Version: May 2007
`
`Rx Only
`
`ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for
`injectable suspension)
`(albumin-bound)
`
`(Patient Information Enclosed)
`
`WARNING
`
`ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for
`injectable suspension) should be administered under the supervision of a
`physician experienced in the use of cancer chemotherapeutic agents.
`Appropriate management of complications is possible only when adequate
`diagnostic and treatment facilities are readily available.
`
`ABRAXANE therapy should not be administered to patients with metastatic
`breast cancer who have baseline neutrophil counts of less than 1,500 cells/mmJ.
`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 aU patients
`receiving ABRAXANE.
`
`Note: An albumin form ofpaclitaxel may substantially affect a drug's
`functional properties relative to those of drug in solution. DO NOT
`SUBSTITUTE FOR OR WITH OTHER PAC UTAXEL FORMULATlONS_
`
`DESCRIPTION
`
`AB RAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable
`
`suspension) is an albumin-bound form ofpaclitaxel with a mean particle size of approximately
`
`130 nanometers. ABRAXANE is supplied as a white to yellow, sterile, lyophilized powder for
`
`reconstitution with 20 mL of 0.9% Sodium Chloride Injection, USP prior to intravenous infusion.
`
`Each single-use vial contains 100 mg of paclitaxel and approximately 900 mg of human albumin.
`
`Each mllliliter (mL) of reconstituted suspension contains 5 mg paclitaxel. ABRAXANE is free
`
`of solvents.
`
`Apotex v. Abraxis - IPR20 18-001 5 1, Ex. 1015, p.OI of26
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`

`

`The active agent in ABRAXANE® is paclitaxel, a natural product with antitumor activity.
`
`Pac1itaxel is obtained from TelXUS media. The chemical name for pac1itaxe l is SP,20-Epoxy-
`
`1,20,4, 7P,I Op,I3a-hexahydroxytax-II -en-9-one 4,1 O-diacetate 2-benzoate 13-ester with (2R,3S)(cid:173)
`
`N -benzoy 1-3 -phen y lisoserine.
`
`Pac1itaxe1 has the following stmctural formula:
`
`AcO
`
`o
`
`Paclitaxel is a white to ofT-white crystalline powde r with the empirical fonnula C47HslN0 14 and
`
`a molecular weight of 853 .9 1. It is highly lipophilic, insoluble in water, and melts at
`
`approximately 216°C to 2 17°C.
`
`CLINICAL PHARMACOLOGY
`Mechanism of Action
`
`ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectabl e
`
`suspension) is an anti microtubule agent that promotes the assembly of micro tubules from tubulin
`
`dimers and stabilizes microtubules by preventing depolymeri zation. This stability res ults in the
`
`inhibition of the normal dynamic reorganization of the microtubule network that is essential for
`
`vita l interphase and mitoti c cellular functi ons. Pac1itaxel induces abnorma l arrays or "'bundles"
`
`of mi crotubules throughout the cell cycle and multiple asters of microtubules during mitosis.
`
`Human Pharmacokinetics
`
`The pharmacokinetics of total paclitaxel following 30 and ISO-minute infusions of ABRAXANE
`at dose levels of 80 to 375 mg/m2 were detenn ined in clinical studies. Dose levels of mg/m2 refer
`
`to mg ofpac1 itaxel in ABRAXANE . Following intravenous admi nistration of ABRAXANE,
`
`pacJitaxel plasma concentrations declined in a biphasic manner, the initial rapid decline
`
`2
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`representing distribution to the peripheral compartment and the slower second phase representing
`
`drug elimination. The terminal half-life was about 27 hours.
`
`The drug exposure (AVCs) was dose proportional over 80 to 375 mg/m2 and the
`
`pharmacokinetics of pac lit axel for ABRAXANE® were independent of the duration of
`administration. At the recommended ABRAXANE clinical dose, 260 mg/m 2
`
`, the mean
`
`maximum concentration of paclitaxel, which occurred at the end of the infusion, was 18,741
`
`ng/mL. The mean total clearance was 15 Llhr/m2. The mean volume of distribution was 632
`Lim2
`
`; the large volume of distribution indicates extensive extravascular distribution and/or tissue
`
`binding of paclitaxel.
`
`The phannacokinetic data of260 mg/m2 ABRAXANE administered over 30 minutes was
`compared to the pharmacokinetics of 175 mg/m2 paclitaxel injection over 3 hours. The clearance
`
`of ABRAXANE was larger (43%) than for the clearance ofpaclitaxel injection and the volume
`
`of distribution of ABRAXANE was also higher (53%). Differences in Cmax and Cmax corrected
`
`for dose reflected differences in tota l dose and rate of infusion. ·fhere were no differences in
`
`terminal half-lives.
`
`In vitro studies of binding to human serum proteins, usi ng paclitaxel concentrations ranging from
`
`0.1 to 50 flg/mL, indicate that between 89% to 98% of drug is bound; the presence of cimetidine,
`
`ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel.
`
`After a 30-minute infusion of260 mg/m2 doses of ABRAXANE, the mean values for cumulative
`
`urinary recovery of unchanged drug (4%) indicated extensive non-renal clearance. Less than 1%
`
`of the total administered dose was excreted in urine as the metabolites 6a-hydroxypac1itaxel and
`
`3' -p-hydroxypaclitaxel. Fecal excretion was approximately 20% of the total dose administered.
`
`In vitro studies with human liver microsomes and tissue s lices showed that paclitaxel was
`
`metabolized primarily to 6a-hydroxypaclitaxel by CYP2C8; and to two minor metabolites, 3'-p(cid:173)
`
`hydroxypaclitaxel and 6a, 3'-p-dihydroxypaclitaxel, by CYP3A4. III vitro, the metabolism of
`
`paclitaxel to 6a-hydroxypaclitaxel was inhibited by a number of agents (ketoconazole,
`
`3
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`Apotex v. Abraxis - IPR2018-00151 , Ex. 1015, p.03 of26
`
`

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`verapamil, diazepam, quinidine, dexamethasone, cyclosporin, teniposide, eto poside, and
`
`vincristine), but the concentrations used exceeded those found in vivo fo llowing nonnal
`
`therapeutic doses. Testosterone, 17a-ethinyl estradiol, retinoic acid, and quercetin, a specific
`
`inhibitor ofCYP2C8, also inhibited the formation of6a-hydroxypaclitaxel ill vitro. The
`
`pharmacokinetics of paclitaxel may also be altered ill vivo as a result of interactions with
`
`compounds that are substrates, inducers, or inhibitors ofCYP2C8 and/or CYP3A4 (see
`
`PRECAUTIONS: Drug In teractio ns). The effect of renal or hepatic dysfunction on the
`
`disposition of ABRAXANE® has not been investi gated.
`
`Possible interactions of paclitaxel with concomitantly administered medications have not been
`
`formally investi gated.
`
`CLINICAL STUDIES
`
`Metastatic Breast Carcinoma:
`
`Data from 106 patients accrued in two single arm open label studies and from 460 patients
`
`enrolled in a randomized comparative study were available to support the use of ABRAXANE in
`
`metastatic breast cancer.
`
`Single Arm Open Label Studies- In one study, ABRAXANE was administered as a 30-minute
`infusion at a dose of 175 mg/m2 to 43 patients with metastatic breast cancer. The second trial
`utilized a dose of 300 mg/m2 as a 30 minute infusion in 63 patients with metastatic breast cancer.
`
`Cycles were administered at 3 week intervals. Objective responses were observed in both
`
`studies.
`
`Randomized Comparative Study- This multicenter trial was conducted in 460 patients with
`
`metastatic breast cancer. Patients were randomized to receive ABRAXANE at a dose of260
`mg/m2 given as a 30-minute infusion, or paclitaxel injection at 175 mg/m2 given as a 3-hour
`
`infusion. Sixty-four percent of patients had impaired perfonnance status (ECOG I or 2) at study
`
`entry; 79% had visceral metastases; and 76% had > 3 sites of metastases. Fourteen percent of the
`
`patients had not received prior chemotherapy; 27% had received chemotherapy in the adjuvant
`
`setting, 40% in the metastatic setting and 19% in both metastatic and adj uvant settings. Fifty-
`
`4
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`nine percent received study drug as second or greater than seco nd-line therapy. Seventy-seven
`
`percent of the patients had been previously exposed to anthracyc1ines.
`
`In this trial, patients in the ABRAXANE® treatment arm had a statistically significantly hi gher
`
`reconci led target lesion response rate (the trial primary endpoint) of 21 .5% (95% C1: 16.2% to
`
`26.7%), compared to 11.1 % (95% CI: 6.9% to 15. 1%) for patients in the pac1itaxel injection
`
`treatment arm. See Table 1. There was no statistica lly significant difference in overall survival
`
`between the two study arms.
`
`Table I : Efficacy Results from Ra ndom ized Trial
`
`ABRAXANE
`260 mglm!
`
`Paclitaxcllnjection
`175 mglm!
`
`Reconciled Target Lesion Response Rate (primary endpoint)
`
`a
`
`Response Rate
`
`50/233 (2 1.5%)
`
`25/227 (11.1%)
`
`All randomized patients
`
`[95% Gil
`
`P-value
`
`[16.19% - 26.73%]
`
`[6.94% - 15.09%]
`
`0.001
`
`Patients who had failed
`
`Response Rate
`
`20/129 (15.5 %)
`
`12/ 143 (8.4%)
`
`combination chemotherapy
`
`[95% GI]
`
`[9.26% - 21.75%]
`
`[3.85% - 12.94%]
`
`or relapsed w ithin 6 months
`
`of adjuvant chemotherapy'
`• Reconciled Ta rget Lesion Response Rate (TLRR) was the prospectively defined protocol
`specific endpoint, based on independent radiologic assessment of tumor responses
`
`reconciled with investigator responses (which also included clinical information) for the first
`
`6 cycles of therapy. The reconciled TLRR was lower than the investigator Reported
`
`Response Rates, which are based on all cycles of therapy.
`b From Cochran-Mantel-Haenszel test stratified by 1st line vs. > 1s1 1ine therapy.
`
`' Prior therapy included an anthracycline unless clin ically contraindicated.
`
`5
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`Apotex v. Abraxis - IPR2018-00 ISI , Ex. 10[5, p.OS of26
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`

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`INDICATION
`
`ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable
`
`suspension) is indicated for the treatment of breast ca ncer after failure of combination
`
`chemotherapy for metastatic disease or relapse withi n 6 mo nths of adjuvant chemotherapy. Prior
`
`therapy should have included an anthracycline un less clinically contraindicated.
`
`CONTRAINDICATIONS
`
`ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500
`cells/mm3
`
`.
`
`WARNINGS
`
`Bone marrow suppression (primarily neutropenia) is dose dependent and a dose limiting toxicity.
`
`ABRAXANE should not be administered to patients with baseline neutrophil co unts of < 1,500
`cells/rum3
`
`. Frequent monitoring of blood counts should be instituted during ABRAXANE
`
`treatment. Patients should not be retreated with subsequent cycles of ABRAXANE until
`neutrophi ls recover to a level > I ,500 cells/nun 3 and platelets recover to a level > I 00,000
`cells/mm3
`
`.
`
`The use of ABRAXANE has not been studied in patients with hepatic or renal dysfunction. In
`
`the randomi zed controlled trial, patients were excluded for baseline serum bilirubin > 1.5 mg/dL
`
`or baseline serum creatinine >2 mg/dL.
`
`Pregnancy - Teratogenic Effects: P regna ncy Category 0 : ABRAXANE can cause fetal
`
`harm when administered to a pregnant woman. Administration of paclitaxel protein-bound
`particles to rats on gestation days 7 to 17 at doses of 6 mg/m2 (approximately 2% of th e dai ly
`maximum recommended human dose on a mg/m2 basis) caused embryo- and fetotoxicity, as
`
`indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of
`
`litters and live fetuses. reduction in fetal body weight and increase in fetal anomalies. Fetal
`
`anomalies included soft tissue and skeletal malfonnations, such as eye bulge, folded retina,
`
`microphthalmia, and dilation of brain ventricles. A lower incidence of soft ti ssue and skeletal
`
`6
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`Apotex v. Abraxis - IPR20 18-00 151 , Ex. 1015, p.06 of 26
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`

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`malformations were also exhibited at 3 mg/m2 (approximately 1% of the da ily ma ximum
`recommended human dose on a mg/m2 basis).
`
`There are no adequate and well-controlled studies in pregnant women using ABRAXANE®. If
`
`th is drug is used duri ng pregnancy, or if the patient becomes pregnant while receiving this drug,
`
`the patient should be apprised of the potential hazard to the fetus. Women of childbearing
`
`potential should be advised to avoid becoming pregnant while receiving treatment with
`
`ABRAXANE.
`
`Use in Males: Men should be advised to not father a child while receiving treatment with
`
`ABRAXANE (see PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`for discussion of effects of ABRAXANE exposure on male fertility and embryonic viability).
`
`Albumin (Human): ABRAXANE contains albumin (human), a deri vative of human blood.
`
`Based on effective donor screening and product manufacturing processes, it carries an extremely
`
`remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt(cid:173)
`
`Jakob Disease (CID) also is considered extremely remote. No cases of transmission of viral
`
`diseases or CJD ha ve ever been identified for albumin
`
`PRECAUTIONS
`
`Drug Interactions: No drug interacti on studies have been conducted with ABRAXANE.
`
`The metabolism ofpaclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal
`
`clinical drug interacti on studies, caution should be exercised when administering ABRAXANE
`
`(paclitaxel protein-bound particles for injectable suspension) concomitantly with known
`
`substrates or inhibitors of CYP2C8 and CYP3A4 (see CLINICAL PHARMACOLOGY).
`
`Potential interactions between paclitaxel, a substrate of CY P3A4, and protease inhibitors (such
`
`as ri tonavir, saquinavir, indinavir, and nelfinavir), which are substrates and/or inhibitors of
`
`CYP3A4, have not been evaluated in clinical trials.
`
`7
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`Apotex v. Abraxis - IPR201 8-00151 , Ex. 1015, p.07 of 26
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`

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`Hematology: ABRAXANE® therapy should not be admi nistered to patients with baseline
`neutrophil counts ofless than 1,500 cells/mm3
`
`. In order to monitor the occurrence of
`
`myelotoxicity, it is recommended that frequent peripheral blood cell counts be performed on all
`
`patients receiving ABRAXANE. Patients should not be retreated with subsequent cycles of
`ABRAXANE until neutrophils recover to a level > I ,500 cells/mm3 and platelets recover to a
`. In the case of severe neutropenia «500 cells/mm3 for seven days or
`level > 100,000 cells/mm3
`
`more) during a course of ABRAXANE therapy, a dose reduction for subsequent courses of
`
`therapy is recommended (see DOSAGE and ADMINISTRATION).
`
`Nervous System: Sensory neuropathy occurs frequently with ABRAXANE. The occurrence
`
`of grade I or 2 sensory neuropathy does not generally require dose modification. If grade 3
`
`sensory neuropathy develops, treatment should be withheld until resolution to grade I or 2
`
`followed by a dose reduction for all subsequent courses of ABRAXANE (see DOSAGE and
`
`ADMINISTRATION).
`
`Injection Site Reaction: Injection site reactions occur infrequently with ABRAXANE and
`
`were mild in the randomized clinical trial. Given the possibility of extravasation, it is advisable
`
`to closely monitor the infusion site for possible infiltration during dnl g administration.
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility: The carcinogenic potential of
`
`ABRAXANE has not been studied.
`
`Paclitaxel has been shown to be c1astogeni c ill vitro (chromosome aberrations in human
`
`lymphocytes) and in vivo (micronucleus test in mice). ABRAXANE was not mutagenic in the
`
`Ames test or the CHOIHGPRT gene mutation assay.
`
`Administration of pac1itaxel protein-bound particles to male rats at 42 mg/m2 on a weekly basis
`(approximately 16% o f the daily maximum recommended human exposure on a mg/m2 basis) for
`
`II weeks prior to mating with untreated female rats resulted in significantly reduced fertility
`
`accompanied by decreased pregnancy rates and increased loss of embryos in mated females. A
`
`low incidence of skel etal and soft tissue fetal anomalies was also observed at doses of3 and 12
`
`8
`
`Apotex v. Abraxis - IPR20 18-00 151 , Ex. lOIS , p.08 of26
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`

`

`mglm2/week in thi s study (approximately I to 5% of the dai ly maximum recommend ed human
`exposure on a mg/m2 basis). Testi cular atrophy/degeneration has also been observed in single(cid:173)
`dose toxicology studies in rodents administered paclitaxel protein-bound particles at 54 mg/m2
`and dogs administered 175 mg/m2 (see WARNINGS).
`
`Pregnancy: Teratogenic Effects: Pregnancy Category 0 : (See \VARNINGS sec ti on).
`
`Nursing Mothers: It is not known whether paclitaxel is exc reted in human milk. Following
`
`intrave nous administration of carbon-14 labeled paclitaxel to rats on days 9 to 10 postpartum,
`
`concentrations ofradioactivity in milk were hi gher than in plasma and declined in parallel with
`
`the plasma concentrations. Because many drugs are excreted in human milk and because of the
`
`potential for serious adverse reacti ons in nursing infants, it is recommended that nurs ing be
`
`disconti nued when receiving ABRAXANE® therapy.
`
`Pediatric Use: The safety and effec tiveness of ABRAXANE in pedi atric pati ents have not
`
`been evaluated.
`
`Geriatric use: Of the 229 patients in the randomized study who received AB RAXANE, 11 %
`were at least 65 years of age and < 2% were 75 years or o lder. No toxicities occ urred notabl y
`
`more frequently among elderly patients who received ABRAXANE.
`
`Information for Patients: (See Patie nt Info r mation Lea flet).
`
`9
`
`Apotex v. Abraxis - IPR20 18-00 151 , Ex. 1015, p.09 of 26
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`ADVERSE REACTIONS:
`
`The following tabl e shows the frequency of important adverse events in the randomized
`
`comparative trial for the patients who received either single-agent ABRAXANE® or pac1itaxel
`
`injection for the treatment of metastatic breast cancer.
`
`Table 2: Fr equencyH of Importa nt Treatment Emergent Adverse Events in the
`
`Randomized Study on an Every-3-Weeks Schedule
`
`Percent of Patients
`
`ABRAXANE'A'
`260/30mi nb
`(n=229)
`
`Paclitaxcllnjcction
`d
`I 75/3h c
`•
`(n~22S)
`
`Bone Marrow
`Neutropenia
`< 2.0x I09/L
`< 0.5 x I09/L
`TIlfombocylopcnia
`< 100 x 109/L
`< SOx I09fL
`Anemia
`< I I gldL
`< SJdL
`Infections
`Febrile NClllfopcnia
`Bleeding
`H Y(ll'rsl'Dsitivify Rl.'llctio n"
`All
`Severef
`Ca rdio" llsc ular
`Vital Sign ChallJ!.csg
`Brad cardia
`Hypotension
`Severe Cardiovascular Eventsf
`Abnormal ECC
`All patients
`Patients with NOnlmi Baseline
`Rl'Spiratory
`Cough
`Dyspnea
`Sensory Neuropathy
`Any Symptoms
`Severe Symptoms
`Myalgia I Arthralgia
`Any Symptollls
`Severe Symptoms
`
`SO
`9
`
`2
`<I
`
`33
`1
`24
`2
`2
`
`4
`0
`
`<I
`5
`3
`
`60
`35
`
`7
`12
`
`71
`10
`
`44
`8
`
`10
`
`82
`22
`
`3
`<I
`
`25
`<I
`20
`1
`2
`
`12
`2
`
`<I
`5
`4
`
`52
`30
`
`6
`9
`
`56
`2
`
`49
`4
`
`Apotex v. Abraxis - IPR20 18-00 151 , Ex. 1015, p. 1 0 of 26
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`

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`Table 2: Frequency9 of Important Treatment Emergent Adverse Events in the
`
`Randomized Study on an Every-3-Weeks Schedule, Continued
`
`Perce nt of Patients
`
`ABRAXAN[~
`260/30minb
`(n~229)
`
`Paclitaxcllnjcction
`1 7 S/3h~·d
`(n~22S)
`
`3.
`3
`
`8
`<I
`
`22
`<I
`
`10
`I
`
`15
`I
`
`6
`0
`.4
`
`Asthenia
`Any Symptoms
`Severe Symptoms
`Fluid Retention/Edema
`Any Symptoms
`Severe Symptoms
`Gastrointestinal
`Nausea
`Any symptoms
`Severe symptoms
`Vomiting
`Any symptoms
`Severe Symptoms
`Diarrhea
`Any Symptoms
`Severe Symptoms
`Mucositis
`Any Symptoms
`Severe Symptoms
`Alopl'(;ia
`Hepatic (Patients with Nomlai
`Baseline)'
`lJilimbin Elevations
`Alkaline Phosphatase Elevations
`AST (SGO'I) Elevations
`Inje(tion Site Readion
`• Based 011 worst grade.
`b ABRA~ANE dose in mg/m2/duration in minutes.
`C pacl itaxel injection dose in mg/nl/durat ion in hours.
`d paclitaxcl injection pts received premedicat ion.
`C Includes treatment-related events rclated to hypersensitivity (e.g. , Oushing, dyspnea, chest pain, hypotension) that
`began on a day or dosi ng.
`f Severe events are defined as at least grade 3 toxic ity.
`! During snldy drug dosing.
`
`47
`8
`
`10
`0
`
`30
`3
`
`18
`4
`
`27
`<I
`
`7
`<I
`90
`
`7
`36
`3.
`<I
`
`7
`31
`32
`I
`
`II
`
`Apotex v. Abrax is - IPR201 8-00151 , Ex. 1015, p.11 of26
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`

`

`Myelosuppression and sensory neuropathy were dose related.
`
`Adverse Event Experiences by Body System: Unless otherwise noted, the following
`
`discussion refers to the primary safety database of 229 patients with metastatic breast cancer
`
`treated wi th single-agent AB RAXANE® in the randomized controlled trial. The frequency and
`
`severity of important adverse events for the study are presented above in ta bular form. In some
`
`instances, rare severe events observed with paclitaxel inj ection may be expected to occur with
`
`ABRAXANE.
`
`Hematologic: Neutropenia, the most important hematologic toxicity, was dose dependent and
`
`reversible. Among patients with metastatic breast cancer in the randomized trial, neutrophil
`counts declined below 500 cellslmm3 (G rade 4) in 9% of the patients treated with a dose of
`260 mg/m2 compared to 22% in patients receiving paclitaxel injection at a dose of 175 mg/m2
`
`.
`
`In the randomized metastatic breast cancer study, infectious episodes were reported in 24% of
`the patients treated with a dose of 260 mg/m2 given as a 30-minute infusion. Oral candidi asis,
`respiratory tract infections and pneumonia were the most frequently reported infectious
`
`complications. Febrile neutropenia was reported in 2% of patients in the ABRAXANE arm and
`
`1 % of patients in the paclitaxel injection arm.
`
`Thrombocytopenia was uncommon. In the randomized metastatic breast cancer study, bleeding
`
`episodes were reported in 2% of the patients in each treatment arm.
`
`Anemia (Hb < I I g/dL) was observed in 33% of patients treated with ABRAXANE in the
`
`randomized trial and was severe (Hb <8 g/dL) in 1% of the cases. Among all patients with
`
`normal baseline hemoglobin, 3 1% became anemic on study and 1% had severe anemia.
`
`Hypersensitivity Reactions (HSRs): In the randomized controlled metastatic breast cancer
`
`study, Grade 1 or 2 HSRs occurred on the day of ABRAXANE admi nistration and consisted of
`
`dyspnea (1 %) and fl ushing, hypotension, chest pain, and arrhythmia (aJI < I %). The use of
`
`12
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`

`

`ABRAXANE® in patients previously exhibiting hypersensitivity to paclitaxel injection or human
`
`albumin has not been studied.
`
`During postmarketing surveillance, rare occurrences of severe hypersensitivity reactions have
`
`been reported with AB RAXANE. The use of ABRAXANE in patients previously exhibiting
`
`hypersensitivity to paclitaxel injection or human albumin has not been studied. Patients who
`
`experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with
`
`the drug.
`
`Cardiovascular: Hypotension, during the 3D-minute infusion, occurred in 5% of patients in the
`
`randomized metastatic breast cancer trial. Bradycardia. during the 3D-minute infusion, occurred
`in < I % of patients. These vital sign changes most often caused no symptoms and required
`
`neither specifi c therapy nor treatment discontinuation.
`
`Severe cardiovasc ular events possibly related to single-agent ABRAXANE occurred in
`
`approximately 3% of patients in the randomized trial. These events included chest pain, cardiac
`
`arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism,
`
`pulmonary emboli, and hypertension. Cases of cerebrovascular attacks (strokes) and transient
`
`ischemic attacks have been reported rarely.
`
`Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG
`
`abnormalities on study did not usually res ult in symptoms, were not dose-limiting, and required
`
`no intervention. ECG abnormalities were noted in 60% of patients in the metastatic breast
`
`cancer randomized trial. Among patients with a normal ECG prior to study entry, 35% of all
`
`patients developed an abnormal tracing while on study. The most frequently reported ECG
`
`modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinus
`
`tachyca rdia.
`
`Respiratory: Reports of dyspnea (12%) and cough (6%) were reported after treatment with
`
`ABRAXANE in the randomized trial. Rare reports «I %) of pneumothorax were reported after
`
`treatment with ABRAXANE. Rare reports of interstitial pneumonia, lung fibrosis, and
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`pulmonary embolism have been received as part of the continuing surveillance of pac lit axel
`
`injection safety and may occur following ABRAXANE treatment. Rare reports of radiation
`
`pneumonitis have been received in paclitaxel injection patients receiving concurrent
`
`radiotherapy. There is no experience with the use of ABRAXANE with concurrent radiotherapy.
`
`Neurologic: The frequency and severity of neurologic manifestations were influenced by prior
`
`andlor concomitant therapy with neurotoxic agents.
`
`In general, the frequency and severity of neurologic manifestations were dose-dependent in
`
`patients receiving single-agent ABRAXANE®. In the randomized trial, sensory neuropathy was
`
`observed in 71 % of patients (10% severe) in the ABRAXANE arm and in 56% of patients (2%
`
`severe) in the paclitaxel injection arm. The frequency of se nsory neuropathy increased with
`
`cumulative dose. Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229
`
`(3%) patients in the randomized trial. In the randomized comparative study, 24 patients (10%)
`
`treated with ABRAXANE developed Grade 3 peripheral neuropathy; of these patients, 14 had
`
`documented improvement after a median of 22 days; 10 patients resumed treatment at a reduced
`dose of ABRAXANE and 2 discontinued due to peripheral neuropathy. Of the to patients
`without documented improvement, 4 discontinued the study due to peripheral neuropathy
`
`No incidences of grade 4 sensory neuropathies were reported in the clinical trial. Only one
`
`incident of motor neuropathy (grade 2) was observed in either ann of the controlled trial.
`
`Cranial nerve palsies have been reported during postmarketing surveillance of ABRAXANE.
`
`Because these events have been reported during clinical practice, true estimates of frequency
`
`cannot be made and a causal relationship to the events has not been established.
`
`Reports of autonomic neuropathy resulting in paralytic ileus have been received as part of the
`
`continuing surveillance of pac lit axel injection safety.
`
`Ocular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE in
`
`single ann and randomized trials and I % were severe. The severe cases (keratitis and blurred
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`vision) were reported in patients in a single arm study who received higher doses than those
`recommended (300 or 375 mg/m2
`
`). These effects generally have been reversible. However, rare
`
`reports in the literature of abnormal visual evoked potentials in patients treated with pac1itaxel
`
`injection have suggested persistent optic nerve damage.
`
`Arthralgia/Myalgia: Forty-four percent of patients treated in the randomized trial experienced
`
`arthralgia/myalgia; 8% experienced severe symptoms. The symptoms were usually transient,
`
`occurred two or three days after ABRAXANE® administration, and resolved within a few days.
`
`Hepatic: Among patients with nonnal baseline liver function treated with ABRAXANE in the
`
`randomized trial, 7%, 36%, and 39% had elevations in bilirubin, alkaline phosphatase, and AST
`
`(SGOT), respectively_ Grade 3 or 4 elevations in GGT were reported for 14% of patients treated
`
`with ABRAXANE and 10% of patients treated with paclitaxel injection in the randomized trial.
`
`Rare reports of hepatic necrosis and hepati c encephalopathy leading to death have been received
`
`as part o f the continuing surveillance of pac lit axel injection safety and may occ ur following
`ABRAXANE treatment.
`
`Renal: Overall II % of patients experienced creatinine elevation, I % severe. No
`
`discontinuations, dose reductions, or dose delays were caused by renal toxicities.
`
`Gastrointestinal (GI): Nausea/vomiting, diarrhea, and mucositis were reported by 33%, 27%,
`
`and 7% of ABRAXANE treated patients in the randomized trial.
`
`Rare reports of intestinal obstmction, intestinal perforation, pancreatitis, and ischemi c colitis
`
`have been received as part of the continuing surveillance ofpaclitaxel injection safety and may
`
`occur following ABRAXANE treatment. Rare reports of neutropenic enterocolitis (typhlitis),
`
`despite the coadministration ofG-CSF, were observed in patients treated with paclitaxel
`
`injection alone and in combination with other chemotherapeutic agents.
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`Injection Site Reaction : Injection site reactions have occurred infrequently with ABRAXANE
`
`and were mild in the randomized clinical trial. Recurrence of skin reactions at a site of previous
`
`extravasation following administration ofpac1itaxel injection at a different site, i.e., "recall", has
`
`been reported rarel y.
`
`Rare reports of more severe events such as phlebitis, cellulitis, induration, skin exfoliation,
`
`necrosis, and fibrosis have been received as part of the continuing surveillance of paclitaxel
`
`injection safety. In some cases the onset of the injection site reaction in paclitaxel injection
`
`patients either occurred during a prolonged infusion or was delayed by a week to ten days.
`
`Given the possibility of extravasation, it is advisable to closely monitor the infusion site for
`
`possible infiltration during drug administration.
`
`Asthenia: Asthenia was reported in 47% of patients (8% severe) treated with ABRAXANE® in
`
`the randomized trial. Asthenia included reports of asthenia, fatigue, weakness, lethargy and
`
`malaise.
`
`Other Clinical Events: Rare cases of cardiac ischemia/i nfarction and thrombosis/embolism
`
`possibly related to ABRAXANE treatment have been reported. Alopecia was observed in almost
`
`all of the patients. Nail changes (changes in pigmentation or discoloration of nail bed) were
`
`uncommon. Edema (fluid retention) was infrequent (10% of randomized trial patients); no
`
`patients had severe edema.
`
`The following rare adverse events have been reported as part of the continuing surveillance of
`
`paclitaxel injection safety and may occur following ABRAXANE treatment: skin abnormalities
`
`related to radiation recall as well as reports of Stevens-Johnson syndrome, toxic epidermal
`
`necrolysis, conjunctivitis, and increased lacrimation. As part of the continuing surveil1ance of
`
`ABRAXANE, skin reactions including generalized or maculo-papular rash, erythema, and
`
`pruritis have been observed. Additionally, there ha ve been case reports of photosensitivity
`
`reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine,
`
`reports of palmar-plantar erythrodysaesthesiae. Because these ewnts ha ve been reported during
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`clinical practice, true estimates of frequency cannot be made and a causal relationship to the
`
`events has not been established.
`
`Accidental Exposure: No reports of accidental exposure to AB RAXANE® have been received.
`
`However, upon inhalation ofpaclitaxel, dyspnea, chest pain, burning eyes, sore throat, and
`
`nausea have been reported. Following topical exposure, events have included tingling, burning,
`
`and redness.
`
`OVERDOSAGE
`
`There is no known antidote for AB RAXANE overdosage. The primary anticipated
`
`complications of overdosage would consist of bone marrow suppression, sensory neurotoxici ty,
`
`and mucositis.
`
`DOSAGE AND ADMINISTRATION
`
`After failure of combination chemotherapy for metastatic breast cancer or relapse within 6
`
`months of adjuvant chemotherapy, the recommended regimen for ABRAXANE for Injectable
`Suspension (paclitaxel protein-bound particles for injectable suspension) is 260 mg/m2
`
`administered intravenously over 30 minutes every 3 weeks.
`
`Hepatic Impairment: The appropriate dose of ABRAXANE for patients wi th bilirubin greater
`
`than 1.5 mg/dL is not known.
`
`Dose Reduction: Patients who experience severe neutropenia (neutrophil <500 cells/mm} for
`
`a week or longer) or severe sensory neuropathy during ABRAXANE therapy should have dosage
`reduced to 220 mg/m2 for subsequent courses of ABRAXANE. For recurrence of severe
`
`neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180
`mg/m2
`
`. For grade 3 sensory neuropathy hold treatment until resolution to grade I or 2, followed
`
`by a dose reduction for all subsequent courses of ABRAXANE.
`
`Preparation and Administration Precautions: ABRAXANE is a cytotoxic anticancer
`
`drug and, as with o