`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
` These highlights do not include all the information needed to use
` ABRAXANE safely and effectively. See full prescribing
`
`
` information for ABRAXANE.
`
`
`
`ABRAXANE® for Injectable Suspension (paclitaxel protein-bound
`
`
`
`
`particles for injectable suspension) (albumin-bound)
`
`Initial U.S. Approv al: 2005
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`• Use caution when handling c ytotoxic drugs. Closely monitor the
`
`
`
`infusion site f or extravasation and infiltration. No premedic ation is
`
`
`required prior to administration. (2.5)
`
`
`
`
`
`--------------------- DOSAGE FORMS AND STRENGTHS -------------------­
`
`
`
`
`
`• Single use vial containing 100 mg of paclitaxel. (3)
`
`
`
`
`------------------------------ CONTRAINDICATIONS ----------------------------­
`• Neutrophil c ounts of < 1,500 c ells/mm3. (4)
`
`
`
`
`
`
`
`• Severe hypers ensitivity reaction to ABRAXANE. (4)
`
`
`
`
`----------------------- WARNINGS AND PRECAUTIONS ---------------------­
`
`
`
`
`• ABRAXANE c aus es myelos uppression. Monitor CBC and withhold
`
`and/or reduc e the dos e as needed. (5.1)
`
`
`
`• Sens ory neuropathy occurs frequently and may require dos e
`
`
`reduction or treatment interruption. (5.2)
`
`
`
`• Severe hypers ensitivity reactions with f atal outc ome have been
`
`reported. Do not re-challenge with this drug. (5.3)
`
`
`
`• Exposure and toxic ity of paclitaxel c an be increas ed in patients with
`
`
`hepatic impairment; theref ore administer with c aution. (5.4)
`
`
`
`• ABRAXANE contains albumin derived from human blood, which has
`
`
`
`
`a theoretical risk of viral transmission. (5.5)
`
`
`
`
`• Fetal harm may occur when administered to a pregnant woman.
`
`
`
`Advise women of childbearing potential to avoid bec oming pregnant
`
`while receiving ABRAXANE. (5.6)
`
`
`
`
`
`
`
`• Advis e men not to father a child while on ABRAXANE. (5.7)
`
`
`
`
`------------------------------ ADVERSE REACTIONS ----------------------------­
`
`
`
`
`
`
`• The most common adverse reactions (≥ 20%) in metastatic breast
`
`
`
`
`cancer are alopecia, neutropenia, sensory neuropathy, abnormal
`
`
`
`
`ECG, f atigue/asthenia, myalgia/arthralgia, AST elevation, alkaline
`
`
`phos phatase elevation, anemia, naus ea, infections, and
`
`
`diarrhea. (6.1)
`
`
`
`
`
`• The most c ommon adverse reactions (≥ 20%) in NSCLC when us ed
`
`in c ombination with c arboplatin are anemia, neutropenia,
`
`
`
`thromboc ytopenia, alopecia, peripheral neuropathy, nausea, and
`
`fatigue. (6.2)
`
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Celgene
`
`Corporation at 1-888-423-5436 or FDA at 1-800-FDA-1088 or
`
`www.fda.gov/medwatch.
`
`
`
`
`------------------------------ DRUG INTERACTIONS -----------------------------­
`
`
`
`• Use c aution when c onc omitantly administering ABRAXANE with
`
`
`
`
`
`inhibitors or induc ers of either CYP2C8 or CYP3A4. (7)
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`
`
`
`FDA-approved patient labeling (Patient Information).
`
`
`
`Revised: XX/XX
`
`
`
`
`
`
`
`
`
`WARNING: NEUTROPENIA
`
`
`See full prescribing information for complete boxed warning.
`
`
`
`• Do not administer ABRAXANE therapy to patients with
`
`baseline neutrophil counts of less than 1,500 cells/mm3. (4)
`
`
`
`
`
`• It is recommended that frequent peripheral blood cell counts
`
`
`
`be performed to monitor the occurrence of bone marrow
`
`suppression. (4, 5.1, 6.1, 6.2)
`
`
`
`DO NOT SUBSTIT UTE FOR OR WITH OTHER PACLITAXEL
`FORM ULATIONS.
`
`
` -------------------------- RECENT MAJOR CHANGES -------------------------­
`
` • Indications and Us age. (1.2)
`
`
`
`
`
` 10/2012
`
`
` • Dosage and Administration. (2.2)
`
`
` 10/2012
`
`
` • W arnings and Prec autions, Hypers ensitivity. (5.3)
`
` 09/2012
`
` -------------------------- INDICATIONS AND USAGE ----------------------------­
`
`
` ABRAXANE is a microtubule inhibitor indic ated f or the treatment of:
`
`
`
`
` • Metastatic Breast Cancer, after failure of combination chemotherapy
`
`
` for metastatic dis eas e or relaps e within 6 months of adjuvant
`
`
` chemotherapy. Prior therapy should have included an anthrac yc line
`
`
` unless clinically c ontraindic ated. (1.1)
`
`
`
`
` • Locally advanced or metas tatic Non-Small Cell Lung Cancer
`
`
`
`
` (NSCLC), as first-line treatment in combination with c arboplatin, in
`
` patients who are not candidates f or curative surgery or radiation
`
`
`
` therapy. (1.2)
`
`
`
`
` ----------------------- DOSAGE AND ADMINISTRATION ---------------------­
` • Metastatic Breast Canc er: Rec ommended dosage of ABRAXANE is
`
`
`
`
`
`260 mg/m2 intravenous ly over 30 minutes every 3 weeks. (2.1)
`
`
`
`
`
`
`
`
`
`
`• Non-Small Cell Lung Canc er: Rec ommended dos age of ABRAXANE
`is 100 mg/m2 intravenously over 30 minutes on Days 1, 8, and 15 of
`
`
`
`
`
`
`
`
`
`each 21-day c ycle; c arboplatin AUC 6 mg• min/mL is given
`
`
`
`
`intravenous ly on Day 1 of eac h 21 day cycle immediately af ter
`
`
`ABRAXANE administration. (2.2)
`
`
`
`
`
`• No adjustment is nec ess ary for patients with mild hepatic
`
`
`
`
`
`impairment. W ithhold ABRAXANE if AST > 10 x ULN or
`
`
`
`
`bilirubin > 5 x ULN. Reduc e starting dos e in patients with moderate
`
`
`to s evere hepatic impairment. (2.3)
`
`
`
`
`• Dose Reductions: Dos e reductions or disc ontinuation may be
`
`
`needed bas ed on severe hematologic or neurologic toxicities. (2.4)
`
`
`
`
`
`
`
`Reference ID: 3320960
`
`
`1
`
`

`

` FULL PRESCRIBING INFORMATION: CONTENTS*
`
` WARNING: NEUTROPENIA
`
`
`
` 1
` INDICATIONS AND USAGE
`
`
`
`
` 1.1 Metastatic Breast Canc er
`
`
`
` 1.2 Non-Small Cell Lung Canc er
`
`
` 2 DOSAGE AND ADMINISTRATION
`
`
`
` 2.1 Metastatic Breast Canc er
`
`
`
` 2.2 Non-Small Cell Lung Canc er
`
`
`
`
` 2.3 Dos age in Patients with Hepatic Impairment
`
`
`
` 2.4 Dos e Reduction/Disc ontinuation Rec ommendations
`
`
` 2.5 Preparation and Administration Prec autions
`
`
`
` 2.6 Preparation for Intravenous Administration
`
`
`
` 2.7 Stability
`
`
`
` 3 DOSAGE FORMS AND STRENGTHS
`
` 4 CONTRAINDICATIONS
`
`
` 5 WARNINGS AND PRECAUTIONS
`
`
` 5.1 Hematologic Effects
`
`
` 5.2 Nervous System
`
`
`
` 5.3 Hypers ensitivity
`
`
`
` 5.4 Hepatic Impairment
`
`
` 5.5 Albumin (Human)
`
`
`
` 5.6 Use in Pregnanc y
`
`
`
` 5.7 Use in Men
`
`
` 6 ADVERSE REACTIONS
`
`
`
`
`
`
`
` 6.1 Clinical Trials Experience in Metas tatic Breast Canc er
`
`
`
` 6.2 Clinical Trials Experience in Non-Small Cell Lung Canc er
`
`
`
`
` 6.3 Post-Marketing Experienc e with ABRAXANE and other
`
`
`
` Paclitaxel Formulations
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 6.4 Accidental Exposure
`
`
`
`
` 7 DRUG INTERACTIONS
`
` 8 USE IN SPECIFIC POPULATIONS
`
` 8.1 Pregnanc y
`
`
`
`
` 8.3 Nursing Mothers
`
`
` 8.4 Pediatric Use
`
`
`
` 8.5 Geriatric Us e
`
`
`
` 8.6 Patients with Hepatic Impairment
`
`
`
` 8.7 Patients with Renal Impairment
`
`
`
`
` 10 OVERDOSAGE
`
`
` 11 DESCRIPTION
`
`
` 12 CLINICAL PHARMACOLOGY
`
`
` 12.1 Mechanism of Action
`
`
` 12.3 Pharmac okinetics
`
`
` 13 NONCLINICAL TOXICOLOGY
`
`
`
`
` 13.1 Carcinogenesis, Mutagenes is, Impairment of Fertility
`
` 14 CLINICAL STUDIES
`
`
`
`
`
` 14.1 Metastatic Breast Canc er
`
`
` 14.2 Non-Small Cell Lung Canc er
`
` 15 REFERENCES
`
`
`
` 16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
` 16.1 How Supplied
`
`
`
` 16.2 Storage
`
`
`
`
` 16.3 Handling and Dispos al
`
`
` 17 PATIENT COUNSELING INFORMATION
`
`
`
`
`
`
`
`* Sections or subs ections omitted from the full prescribing information
`
`
`are not listed.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3320960
`
`2
`
`

`

` FULL PRESCRIBING INFORM ATION
`
`
`
`
` ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound)
`
`
`
`
`
`
` WARNING: NEUTROPENIA
`
` • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1,500
`
`
`
`
`
` cells/mm3 . In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which
`
`
`may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be
`
`
`
`
`performed on all patients receiving ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1)
`
`
`
`
`
`and Adverse Reactions (6.1, 6.2)].
`
`
`
`• Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those
`
`
`
`
`
` of drug in solution. DO NOT SUBSTIT UTE FOR OR WITH OTHER PACLIT AXEL FORM ULATIONS.
`
`
`
`
`
`
`
`
`
`
`INDICATIONS AND USAGE
`
`
`DOSAGE AND ADMINISTRATION
`
`
`
`1
`
`M etastatic Breast Cancer
`1.1
`
`
`ABRAXANE is indic ated f or the treatment of breast c anc er after f ailure of combination chemotherapy f or metastatic dis eas e or
`
`
`
`
`
`relaps e within 6 months of adjuvant chemotherapy. Prior therapy s hould have included an anthrac yc line unless clinically
`
`
`
`
`contraindic ated.
`
`
`Non-Small Cell Lung Cancer
`1.2
`
`
`ABRAXANE is indicated f or the first-line treatment of loc ally advanc ed or metastatic non-small c ell lung c anc er, in combination with
`
`
`
`
`
`carboplatin, in patients who are not c andidates for curative s urgery or radiation therapy.
`
`
`
`
`
`
`2
`
`M etastatic Breast Cancer
`2.1
`
`
`After failure of c ombination chemotherapy f or metastatic breast cancer or relaps e within 6 months of adjuvant c hemother apy, the
`
`
`
`
`
`rec ommended regimen f or ABRAXANE is 260 mg/m2 administered intravenous ly over 30 minutes every 3 weeks.
`
`
`
`
`
`
`Non-Small Cell Lung Cancer
`2.2
`
`
`The rec ommended dos e of ABRAXANE is 100 mg/m2 administered as an intravenous infusion over 30 minutes on Days 1, 8, and
`
`
`
`
`
`
`
`
`15 of eac h 21-day c ycle. The rec ommended dos e of c arboplatin is AUC = 6 mg• min/mL on D ay 1 only of each 21-day cycle,
`
`
`
`
`
`
`
`
`beginning immediately after the c ompletion of ABRAXANE administration.
`
`
`
`
`Dosage in Patients with Hepatic Impairment
`2.3
`
`
`
`
`No dos e adjustment is nec ess ary f or patients with mild hepatic impairment. Patients with moderate and s evere hepatic impairment
`
`
`
`
`
`
`
`treated with ABRAXANE may be at increas ed ris k of toxic ities known to paclitaxel. W ithhold ABRAXANE if AST >10 x ULN or
`
`
`
`
`
`
`
`
`bilirubin > 5 x ULN. Rec ommendations f or dos age adjustment f or the first course of therapy are shown in T able 1.
`
`
`
`
`
`
`
`For metastatic breast c anc er, the dos e of ABRAXANE c an be increas ed from 130 mg/m2 up to 200 mg/m2 in patients with s evere
`
`
`
`
`
`hepatic impairment in subsequent c ycles bas ed on individual tolerance.
`
`
`
`
`
`For non-small c ell lung c anc er, reduc e the dose of ABRAXANE to 50 mg/m2 in patients with s evere hepatic impairment. In
`
`
`
`
`
`
`
`
`subs equent c ycles, the dose of ABRAXANE may be increas ed to 75 mg/m2 as tolerated.
`
`
`
`
`
`
`
`Monitor patients clos ely [see Warnings and Precautions (5.4), Use in Spec ific Populations (8.6), and Clinical Pharmacology (12.3)].
`
`
`
`
`
`
`
`
`
`
`
`
`Mild
`
`
`
`
` Moderate
`
`
`
` Severe
`
`
`Table 1: Recommendations for Starting Dose in Patients with Hepatic Impairment
`
`
`
`
` ABRAXANE Dosea
`
`
`
` NSCLC
`
` MBC
`260 mg/m2
`100 mg/m2
`
`SGOT (AST) Levels
`
`
`
`
`Bilirubin Levels
`
`
`< 10 x ULN
`
`
`> ULN to ≤ 1.25 x ULN
`
`
`
`
`
`
`
`
`
`
`
`
` < 10 x ULN
`
`
`
` < 10 x ULN
`
`
`
` AND
`
`
`
` 1.26 to 2 x ULN
`
`
`
` 2.01 to 5 x ULN
`
`
`
` 200 mg/m2
`
`
`
` 130 mg/m2 b
`
`
`
` 75 mg/m2
`
`
`
` 50 mg/m2 c
`
` OR
` > 10 x ULN
`
`
`
`
`
` > 5 x ULN
`MBC = Metastatic Breas t Canc er; NSCLC = Non-Small Cell Lung Canc er.
`
`
`
`
` a Dos age rec ommendations are for the first c ours e of therapy. The need f or further dose adjustments in subs equent c ours es should
`
`
` be bas ed on individual toleranc e.
`
`
`
` b A dos e increas e to 200 mg/m2 in s ubs equent c ours es should be c onsidered bas ed on individual tolerance.
`
`c Increas e dos e to 75 mg/m2 in s ubs equent c ours es, as tolerated.
`
`
`
`
`
`
`
`
`
` not eligible
`
`
`
` not eligible
`
`
`
`
`Reference ID: 3320960
`
`
`3
`
`

`

`
`
` Dose Reduction/Discontinuation Recommendations
`
`
` 2.4
`
`
`
` Metastatic Breast Cancer
` Patients who experienc e s evere neutropenia (neutrophil <500 c ells/mm3 for a week or longer) or s evere s ens ory neuropathy during
`
`
`
`
`
`
`
`ABRAXANE therapy should have dos age reduc ed to 220 mg/m2 for subs equent c ours es of ABRAXANE. For recurrenc e of s evere
`
`
`neutropenia or s evere s ens ory neuropathy, additional dos e reduction should be made to 180 mg/m2. For Grade 3 s ens ory
`
`
`
`
`
`
`neuropathy hold treatment until res olution to Grade 1 or 2, f ollowed by a dos e reduction for all s ubs equent courses of ABRAXANE
`
`
`
`
`
`
`
`
`[see Contraindications (4), Warnings and Precautions (5.1, 5.2) and Adverse Reactions (6.1)].
`
`
`
`
`Non-Small Cell Lung Cancer
`
`
`• Do not administer ABRAXANE on Day 1 of a c ycle until abs olute neutrophil c ount (ANC) is at least 1500 c ells/mm3 and platelet
`
`
`
`
`
`
`
`
`
`
`
`count is at leas t 100,000 cells/mm3 [see Contraindications (4),Warnings and Precautions (5.1) and Adverse Reactions (6.2)].
`
`
`
`
`
`
`
`• In patients who develop s evere neutropenia or thromboc ytopenia withhold treatment until c ounts rec over to an abs olute neutrophil
`
`
`
`
`count of at least 1500 c ells/mm3 and platelet c ount of at least 100,000 c ells/mm3 on Day 1 or to an abs olute neutrophil c ount of at
`
`
`
`
`
`
`
`
`
`
`least 500 cells/mm3 and platelet c ount of at leas t 50,000 c ells/mm3 on Days 8 or 15 of the c ycle. Upon resumption of dos ing,
`
`
`
`
`
`
`
`
`permanently reduc e ABRAXANE and c arboplatin dos es as outlined in Table 2.
`
`
`
`
`• W ithhold ABRAXANE for Grade 3-4 peripheral neuropathy. Resume ABRAXANE and c arboplatin at reduc ed dos es (s ee T able 2)
`
`
`
`when peripheral neuropathy improves to Grade 1 or c ompletely res olves [s ee Warnings and Precautions (5.2) and Adverse
`
`
`
`
`
`
`
`Reactions (6.2)].
`
`
`
`
`Table 2: Permanent Dose Reductions for Hematologic and Neurologic Adverse Drug Reactions in NSCLC
`
`
`
`
`
`
`
`
`
`
`Adverse Drug Reaction
`
`
`
`Occurrence
`
`
`Weekly
`
`ABRAXANE Dose
`
`
`(mg/m2)
`
`
`Every 3-Week
`Carboplatin Dose
`
`
`(AUC mg•min/mL)
`
`
`Neutropenic Fever (ANC less than 500/mm3 with fever
`
`
`
`
`
`
` >38°C)
`
`First
`
`
`
`Sec ond
`
`
`Third
`
`First
`
`
`
`Sec ond
`
`First
`
`
`
`
`Sec ond
`
`
`Third
`
`75
`
`
`
`50
`
`75
`
`
`
`75
`
`
`50
`
`4.5
`
`
`
`3
`
`
`Discontinue Treatment
`
`4.5
`
`
`
`Discontinue Treatment
`
`
`4.5
`
`
`3
`
`
`Discontinue Treatment
`
` OR
`
` Delay of next cycle by more than 7 days for ANC less than
`
`1500/mm3
`
`
`
`
`
`
`
`
`
`
`OR
`
`ANC less than 500/mm3 for more than 7 days
`
`
`
`
`Platelet c ount less than 50,000/mm3
`
`
`
`
`
`
`
`
`Severe s ens ory Neuropathy – Grade 3 or 4
`
`
`
`
`Preparation and Administration Precautions
`2.5
`
`
`
`
`ABRAXANE is a c ytotoxic drug and, as with other potentially toxic paclitaxel compounds, caution should be exercis ed in handling
`
`
`
`
`
`ABRAXANE. The us e of gloves is rec ommended. If ABRAXANE (lyophilized c ake or rec onstituted suspension) contacts the skin,
`
`
`
`
`
`
`
`was h the skin immediately and thoroughly with s oap and water. Following topical exposure to paclitaxel, events may include tingling,
`
`
`
`
`
`
`
`burning and redness. If ABRAXANE c ontacts muc ous membranes , the membranes should be flushed thoroughly with water.
`
`
`
`
`
`
`
`
`Given the possibility of extravas ation, it is advis able to clos ely monitor the infusion site f or possible infiltration during drug
`
`
`
`
`
`administration. Limiting the infusion of ABRAXANE to 30 minutes, as direc ted, reduces the likelihood of infusion-related reactions
`
`
`
`[see Advers e Reactions (6.3)].
`
`
`
`
`
`
`
`Premedic ation to prevent hypers ensitivity reactions is generally not needed prior to the administration of ABRAXANE.
`
`
`
`
`
`Premedic ation may be need ed in patients who have had prior hypersensitivity reactions to ABRAXANE. Patients who experienc e a
`
`
`
`
`
`severe hypersensitivity reaction to ABRAXANE should not be re-challenged with this drug [see Warnings and Precautions (5.3)].
`
`
`
`
`Reference ID: 3320960
`
`
`4
`
`

`

`
`
` Preparation for Intravenous Administration
`
`
`
`
` 2.6
`
` ABRAXANE is supplied as a sterile lyophilized powder f or rec onstitution bef ore use. AVOID ERRORS, READ ENTIRE
`
`
`
` PREPARATION INSTRUCTIONS PRIOR TO RECONSTITUTION.
`
`
`
`
` 1.
`
` 2.
`
`
`
`
`
`
`
`
`
` Aseptic ally, rec onstitute eac h vial by injecting 20 mL of 0.9% Sodium Chloride Injection, USP.
` Slowly inject the 20 mL of 0.9% Sodium Chloride Injec tion, USP, over a minimum of 1 minute, using the
`
`
`
`
`
` sterile s yringe to direct the s olution flow onto the INSIDE W ALL OF THE VIAL.
`
`
`
`
`
`
`3.
`
`
`4.
`
`
`5.
`
`
`
`DO NOT INJECT the 0.9% Sodium Chloride Injection, USP, directly onto the lyophilized cake as this will
`
`
`
`
`
`result in f oaming.
`
`Onc e the injection is c omplete, allow the vial to sit f or a minimum of 5 minutes to ens ure proper wetting of
`
`
`
`
`
`
`the lyophilized c ake/powder.
`
`Gently swirl and/or invert the vial slowly f or at least 2 minutes until complete dissolution of any c ake/powder
`
`
`
`
`
`
`occurs. Avoid generation of f oam.
`
`If foaming or clumping occ urs, stand s olution f or at least 15 minutes until f oam subsides.
`
`
`
`
`
`6.
`
`
`Each mL of the rec onstituted formulation will c ontain 5 mg/mL paclitaxel.
`
`
`
`
`Calculate the exact total dosing volume of 5 mg/mL suspension required f or the patient: Dosing volume (mL) = T otal dos e (mg)/5
`
`
`
`(mg/mL).
`
`
`The rec onstituted suspension should be milky and homogenous without visible particulates. If particulates or s ettling are visible, the
`
`
`
`
`vial should be gently inverted again to ensure c omplete res uspension prior to use. Discard the reconstituted suspension if
`
`
`
`precipitates are obs erved. Disc ard any unus ed portion.
`
`
`
`
`Injec t the appropriate amount of rec onstituted ABRAXANE into an empty, sterile intravenous bag [plasticized polyvinyl chloride
`
`
`
`(PVC) containers, PVC or non-PVC type intravenous bag]. The us e of specialized DEHP-free s olution c ontainers or administration
`
`
`
`
`
`
`
`sets is not nec ess ary to prepare or administer ABRAXANE infusions. The us e of an in-line filter is not rec ommended.
`
`
`
`
`
`
`
`Parenteral drug products should be inspected visually f or partic ulate matter and discoloration prior to administration whenever
`
`
`
`
`
`solution and c ontainer permit.
`
`
`Stability
`2.7
`
`
`Unopened vials of ABRAXANE are stable until the date indic ated on the pac kage when stored between 20ºC to 25ºC (68ºF to 77ºF)
`
`
`
`
`
`
`
`
`in the original pac kage. Neither freezing nor refrigeration advers ely af fects the stability of the product.
`
`
`
`
`Stability of Reconstituted Suspens ion in the Vial
`
`Rec onstituted ABRAXANE in the vial should be us ed immediately, but may be refrigerated at 2ºC to 8ºC (36ºF to 46ºF) f or a
`
`
`
`maximum of 8 hours if nec ess ary. If not us ed immediately, eac h vial of rec onstituted suspension should be replac ed in the original
`
`
`
`
`
`carton to protect it from bright light. Disc ard any unus ed portion.
`
`
`
`Stability of Reconstituted Suspens ion in the Infus ion Bag
`
`The suspension for infusion when prepared as rec ommended in an infusion bag should be us ed immediately but may be stored at
`
`
`
`
`
`
`
`ambient temperature (approximately 25ºC) and lighting c onditions f or up to 4 hours. Discard any unused portion.
`
`
`
`
`3
`DOSAGE FORMS AND STRENGTHS
`
`
`Single us e vials c ontaining 100 mg of pac litaxel.
`
`
`
`
`4
`
`CONTRAINDICATIONS
`
`• ABRAXANE should not be us ed in patients who have bas eline neutrophil c ounts of < 1,500 cells/mm3 .
`
`
`
`
`
`• Patients who experienc e a s evere hypers ensitivity reac tion to ABRAXANE should not be rechallenged with the drug.
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3320960
`
`
`5
`
`

`

`
`
`
`WARNINGS AND PRECAUTIONS
`
`5
`
`
`
`Hematologic Effects
`5.1
`
`
`
`Bone marrow s uppression (primarily neutropenia) is dos e-dependent and a dose-limiting toxicity of ABRAXANE. In clinical studies,
`
`
`
`
`
`Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast c anc er (MBC) and 47% of patients with non-small cell
`
`lung c anc er (NSCLC).
`
`
`
`
`
`Monitor f or myelotoxicity by perf orming c omplete blood c ell c ounts frequently, including prior to dosing on Day 1 (f or MBC) and
`
`
`
`
`
`
`
`
`Days 1, 8, and 15 (for NSCLC). Do not administer ABRAXANE to patients with baseline abs olute neutrophil c ounts (ANC) of less
`than 1,500 c ells/mm3. In the c as e of s evere neutropenia (<500 c ells/mm3 for s even days or more) during a c ours e of ABRAXANE
`
`
`
`
`therapy, reduc e the dos e of ABRAXANE in subs equent c ours es in patients with either MBC or NSCLC.
`
`
`
`
`
`
`
`
`
`In patients with MBC, res ume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1,500 c ells/mm3
`
`
`
`
`
`
`
`
`and platelets rec over to a level >100,000 c ells/mm3 .
`
`
`
`In patients with NSCLC, res ume treatment if rec ommended (s ee Dos age and Administration, T able 2) at permanently reduc ed
`
`
`
`
`
`
`dos es f or both weekly ABRAXANE and every-3-week c arboplatin after ANC rec overs to at least 1500 cells/mm3 and platelet c ount
`
`
`
`
`
`
`
`
`
`of at leas t 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 c ells/mm3 and platelet c ount of at leas t 50,000 c ells/mm3 on
`
`
`
`
`
`
`
`
`
`
`Days 8 or 15 of the c ycle [s ee Dosage and Administration (2.4)].
`
`
`
`
`
`Nervous System
`5.2
`
`
`Sens ory neuropathy is dos e- and schedule-dependent [see Adverse Reactions (6.1, 6.2)]. The occurrenc e of Grade 1 or 2 s ens ory
`
`
`
`
`
`
`
`neuropathy does not generally require dos e modific ation. If ≥ Grade 3 s ens ory neuropathy develops, treatment should be withheld
`
`
`
`
`until res olution to Grade 1 or 2 for metastatic breas t c anc er or until resolution to ≤ Grade 1 f or NSCLC f ollowed by a dos e reduction
`
`
`
`
`
`
`
`
`
`
`
`for all subs equent c ours es of ABRAXANE [s ee Dosage and Administration (2.4)].
`
`
`
`
`
`Hypersensitivity
`5.3
`
`
`Severe and s ometimes f atal hypers ensitivity reactions, including anaphylac tic reactions, have been reported. Patients who
`
`
`
`
`
`experienc e a s evere hypers ens itivity reac tion to ABRAXANE should not be re-challenged with this drug.
`
`
`
`
`
`Hepatic Impairment
`5.4
`
`
`Bec aus e the expos ure and toxic ity of paclitaxel c an be increased with hepatic impairment, administration of ABRAXANE in patients
`
`
`
`
`
`with hepatic impairment s hould be perf ormed with c aution. The starting dose should be reduc ed f or patients with moderate or
`
`
`
`severe hepatic impairment [s ee Dosage and Administration (2.3), Us e in Spec ific Populations (8.6) and Clinical Pharmac ology
`
`
`
`(12.3)].
`
`
`Albumin (Human)
`5.5
`
`
`ABRAXANE c ontains albumin (human), a derivative of human blood. Based on eff ective donor screening and product manuf acturing
`
`
`
`
`
`proc ess es, it c arries a remote risk f or transmission of viral diseases. A theoretic al risk for trans mission of Creutzf eldt-J akob Dis eas e
`
`
`
`
`
`(CJD) als o is c onsidered extremely remote. No cases of transmission of viral dis eas es or CJD have ever been identified f or al bumin.
`
`
`
`
`
`
`
`Use in Pregnancy
`5.6
`
`
`ABRAXANE c an c aus e f etal harm when administered to a pregnant woman. Administration of pac litaxel protein-bound particles to
`
`
`
`
`
`rats during pregnanc y at dos es lower than the maximum rec ommended human dose, based on body surface area, c aus ed embryo-
`
`
`
`
`fetal toxicities, including intrauterine mortality, increas ed res orptions, reduc ed numbers of live f etuses, and malf ormations.
`
`
`
`
`
`
`There are no adequate and well-c ontrolled studies in pregnant women rec eiving ABRAXANE. If this drug is used during pregnancy,
`
`
`
`
`or if the patient bec omes pregnant while rec eiving this drug, the patient should be appris ed of the potential hazard to the fetus.
`
`
`
`
`
`
`W omen of childbearing potential s hould be advis ed to avoid becoming pregnant while receiving ABRAXANE [see Use in Spec ific
`
`
`
`
`Populations (8.1)].
`
`
`Use in M en
`5.7
`
`
`Men should be advis ed not to father a child while rec eiving ABRAXANE [see Nonclinical Toxicology (13.1)].
`
`
`
`
`
`
`6
`ADVERSE REACTIONS
`
`
`Bec aus e clinic al trials are c onducted under widely varying conditions, advers e reaction rates obs erved in the clinic al trials of a drug
`
`
`
`
`
`
`cannot be directly c ompared to rates in the clinic al trials of another drug and may not reflect the rates observed in practic e.
`
`
`
`
`
`
`
`The most c ommon advers e reactions (≥ 20%) with single-agent us e of ABRAXANE in metastatic breast c anc er are alopecia,
`
`
`
`
`
`
`
`
`neutropenia, s ens ory neuropathy, abnormal ECG, f atigue/as thenia, myalgia/arthralgia, AST elevation, alkaline phos phatas e
`
`
`
`
`
`elevation, anemia, naus ea, infections, and diarrhea [see Adv erse Reactions (6.1)].
`
`
`
`
`
`
`The most c ommon advers e reactions (≥ 20%) of ABRAXANE in c ombination with carboplatin f or non-small c ell lung c anc er are
`
`
`
`
`
`
`
`anemia, neutropenia, thromboc ytopenia, alopecia, peripheral neuropathy, nausea, and f atigue [see Adverse Reactions (6.2)] The
`
`
`
`
`
`most common s erious advers e reactions of ABRAXANE in c ombination with c arboplatin f or non-small c ell lung c anc er are anemia
`
`
`
`
`
`
`
`
`(4%) and pneumonia (3%). The most c ommon advers e reac tions res ulting in permanent disc ontinuation of ABRAXANE were
`
`
`
`
`
`
`neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%). The most common advers e reactions resulting in dos e
`
`
`
`
`reduction of ABRAXANE were neutropenia (24%), thromboc ytopenia (13%), and anemia (6%). The mos t c ommon advers e
`
`reactions leading to withholding or delay in ABRAXANE dosing were neutropenia (41%), thromboc ytopenia (30%), and anemia
`
`
`
`(16%).
`
`
`
`Reference ID: 3320960
`
`
`6
`
`

`

`
`Clinical Trials Experience in M etastatic Breast Cancer
`6.1
`
`
`
`Table 3 s hows the frequenc y of important advers e events in the randomized c omparative trial f or the patients who received either
`
`
`
`
`
`
`
`
`single-agent ABRAXANE or paclitaxel injection f or the treatment of metastatic breast c ancer.
`
`
`
`
`
`
`Table 3: Frequencya of Important Treatment Emergent Adverse Events in the Randomiz ed M etastatic Breast
`
`
`
`
`
`
`
`
`
`Cancer Study on an Ev ery-3-Weeks Schedule
`
`
`
`
`
`
`
`
`
`
`
` Bone Marrow
`
`
` Neutropenia
` < 2.0 x 109/L
`
`
`
`
` < 0.5 x 109/L
`
`
`
` Thromboc ytopenia
`
` < 100 x 109/L
`
`
`< 50 x 109/L
`
`
`
` Anemia
`
`
`
` < 11 g/dL
`
`
`
` < 8 g/dL
`
` Inf ections
`
`
`
` Febrile Neutropenia
`
`
` Neutropenic Sepsis
`
` Bleeding
`
` Hypersensitivity Reactionc
`
`
` All
`
`
` Severed
` Cardiovascular
`
`
`
` Vital Sign Changes During Administration
`
` Bradycardia
`
`
` Hypotens ion
`
`
` Severe Cardiovascular Eventsd
` Abnormal ECG
`
`
`
` All Patients
`
` Patients with Normal Bas eline
` Respiratory
`
`
`
` Cough
`
`
` Dyspnea
`
` Sensory Neuropathy
`
`
` Any Symptoms
`
` Severe Symptomsd
`
`
` Myalgia / Arthralgia
`
`
` Any Symptoms
`
` Severe Symptomsd
` Asthenia
`
`
` Any Symptoms
`
`
` Severe Symptomsd
`
`
` Fluid Retention/Edema
`
`
` Any Symptoms
`
` Severe Symptomsd
` Gastrointestinal
`
`
`
` Naus ea
`
`
` Any Symptoms
`
` Severe Symptoms d
`
` Vomiting
`
`
`
` Any Symptoms
`
` Severe Symptomsd
`
` Diarrhea
`
`
` Any Symptoms
`
` Severe Symptomsd
`
`
`
` Muc ositis
`
`
` Any Symptoms
`
` Severe Symptomsd
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Percent of Patients
`
` Paclitaxel Injection
`
` ABRAXANE
`
` 175 mg/m2 over 3 hb
` 260 mg/m2 over 30 min
`
`
`
`
` (n=229)
`
` (n=225)
`
`
`
`
`
`
`
` 80
` 82
`
` 22
`
` 9
`
`
`2
`
`3
`
`<1
`
`<1
`
`
`
`
`
` 33
` 25
`
` <1
`
` 1
`
` 24
`
` 20
`
`
` 2
` 1
`
`
` <1
` <1
`
`
` 2
` 2
`
`
`
`
` 4
` 12
`
`
` 0
` 2
`
`
`
`
`
`
` <1
` <1
`
`
` 5
` 5
`
` 3
`
` 4
`
`
`
`
` 60
` 52
`
` 30
`
` 35
`
`
`
` 7
`
` 6
`
` 12
`
` 9
`
`
`
`
` 71
` 56
`
`
` 10
` 2
`
`
`
`
` 44
` 49
`
`
` 8
` 4
`
`
`
`
` 47
` 39
`
`
` 8
` 3
`
`
`
` 10
`
` 8
`
`
` <1
` 0
`
`
`
`
`
`
` 30
` 22
`
` <1
`
` 3
`
`
`
`
` 18
` 10
`
`
` 4
` 1
`
`
`
`
` 27
` 15
`
`
` <1
` 1
`
`
`
` 7
`
` 6
` <1
`
` 0
`
`
`
`Reference ID: 3320960
`
`
`7
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Percent of Patients
`
` Paclitaxel Injection
`
` ABRAXANE
`
` 175 mg/m2 over 3 hb
`
`
` 260 mg/m2 over 30 min
`
`
` (n=225)
`
` (n=229)
`
`
` Alopecia
`
` 94
`
` 90
` Hepatic (Patients with Normal Bas eline)
`
`
`
`
`
` 7
`
` 7
` Bilirubin Elevations
`
`
`
` 31
`
` 36
`
` Alkaline Phosphatase Elevations
`
` 32
`
` 39
`
` AST (SGOT) Elevations
`
` Injection Site Reaction
`
`
`
` <1
` 1
` a Bas ed on worst grade by NCI Common T erminology Criteria f or Advers e Events (CTCAE) version 2.
`
`
`
`
` b Paclitaxel injection patients rec eived premedic ation.
`
`
`
` c Includes treatment-related events related to hypers ensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that began
`
`
` on a day of dosing.
` d Severe events are defined as at least grade 3 toxic ity.
`
` Adverse Event Experiences by Body System
`
`
`Hematologic Disorders
`
`
`
`
`
`Neutropenia was dos e dependent and revers ible. Among patients with metastatic breast cancer in the randomized trial, neutrophil
`counts dec lined below 500 c ells/mm3 (Grade 4) in 9% of the patients treated with a dos e of 260 mg/m2 c ompared to 22% in patients
`
`
`
`
`
`
`
`receiving paclitaxel injection at a dose of 175 mg/m2. Panc ytopenia has been obs erved in clinic al trials.
`
`
`
`
`
`
`
`
`Infections
`
`Inf ectious epis odes were reported in 24% of the patients treated with ABRAXANE. Oral c andidiasis, respiratory tract inf ections and
`
`
`
`
`pneumonia were the most frequently reported infectious c omplications.
`
`
`Hypersensitivity Reactions (HSRs)
`
`Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and c onsisted of dyspnea (1%) and flushing, hypotens ion,
`
`
`
`
`
`
`
`
`chest pain, and arrhythmia (all <1%). The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection
`
`
`
`
`
`
`
`
`or human albumin has not been studied.
`
`
`
`
`
`Cardiovascular
`
`Hypotension, during the 30-minute infusion, occ urred in 5% of patients. Bradyc ardia, during the 30-minute infusion, occurred in <1%
`
`
`
`
`
`of patients. Thes e vital sign c hanges most often c aus ed no symptoms and required neither specific therapy nor treatment
`
`
`
`
`
`
`discontinuation.
`
`
`Severe c ardiovasc ular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients. Thes e events
`
`
`
`
`
`included c ardiac ischemia/inf arction, chest pain, c ardiac arrest, supraventricular tachycardia, edema, thrombos is, pulmonary
`
`
`
`
`
`thromboembolis m, pulmonary emboli, and hypertens ion. Cas es of c erebrovascular attacks (strokes) and transient ischemic attacks
`
`
`
`
`
`
`
`have been reported.
`
`
`Electroc ardiogram (ECG) abnormalities were c ommon among patients at baseline. ECG abnormalities on study did not usually
`
`
`
`
`
`
`
`
`result in s ymptoms, were not dos e-limiting, and required no intervention. ECG abnormalities were noted in 60% of patients. 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 modific ations were non-s pecific repolarization abnormalities, sinus bradycardia, and sinus tac hyc ardia.
`
`
`
`
`
`
`
`Respiratory
`
`
`Dyspnea (12%), c ough (7%), and pneumothorax (<1%) were reported after treatment with ABRAXANE.
`
`
`
`
`Neurologic
`
`
`The frequenc y and s everity of s ens ory neuropathy increas ed with cumulative dos e. Sens ory neuropathy was the cause of
`
`
`
`
`
`
`
`
`ABRAXANE disc ontinuation in 7/229 (3%) patients. T wenty-four 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 res umed
`
`
`
`
`
`
`treatment at a reduc ed dos e of ABRAXANE and 2 discontinued due to peripheral neuropathy. Of the 10 patients without
`
`
`
`
`
`
`documented improvement, 4 discontinued the study due to peripheral neuropathy.
`
`
`
`
`No Grade 4 s ens ory neuropathies were reported. Only one incident of motor neuropathy (Grade 2) was obs erved in either arm of
`
`
`
`
`
`
`
`
`the c ontrolled trial.
`
`
`Vision Disorders
`
`Ocular/vis ual disturbanc es occ urred in 13% of all patients (n=366) treated with ABRAXANE and 1% were s evere. The s evere c as es
`
`
`
`
`
`
`(keratitis and blurred visio