EXHIBIT 2001
`
`EXHIBIT 2001
`
`Cephalon Exhibit 2001
`
`IPR2016-00026
`
`Agila V. Cephalon
`
`

`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use TREANDA safely
`and effectively. See full prescribing information for TREANDA.
`TREANDA® (bendamustine hydrochloride) injection, for intravenous use
`TREANDA® (bendamustine hydrochloride) for injection, for intravenous use
`Initial U.S. Approval: 2008
` RECENT MAJOR CHANGES
`Dosage and Administration (2)
`09/2015
`Selection of TREANDA Formulation to Administer (2.1)
`09/2015
`Preparation for Intravenous Administration (2.4)
`09/2015
`Admixture Stability (2.5)
`03/2015
`Warnings and Precautions, Infections (5.2)
`11/2015
` INDICATIONS AND USAGE
`TREANDA is an alkylating drug indicated for treatment of patients with:
`• Chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other
`than chlorambucil has not been established. (1.1)
`• Indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within
`six months of treatment with rituximab or a rituximab-containing regimen. (1.2)
` DOSAGE AND ADMINISTRATION
`TREANDA is available in two formulations, a solution (TREANDA Injection) and a
`lyophilized powder (TREANDA for Injection). (2.1)
`Do not use TREANDA injection with devices that contain polycarbonate or acrylo-
`nitrile-butadiene-styrene (ABS), including most Closed System Transfer Devices
`(CSTDs). (2.1, 2.4)
`For CLL:
`• 100 mg/m2 infused intravenously over 30 minutes on Days 1 and 2 of a 28-day
`cycle, up to 6 cycles (2.2)
`• Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce
`dose to 50 mg/m2 on Days 1 and 2; if Grade 3 or greater toxicity recurs, reduce
`dose to 25 mg/m2 on Days 1 and 2. (2.2)
`• Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or
`greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle. (2.2)
`• Dose re-escalation may be considered. (2.2)
`For NHL:
`• 120 mg/m2 infused intravenously over 60 minutes on Days 1 and 2 of a 21-day
`cycle, up to 8 cycles (2.3)
`• Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose
`to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the
`dose to 60 mg/m2 on Days 1 and 2 of each cycle. (2.3)
`• Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity,
`reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater
`toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. (2.3)
`General Dosing Considerations:
`• Delay treatment for Grade 4 hematologic toxicity or clinically significant ≥ Grade 2
`non-hematologic toxicity. (2.2, 2.3)
` DOSAGE FORMS AND STRENGTHS
`Injection: solution-45 mg/0.5 mL or 180 mg/2 mL in a single-dose vial. (3)
`For Injection: 25 mg or 100 mg lyophilized powder in a single-dose vial for recon-
`stitution. (3)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`1.1 Chronic Lymphocytic Leukemia (CLL)
`1.2 Non-Hodgkin Lymphoma (NHL)
`2 DOSAGE AND ADMINISTRATION
`2.1 Selection of TREANDA Formulation to Administer
`2.2 Dosing Instructions for CLL
`2.3 Dosing Instructions for NHL
`2.4 Preparation for Intravenous Administration
`2.5 Admixture Stability
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Myelosuppression
`5.2 Infections
`5.3 Anaphylaxis and Infusion Reactions
`5.4 Tumor Lysis Syndrome
`5.5 Skin Reactions
`5.6 Other Malignancies
`5.7 Extravasation Injury
`5.8 Embryo-fetal Toxicity
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`7 DRUG INTERACTIONS
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.3 Nursing Mothers
`
` CONTRAINDICATIONS
`TREANDA is contraindicated in patients with a history of a hypersensitivity reaction to
`bendamustine. Reactions have included anaphylaxis and anaphylactoid reactions. (5.3)
` WARNINGS AND PRECAUTIONS
`• Myelosuppression: Delay or reduce dose. Restart treatment based on ANC and
`platelet count recovery. (2.2) Complications of myelosuppression may lead to
`death. (5.1)
`• Infections: Monitor for fever and other signs of infection or reactivation of infec-
`tions and treat promptly. (5.2)
`• Anaphylaxis and Infusion Reactions: Severe and anaphylactic reactions have
`occurred; monitor clinically and discontinue TREANDA. Pre-medicate in subsequent
`cycles for milder reactions. (5.3)
`• Tumor Lysis Syndrome: Acute renal failure and death; anticipate and use support-
`ive measures. (5.4)
`• Skin Reactions: Discontinue for severe skin reactions. Cases of SJS and TEN,
`some fatal, have been reported when TREANDA was administered concomitantly
`with allopurinol and other medications known to cause these syndromes. (5.5)
`• Other Malignancies: Pre-malignant and malignant diseases have been reported.
`(5.6)
`• Extravasation Injury: Assure good venous access and monitor infusion site during
`and after administration. (5.7)
`• Embryo-fetal toxicity: Fetal harm can occur when administered to a pregnant
`woman. Women should be advised to avoid becoming pregnant when receiving
`TREANDA. (5.8, 8.1)
` ADVERSE REACTIONS
`• Most common non-hematologic adverse reactions for CLL (frequency ≥15%) are
`pyrexia, nausea, and vomiting. (6.1)
`• Most common non-hematologic adverse reactions for NHL (frequency ≥15%) are
`nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, head-
`ache, weight decreased, dyspnea, rash, and stomatitis. (6.1)
`• Most common hematologic abnormalities for both indications (frequency ≥15%)
`are lymphopenia, anemia, leukopenia, thrombocytopenia, and neutropenia. (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals at
`1-800-896-5855 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
` DRUG INTERACTIONS
`Concomitant CYP1A2 inducers or inhibitors have the potential to affect the exposure
`of bendamustine. (7)
` USE IN SPECIFIC POPULATIONS
`• Renal Impairment: Do not use if CrCL is <40 mL/min. Use with caution in lesser
`degrees of renal impairment. (8.6)
`• Hepatic Impairment: Do not use in moderate or severe hepatic impairment. Use
`with caution in mild hepatic impairment. (8.7)
`See 17 for PATIENT COUNSELING INFORMATION
`
`Revised: 11/2015
`
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`8.8 Effect of Gender
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Chronic Lymphocytic Leukemia (CLL)
`14.2 Non-Hodgkin Lymphoma (NHL)
`15 REFERENCES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 Safe Handling and Disposal
`16.2 How Supplied
`16.3 Storage
`17 PATIENT COUNSELING INFORMATION
`*Sections or subsections omitted from the full prescribing information are not listed
`
`1
`
`CEPHALON, INC. -- EXHIBIT 2001 0001
`
`

`
`TREANDA® (bendamustine hydrochloride) Injection
`TREANDA® (bendamustine hydrochloride) for Injection
`
`TREANDA® (bendamustine hydrochloride) Injection
`TREANDA® (bendamustine hydrochloride) for Injection
`
`FULL PRESCRIBING INFORMATION
`1
`INDICATIONS AND USAGE
`1.1
`Chronic Lymphocytic Leukemia (CLL)
`TREANDA® is indicated for the treatment of patients with chronic lymphocytic leu-
`kemia. Efficacy relative to first line therapies other than chlorambucil has not been
`established.
`1.2
`Non-Hodgkin Lymphoma (NHL)
`TREANDA is indicated for the treatment of patients with indolent B-cell non-Hodgkin
`lymphoma that has progressed during or within six months of treatment with ritux-
`imab or a rituximab-containing regimen.
`2
`DOSAGE AND ADMINISTRATION
`2.1
`Selection of TREANDA Formulation to Administer
`TREANDA is available in two formulations, a solution (TREANDA Injection) and a
`lyophilized powder (TREANDA for Injection).
`Do not use TREANDA Injection if you intend to use closed system transfer devices
`(CSTDs), adapters and syringes containing polycarbonate or acrylonitrile-
`butadiene-styrene (ABS) prior to dilution in the infusion bag [see Dosage and
`Administration (2.4)].
`If using a syringe to withdraw and transfer TREANDA Injection from the vial into
`the infusion bag, only use a polypropylene syringe with a metal needle and poly-
`propylene hub to withdraw and transfer TREANDA Injection into the infusion bag.
`Polypropylene syringes are translucent in appearance.
`TREANDA Injection and the reconstituted TREANDA for Injection have different
`concentrations of bendamustine hydrochloride. The concentration of bendamustine
`hydrochloride in the solution is 90 mg/mL and the concentration of bendamustine
`hydrochloride in the reconstituted solution of lyophilized powder is 5 mg/mL. Do not
`mix or combine the two formulations.
`TREANDA Injection must be withdrawn and transferred for dilution in a biosafety
`cabinet (BSC) or containment isolator using a polypropylene syringe with a metal
`needle and a polypropylene hub.
`If a CSTD or adapter that contains polycarbonate or ABS is used as supplemental
`protection prior to dilution1, only use TREANDA for Injection, the lyophilized powder
`formulation [see How Supplied/Storage and Handling (16.1)].
`2.2
`Dosing Instructions for CLL
`Recommended Dosage:
`The recommended dose is 100 mg/m2 administered intravenously over 30 minutes
`on Days 1 and 2 of a 28-day cycle, up to 6 cycles.
`Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL:
`TREANDA administration should be delayed in the event of Grade 4 hematologic toxic-
`ity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic
`toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute
`Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reiniti-
`ated at the discretion of the treating physician. In addition, dose reduction may be
`warranted. [see Warnings and Precautions (5.1)]
`Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce
`the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity
`recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle.
`Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or
`greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle.
`Dose re-escalation in subsequent cycles may be considered at the discretion of the
`treating physician.
`2.3
`Dosing Instructions for NHL
`Recommended Dosage:
`The recommended dose is 120 mg/m2 administered intravenously over 60 minutes
`on Days 1 and 2 of a 21-day cycle, up to 8 cycles.
`Dose Delays, Dose Modifications and Reinitiation of Therapy for NHL:
`TREANDA administration should be delayed in the event of a Grade 4 hematologic tox-
`icity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic
`toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute
`Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reiniti-
`ated at the discretion of the treating physician. In addition, dose reduction may be
`warranted. [see Warnings and Precautions (5.1)]
`Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to
`90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to
`60 mg/m2 on Days 1 and 2 of each cycle.
`Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity,
`reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater
`toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle.
`2.4
`Preparation for Intravenous Administration
`TREANDA is a cytotoxic drug. Follow applicable special handling and disposal pro-
`cedures.1
`TREANDA Injection (45 mg/0.5 mL or 180 mg/2 mL solution)
`TREANDA Injection must be diluted in a biosafety cabinet (BSC) or containment iso-
`lator.
`• When preparing and transferring the concentrated TREANDA Injection solution
`into the infusion bag, do not use devices that contain polycarbonate or ABS.
`However, after dilution of TREANDA Injection into the infusion bag, devices
`that contain polycarbonate or ABS, including infusion sets, may be used.
`
`TREANDA Injection contains N,N-dimethylacetamide (DMA), which is incompat-
`ible with devices that contain polycarbonate or ABS. Devices, including CSTDs,
`adapters, and syringes that contain polycarbonate or ABS have been shown to dis-
`solve when they come in contact with DMA which is present in the product. This
`incompatibility leads to device failure (e.g., leaking, breaking, or operational failure
`of CSTD components), possible product contamination, and potential serious
`adverse health consequences to the practitioner, including skin reactions; or to
`the patient, including but not limited to, the risk of small blood vessel blockage if
`they receive product contaminated with dissolved ABS or polycarbonate. Devices
`that are compatible for use in dilution of TREANDA Injection are available.
`• If using a syringe to withdraw and transfer TREANDA Injection from the vial into
`the infusion bag, only use a polypropylene syringe with a metal needle and a poly-
`propylene hub to withdraw and transfer TREANDA Injection into the infusion bag.
`• Each vial of TREANDA Injection is intended for single dose only.
`• Aseptically withdraw the volume needed for the required dose from the 90 mg/mL
`solution using a polypropylene syringe with a metal needle and a polypropylene hub.
`• Immediately transfer the solution to a 500 mL infusion bag of 0.9% Sodium
`Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride
`Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45%
`Sodium Chloride Injection, USP, may be considered. The resulting final concentra-
`tion of bendamustine HCl in the infusion bag should be within 0.2 – 0.7 mg/mL.
`• After dilution of TREANDA Injection into the infusion bag, devices that contain
`polycarbonate or ABS, including infusion sets, may be used.
`• Visually inspect the filled syringe and the prepared infusion bag to ensure the lack
`of visible particulate matter prior to administration. The admixture should be a
`clear colorless to yellow solution.
`Use either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium
`Chloride Injection, USP, for dilution, as outlined above. No other diluents have been
`shown to be compatible.
`TREANDA for Injection (25 mg/vial or 100 mg/vial lyophilized powder)
`If a closed system transfer device or adapter that contains polycarbonate or ABS is
`to be used as supplemental protection during preparation1, only use TREANDA for
`Injection, the lyophilized formulation.
`• Each vial of TREANDA for Injection is intended for single dose only.
`• Aseptically reconstitute each TREANDA for Injection vial as follows:
` ◦ 25 mg TREANDA for Injection vial: Add 5 mL of only Sterile Water for Injection,
`USP.
` ◦ 100 mg TREANDA for Injection vial: Add 20 mL of only Sterile Water for Injection,
`USP.
`• Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine
`HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve
`in 5 minutes. The reconstituted solution must be transferred to the infusion bag
`within 30 minutes of reconstitution. If particulate matter is observed, the recon-
`stituted product should not be used.
`• Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL
`concentration) and immediately transfer to a 500 mL infusion bag of 0.9% Sodium
`Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride
`Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45%
`Sodium Chloride Injection, USP, may be considered. The resulting final concentra-
`tion of bendamustine HCl in the infusion bag should be within 0.2 – 0.6 mg/mL.
`After transferring, thoroughly mix the contents of the infusion bag.
`• Visually inspect the filled syringe and the prepared infusion bag to ensure the lack
`of visible particulate matter prior to administration. The admixture should be a
`clear and colorless to slightly yellow solution.
`Use Sterile Water for Injection, USP, for reconstitution and then either 0.9% Sodium
`Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP,
`for dilution, as outlined above. No other diluents have been shown to be compatible.
`General Information
`Parenteral drug products should be inspected visually for particulate matter and dis-
`coloration prior to administration whenever solution and container permit. Any unused
`solution should be discarded according to institutional procedures for antineoplastics.
`2.5
` Admixture Stability
`TREANDA Injection and TREANDA for Injection contain no antimicrobial preserva-
`tive. The admixture should be prepared as close as possible to the time of patient
`administration.
`TREANDA Injection (45 mg/0.5 mL or 180 mg/2 mL solution)
`Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dex-
`trose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours
`when stored under refrigerated conditions at 2-8°C (36-46°F) or for 2 hours when
`stored at room temperature (15° to 30°C or 59° to 86°F) and room light. Administra-
`tion of diluted TREANDA Injection must be completed within this period.
`TREANDA for Injection (25 mg/vial or 100 mg/vial lyophilized powder)
`Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45%
`Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored
`under refrigerated conditions at 2°-8°C (36° to 46°F) or for 3 hours when stored at
`room temperature (15° to 30°C or 59° to 86°F) and room light. Administration of
`reconstituted and diluted TREANDA for Injection must be completed within this period.
`3
`DOSAGE FORMS AND STRENGTHS
`• TREANDA Injection: 45 mg/0.5 mL or 180 mg/2 mL in a single-dose vial.
`• TREANDA for Injection: 25 mg or 100 mg white to off-white lyophilized powder in
`a single-dose vial for reconstitution.
`
`2
`
`CEPHALON, INC. -- EXHIBIT 2001 0002
`
`

`
`TREANDA® (bendamustine hydrochloride) Injection
`TREANDA® (bendamustine hydrochloride) for Injection
`
`TREANDA® (bendamustine hydrochloride) Injection
`TREANDA® (bendamustine hydrochloride) for Injection
`
`ADVERSE REACTIONS
`6
`The following serious adverse reactions have been associated with TREANDA in clini-
`cal trials and are discussed in greater detail in other sections of the label.
`• Myelosuppression [see Warnings and Precautions (5.1)]
`• Infections [see Warnings and Precautions (5.2)]
`• Anaphylaxis and Infusion Reactions [see Warnings and Precautions (5.3)]
`• Tumor Lysis Syndrome [see Warnings and Precautions (5.4)]
`• Skin Reactions [see Warnings and Precautions (5.5)]
`• Other Malignancies [see Warnings and Precautions (5.6)]
`• Extravasation Injury [see Warnings and Precautions (5.7)]
`Clinical Trials Experience
`6.1
`Because clinical trials are conducted under widely varying conditions, adverse reac-
`tion rates observed in the clinical trials of a drug cannot be directly compared to rates
`in the clinical trials of another drug and may not reflect the rates observed in practice.
`Chronic Lymphocytic Leukemia
`The data described below reflect exposure to TREANDA in 153 patients with CLL stud-
`ied in an active-controlled, randomized trial. The population was 45-77 years of age,
`63% male, 100% white, and were treatment naïve. All patients started the study at a
`dose of 100 mg/m2 intravenously over 30 minutes on Days 1 and 2 every 28 days.
`Adverse reactions were reported according to NCI CTC v.2.0. Non-hematologic
`adverse reactions (any grade) in the TREANDA group that occurred with a frequency
`greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%).
`Other adverse reactions seen frequently in one or more studies included asthenia,
`fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; head-
`ache; mucosal inflammation and stomatitis.
`Worsening hypertension was reported in 4 patients treated with TREANDA in the
`CLL trial and in none treated with chlorambucil. Three of these 4 adverse reactions
`were described as a hypertensive crisis and were managed with oral medications
`and resolved.
`The most frequent adverse reactions leading to study withdrawal for patients receiv-
`ing TREANDA were hypersensitivity (2%) and pyrexia (1%).
`Table 1 contains the treatment emergent adverse reactions, regardless of attribution,
`that were reported in ≥ 5% of patients in either treatment group in the randomized
`CLL clinical study.
`Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical
`Study in at Least 5% of Patients
`
`CONTRAINDICATIONS
`4
`TREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic
`and anaphylactoid reactions) to bendamustine. [see Warnings and Precautions (5.3)]
`5
`WARNINGS AND PRECAUTIONS
`5.1 Myelosuppression
`TREANDA caused severe myelosuppression (Grade 3-4) in 98% of patients in the two
`NHL studies (see Table 4). Three patients (2%) died from myelosuppression-related
`adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with
`Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV).
`In the event of treatment-related myelosuppression, monitor leukocytes, platelets,
`hemoglobin (Hgb), and neutrophils frequently. In the clinical trials, blood counts were
`monitored every week initially. Hematologic nadirs were observed predominantly in
`the third week of therapy. Myelosuppression may require dose delays and/or subse-
`quent dose reductions if recovery to the recommended values has not occurred by the
`first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy,
`the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [see
`Dosage and Administration (2.2) and (2.3)]
`5.2
`Infections
`Infection, including pneumonia, sepsis, septic shock, hepatitis and death has occurred
`in adult and pediatric patients in clinical trials and in postmarketing reports. Patients
`with myelosuppression following treatment with TREANDA are more susceptible to
`infections. Advise patients with myelosuppression following TREANDA treatment to
`contact a physician if they have symptoms or signs of infection.
`Patients treated with TREANDA are at risk for reactivation of infections including
`(but not limited to) hepatitis B, cytomegalovirus, Mycobacterium tuberculosis, and
`herpes zoster. Patients should undergo appropriate measures (including clinical and
`laboratory monitoring, prophylaxis, and treatment) for infection and infection reacti-
`vation prior to administration.
`5.3
`Anaphylaxis and Infusion Reactions
`Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms
`include fever, chills, pruritus and rash. In rare instances severe anaphylactic and
`anaphylactoid reactions have occurred, particularly in the second and subsequent
`cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Ask
`patients about symptoms suggestive of infusion reactions after their first cycle of
`therapy. Patients who experience Grade 3 or worse allergic-type reactions should not
`be rechallenged. Consider measures to prevent severe reactions, including antihis-
`tamines, antipyretics and corticosteroids in subsequent cycles in patients who have
`experienced Grade 1 or 2 infusion reactions. Discontinue TREANDA for patients with
`Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusions reactions
`as clinically appropriate considering individual benefits, risks, and supportive care.
`5.4
`Tumor Lysis Syndrome
`Tumor lysis syndrome associated with TREANDA treatment has occurred in patients
`in clinical trials and in postmarketing reports. The onset tends to be within the first
`treatment cycle of TREANDA and, without intervention, may lead to acute renal fail-
`ure and death. Preventive measures include vigorous hydration and close monitoring
`of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also
`been used during the beginning of TREANDA therapy. However, there may be an
`increased risk of severe skin toxicity when TREANDA and allopurinol are adminis-
`tered concomitantly [see Warnings and Precautions (5.5)].
`Skin Reactions
`5.5
`Skin reactions have been reported with TREANDA treatment in clinical trials and
`postmarketing safety reports, including rash, toxic skin reactions and bullous exan-
`thema. Some events occurred when TREANDA was given in combination with other
`anticancer agents.
`In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic
`epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see ritux-
`imab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some
`fatal, have been reported when TREANDA was administered concomitantly with allo-
`purinol and other medications known to cause these syndromes. The relationship to
`TREANDA cannot be determined.
`Where skin reactions occur, they may be progressive and increase in severity with
`further treatment. Monitor patients with skin reactions closely. If skin reactions are
`severe or progressive, withhold or discontinue TREANDA.
`5.6
`Other Malignancies
`There are reports of pre-malignant and malignant diseases that have developed in
`patients who have been treated with TREANDA, including myelodysplastic syndrome,
`myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The
`association with TREANDA therapy has not been determined.
`5.7
`Extravasation Injury
`TREANDA extravasations have been reported in post marketing resulting in hospital-
`izations from erythema, marked swelling, and pain. Assure good venous access prior
`to starting TREANDA infusion and monitor the intravenous infusion site for redness,
`swelling, pain, infection, and necrosis during and after administration of TREANDA.
`5.8
`Embryo-fetal Toxicity
`TREANDA can cause fetal harm when administered to a pregnant woman. Single
`intraperitoneal doses of bendamustine in mice and rats administered during organo-
`genesis caused an increase in resorptions, skeletal and visceral malformations, and
`decreased fetal body weights. [see Use in Specific Populations (8.1)]
`
`3
`
`Number (%) of patients
`TREANDA
`Chlorambucil
`(N=153)
`(N=143)
`Grade
`Grade
`3/4
`3/4
`
`All
`Grades
`
`All
`Grades
`
`121 (79)
`
`52 (34)
`
`96 (67)
`
`25 (17)
`
`1 (<1)
`
`00
`
`1 (<1)
`1 (<1)
`2 (1)
`
`21 (15)
`9 (6)
`5 (3)
`
`31 (20)
`24 (16)
`14 (9)
`
`36 (24)
`14 (9)
`13 (8)
`9 (6)
`
`7 (5)
`
`10 (7)
`9 (6)
`5 (3)
`
`11 (7)
`
`System organ class
`Preferred term
`Total number of patients
`with at least 1 adverse reaction
`Gastrointestinal disorders
`Nausea
`Vomiting
`Diarrhea
`General disorders and
`administration site conditions
`Pyrexia
`Fatigue
`Asthenia
`Chills
`Immune system disorders
`Hypersensitivity
`Infections and infestations
`Nasopharyngitis
`Infection
`Herpes simplex
`Investigations
`Weight decreased
`Metabolism and
`nutrition disorders
`Hyperuricemia
`Respiratory, thoracic and
`mediastinal disorders
`Cough
`Skin and subcutaneous
`tissue disorders
`3 (2)
`7 (5)
`4 (3)
`12 (8)
`Rash
`0
`2 (1)
`0
`8 (5)
`Pruritus
`The Grade 3 and 4 hematology laboratory test values by treatment group in the
`randomized CLL clinical study are described in Table 2. These findings confirm the
`myelosuppressive effects seen in patients treated with TREANDA. Red blood cell
`transfusions were administered to 20% of patients receiving TREANDA compared
`with 6% of patients receiving chlorambucil.
`
`2 (1)
`
`000 0 0
`
`1 (<1)
`
`0 0 0
`
`8 (6)
`8 (6)
`6 (4)
`1 (<1)
`
`3 (2)
`
`12 (8)
`1 (<1)
`7 (5)
`
`5 (3)
`
`6 (4)
`2 (1)
`
`00
`
`2 (1)
`
`0
`3 (2)
`
`0 0
`
`11 (7)
`
`3 (2)
`
`2 (1)
`
`6 (4)
`
`1 (<1)
`
`7 (5)
`
`1 (<1)
`
`CEPHALON, INC. -- EXHIBIT 2001 0003
`
`

`
`TREANDA® (bendamustine hydrochloride) Injection
`TREANDA® (bendamustine hydrochloride) for Injection
`
`TREANDA® (bendamustine hydrochloride) Injection
`TREANDA® (bendamustine hydrochloride) for Injection
`
`Number (%) of patients*
`
`Laboratory Abnormality
`
`Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who
`Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study
`TREANDA
`Chlorambucil
`N=150
`N=141
`All Grades
`Grade 3/4
`All Grades
`Grade 3/4
`n (%)
`n (%)
`n (%)
`n (%)
`Hemoglobin Decreased
`134 (89)
`20 (13)
`115 (82)
`12 (9)
`116 (77)
`16 (11)
`110 (78)
`14 (10)
`Platelets Decreased
`Leukocytes Decreased
`92 (61)
`42 (28)
`26 (18)
`4 (3)
`Lymphocytes Decreased
`102 (68)
`70 (47)
`27 (19)
`6 (4)
`113 (75)
`65 (43)
`86 (61)
`30 (21)
`Neutrophils Decreased
`In the CLL trial, 34% of patients had bilirubin elevations, some without associated
`significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in
`3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3%
`of patients, respectively. Patients treated with TREANDA may also have changes in
`their creatinine levels. If abnormalities are detected, monitoring of these parameters
`should be continued to ensure that further deterioration does not occur.
`Non-Hodgkin Lymphoma
`The data described below reflect exposure to TREANDA in 176 patients with indolent
`B-cell NHL treated in two single-arm studies. The population was 31-84 years of age,
`60% male, and 40% female. The race distribution was 89% White, 7% Black, 3%
`Hispanic, 1% other, and <1% Asian. These patients received TREANDA at a dose of
`120 mg/m2 intravenously on Days 1 and 2 for up to eight 21-day cycles.
`The adverse reactions occurring in at least 5% of the NHL patients, regardless of
`severity, are shown in Table 3. The most common non-hematologic adverse reac-
`tions (≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%)
`and pyrexia (34%). The most common non-hematologic Grade 3 or 4 adverse reac-
`tions (≥5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypoka-
`lemia and dehydration, each reported in 5% of patients.
`Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL
`Patients Treated with TREANDA by System Organ Class and Preferred Term (N=176)
`Number (%) of patients*
`
`All Grades
`
`Grade 3/4
`
`176 (100)
`
`94 (53)
`
`0
`
`7 (4)
`5 (3)
`6 (3)
`1 (<1)
`1 (<1)
`2 (1)
`
`00
`
`1 (<1)
`
`00
`
`19 (11)
`3 (2)
`0
`1 (<1)
`4 (2)
`1 (<1)
`
`000
`
`5 (3)
`0
`4 (2)
`0
`9 (5)
`11 (6)
`2 (1)
`0
`
`3 (2)
`
`3 (2)
`8 (5)
`1 (<1)
`9 (5)
`
`4
`
`13 (7)
`
`132 (75)
`71 (40)
`65 (37)
`51 (29)
`27 (15)
`22 (13)
`20 (11)
`18 (10)
`15 (9)
`8 (5)
`8 (5)
`
`101 (57)
`59 (34)
`24 (14)
`23 (13)
`19 (11)
`11 (6)
`11 (6)
`10 (6)
`8 (5)
`
`18 (10)
`18 (10)
`17 (10)
`15 (9)
`14 (8)
`11 (6)
`11 (6)
`11 (6)
`
`31 (18)
`
`40 (23)
`24 (14)
`22 (13)
`15 (9)
`
`System organ class
`Preferred term
`Total number of patients with at least
`1 adverse reaction
`Cardiac disorders
`Tachycardia
`Gastrointestinal disorders
`Nausea
`Vomiting
`Diarrhea
`Constipation
`Stomatitis
`Abdominal pain
`Dyspepsia
`Gastroesophageal reflux disease
`Dry mouth
`Abdominal pain upper
`Abdominal distension
`General disorders and administration s