee
`eeeek Administration site reaction includes administration site reaction, catheter site (cellulitis, erythema,
`hemorrhage, and pain), and infusion site reaction(erythema, edema, and pain)
`The following safety data are based on 196 patients with Hairy Cell Leukemia: the
`original cohort of 124 patients plus an additional 72 patients enrolledat the same two
`centers after the onginal enrollment cutoff In Month | of the Hairy Cell Leukemia
`clinical trials, severe neutropenia was noted in 70%of patients, fever in 69%, and
`infection was documented in 28%. Most non-hematologic adverse experiences were
`muld to moderate in severity.
`
`Myelosuppression was frequently observed during the first month after starting
`treatment. Neutropenia (ANC<500 x 10°/L) was noted in 70%of patients, compared
`with 26% in whom it was present initially. Severe anemia (Hemoglobin < 8.5 g/dL)
`developed in 37%of patients, compared with 10%initially and thrombocytopenia
`(Platelets < 20 x 10°/L) developed in 12%ofpatients, compared to 4% in whomit
`was noted initially.
`
`During the first month, 54 of 196 patients (28°} exhibited documented evidence of
`infection. Serious infections (e.2., septicernia, pneumonia} were reported in 6%ofail
`12
`
`Reference ID: 3168717
`
`

`

`patients; the remainder were mild or moderate. Several deaths were attributable to
`infection and/or complications related to the underlying disease. During the second
`rnonth, the overall rate of documented infection was 6%; these infections were mild
`to moderate and no severe systemic infections were seen. After the third month, the
`monthly incidence of infection was either less than or equal to that of the months
`imimediately preceding LEUSTATINtherapy.
`
`During the first month, 11% of patients experienced severe fever (Le. =104°F).
`Documented infections were noted in fewer than one-third of febrile episodes. Of the
`196 patients studied, 19 were noted to have a documented infection in the month prior
`to treatment. In the month following treatment, there were 54 episodes of documented
`infection: 23 (42%) were bacterial, 11 (20%) were viral and 11 (20%} were fungal.
`Seven (7) of 8 documented episodes of herpes zoster occurred during the month
`following treatment. Fourteen (14) of 16 episodes of documented fungal infections
`occurred in the first two months following treatment. Virtually all of these patients
`were treated ernpirically with antibiotics. (see WARNINGS and PRECAUTIONS)
`
`Analysis of lymphocyte subsets indicates that treatment with cladribine is associated
`with prolonged depression of the CD4 counts. Prior to treatment, the mean CD4 count
`was 766/nL. The mean CD4 count nadir, which occurred 4 to 6 months following
`treatment, was 272/uL. Fifteen {15} months after treatment, mean CD4 counts
`remained below 500/uL. CD8 counts behaved similarly, though increasing counts
`were observed after 9 months. The clinical stentficance of the prolonged CD4
`lymphopenia is unclear,
`
`Another event of unknown clinical significance includes the observation of prolonged
`bone marrow bypocellularity. Bone marrowcellularity of < 35% was noted after
`4months in 42 of 124 patients G4%)
`treated in the two pivotal
`tnals. This
`hypocellularity was noted as late as day 1010.
`ft
`is not known whether
`the
`hypocellularity is the result of disease related marrow fibrosis or if it is the result of
`cladribine toxicity. There was no apparent clinical effect on the peripheral blood
`counts.
`
`The vast majority of rashes were mild. Most episodes of nausea were mild, not
`accompanied by vonuting, and did not require treatment with antiemetics. In patients
`requiring antiemetics,
`nausea was
`easily
`controlled, most
`frequently with
`chlorpromazine.
`
`When used in other clinical settings the following ADRs were reported: bacteremia,
`cellulitis, localized infection, pneumonia, anemia, thrombocytopenia Gvwith bleeding
`or petechiae), phiebitis, purpura, crepitations, localized edema and edema.
`
`Reference ID: 3168717
`
`

`

`For a description of adverse reactions associated with use of high doses in non-Hairy
`Cell Leukemia patients, see WARNINGS.
`
`Postmarketing Experience
`The following additional adverse reactions have been reported since the drug became
`commercially available. These adverse reactions have been reported