Usual Adult Dose for Breast Cancer

600 mg orally once a day for 21 consecutive days followed by 7 days off for a complete cycle of 28 days; continue until disease progression or unacceptable toxicity

Comments:

• Refer to the manufacturer product information for dosing and administration recommendations for the co-administered aromatase inhibitor (e.g., letrozole).
• When given with this drug, the recommended dose of fulvestrant is 500 mg administered on Days 1, 15, 29, and once monthly thereafter. Refer to the full prescribing information of fulvestrant.
• Pre/perimenopausal women treated with the combination of this drug plus an aromatase inhibitor or fulvestrant should be treated with a luteinizing hormone-releasing hormone (LHRH) agonist according to current clinical practice standards.

Uses:

• In combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.
• In combination with fulvestrant for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine based therapy or following disease progression on endocrine therapy.

Renal Dose Adjustments

• Mild (CrCl 60 to less than 90 mL/min) or moderate (CrCl 30 to less than 60 mL/min): No adjustment recommended.
• Severe renal impairment CrCl 15 to less than 30 mL/min): A starting dose of 200 mg is recommended.

Liver Dose Adjustments

• Mild hepatic impairment (Child-Pugh A): No adjustment recommended.
• Moderate and severe hepatic impairment (Child-Pugh B/C): Initial Dose: 400 mg orally once a day

HEPATIC TOXICITY:
AST and/or ALT elevations from baseline WITHOUT increase in total bilirubin above 2 times the upper limit of normal (ULN):
GRADE 1 (greater than ULN to 3 x ULN): No adjustment recommended.
GRADE 2 (greater than 3 to 5 x ULN):

• Baseline less than Grade 2: Interrupt therapy until recovery to baseline grade or less; resume at next lower dose level.
• Baseline at Grade 2: No adjustment recommended.
• Grade 3 (greater than 5 to 20 x ULN): Interrupt therapy until recovery to baseline grade or less; resume at the next lower dose level; if Grade 3 recurs, discontinue therapy.

GRADE 4: Discontinue therapy.

COMBINED ELEVATIONS IN ALT and/or AST ELEVATIONS WITH TOTAL BILIRUBIN INCREASE IN THE ABSENCE OF CHOLESTASIS:
ALT and/or AST greater than 3 x ULN along with total bilirubin greater than 2 x ULN irrespective of baseline Grade: Discontinue therapy

Dose Adjustments

DOSE REDUCTIONS FOR ADVERSE REACTIONS/TOXICITIES:

• Starting dose: 600 mg orally once a day
• First Dose Reduction: 400 mg orally once a day
• Second Dose Reduction: 200 mg orally once a day
• If further dose reduction required below 200 mg/day: Discontinue therapy

DOSE MODIFICATIONS FOR ADVERSE REACTIONS:
NEUTROPENIA:
Absolute neutrophil count (ANC):

• Grade 1 or 2 (ANC 1000/mm3 to less than lower limit of normal [LLN]): No adjustment recommended.
• Grade 3 (ANC 500 to less than 1000/mm3): Interrupt therapy until recovery to Grade 2 or less; resume therapy at the same dose level; if toxicity recurs at Grade 3, interrupt therapy until recovery then resume at the next lower dose level.
• Grade 3 febrile neutropenia (with single episode of fever greater than 38.3C or above 38C for more than 1 hour and/or concurrent infection: Interrupt therapy until recovery of neutropenia to Grade 2 or less; resume therapy at the next lower dose level.
• Grade 4: Interrupt therapy until recovery of neutropenia to Grade 2 or less; resume therapy at the next lower dose level.

QT PROLONGATION:

• ECGs with QTcF GREATER THAN 480 MSEC: Interrupt therapy; if QTcF resolves to less than 481 msec, resume therapy at the next lower dose level. If QTcF of 481 msec or greater recurs, interrupt dose until QTcF resolves to less than 481 msec; then resume at next lower dose level.
• ECGs with QTcF GREATER THAN 500 MSEC: Interrupt therapy if QTcF greater than 500 msec; if QTcF prolongation resolves to less than 481 msec, resume therapy the next lower dose level.
• Permanently discontinue therapy if QTcF interval prolongation is either greater than 500 msec or greater than 60 msec change from baseline AND associated with any of the following: Torsades de Pointes, polymorphic ventricular tachycardia, unexplained syncope, or signs/symptoms of serious arrhythmia.

INTERSTITIAL LUNG DISEASE (ILD)/PNEUMONITIS:

• Grade 1 (asymptomatic): No dose interruption or adjustment is required; initiate medical therapy and monitor as indicated.
• Grade 2 (symptomatic): Interrupt therapy until recovery to Grade 1 or less; consider resuming at the next lower dose level; if Grade 2 recurs, discontinue therapy.
• Grade 3 (severe symptomatic) OR Grade 4 (life-threatening): Discontinue therapy.

CUTANEOUS ADVERSE REACTIONS, INCLUDING SEVERE CUTANEOUS ADVERSE REACTIONS (SCARS):

• Grade 1 or 2 (less than 10% to 30% body surface area [BSA] with active skin toxicity, no signs of systemic involvement): No adjustment recommended.
• Grade 3 (severe rash not responsive to medical management; grater than 30% BSA with active skin toxicity, signs of systemic involvement present; Stevens-Johnson Syndrome):
• Interrupt treatment until the etiology of the reaction has been determined.
• Permanently discontinue treatment if the etiology is a SCAR.
• If the etiology is not a SCAR, interrupt dose until recovery to Grade 1 or less, then resume at same dose level.
• If the cutaneous adverse reaction still recurs at Grade 3, resume at the next lower dose level.
• Grade 4 (any % BSA associated with extensive superinfection, with IV antibiotics indicated; life threatening consequences; toxic epidermal necrolysis): Permanently discontinue therapy.

OTHER TOXICITIES:

• Grade 1 or 2: No adjustment recommended; initiate medical therapy and monitor as indicated.
• Grade 3: Interrupt dose; upon recovery to Grade 1 or less, resume therapy at same dose level.
• Grade 3 Recurrence: Interrupt dose; upon recovery to Grade 1 or less, resume therapy at the next lower dose level.
• Grade 4: Discontinue therapy.

Comments: Consult the manufacturer product information for dose adjustment guidelines in the event of toxicity and other relevant safety information for the coadministered agents.

CONCOMITANT USE WITH STRONG CYP450 3A INHIBITORS: Avoid concomitant use if possible and consider an alternative concomitant medication with less potential for CYP450 3A inhibition.

• If concomitant use necessary: Reduce dose of this drug to 400 mg orally once a day.
• If strong CYP450 3A inhibitor discontinued: Change dose of this drug (after at least 5 half-lives of the strong CYP450 3A Inhibitor) to the dose used prior to the initiation of the inhibitor.

Precautions

CONTRAINDICATIONS:

• None

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Dialysis

Data not available

Other Comments

Administration Advice:

• Administer this drug with or without food, and at approximately the same time each day (preferably in the morning).
• Missed and vomited doses should not be replaced; dosing should be resumed with the next scheduled daily dose.

Storage Requirements:

• Store in the original package at 20 to 25 degrees Celsius (68 to 77 Fahrenheit).

General:

• In studies using patient-derived estrogen receptor positive breast cancer xenograft models, the combination of this drug with an antiestrogen (e.g., letrozole) resulted in increased tumor growth inhibition compared to each drug alone.
• There are no known cases of overdose with this drug; initiate general symptomatic and supportive measures in all cases of overdosage as necessary.

Monitoring:

• Cardiac: ECGs (before treatment initiation, at approximately Day 14 of the first cycle, at the beginning of the second cycle, and as clinically indicated; more frequent monitoring if QTcF prolongation occurs at any given time during treatment); serum electrolytes (before treatment initiation, at the beginning of the first 6 cycles, and as clinically indicated)
• Hematological: CBC (before treatment initiation, every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated)
• Hepatic: LFTs (before treatment initiation, every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated; more frequent monitoring if Grade 2 or greater abnormalities noted)
• Respiratory: Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis.

Patient Advice:

• Avoid pomegranates/pomegranate juice, grapefruit/grapefruit juice during treatment with this drug.
• Advise patients to immediately report new or worsening respiratory symptoms.
• Advise patients to contact their healthcare provider immediately if they develop signs and symptoms of severe cutaneous adverse reactions.