`
` 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
`
`
`
`
`
`WARNING: NEUTROPENIA
`
`
`See full prescribing information for complete boxed warning.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`--------------------- DOSAGE FORMS AND STRENGTHS -------------------­
`
`
`
`
`• For injectable s uspension: lyophilized powder c ontaining 100 mg of
`
`
`
`paclitaxel in single-use vial f or rec onstitution. (3)
`
`
`
`
`------------------------------ CONTRAINDICATIONS ----------------------------­
`• Neutrophil counts of < 1,500 cells/mm3. (4)
`
`
`
`
`• Severe hypers ensitivity reaction to ABRAXANE. (4)
`
`
`
`----------------------- WARNINGS AND PRECAUTIONS ---------------------­
`
`
`
`
`• ABRAXANE caus 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)
`
`
`• Sepsis occurred in patients with or without neutropenia who received
`
`
`
`
`ABRAXANE in combination with gemcitabine; interrupt ABRAXANE
`
`
`and gemcitabine until sepsis res olves, and if neutropenic, until
`
`
`neutrophils are at least 1500 cells/mm3, then resume treatment at
`
`
`
`
`
`
`
`
`reduced dose levels . (5.3)
`
`
`
`
`• Pneumonitis occurred with the us e of ABRAXANE in c ombination
`
`with gemcitabine; permanently disc ontinue treatment with
`
`
`ABRAXANE and gemc itabine. (5.4)
`
`
`
`• Severe hypers ensitivity reactions with f atal outc ome have been
`
`reported. Do not re-challenge with this drug. (5.5)
`
`
`
`• Exposure and toxic ity of paclitaxel c an be increas ed in patients with
`
`
`hepatic impairment; theref ore administer with c aution. (5.6)
`
`
`
`• ABRAXANE c ontains albumin derived from human blood, which has
`
`
`
`a theoretic al ris k of viral transmission. (5.7)
`
`
`
`
`• Fetal harm may occur when administered to a pregnant woman.
`
`
`
`Advise women of childbearing potential to avoid bec oming pregnant
`
`while rec eiving ABRAXANE. (5.8)
`
`
`
`
`
`
`
`• Advise men not to father a child while on ABRAXANE. (5.9)
`
`
`
`
`------------------------------ ADVERSE REACTIONS ----------------------------­
`
`
`
`
`
`• The most common adverse reactions (≥ 20%) in metastatic breast
`
`
`
`
`cancer are alopecia, neutropenia, s ens ory neuropathy, abnormal
`
`
`
`
`ECG, f atigue/asthenia, myalgia/arthralgia, AST elevation, alkaline
`
`
`phosphatase elevation, anemia, naus ea, infections, and
`
`
`diarrhea. (6.1)
`
`
`
`
`
`• The most common adverse reactions (≥ 20%) in NSCLC are anemia,
`
`
`
`neutropenia, thrombocytopenia, alopecia, peripheral neuropathy,
`
`
`nausea, and f atigue. (6.2)
`
`
`
`
`
`• The most common (≥ 20%) advers e reactions of ABRAXANE in
`
`
`
`adenoc arcinoma of the pancreas are neutropenia, fatigue, peripheral
`
`
`
`
`neuropathy, naus ea, alopecia, peripheral edema, diarrhea, pyrexia,
`
`
`
`vomiting, decreased appetite, rash, and dehydration. (6.3)
`
`
`
`
`
`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 INFORM ATION and
`
`
`FDA-approved patient labeling.
`
`
`
`Revised: October 2013
`
`
`
`
`
`
`• 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, 6.3)
`
`
`
`DO NOT SUBSTIT UTE FOR OR WITH OTHER PACLITAXEL
`FORM ULATIONS.
`
`
` -------------------------- RECENT MAJOR CHANGES -------------------------­
`
` • Indic ations and Us age (1.3)
`
`
`
`
`
` 09/2013
`
`
` • Dos age and Administration (2.3, 2.5)
`
` 09/2013
`
` • W arnings and Prec autions, Hematologic Effects (5.1), Nervous
`
`
`
`
` System (5.2), Sepsis (5.3), Pneumonitis (5.4)
` 09/2013
`
`
`
`
`
` -------------------------- INDICATIONS AND USAGE ---------------------------­
`
`
`
` ABRAXANE is a microtubule inhibitor indic ated f or the treatment of:
`
`
` • Metastatic breast canc er, after failure of c ombination chemotherapy
`
`
`
`
` for metastatic dis eas e or relapse within 6 months of adjuvant
`
`
` chemotherapy. Prior therapy should have included an anthrac yc line
`
`
` unless clinic ally c ontraindic ated. (1.1)
`
`
`
` • Loc ally advanc ed or metas tatic non-small c ell lung c anc er (NSCLC),
`
`
`
` as first-line treatment in c ombination with c arboplatin, in patients who
`
`
`
`
` are not c andidates f or curative s urgery or radiation therapy. (1.2)
`
`
`
` • Metastatic adenocarcinoma of the pancreas as first-line treatment, in
`
`
`
`
`
`
` combination with gemcitabine. (1.3)
`
`
`
` ----------------------- DOSAGE AND ADM INISTRATION ---------------------­
`
`
` • Metastatic Breast Canc er: Rec ommended dos age 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; administer c arboplatin on Day 1 of each 21-day
`
`
`
`cycle immediately after ABRAXANE. (2.2)
`
`
`
`• Adenoc arcinoma of the Pancreas: Rec ommended dos age of
`ABRAXANE is 125 mg/m2 intravenous ly over 30-40 minutes on Days
`
`
`
`
`
`
`
`
`
`1, 8 and 15 of each 28-day cycle; administer gemcitabine on Days 1,
`
`
`
`
`8 and 15 of each 28-day c ycle immediately after ABR AXANE. (2.3)
`
`
`
`
`• 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. (2.4)
`
`
`
`
`• Dos e Reductions: Dos e reductions or disc ontinuation may be
`
`
`
`
`needed bas ed on severe hematologic, neurologic, cutaneous , or
`
`
`gastrointestinal toxicities. (2.5)
`
`
`
`• Use caution when handling c ytotoxic drugs. Clos ely monitor the
`
`
`infusion site f or extravas ation and infiltration. No premedic ation is
`
`
`required prior to administration. (2.6)
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3399014
`
`
`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
`
`
` 1.3 Adenoc arcinoma of the Pancreas
`
` 2 DOSAGE AND ADMINISTRATION
`
`
`
`
` 2.1 Metastatic Breast Canc er
`
`
`
` 2.2 Non-Small Cell Lung Canc er
`
`
`
`
` 2.3 Adenoc arcinoma of the Pancreas
`
`
`
` 2.4 Dos age in Patients with Hepatic Impairment
`
`
`
`
` 2.5 Dos e Reduction/Disc ontinuation Rec ommendations
`
`
` 2.6 Preparation and Administration Prec autions
`
`
`
` 2.7 Preparation for Intravenous Administration
`
`
`
` 2.8 Stability
`
`
`
` 3 DOSAGE FORMS AND STRENGTHS
`
` 4 CONTRAINDICATIONS
`
`
` 5 WARNINGS AND PRECAUTIONS
`
`
` 5.1 Hematologic Effects
`
`
` 5.2 Nervous System
`
`
`
` 5.3 Sepsis
`
`
`
`
` 5.4 Pneumonitis
`
`
`
` 5.5 Hypers ensitivity
`
`
` 5.6 Hepatic Impairment
`
`
` 5.7 Albumin (Human)
`
`
`
` 5.8 Use in Pregnanc y
`
`
`
` 5.9 Use in Men
`
`
` 6 ADVERSE REACTIONS
`
`
`
`
`
`
`
` 6.1 Clinical Trials Experience in Metastatic Breast C ancer
`
`
`
` 6.2 Clinical Trials Experience in Non-Small Cell Lung Cancer
`
`
`
`
` 6.3 Clinical Trials Experience in Adenocarcinoma of the
`
`
`
`
`
`
` Pancreas
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 6.4 Post-Marketing Experience with ABRAXANE and other
`
`
` Paclitaxel Formulations
`
`
` 6.5 Accidental Exposure
`
`
`
`
` 7 DRUG INTERACTIONS
`
` 8 USE IN SPECIFIC POPULATIONS
`
` 8.1 Pregnancy
`
`
`
`
` 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 Pharmacokinetics
`
`
` 13 NONCLINICAL TOXICOLOGY
`
`
`
`
` 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
` 14 CLINICAL STUDIES
`
`
`
`
`
` 14.1 Metastatic Breast C ancer
`
`
`
` 14.2 N on-Small Cell Lung Cancer
`
`
` 14.3 Adenoc arcinoma of the Pancreas
`
` 15 REFERENCES
`
`
`
` 16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
` 16.1 How Supplied
`
`
`
` 16.2 Storage
`
`
`
`
` 16.3 Handling and Dispos al
`
`
` 17 PATIENT COUNSELING INFORM ATION
`
`
`
`
`
`* Sections or subs ections omitted from the Full Prescribing Inf ormation
`
`
`are not listed.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3399014
`
`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, 6.3)].
`
`
`
`• 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 FORMULATIONS.
`
`
`
`
`
`
`
`
` INDICATIONS AND USAGE
`
`
`
`
`
` 1
`
`M etastatic Breast Cancer
`1.1
`
`
`ABRAXANE is indic ated f or the treatment of breast c anc er after f ailure of c ombination chemotherapy f or metastatic dis eas e or
`
`
`
`
`
`
`relaps e within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthrac ycline 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 metas tatic 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.
`
`
`
`
`
`
`Adenocarcinoma of the Pancreas
`1.3
`
`
`
`
`
`
`ABRAXANE is indicated f or the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in c ombination with
`
`gemcitabine.
`
`
` 2
`
` M etastatic Breast Cancer
` 2.1
`
`
`
`
`
`
`
` After failure of c ombination chemotherapy f or metastatic breast c ancer or relapse within 6 months of adjuvant c hemotherapy, 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 D ays 1, 8, and
`
`
`
`
`
`
`
`
`
`
`
`
`15 of eac h 21-day cycle. Administer c arboplatin on Day 1 of eac h 21 day c ycle immediately after ABRAXANE [see Clinical Studies
`
`
`(14.2)].
`
`
`
`
`Adenocarcinoma of the Pancreas
`2.3
` The rec ommended dos e of ABRAXANE is 125 mg/m2 administered as an intravenous infusion over 30-40 minutes on Days 1, 8 and
`
`
`
`
`
`15 of eac h 28-day c ycle. Administer gemcitabine immediately after ABRAXANE on Days 1, 8 and 15 of each 28-day cycle [see
`
`
`
`
`
`Clinic al Studies (14.3)].
`
`
`
`
`Dosage in Patients with Hepatic Impairment
`2.4
`
`
`
`
`
`
`
`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 subs equent 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 (5.6), Use in Spec ific Populations (8.6) and Clinical Pharmac ology (12.3)].
`
`
`
`
`
`
`
`
`
`
`
`
` DOSAGE AND ADMINISTRATION
`
`
`
`
`
`
`
`
`Reference ID: 3399014
`
`
`3
`
`

`

`
`
` Table 1: Recommendations for Starting Dose in Patients with Hepatic Impairment
`
`
`SGOT (AST)
`Bilirubin
`
` Levels
`
` Levels
`
`
`
`
`
`
`
` ABRAXANE Dosea
`
`
`
`
`
` NSCLC c
`
`
` 100 mg/m2
`
` 75 mg/m2
`
` 50 mg/m2
`
`
`not rec ommended
`
` Pancreatic c
`
`
` Adenocarcinoma
`
` 125 mg/m2
`
` not rec ommended
`
` not rec ommended
`
`
`not rec ommended
`
`
`
`
`
`
`
` M BC
`
`
` 260 mg/m2
`
` Mild
` > ULN to ≤ 1.25 x ULN
`
`
`
`
` AND
`
` < 10 x ULN
`
`
` 200 mg/m2
`
` 1.26 to 2 x ULN
`
` AND
`
` < 10 x ULN
`
` Moderate
`130 mg/m2 b
`2.01 to 5 x ULN
`AND
`< 10 x ULN
`Severe
`
`
`
`
`
`
`
`
`
`
`
`not rec ommended
`> 5 x ULN
`OR
`> 10 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 dos e 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 Patients with bilirubin levels above the upper limit of normal were excluded from clinical trials f or pancreatic or lung c anc er.
`
`
`
`
`
`
`2.5
`
`
`
`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 dose 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 c ours es 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 T able 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)].
`
`
`
`
`
`
`
`
`
`
`
`Dose Reduction/Discontinuation Recommendations
`
`
`
`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)
`
` 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
`
`
`
`
`
`
`
`
`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
`
`
`
`Reference ID: 3399014
`
`
`4
`
`

`

` Adenoc arc inoma of the Pancreas
`
`
`
`
`
`
`
`
`
`
`Dos e level reductions for patients with adenoc arcinoma of the pancreas, as ref erenc ed in T ables 4 and 5, are provided in Table 3.
`
`
`Table 3: Dose Level Reductions for Patients with Adenocarcinoma of the Pancreas
`
`
`
`
`
` Dose Level
`
`
`Full dos e
`1st dos e reduction
`
`
`2nd dos e reduction
`
`
`
`If additional dos e reduction required
`
`
`
` ABRAXANE (mg/m2)
`
`125
`
`
`
` Gemcitabine (mg/m2)
`
`1000
`
`
` 100
`
` 75
`
`Discontinue
`
`
` 800
`
` 600
`
`Discontinue
`
`
`
`
`
`
`
`Rec ommended dos e modific ations for neutropenia and thromboc ytopenia f or patients with adenoc arcinoma of the pancreas are
`
`provided in T able 4.
`
`
`
`
`
`
`
`Table 4: Dose Recommendation and M odifications for Neutropenia and/or Thrombocytopenia at the Start of a Cycle or
`
`
`
`
`within a Cycle for Patients with Adenocarcinoma of the Pancreas
`
`ANC (cells/mm3)
`
`
`
`
`Platelet count (cells/mm3)
`
`
`ABRAXANE / Gemcitabine
`
`
`Delay doses until recovery
`
`
`
`Reduc e 1 dos e level
`
`
`W ithhold dos es
`
`
`Reduc e 1 dos e level from Day 8
`
`
`
`
`W ithhold dos es
`
`
`Cycle
`
`Day
`Day 1
`
`Day 8
`
`
`
`< 1500
`
`
`
`500 to < 1000
`
`
`< 500
`
`
`OR
`
`
`OR
`
`
`OR
`
`
`< 100,000
`
`
`50,000 to < 75,000
`
`
`< 50,000
`
`
`Day 15: IF Day 8 doses were reduced or given without modification:
`
`
`
`
`
`
`
`
`
`500 to < 1000
`
`
`< 500
`
`
`OR
`
`OR
`
`
`50,000 to < 75,000
`
`
`< 50,000
`
`
`
`
`
`Day 15: IF Day 8 doses were withheld:
`
`
`
`
`
`
`
`≥ 75,000
`OR
`≥ 1000
`
`
`
`
`
`50,000 to < 75,000
`OR
`500 to < 1000
`
`
`
`
`< 50,000
`OR
`< 500
`
`
`
`Abbreviations: ANC = Abs olute Neutrophil Count
`
`
`
`
`
`
`Rec ommended dos e modific ations for other advers e drug reactions in patients with adenoc arcinoma of the pancreas are provided in
`
`
`Table 5.
`
`
`
`
`
`
`Reduc e 1 dos e level from Day 1
`
`
`
`
`Reduc e 2 dos e levels from Day 1
`
`W ithhold dos es
`
`
`
`
`
`Table 5: Dose M odifications for Other Adverse Drug Reactions in Patients with Adenocarcinoma of the Pancreas
`
`
`
`Adverse Drug Reaction
`Febrile Neutropenia:
`
`
`
`Grade 3 or 4
`Peripheral Neuropathy:
`
`
`
`Grade 3 or 4
`Cutaneous Toxicity:
`
`
`Grade 2 or 3
`
`Gastrointestinal Toxicity:
`
`
`Grade 3 mucositis or diarrhea
`
`
`
`ABRAXANE
`
`Gemcitabine
`
`
`
`
`
`
`
`
`
`W ithhold until f ever res olves and ANC ≥ 1500; res ume at next lower dos e level
`
`
`
`
`
`W ithhold until improves to ≤ Grade 1;
`
`
`
`resume at next lower dos e level
`
`
`No dos e reduction
`
`Reduc e to next lower dos e level; discontinue treatment if toxic ity persists
`
`
`
`
`W ithhold until improves to ≤ Grade 1;
`
`
`
`
`resume at next lower dos e level
`
`
`
`
`
`Preparation and Administration Precautions
`2.6
`
`
`ABRAXANE is a c ytotoxic drug and, as with other potentially toxic paclitaxel c ompounds, c aution should be exercised in handling
`
`
`
`
`
`
`ABRAXANE. The us e of gloves is rec ommended. If ABRAXANE (lyophilized c ake or reconstituted suspension) contacts the skin,
`
`
`
`
`
`was h the skin immediately and thoroughly with s oap and water. Following topic al exposure to paclitaxel, events may include
`
`
`
`tingling, burning and redness. If ABRAXANE c ontacts muc ous mem branes, the membranes should be flushed thoroughly with
`
`
`
`water.
`
`
`
`
`Reference ID: 3399014
`
`
`5
`
`

`

`
`
`
`
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
` Given the possibility of extravas ation, it is advis able to closely monitor the infusion site f or possible infiltration during drug
`
` administration. Limiting the infusion of ABRAXANE to 30 minutes, as directed, reduces the likelihood of infusion-related reactions
`
`
`
`
`
`
` [see Advers e Reactions (6.4)].
`
`
`
`
`
`
`
` 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 hypers ensitivity reaction to ABRAXANE should not be re-challenged with this drug [see Warnings and Precautions (5.5)].
`
`
`
`
`
`
`
` 2.7
`
`
`
` Preparation for Intravenous Administration
` ABRAXANE is supplied as a sterile lyophilized powder f or rec onstitution bef ore us e. AVOID ERRORS, READ ENTIRE
`
`
`
` PREPARATION INSTRUCTIONS PRIOR TO RECONSTITUTION.
`
`
`
`
`
`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 subs ides .
`
`
`
`
`
`3.
`
`
`4.
`
`
`5.
`
`
`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. Disc ard the rec onstituted sus pension 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 spec ialized 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
`2.8
`
`
`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 package. Neither freezing nor refrigeration advers ely affects 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, each 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 used immediately but may be stored at
`
`
`
`
`ambient temperature (approximately 25ºC) and lighting c onditions f or up to 4 hours. Disc ard any unus ed portion.
`
`
`
`
`
` DOSAGE FORMS AND STRENGTHS
` 3
`
`
`
`
`
` For injectable s uspension: lyophilized powder containing 100 mg of paclitaxel in single-us e vial f or rec onstitution.
`
` 4
`
`
`
`
`
`
`
`
`
`
`
` CONTRAINDICATIONS
`
`
` • ABRAXANE should not be us ed in patients who have bas eline neutrophil c ounts of < 1,500 c ells/mm3 .
`
`
`
`
`
` • Patients who experienc e a s evere hypers ensitivity reac tion to ABRAXANE should not be rechallenged with the drug.
`
`
`
`
`
`
`Reference ID: 3399014
`
`
`6
`
`

`

`
`
` 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 cancer (MBC), 47% of patients with non-small cell lung
`
`
`
`canc er (NSCLC), and 38% of patients with pancreatic c anc er.
`
`
`
`
`
`
`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 and f or pancreatic c anc er). Do not administer ABRAXANE to patients with bas eline abs olute
`neutrophil c ounts (ANC) of less than 1,500 c ells/mm3 . In the c as e of severe neutropenia (<500 c ells/mm3 f or s even days or more)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`during a c ours e of ABRAXANE therapy, reduc e the dose 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 c yc les of ABRAXANE after ANC rec overs 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 (2.5)].
`
`
`
`
`
`In patients with adenoc arcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 c ells/mm3 or
`
`
`
`
`
`platelets are less than 50,000 c ells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 c ells/mm3 or platelet c ount
`
`
`
`
`
`
`
`
`
`is less than 100,000 cells/mm3 on Day 1 of the c yc le. Res ume treatment with appropriate dos e reduction if rec ommended [see
`
`
`
`
`
`
`
`
`
`
`
`Dosage and Administration (2.5)].
`
`
`
`Nervous System
`5.2
`
`
`
`
`
`
`Sens ory neuropathy is dos e- and schedule-dependent [see Adverse Reactions (6.1, 6.2, 6.3)]. The occurrenc e of Grade 1 or 2
`
`
`
`
`
`
`
`
`
`sens ory neuropathy does not generally require dos e modific ation. If ≥ Grade 3 s ens ory neuropathy develops, withhold ABRAXANE
`
`
`
`
`
`
`
`
`
`
`
`
`
`treatment until res olution to Grade 1 or 2 for metastatic breas t c anc er or until res olution to ≤ Grade 1 for NSCLC and pancreatic
`
`
`
`
`
`
`canc er f ollowed by a dos e reduction f or all subsequent courses of ABRAXANE [see Dosage and Administration (2.5)].
`
`
`
`Sepsis
`5.3
`
`
`
`
`
`
`
`Sepsis occ urred in 5% of patients with or without neutropenia who received ABRAXANE in c ombination with gemcitabine. Biliary
`
`
`
`
`
`
`
`
`obstruction or pres enc e of biliary stent were ris k f actors f or s evere or fatal s epsis. If a patient bec omes f ebrile (regardless of ANC)
`
`
`
`
`
`
`
`initiate treatment with broad spectrum antibiotics. For f ebrile neutropenia, interrupt ABRAXANE and gemc itabine until f ever res olves
`
`
`
`
`
`
`
`
`
`and ANC ≥ 1500, then res ume treatment at reduc ed dos e levels [see Dosage and Administration (2.5)].
`
`
`Pneumonitis
`5.4
`
`
`
`
`
`
`
`Pneumonitis, including s ome c as es that were f atal, occurred in 4% of patients rec eiving ABRAXANE in combination with
`
`
`
`
`
`
`
`
`
`
`gemcitabine. Monitor patients f or signs and s ymptoms of pneumonitis and interrupt ABRAXANE and gemcitabine during evaluation
`
`
`
`
`
`
`of suspected pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue
`
`
`treatment with ABRAXANE and gemcitabine.
`
`
`
`Hypersensitivity
`5.5
`
`
`
`
`
`
`Severe and s ometimes f atal hypers ens itivity reac tions, including anaphylactic 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. 6
`
`
`
`
`
`
`
`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 dos e should be reduc ed f or patients with moderate or
`
`severe hepatic impairment [s ee Dosage and Administration (2.4), Us e in Spec ific Populations (8.6) and Clinical Pharmac ology
`
`
`
`(12.3)].
`
`
`
`Albumin (Human)
`5.7
`
`
`
`
`
`ABRAXANE c ontains albumin (human), a derivative of human blood. Bas ed on eff ective donor screening and product manuf acturing
`
`
`
`
`
`proc ess es, it c arries a remote risk f or transmission of viral dis eases. A theoretic al risk for trans mission of Creutzf eldt-J akob Dis eas e
`
`
`
`
`
`
`
`
`(CJD) als o is c onsidered extremely remote. No c as es of trans mission of viral dis eas es or CJD have ever been identified for
`
`albumin.
`
`
`
`Use in Pregnancy
`5.8
`
`
`
`
`ABRAXANE c an c aus e f etal harm when administered to a pregnant woman. Administration of paclitaxel protein-bound particles to
`
`
`
`
`
`
`rats during pregnanc y at dos es lower than the maximum rec ommended human dose, based on body surface area, caus ed embryo-
`
`
`
`
`
`
`fetal toxicities, including intrauterine mortality, increased resorptions, reduced numbers of live f etus es, and malf ormations.
`
`
`
`
`
`There are no adequate and well-c ontrolled studies in pregnant women rec eiving ABRAXANE. If this drug is us ed during pregnanc y,
`
`
`
`
`
`
`or if the patient bec omes pregnant while rec eiving this drug, the patient should be apprised of the potential hazard to the fetus.
`
`W omen of childbearing potential s hould be advis ed to avoid bec oming pregnant while rec eiving ABRAXANE [see Use in Specific
`
`
`Populations (8.1)].
`
`
`Reference ID: 3399014
`
`
`7
`
`

`

`
`
`
`
`
`Use in M en
`5.9
`
`
`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 prac tic 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 mos t c ommon advers e reactions res ulting in permanent disc ontinuation of ABRAXANE are
`
`
`
`neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%). The most c ommon advers e reactions resulting in dos e
`
`
`
`
`reduction of ABRAXANE are neutropenia (24%), thromboc ytopenia (13%), and anemia (6%). The most c ommon advers e reactions
`
`
`