I
`/·
`lj
`
`PDR®
`
`1995
`PHYS CANS'
`DESK
`REFERENCE®
`
`Medical Consultant
`Ronald Arky, MD, Charles S. Davidson Professor of Medicine and Master, Francis Weld Peabody Society, Harvard Medical School
`
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`~ Copyright© 1995 and pubilshed by Medic~! Economics 'Data Production Corn'pany ·at Montvale, NJ 07645-17 42. All rights reserved. None of the content
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`@Printed on recycled paper
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`ISBN: 1-56363-087·7
`
`Actavis - IPR2017-01100
`Ex. 1008, p. 1 of 6
`
`

`

`BRISTOL-MYERS SQUIBB ONCOLOGY P. 663 RX
`
`BRISTOL-MYERS SQUIBB ONCOLOGY P. 686 C·lll
`
`BURROUGHS ~ELLCOME
`
`P. 757 RX
`
`BURROUGHS \YELLCOME
`
`P. 783 RX
`
`BURROUGHS WELLCOME
`
`P. 827
`
`PRODUCT IDENTIFICATION GUIDE/307
`
`,,
`
`25 mg
`
`50 mg
`Cytoxan"
`(cyclophosphamide tablets, USP)
`
`RX
`
`BRISTOL-MYERS SQUIBB ONCOLOGY P. 665
`~
`
`1g
`
`lfex"
`(sterile lfosfamide)
`BRISTOL-MYERS SQUIBB ONCOLOGY P. 669
`
`nx
`
`100 mg
`
`Also available in 150 mg, 500 mg, 1 g
`
`VePesid"
`(etoposlde for Injection)
`DRISTOL·MYERS SQUIBB ONCOLOGY P, 686
`
`RX
`
`50 mg
`
`I /1 I
`
`VePesid"
`(etoposlde)
`BRISTOL-MYERS SQUIBB ONCOLOGY P. 688
`
`RX
`
`325 mg/30 mg
`Empirin® with Codeine No.3
`(aspirtn, codeine phosphate)
`
`BURROUGHS WELLCOME
`
`P. 757 RX
`
`I I
`
`250 mg
`Mepron"
`(atovaquone)
`BURROUGHS WELLCOME
`
`P. 790 RX
`
`~l!_
`
`200 mg
`tZovirax"
`(acyclovir)
`BURROUGHS WELLCOME
`
`P. 827
`
`325 mg/60 mg
`Empirin" with Codeine No.4
`(aspirin, codeine phosphate)
`BURROUGHS WELLCOME
`
`RX
`
`P. 762 RX
`
`Myleran"
`(busulfan)
`BURROUGHS WELLCOME
`
`P. 799 RX
`
`400 mg
`tZovirax"
`(acyclovir)
`BURROUGHS WELLCOME
`
`P. 827
`
`2Dmg
`
`40 mg
`Megace"
`(megestrol acetate tablets, USP)
`BRISTOL-MYERS SQUIBB ONCOLOGY P. 668
`
`RX
`
`40 mg/ml oral suspension
`Megace"
`(megestrol acetate)
`BRISTOL-MYERS SQUIBB ONCOLOGY P. 670
`
`RX
`
`,=i
`\:
`
`e
`'r
`
`I \')
`
`100 mg
`Videx"
`(didanosine)
`BRISTOL·MYERS SQUIBB ONCOLOGY P, 697
`
`RX
`
`RX
`
`RX
`
`50mg
`
`tlmuran"
`(azathioprine)
`BURROUGHS WELLCOME
`
`100 mg
`200 mg
`Proloprim"
`(trimethoprim)
`BURROUGHS WELLCOME
`
`P. 800 RX
`
`P. 764 RX
`
`BOO mg
`tZovirax"
`BURROUGHS WELLCOME
`
`P. 834
`
`5 mg
`
`Kemadrin"
`(procyclidine HCI)
`BURROUGHS WELLCOME
`
`P. 765 RX
`
`50 mg
`Purinethol"
`(mercaptopurine)
`BURROUGHS WELLCOME
`
`p, 802
`
`100 mg
`
`20 mg
`
`"'
`
`0.05 mg
`
`0.1 mg
`
`100 mg
`
`300 mg
`Zyloprim"
`(allopurinol)
`
`CARN RICK
`
`RX
`
`CARNRICK
`
`tRetrovir"
`(zldovudlne)
`BURROUGHS WELLCOME
`
`p. 810
`
`RX
`
`P. 839
`
`o.2mg
`
`Lanoxicaps"
`(dlgoxln solution)
`BURROUGHS WElLCOME
`
`RX
`
`Semprex™-D
`(acrivastine and pseudoephedrine HCI)
`8 mg/60 mg
`BURROUGHS WELLCOME
`
`P. 816
`
`P. 776 RX
`
`0.125 mg
`
`0.25 mg
`
`tSeptra"
`{trimethoprlm, sulfamethoxazole)
`80 mg/ 400 mg
`BURROUGHS WELLCOME
`
`P. 816
`
`RX
`
`10 mg
`
`Amen"
`(medroxyprogesterone acetate tablets, USP)
`C-111
`CARNRICK
`
`P. 841
`
`35 mg
`Bontril" PDM
`(phendlmetrazine tartrate tablets, USP)
`C-111
`CARNRICK
`P. 841
`
`8647
`
`105 mg
`Bontril" Slow-Release
`(phendimetrazlne tartrate)
`CARNRICK
`
`P. 841
`
`CV
`
`2 mg
`Alkeran"
`(melphalan)
`BURrtOUGHS WELLCOME
`
`RX
`
`0.5mg
`tLanoxin"
`(dlgoxln)
`
`tSeptra" DS
`(trlmethoprlm, sulfamethoxazole)
`160 mg / 800 mg
`
`P. 749 RX
`
`BURROUGHS WELLCOME
`
`P. 780 RX
`
`BURROUGHS WELLCOME
`
`P. 818
`
`200 mg
`
`1g
`
`400 mg
`Mesnex"
`(mesna Injection)
`BRISTOL-MYERS SQUIBB ONCOLOGY P, 6 71
`
`40 mg
`A/so available In 5 mg and 20 mg
`
`Mutamycin"
`(mitomycin for injection, USP)
`BRISTOL-MYERS SQUIBB ONCOLOGY P. 673
`
`30 mg
`
`40 mg
`
`Zerit™
`(stavudine capsules)
`
`While every effort has been made
`to reproduce products faithfully,
`this section is to be considered a
`quick reference Identification aid.
`In cased of suspected overdosage,
`etc., chemical analysis of the
`product should be done.
`
`RX
`
`BURROUGHS WELLCOME
`
`P. 746
`
`RX
`
`nx
`
`nx
`
`nx
`
`li,
`~ ~ .~
`t l
`
`50 mg
`
`450 mg
`150 mg
`Paraplatin"
`(carboplatin for Injection)
`BRISTOL-MYERS SQUIBB ONCOLOGY P. 678
`
`'
`
`I t
`
`50 mg/100 mg
`Platinol®-AQ
`(cisplatin for Injection)
`BRISTOL-MYERS SQUIBB ONCOLOGY P. 682
`
`!r?_l~
`
`RX
`
`Single dose vial
`
`Taxol"
`(paclitaxel for injection concentrate)
`30 mg/5 ml (6 mg/ml) per 5 ml
`
`10 mg
`Car dilate"
`(erythrityl tetranitrate)
`BURROUGHS WELLCOME
`
`/. j
`
`5 mg
`25 mg
`tLeucovorin Calcium
`tablets, Wellcovorin® brand
`(leucovorin calcium)
`
`40 mg
`Thioguanine tablets
`TABLOID" brand
`(thloguanlne)
`
`P. 754 RX
`
`BURROUGHS WELLCOME
`
`P. 781 RX
`
`P. 824 RX
`
`Capital" and Codeine
`Suspension
`(acetaminophen, codeine phosphate)
`120 mg/5 ml, 12 mg/5 ml
`CARNRICK
`
`P. 841
`
`25 mg
`
`Daraprim"
`(pyrimethamine)
`
`2mg
`
`Leukeran"
`(chlorambucil)
`
`100 mg
`75 mg
`Wellbutrin"
`(bupropion HCI)
`
`Exgest'" LA
`(phenyJpropanolamine HCI, gualfenesln)
`75 mg/ 400 mg
`
`Actavis - IPR2017-01100
`Ex. 1008, p. 2 of 6
`
`

`

`682/PHYSICIANS' DESK REFERENCE®
`
`Bristol-Myers Squibb-Cont.
`
`5. Clinical Oncological Society of Australia . Guidelines and
`Recommendations for Safe Handling of Antineoplastic
`Agents. Med J Australia 1983; 1:426-428.
`6. Jones RB, et al: Safe Handling of Chemotherapeutic
`Agents: A Report from the Mount Sinai Medical Center.
`CA-A Cancer Journal for Clinicians 1983; (Sept/Oct)
`258-263.
`7. American Society of Hospital Pharmacists Technical As(cid:173)
`sistance Bulletin on Handling Cytotoxic and Hazardous
`Drugs. Am J Hosp Pharm 1990; 47:1033-1049.
`8. OSHA Work-Practice Guidelines for Personnel Dealing
`with Cytotoxic (Antineoplastic) Drugs. Am J Hosp Pharm
`1986; 43:1193-1204.
`January 1994
`
`3351DIM-03
`
`TAXOL®
`[taks'o ZJ
`(paclitaxel) for Injection
`Concentrate
`
`WARNING
`TAXOL® (paclitaxel) should be administered under the
`supervision of a physician experienced in the use of
`cancer chemotherapeutic agents. Appropriate manage(cid:173)
`ment of complications is possible only when adequate
`diagnostic and
`treatment
`facilities are
`readily
`available.
`Severe hypersensitivity reactions characterized by dys(cid:173)
`pnea and hypotension requiring treatment, angioe(cid:173)
`dema, and generalized urticaria have occurred in 2% of
`patients receiving TAXOL. One of these reactions was
`fatal in a patient treated without premedication in a
`Phase 1 study. Patients receiving TAXOL should be
`pretreated with corticosteroids, diphenhydramine, and
`H 2 antagonists to prevent these reactions. (See "DOS(cid:173)
`AGE AND ADMINISTRATION" section.) Patients who
`experience severe hypersensitivity reactions to TAXOL
`should not be rechallenged with the drug.
`TAXOL therapy should not be given to patients with
`baseline neutrophil counts ofless than 1.500 cells/mm3.
`In order to monitor the occurrence of bone marrow sup(cid:173)
`pression, 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 TAXOL.
`
`DESCRIPTION
`TAXOL (paclitaxel) for Injection Concentrate is a clear col(cid:173)
`orless to slightly yellow viscous solution. It is supplied as a
`nonaqueous solution intended for dilution with a suitable
`parenteral fluid prior to intravenous infusion. TAXOL is
`available in 30 mg (5 mL) single-dose vials. Each mL of sterile
`nonpyrogenic solution contains 6 mg paclitaxel, 527 mg of
`Cremophor® EL• (polyoxyethylated castor oil) and 49. 7 %
`(v/v) dehydrated alcohol, USP.
`Paclitaxel is a natural product with antitumor activity. The
`chemical name for paclitaxel is 5/3, 20-Epoxy-1,2a,4,7,B, 10/3,
`13a-hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate
`13-ester with (2R, 38)-N-benzoyl-3-phenylisoserine.
`Paclitaxel has the following structural formula:
`
`Paclitaxei is a white to off-white crystalline powder with the
`empirical formula C47H51N014 and a molecular weight of
`853.9. It is highly lipophilic, insoluble in water, and melts at
`around 216-217° C.
`CLINICAL PHARMACOLOGY
`Paclitaxel is a novel antimicrotubule agent that promotes
`the assembly of microtubules from tubulin dimers and stabil(cid:173)
`izes microtubules by preventing depolymerization. This sta(cid:173)
`bility results in the inhibition of the normal dynamic reorga(cid:173)
`nization of the microtubule network that is essential for vital
`interphase and mitotic cellular functions. In addition, pa(cid:173)
`clitaxel induces abnormal arrays or "bundles" of mi(cid:173)
`crotubules throughout the cell cycle and multiple asters of
`microtubules during mitosis.
`
`• Cremophor® EL is the registered trademark of BASF
`Aktiengesellschaft.
`
`Summary of Non-Compartment Pharmacokinetic Parameters
`Mean(% Coefficient of Variation) Values by Single-Dose and Infusion
`
`Dose
`(mg/m 2)
`
`Infusion
`Duration (h)
`
`N
`(patients)
`
`135
`175
`135
`175
`
`24
`24
`3
`3
`
`2
`4
`7
`5
`
`Cm ax
`(ng/ml)
`
`195
`365 (33)
`2170 (21)
`3650 (30)
`
`AUC (0-oo)
`(ng-h/mD
`
`6300
`7993 (29)
`7952 (23)
`15007 (27)
`
`T-HALF
`(h)
`
`52.7
`15.7 (56)
`13.1 (45)
`20.2 (85)
`
`CLrl
`(L/h/m2)
`
`21.7
`23.8 (35)
`17.7 (20)
`12.2 (25)
`
`Cmux· Maximum plasma concentration
`AUC (0-oo) - Area under the plasma concentration-time curve from time 0 to infinity
`CLy- Total body clearance
`
`Key Efficacy Parameters in the Phase 3 Ovarian Carcinoma Study
`
`.. Response
`
`rate (percent)
`95% Confidence Interval
`" Time to Progression
`median (months)
`.. Survival
`95% Confidence Interval
`
`median (months)
`95% Confidence Interval
`
`175/3
`(n=96)
`
`14.6
`(8.5-23.6)
`
`4.4
`(3.0-5.6)
`
`11.5
`(8.4-14.4)
`
`175/24
`(n=106)
`
`21.7
`(14.5-31.0)
`
`4.2
`(3.5-5.1)
`
`11.8
`(8.9-14.6)
`
`135/3
`(n=99)
`
`15.2
`(9.0-24.1)
`
`3.4
`(2.8-4.2)
`
`13.1
`(9.1-14.6)
`
`135/24
`(n=106)
`
`13.2
`(7.7-21.5)
`
`2.8
`(1.9-4.0)
`
`10.7
`(8.1-13.6)
`
`Following intravenous administration ofTAXOL, paclitaxel
`plasma concentrations declined in· a biphasic manner. The
`initial rapid decline represents distribution to the peripheral
`compartment and elimination of the drug. The later phase is
`due, in part, to a relatively slow efflux ofpaclitaxel from the
`peripheral compartment.
`Pharmacokinetic parameters of paclitaxel following 3- and
`24-hour infusions of TAXOL at dose levels of 135 and 175
`mg/m 2 were determined in a Phase 3 randomized study in
`ovarian cancer patients and are summarized in the following
`table:
`[See first table above.]
`It appeared.that with the 24-houdnfusion ofTAXOL, a 30%
`increase in dose (135 mg/m 2 versus 175 mg/m2) increased
`the Cmnx by 87% whereas the AUC (0-oo) remained propor(cid:173)
`tional. However, with a 3-hour infusion, for a 30% increase
`in dose, the Cmax and AUC (0-oo) were increased by 68% and
`89%, respectively. The mean apparent volume of distribu(cid:173)
`tion at steady state, with the 24-hour infusion of TAXOL
`ranged from 227 to 688 L/m2, indicating extensive extravas(cid:173)
`cular distribution and/or tissue binding of paclitaxel.
`The pharmacokinetics of paclitaxel were also evaluated in
`adult cancer patients who received single doses of 15-135
`mg/m2 given by 1-hour infusions (n=15), 30-275 mg/m 2
`given by 6-hour infusions (n=36), and 200-275 mg/m2 given
`by 24-hour infusions (n=54) in Phase 1 & 2 studies.Values
`for total body clearance and volume of distribution were
`consistent with the findings in the Phase 3 study.
`In uitro studies of binding to human serum proteins, using
`paclitaxel concentrations ranging from 0.1 to 50 µg/mL,
`indicate that between 89-98% of drug is bound; the presence
`of cimetidine, ranitidine, dexamethasone, or diphenhydra(cid:173)
`mine did not affect protein binding of paclitaxel.
`The disposition of paclitaxel has not been fully elucidated in
`humans. After intravenous administration of 15-275 mg/m2
`doses ofTAXOL as 1, 6, or 24-hour infusions, mean (SD) val(cid:173)
`ues for cumulative urinary recovery of unchanged drug
`ranged from 1.3% (0.5%) to 12.6% (16.2%) of the dose, indi(cid:173)
`cating extensive non-renal clearance. TAXOL has been dem(cid:173)
`onstrated to be metabolized in the liver in animals and there
`is evidence suggesting hepatic metabolism in humans. High
`paclitaxel concentrations have been reported in the bile of
`patients treated with TAXOL. The effect of renal or hepatic
`dysfunction on the disposition of paclitaxel has not been
`investigated.
`Possible interactions of paclitaxel with concomitantly ad(cid:173)
`ministered medications have not been formally investigated.
`CLINICAL STUDIES:
`Ovarian Carcinoma: Data from five Phase 1 and 2 clinical
`studies (189 patients), a multicenter, randomized Phase 3
`study (407 patients), as well as an interim analysis of data
`from more than 300 patients enrolled in a treatment referral
`center program were used in support of the use ofTAXOL in
`patients who have failed initial or subsequent chemotherapy
`for metastatic carcinoma of the ovary. Two of the Phase 2
`studies (92 patients) utilized an initial dose of 135 to 170 mg/
`m2 in most patients ( > 90%) administered over 24 hours by
`continuous infusion. Response rates in these two studies
`were 22% (95% Cl= 11-37%) and 30% (95% Cl = 18-46%)
`with a total of six complete and 18 partial responses in 92
`patients. The median duration of overall response in these
`two studies measured from the first day of treatment was 7.2
`
`months (range: 3.5-15.8 months) and 7.5 months (range: 5.3
`- 17.4 months), respectively. The median survival was 8.1
`months (range: 0.2 - 36.7 months) and 15.9 months (range:
`1.8 - 34.5+ months).
`The Phase 3 study had a bifactorial design and compared the
`efficacy and safety of TAXOL, administered at two different
`doses (135 or 175 mg/m 2) and schedules (3- or 24-hour infu.
`sion). The overall response rate for the 407 patients was
`16.2% (95% Cl = 12.8-20.2%), with 6 complete and 60 par(cid:173)
`tial responses. Duration ofresponse, measured from the first
`day of treatment was. 8.3 months (range: 3.2-21.6 months).
`Median
`time
`to progression was 3.7 months (range:
`0.1 +-25.1 +months). Median survival was 11.5 months
`(range: 0.2-26.3+ months).
`Response rates, median survival and median time to progres(cid:173)
`sion for the 4 arms are given in the following table. The arms
`are listed by doses and schedule (mg .m2 /hours). Comparisons
`between study arms should be done with caution in view of
`the bifactorial study design and small sample sizes per arm.
`[See second table above.]
`Analyses were performed as planned by the study protocol,
`by comparing the two doses (135 or 175 mg/m2 ) irrespective
`of the schedule (3 or 24 hours) and the two schedules irre(cid:173)
`spective of dose.
`Patients receiving the 175 mg/m2 dose achieved a higher
`response rate than those receiving the 135 mg/m 2 dose: 18%
`vs. 14% (p=0.28). No difference in response rate was de(cid:173)
`tected when comparing the 3-hour with the 24-hour infusion:
`15% vs. 17% (p=0.50). Patients receiving the 175 mg/m2
`dose of TAXOL (paclitaxe]) for Injection Concentrate had a
`longer time to progression than those receiving the 135 mg/
`m2 dose: median 4.2 vs. 3.1 months (p= 0.03). Time to pro(cid:173)
`gression was longer for patients receiving the 3-hour vs. the
`24-hour infusion: 4.0 months vs. 3.7 months (p=0.08). No
`difference in survival according to dose or schedule was ob(cid:173)
`served.
`TAXOL remained active in patients who had developed re(cid:173)
`sistance to platinum-containing therapy (defined as tumor
`progression while on, or tumor relaps.ed within 6 months
`from completion of, platinum containing regimens) with
`response rates of 14% in the Phase 3 study and 31 o/o in the
`Phase 1 & 2 clinical studies.
`The adverse event profile in the Phase 3 study was consistent
`with that seen for a pooled analysis performed on 812 pa(cid:173)
`tients treated in ten clinical studies (see, "ADVERSE REAC.
`TIONS" section). For the 403 patients who received TAXOL
`in the Phase 3 study, the following table shows the incidence
`of some key adverse events by treatment arm. The arms are
`listed by dose and schedule (mg/m2/hours).
`[See first table on top of next page.]
`Myelosuppression was dose and schedule related, with the
`schedule effect being more prominent. The development of
`severe hypersensitivity reactions (HS Rs) was rare; 1 % of the
`patients and 0.2% of the courses overall. There was no ap(cid:173)
`parent dose or schedule effect seen for the HSRs. Addition(cid:173)
`ally, peripheral neuropathy was clearly dose-related, but
`schedule did not appear to affect the incidence.
`The results of the randomized stu?' support the use of
`TAXOL at doses of 135 or 175 mg/m , administered by a 3-
`hour infusion. The same doses administered by 24-hour infu·
`sion were more toxic; the bifactorial study design and small
`sample size per arm preclude definitive conclusions regard(cid:173)
`ing relative efficacy between the 4 arms of the study.
`Breast Carcinoma: Data from 83 patients accrued in thr;e
`phase 2 open label studies and from 471 patients enrolled in
`
`Information will be superseded by supplements and subsequent editions
`
`Actavis - IPR2017-01100
`Ex. 1008, p. 3 of 6
`
`

`

`Frequency of Key Adverse Events in the Phase 3 Ovarian Carcinoma Study
`
`PRODUCT INFORMATION/683
`
`175/3
`(n=95)
`
`Percent of Patients
`175/24
`135/3
`(n=105)
`(n=98)
`
`135/24
`(n=105)
`
`.. Bone Marrow
`
`Neutropenia
`
`Thrombocytopenia
`
`Anemia
`
`Infections
`
`All
`Severe
`
`.. Hypersensitivity Reaction'
`.. Peripheral Neuropathy
`.. Mucositis
`
`Any symptoms
`Severe symptoms
`
`Any symptoms
`Severe symptoms
`
`<2,000/mm2
`<500/mm2
`< 100,000/mm2
`<50,000/mm2
`< 11 g/dL
`<8 g/dL
`
`78
`27
`4
`1
`84
`11
`26
`
`41
`2
`
`63
`1
`
`17
`0
`
`98
`75
`18
`7
`-90
`12
`29
`
`45
`0
`
`60
`2
`
`35
`3
`
`78
`14
`8
`2
`68
`6
`20
`
`38
`2
`
`55
`0
`
`21
`0
`
`98
`67
`6
`1
`88
`10
`18
`
`45
`1
`
`42
`0
`
`25
`2
`
`135/3
`(n=236)
`
`22
`(17-27)
`
`3.0
`(2.5-3.8)
`
`10.5
`(9.0--12.8)
`
`All patient;; received wemedication
`
`Key Efficacy Parameters in the Phase 3 Breast Carcinoma Study
`
`.. Response .
`.. Time to Progression
`.. Survival
`
`-rate (percent)
`-95% Confidence Interval
`
`-median (months)·
`-95% Confidence Interval
`
`-median (months)
`-95% Confidence Interval
`
`175/3
`(n=235)
`
`28
`(22-34)
`
`4.2
`(3.2-4.6)
`
`11.7
`(10.0--13.8)
`
`Frequency of Key Adverse Events in the Phase 3 Breast Carcinoma Study
`
`<2,000/mm 3
`<500/mm2
`< 100,000/mm2
`< 50,000/mm2
`< 11 g/dL
`<8 g/dL
`
`Bone Marrow
`-N eutropenia •
`
`Thrombocytopenia'
`
`-Anemia'
`
`-Infections
`-Febrile Neutropenia
`Hypersensitivity Reaction"
`-All
`-Severe
`Peripheral Neuropathy
`-Any symptoms
`-Severe symptoms
`Mucositis
`-Any symptoms
`-Severe symptoms
`
`Percent of Patients
`175 mg/m 2
`135 mg/m 2
`(n=229)
`(n=229)
`
`90
`28
`11
`3
`55
`4
`23
`2
`
`36
`0
`
`70
`7
`
`23
`3
`
`81
`19
`7
`2
`47
`2
`15
`2
`
`31
`<l
`
`46
`3
`
`17
`<l
`
`Based on worst course analysis
`•• All patient;; received premedication
`
`requiring pacemaker placement. If patients develop signifi(cid:173)
`cant conduction abnormalities during TAXOL infusion, ap(cid:173)
`propriate therapy should be administered and continuous
`cardiac monitoring should be performed during subsequent
`therapy with TAXOL.
`TAXOL may cause fetal harm when administered to a preg(cid:173)
`nant woman. TAXOL has been shown to be embryo- and feto(cid:173)
`toric in rats and rabbits and to decrease fertility in rats. In
`these studies, TAXOL was shown to result in abortions, de(cid:173)
`creased corpora lutea, a decrease in implantations and live
`fetuses, and increased resorptions and embryo-fetal deaths.
`No gross external, soft tissue or skeletal alterations oc(cid:173)
`curred. There are no studies in pregnant women. If T AXOL
`is used during pregnancy, or ifthe patient becomes pregnant
`while receiving this drug, the patient should be apprised of
`the potential hazard. Women of childbearing potential
`should be advised to avoid becoming pregnant during
`therapy with TAXOL.
`PRECAUTIONS
`Contact of the undiluted concentrate with plasticized polyvi(cid:173)
`nyl chloride (PVC) equipment or devices used to prepare
`solutions for infusion is not recommended. In order to mini(cid:173)
`mize patient exposure to the plasticizer DEHP [di-{2-<ithylex(cid:173)
`yl)phthalate, which may be leached from PVC infusion bags
`or sets, diluted TAXOL solutions should preferably be stored
`in bottles (glass, polypropylene) or plastic bags (polypropyl-
`
`ene, polyolefin) and administered through polyethylene(cid:173)
`lined administration sets.
`TAXOL should be administered through an in-line filter
`with a microporous membrane not greater than 0.22 mi(cid:173)
`crons. Use of filter devices such as IVEX-2® filters which
`incorporate short inlet and outlet PVC-coated tubing has not
`resulted in significant leaching of DEHP.
`Drug Interaction: In a Phase I trial1 using escalating doses
`of TAXOL (110--200 mg/m2) and cisplatin (50 or 75 mg/m2)
`given as sequential infusions, myelosuppression was more
`profound when TAXOL was given after cisplatin than with
`the alternate sequence (i.e., TAXOL before cisplatin). Phar(cid:173)
`macokinetic data from these patients demonstrated a de(cid:173)
`crease in paclitaxel clearance of approximately 33% when
`TAXOL was administered following cisplatin.
`Based on in vitro data, there is the possibility of an inhibition
`ofTAXOL metabolism in patients treated with ketoconazole.
`As a result, caution should be exercised when treating pa(cid:173)
`tients with TAXOL when they are receiving ketoconazole as
`concomitant therapy.
`Hematology: TAXOL therapy should not be administered
`to patients with baseline neutrophil counts of less than 1,500
`cells/mm3. In order to monitor the occurrence of myelotoxic(cid:173)
`ity, it is recommended that frequent peripheral blood cell
`
`Continued on next page
`
`Consult 1995 supplements and future editions for revisions
`
`r, b•• 3 """domired ""'' ~'" """''""" 00 '"""" "'' ""
`~·
`~ f rAXOL in patients with metastatic breast carcinoma.
`I. ~hose 2 open label studies: Two studies were conducted in 53
`
`tients previously treated with a maximum of one prior
`p~ motherapeutic regimen. T AXOL was administered in
`~h:se 2 trials as a 24-hour infusion at initial doses of 250 mg/
`Ill2 (with G-CSF support) or 200 mg/m2. The response rates
`re 57% (95% CJ: 37-75%) and 52% (95% CJ: 32-72%), re(cid:173)
`w;,ctiveJy. The third phase 2 study evaluated quality of life
`\anges and was conducted in extensively pretreated pa(cid:173)
`~· nts who had failed anthracycline therapy and who had
`16ceived a minimum of 2 chemotherapy regimens for the
`~eeatment of metastatic disease. The dose ofTAXOL was 200
`r g/m2 as a 24-hour infusion with G-CSF support. Nine of the
`W patients analyzed achieved a partial response, for a re-
`nse rate of 30% (95% CJ: 15-50%).
`~ose 3 randomized study: This multicenter trial was con(cid:173)
`ducted in patients previously treated with one or two regi(cid:173)
`mens of chemotherapy. Patients were randomized to re(cid:173)
`ceived TAXOL at a dose of either 175 mg/m2 or 135 mg/m2
`'ven as a 3-hour infusion. In the 471 patients enrolled, 60%
`rad symptomatic disease with impaired performance status
`at study entry, and 73% had visceral metastases. These pa(cid:173)
`tients had failed prior chemotherapy either in the adjuvant
`setting (30%), the metastatic setting (39%), or both (31 %).
`Sixty-seven percent of the patients had been previously ex(cid:173)
`posed to anthracyclines and 23% of them had disease consid(cid:173)
`ered resistant to this class of agents.
`The overall response rate for the 454 evaluable patients was
`26% (95% Cl: 22-30%), with 17 complete and 99 partial re(cid:173)
`sponses. The median duration of response, measured from
`the first day of
`treatment, was 8.1 months (range:
`3.4-18.1 + months). Overall for the 471 patients, the me(cid:173)
`dian time to progression was 3.5 months (range: 0.03-17.1
`months). Median survival was 11.7 months (range: 0-18.9
`months).
`Response rates, median survival and median time to progres(cid:173)
`sion for the 2 arms are given in the following table. The. arms
`are listed by dose and schedule (mg<>m2/hours).
`[See second table at right.]
`For the 458 patients who received TAXOL (paclitaxoi) for
`Injection Concentrate in the Phase 3 study, the following
`table shows the incidence of some key adverse events by
`treatment arm (each arm was administered by a 3-hour infu(cid:173)
`sion).
`[See third table at right.]
`Myelosuppression and peripheral neuropathy were dose
`related. There was one severe hypersensitivity reaction
`(HSR) observed at the dose of 135 mg/m2.
`INDICATIONS
`TAXOL is indicated, after failure of first-line or subsequent
`chemotherapy for the treatment of metastatic carcinoma of
`the ovary.
`TAXOL is indicated for the treatment of breast cancer after
`failure of combination chemotherapy for metastatic disease
`or relapse within 6 months of adjuvant chemotherapy. Prior
`therapy should have included an anthracycline unless clini(cid:173)
`cally contraindicated.
`CONTRAINDICATIONS
`TAXOL is contraindicated in patients who have a history of
`hypersensitivity reactions to T AXOL or other drugs formu(cid:173)
`lated in Cremophor® EL (polyoxyethylated castor oil).
`TAXOL should not be used in patients with baseline
`neutropenia 0f < 1,500 cells/mm3•
`WARNINGS
`Patients should be pretreated with corticosteroids (such as
`dexamethasone), diphenhydramine and H2 antagonists
`(such as cimetidine or ranitidine) before receiving T AXOL.
`(See "DOSAGE AND ADMINISTRATION" section.) Severe
`hypersensitivity reactions characterized by dyspnea and
`~ypotension requiring treatment, angioedema, and general(cid:173)
`ized urticaria have occurred in 2% of patients receiving
`TAXOL. These reactions are probably histamine-mediated.
`One of these reactions was fatal in a patient with pulmonary
`metastases who was a participant in a Phase I trial. This
`patient received no premedication; the first course of
`TAXOL, which was uneventful, was administered at 190
`mg/m2 infused over three hours. Within a few minutes from
`the beginning of a second course of T AXOL, the patient de(cid:173)
`veloped severe hypotension and died. Patients who experi(cid:173)
`ence severe hypersensitivity reactions to T AXOL should not
`be rechallenged with the drug. ·
`Bone marrow suppression (primarily neutropenia) is dose(cid:173)
`d:pendent and is the dose-limiting toxicity. Neutrophil na(cid:173)
`dirs occurred at a median of 11 days. TAXOL should not be
`administered in patients with baseline neutrophil counts of
`less than 1,500 cells/mm3. Frequent monitoring of blood
`~unts should be instituted during TAXOL treatment. Pa-
`ents should not be re-treated with subsequent cycles of
`AXOL until neutrophils recover to a level > 1,500 cells/
`mm3 and platelets recover to a level > 100,000 cells/mm3.
`Severe conduction abnormalities have been documented in
`<1% of patients duringTAXOL therapy and in some cases
`
`Th
`
`Actavis - IPR2017-01100
`Ex. 1008, p. 4 of 6
`
`

`

`684/PHYSICIANS' DESK REFERENCE®
`
`Bristol-Myers Squibb-Cont.
`
`counts be performed on all patients receiving TAXOL. Pa(cid:173)
`tients should not be re-treated with subsequent cycles of
`TAXOL until neutrophils recover to a level > 1,500 cells/
`mm3 and platelets recover to a level > 100,000 cells/mm3. In
`the case of severe neutropenia ( < 500 cells/mm3 for seven
`days or more) during a course ofTAXOL therapy, a 20% re(cid:173)
`duction in dose for subsequent courses of therapy is recom(cid:173)
`mended.
`Hypersensitivity Reactions: Patients with a history of se(cid:173)
`vere hypersensitivity reactions
`to products containing
`Cremophor® EL (e.g., cyclosporin for injection concentrate
`and teniposide for injection concentrate) should not be
`treated with TAXOL. In order to avoid the occurrence of
`severe hypersensitivity reactions, all patients treated with
`TAXOL should be premedicated with corticosteroids \such as
`dexamethasone), diphenhydramine and H2 antagonists
`(such as cimetidine or ranitidine). Minor symptoms such as
`flushing, skin reactions, dyspnea, hypotension or tachycar(cid:173)
`dia do not require interruption of therapy. However, severe
`reactions, such as hypotension requiring treatment, clyspnea
`requiring bronchodilators, angiodema or generalized urtica(cid:173)
`ria require immediate discontinuation of TAXOL and ag(cid:173)
`gressive symptomatic therapy. Patients who have developed
`severe hypersensitivity reactions should not be rechallenged
`with TAXOL.
`Cardiovascular: Hypotension and bradycardia have been
`observed during administration ofTAXOL, but generally do
`not require treatment. Frequent vital sign monitoring, par(cid:173)
`ticularly during the first hour ofTAXOL infusion, is recom(cid:173)
`mended. Continuous cardiac monitoring is not required ex(cid:173)
`cept for patients with serious conduction abnormalities. (See
`"WARNINGS" section.)
`Nervous System: Although, the occurrence of peripheral
`neurcipathy is frequent, the development of severe symptom(cid:173)
`atology is unusual and requires a dose reduction of 20% for
`all subsequent courses of TAXOL.
`Hepatic: There is no evidence that the toxicity ofTAXOL is
`enhanced in patients with elevated liver enzymes, but no
`data are available for patients with severe baseline cholesta(cid:173)
`sis. However, evidence suggests that the liver plays an im(cid:173)
`portant role in the metabolism ofTAXOL. As a result, since
`there are no data available from patients with severe liver
`disease, caution should be exercised when administering
`TAXOL to patients with severe hepatic impairment.
`Carcinogenesis, Mutagenesis, Impairment of Fertility: The
`carcinogenic potential of TAXOL has not been studied.
`TAXOL has been shown to be mutagenic in vitro (chromo(cid:173)
`some aberrations in human lymphocytes) and in vivo (micro(cid:173)
`nucleus test in mice) mammalian test systems, however, it
`did not induce mutagenicity in the Ames test or the CHO/
`HGPRT gene mutation assay. TAXOL at an I.V. dose of 1
`mg/kg (6 mg/m 2) produced low fertility and fetal toxicity in
`rats. TAXOL has also been shown to be maternal and em(cid:173)
`bryo-fetal toxic in rabbits receiving the drug at an I.V. dose
`of 3 mg/kg (33 mg/m2) during organogenesis. (See "WARN(cid:173)
`INGS" section.)
`Pregnancy: Pregnancy "Category D." (See "WARNINGS"
`section.)
`Nursing Mothers: It is not known whether the drug is ex(cid:173)
`creted in human milk. Because many drugs are excreted in
`human milk and because of the potential for serious adverse
`reactions in nursing infants, it is recommended that nursing
`be discontinued when receiving TAXOL therapy:
`Pediatric Use: The safety a