FULVESTRANT injection

United States - English - NLM (National Library of Medicine)

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Active ingredient:
FULVESTRANT (UNII: 22X328QOC4) (FULVESTRANT - UNII:22X328QOC4)
Available from:
Mylan Institutional LLC
Administration route:
INTRAMUSCULAR
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Monotherapy:  Fulvestrant injection is indicated for the treatment of: Combination Therapy: Fulvestrant injection is indicated for the treatment of: Fulvestrant injection is contraindicated in patients with a known hypersensitivity to the drug or to any of its components. Hypersensitivity reactions, including urticaria and angioedema, have been reported in association with fulvestrant injection [see Adverse Reactions (6.2)]. Based on findings from animal studies and its mechanism of action, fulvestrant injection can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of fulvestrant to pregnant rats and rabbits during organogenesis caused embryo-fetal toxicity, including skeletal malformations and fetal loss, at daily doses that were 6% and 30% of the maximum recommended human dose based on mg/m2 , respectively [see Data] . Advise pregnant wome
Product summary:
Fulvestrant Injection is supplied as two 5 mL clear neutral glass (Type 1) barrels, each containing 250 mg/5 mL of fulvestrant solution for intramuscular injection and fitted with a tamper evident closure. NDC 67457-311-05 carton containing 2 x 5 mL single-dose prefilled syringes with 21 gauge x 1 ½ inch needles The single-dose prefilled syringes are presented in a tray with polystyrene plunger rod and safety needles (SafetyGlide™ ) for connection to the barrel. Discard each syringe after use. If a patient dose requires only one syringe, unused syringe should be stored as directed below. Storage:  REFRIGERATE, 2° to 8°C (36° to 46°F). TO PROTECT FROM LIGHT, STORE IN THE ORIGINAL CARTON UNTIL TIME OF USE.
Authorization status:
Abbreviated New Drug Application
Authorization number:
67457-311-00, 67457-311-05

FULVESTRANT- fulvestrant injection

Mylan Institutional LLC

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use FULVESTRANT INJECTION safely and

effectively. See full prescribing information for FULVESTRANT INJECTION.

FULVESTRANT injection, for intramuscular use

Initial U.S. Approval: 2002

INDICATIONS AND USAGE

Fulvestrant injection is an estrogen receptor antagonist indicated for the treatment of:

DOSAGE AND ADMINISTRATION

DOSAGE FORMS AND STRENGTHS

Fulvestrant injection, an injection for intramuscular administration, is supplied as 250 mg/5 mL fulvestrant. (3)

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

ADVERSE REACTIONS

To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at

1-800-FDA-1088 or www.fda.gov/medwatch.

Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer

in postmenopausal women not previously treated with endocrine therapy. (1)

HR-positive advanced breast cancer in postmenopausal women with disease progression following endocrine

therapy. (1)

HR-positive, HER2-negative advanced or metastatic breast cancer in postmenopausal women in combination with

ribociclib, as initial endocrine based therapy or following disease progression on endocrine therapy. (1)

HR-positive, HER2-negative advanced or metastatic breast cancer in combination with palbociclib or abemaciclib in

women with disease progression after endocrine therapy. (1)

Fulvestrant injection 500 mg should be administered intramuscularly into the buttocks (gluteal area) slowly (1 - 2

minutes per injection) as two 5 mL injections, one in each buttock, on Days 1, 15, 29, and once monthly thereafter.

(2.1, 14)

A dose of 250 mg is recommended in patients with moderate hepatic impairment to be administered intramuscularly

into the buttock (gluteal area) slowly (1 - 2 minutes) as one 5 mL injection on Days 1, 15, 29, and once monthly

thereafter. (2.2, 5.2, 8.6)

Hypersensitivity (4)

Risk of Bleeding: Use with caution in patients with bleeding diatheses, thrombocytopenia, or anticoagulant use. (5.1)

Increased Exposure in Patients with Hepatic Impairment: Use a 250 mg dose for patients with moderate hepatic

impairment. (2.2, 5.2, 8.6)

Injection Site Reaction: Use caution while administering fulvestrant injection at the dorsogluteal injection site due to

the proximity of the underlying sciatic nerve. (5.3)

Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus

and to use effective contraception. (5.4, 8.1, 8.3)

Immunoassay Measurement of Serum Estradiol: Fulvestrant injection can interfere with estradiol measurement by

immunoassay, resulting in falsely elevated estradiol levels. (5.5)

The most common adverse reactions occurring in ≥ 5% of patients receiving fulvestrant injection 500 mg were:

injection site pain, nausea, bone pain, arthralgia, headache, back pain, fatigue, pain in extremity, hot flash, vomiting,

anorexia, asthenia, musculoskeletal pain, cough, dyspnea, and constipation. (6.1)

Increased hepatic enzymes (ALT, AST, ALP) occurred in > 15% of fulvestrant injection patients and were not dose-

dependent. (6.1)

DRUG INTERACTIONS

USE IN SPECIFIC POPULATIONS

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 6/2020

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose

2.2 Dose Modification

2.3 Administration Technique

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Risk of Bleeding

5.2 Increased Exposure in Patients with Hepatic Impairment

5.3 Injection Site Reaction

5.4 Embryo-Fetal Toxicity

5.5 Immunoassay Measurement of Serum Estradiol

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Impairment

8.7 Renal Impairment

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

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

There are no known drug-drug interactions. (7)

Lactation: Advise not to breastfeed. (8.2)

Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Monotherapy: Fulvestrant injection is indicated for the treatment of:

Combination Therapy: Fulvestrant injection is indicated for the treatment of:

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose

Monotherapy

The recommended dose of fulvestrant injection is 500 mg to be administered intramuscularly into the

buttocks (gluteal area) slowly (1 - 2 minutes per injection) as two 5 mL injections, one in each buttock,

on Days 1, 15, 29, and once monthly thereafter [see Clinical Studies (14)].

Combination Therapy

When fulvestrant injection is used in combination with palbociclib, abemaciclib, or ribociclib, the

recommended dose of fulvestrant injection is 500 mg to be administered intramuscularly into the

buttocks (gluteal area) slowly (1 - 2 minutes per injection) as two 5 mL injections, one in each buttock,

on Days 1, 15, 29, and once monthly thereafter.

When fulvestrant injection is used in combination with palbociclib, the recommended dose of

palbociclib is a 125 mg capsule taken orally once daily for 21 consecutive days followed by 7 days off

treatment to comprise a complete cycle of 28 days. Palbociclib should be taken with food. Refer to the

Full Prescribing Information for palbociclib.

When fulvestrant injection is used in combination with abemaciclib, the recommended dose of

abemaciclib is 150 mg orally, twice daily. Abemaciclib may be taken with or without food. Refer to the

Full Prescribing Information for abemaciclib.

When fulvestrant injection is used in combination with ribociclib, the recommended dose of ribociclib

is 600 mg taken orally, once daily for 21 consecutive days followed by 7 days off treatment resulting in

a complete cycle of 28 days. Ribociclib can be taken with or without food. Refer to the Full

Prescribing Information for ribociclib.

Pre/perimenopausal women treated with the combination of fulvestrant injection plus palbociclib,

abemaciclib, or ribociclib, should be treated with luteinizing hormone-releasing hormone (LHRH)

agonists according to current clinical practice standards [see Clinical Studies (14)].

Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative

advanced breast cancer in postmenopausal women not previously treated with endocrine therapy,

HR-positive advanced breast cancer in postmenopausal women with disease progression

following endocrine therapy.

HR-positive, HER2-negative advanced or metastatic breast cancer in postmenopausal women in

combination with ribociclib as initial endocrine based therapy or following disease progression

on endocrine therapy.

HR-positive, HER2-negative advanced or metastatic breast cancer in combination with palbociclib

or abemaciclib in women with disease progression after endocrine therapy.

2.2 Dose Modification

Monotherapy

Hepatic Impairment

A dose of 250 mg is recommended for patients with moderate hepatic impairment (Child-Pugh class B)

to be administered intramuscularly into the buttock (gluteal area) slowly (1 - 2 minutes) as one 5 mL

injection on Days 1, 15, 29, and once monthly thereafter.

Fulvestrant injection has not been evaluated in patients with severe hepatic impairment (Child-Pugh class

C) [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6)].

Combination Therapy

When fulvestrant injection is used in combination with palbociclib, abemaciclib, or ribociclib, refer to

monotherapy dose modification instructions for fulvestrant injection.

Refer to the Full Prescribing Information of co-administered palbociclib, abemaciclib, or ribociclib for

dose modification guidelines in the event of toxicities, for use with concomitant medications, and other

relevant safety information.

2.3 Administration Technique

Administer the injection according to the local guidelines for performing large volume intramuscular

injections.

NOTE: Due to the proximity of the underlying sciatic nerve, caution should be taken if administering

fulvestrant injection at the dorsogluteal injection site [see Warnings and Precautions (5.3) and Adverse

Reactions (6.1)].

The proper method of administration of fulvestrant injection for intramuscular use is described in the

following instructions.

For each single-dose prefilled syringe:

Fig ure 1

Remove glass syringe barrel from tray and check that it is not damaged.

Remove perforated patient record label from syringe.

Inspect drug product in glass syringe for any visible particulate matter or discoloration prior to

use. Discard if particulate matter or discoloration is present.

Peel open the safety needle (SafetyGlide™) outer packaging.

Hold the syringe upright on the ribbed part (C). With the other hand, take hold of the cap (A) and

carefully tilt cap back and forth (DO NOT TWIST CAP) until the cap disconnects for removal

(see Figure 1).

Fig ure 2

Fig ure 3

For Administration:

Fig ure 4

Pull the cap (A) off in a straight upward direction. DO NOT TOUCH THE STERILE SYRINGE

TIP (Luer-Lok) (B) (see Figure 2).

Attach the safety needle to the syringe tip (Luer-Lok). Twist needle until firmly seated (see Figure

3). Confirm that the needle is locked to the Luer connector before moving or tilting the syringe

out of the vertical plane to avoid spillage of syringe contents.

Pull shield straight off needle to avoid damaging needle point.

Remove needle sheath.

Expel excess gas from the syringe (a small gas bubble may remain).

Administer intramuscularly slowly (1 - 2 minutes/injection) into the buttock (gluteal area). For user

convenience, the needle ‘bevel up’ position is orientated to the lever arm, as shown in Figure 4.

Fig ure 5

How to Use Fulvestrant Injection

For the 2 x 5 mL syringe package, the contents of both syringes must be injected to receive the 500 mg

recommended dose.

SAFETYGLIDE INSTRUCTIONS FROM BECTON DICKINSON

SafetyGlide

is a trademark of Becton Dickinson and Company.

Important Administration Information

To help avoid HIV (AIDS), HBV (Hepatitis), and other infectious diseases due to accidental

needlesticks, contaminated needles should not be recapped or removed, unless there is no alternative or

that such action is required by a specific medical procedure. Hands must remain behind the needle at all

times during use and disposal.

Do not autoclave SafetyGlide™ Needle before use.

Becton Dickinson guarantees the contents of their unopened or undamaged packages to be sterile, non-

toxic and non-pyrogenic.

3 DOSAGE FORMS AND STRENGTHS

Fulvestrant Injection, an injection for intramuscular administration, is supplied as 5-mL single-dose

prefilled syringes containing 250 mg/5 mL fulvestrant.

4 CONTRAINDICATIONS

Fulvestrant injection is contraindicated in patients with a known hypersensitivity to the drug or to any of

its components. Hypersensitivity reactions, including urticaria and angioedema, have been reported in

association with fulvestrant injection [see Adverse Reactions (6.2)].

5 WARNINGS AND PRECAUTIONS

After injection, immediately activate the lever arm to deploy the needle shielding by applying a

single-finger stroke to the activation assisted lever arm to push the lever arm completely forward.

Listen for a click. Confirm that the needle shielding has completely covered the needle (see

Figure 5). NOTE: Activate away from self and others.

Discard the empty syringe into an approved sharps collector in accordance with applicable

regulations and institutional policy.

Repeat steps 1 through 13 for second syringe.

5.1 Risk of Bleeding

Because fulvestrant injection is administered intramuscularly, it should be used with caution in patients

with bleeding diatheses, thrombocytopenia, or anticoagulant use.

5.2 Increased Exposure in Patients with Hepatic Impairment

The safety and pharmacokinetics of fulvestrant injection were evaluated in a study in seven subjects with

moderate hepatic impairment (Child-Pugh class B) and seven subjects with normal hepatic function.

Exposure was increased in patients with moderate hepatic impairment, therefore, a dose of 250 mg is

recommended [see Dosage and Administration (2.2)].

Fulvestrant injection has not been studied in patients with severe hepatic impairment (Child-Pugh class

C) [see Use in Specific Populations (8.6)].

5.3 Injection Site Reaction

Injection site related events including sciatica, neuralgia, neuropathic pain, and peripheral neuropathy

have been reported with fulvestrant injection. Caution should be taken while administering fulvestrant

injection at the dorsogluteal injection site due to the proximity of the underlying sciatic nerve [see

Dosage and Administration (2.3) and Adverse Reactions (6.1)].

5.4 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, fulvestrant injection can cause fetal

harm when administered to a pregnant woman. In animal reproduction studies, administration of

fulvestrant to pregnant rats and rabbits during organogenesis resulted in embryo-fetal toxicity at daily

doses that are significantly less than the maximum recommended human dose. Advise pregnant women of

the potential risk to a fetus. Advise females of reproductive potential to use effective contraception

during treatment with fulvestrant injection and for one year after the last dose [see Use in Specific

Populations (8.1), (8.3) and Clinical Pharmacology (12.1)].

5.5 Immunoassay Measurement of Serum Estradiol

Due to structural similarity of fulvestrant and estradiol, fulvestrant injection can interfere with estradiol

measurement by immunoassay, resulting in falsely elevated estradiol levels.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in more detail in other sections of the labeling:

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates

observed cannot be directly compared to rates in other trials and may not reflect the rates observed in

clinical practice.

Monotherapy

Comparison of Fulvestrant Injection 500 mg and Fulvestrant Injection 250 mg (CONFIRM)

The following adverse reactions (ARs) were calculated based on the safety analysis of CONFIRM

comparing the administration of fulvestrant injection 500 mg intramuscularly once a month with

Risk of Bleeding [see Warnings and Precautions (5.1)]

Increased Exposure in Patients with Hepatic Impairment [see Warnings and Precautions (5.2)]

Injection Site Reaction [see Warnings and Precautions (5.3)]

Embryo-Fetal Toxicity [see Warnings and Precautions (5.4)]

fulvestrant injection 250 mg intramuscularly once a month. The most frequently reported adverse

reactions in the fulvestrant injection 500 mg group were injection site pain (11.6% of patients), nausea

(9.7% of patients), and bone pain (9.4% of patients); the most frequently reported adverse reactions in

the fulvestrant injection 250 mg group were nausea (13.6% of patients), back pain (10.7% of patients),

and injection site pain (9.1% of patients).

Table 1 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessed

causality, from CONFIRM.

Table 1: Adverse Reactions in CONFIRM (≥ 5% in Either Treatment Group)

Adverse Reactions

Fulvestrant Injection 500 mg

N = 361

%

Fulvestrant Injection 250 mg

N = 374

%

Body as a Whole

Injection Site Pain

Headache

Back Pain

Fatigue

Pain in Extremity

Asthenia

Vascular System

Hot Flash

Digestive System

Nausea

Vomiting

Anorexia

Constipation

Musculoskeletal System

Bone Pain

Arthralgia

Musculoskeletal Pain

Respiratory System

Cough

Dyspnea

In the pooled safety population (N = 1127) from clinical trials comparing fulvestrant injection 500 mg to

fulvestrant injection 250 mg, post-baseline increases of ≥ 1 CTC grade in either AST, ALT, or alkaline

phosphatase were observed in > 15% of patients receiving fulvestrant injection. Grade 3-4 increases

were observed in 1-2% of patients. The incidence and severity of increased hepatic enzymes (ALT,

AST, ALP) did not differ between the 250 mg and the 500 mg fulvestrant injection arms.

Comparison of Fulvestrant Injection 500 mg and Anastrozole 1 mg (FALCON)

The safety of fulvestrant injection 500 mg versus anastrozole 1 mg was evaluated in FALCON. The data

described below reflect exposure to fulvestrant injection in 228 out of 460 patients with HR-positive

advanced breast cancer in postmenopausal women not previously treated with endocrine therapy who

received at least one (1) dose of treatment in FALCON.

Permanent discontinuation associated with an adverse reaction occurred in 4 of 228 (1.8%) patients

receiving fulvestrant injection and in 3 of 232 (1.3%) patients receiving anastrozole. Adverse reactions

Including more severe injection site related sciatica, neuralgia, neuropathic pain, and peripheral neuropathy.

leading to discontinuation for those patients receiving fulvestrant injection included drug

hypersensitivity (0.9%), injection site hypersensitivity (0.4%), and elevated liver enzymes (0.4%).

The most common adverse reactions (≥ 10%) of any grade reported in patients in the fulvestrant

injection arm were arthralgia, hot flash, fatigue, and nausea.

Adverse reactions reported in patients who received fulvestrant injection in FALCON at an incidence of

≥ 5% in either treatment arm are listed in Table 2, and laboratory abnormalities are listed in Table 3.

Table 2: Adverse Reactions in FALCON

Adverse Reactions

Fulvestrant Injection 500 mg

N = 228

Anastrozole 1 mg

N = 232

All Grades

%

Grade 3 or 4

%

All Grades

%

Grade 3 or 4

%

Vascular Disorders

Hot flash

Gastrointestinal Disorders

Nausea

< 1

Diarrhea

< 1

Musculoskeletal and Connective Tissue Disorders

Arthralgia

Myalgia

Pain in extremity

Back pain

< 1

General Disorders and Administration Site Conditions

Fatigue

< 1

< 1

Table 3: Laboratory Abnormalities in FALCON

Laboratory

Parameters

Fulvestrant Injection 500 mg

N = 228

Anastrozole 1 mg

N = 232

All Grades

%

Grade 3 or 4

%

All Grades

%

Grade 3 or 4

%

Alanine

aminotransferase

increased (ALT)

Aspartate

aminotransferase

increased (AST)

< 1

Comparison of Fulvestrant Injection 250 mg and Anastrozole 1 mg in Combined Trials (Studies 0020 and

0021)

The most commonly reported adverse reactions in the fulvestrant injection and anastrozole treatment

groups were gastrointestinal symptoms (including nausea, vomiting, constipation, diarrhea, and

abdominal pain), headache, back pain, vasodilatation (hot flashes), and pharyngitis.

Injection site reactions with mild transient pain and inflammation were seen with fulvestrant injection and

occurred in 7% of patients given the single 5 mL injection (Study 0020) and in 27% of patients given the

*

In FALCON, post-baseline increases of ≥ 1 CTC grade in either AST, ALT, or alkaline phosphatase were

observed in > 10% of patients receiving fulvestrant injection. Grade 3-4 increases were observed in 1%-3% of

patients.

2 x 2.5 mL injections (Study 0021) in the two clinical trials that compared fulvestrant injection 250 mg

and anastrozole 1 mg.

Table 4 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessed

causality, from the two controlled clinical trials comparing the administration of fulvestrant injection

250 mg intramuscularly once a month with anastrozole 1 mg orally once a day.

Table 4: Adverse Reactions in Studies 0020 and 0021 (≥ 5% from Combined Data)

Adverse Reactions

Fulvestrant Injection 250 mg

N = 423

%

Anastrozole 1 mg

N = 423

%

Body as a Whole

Asthenia

Pain

Headache

Back Pain

Abdominal Pain

Injection Site Pain

Pelvic Pain

Chest Pain

Flu Syndrome

Fever

Accidental Injury

Cardiovascular System

Vasodilatation

Digestive System

Nausea

Vomiting

Constipation

Diarrhea

Anorexia

Hemic and Lymphatic

Sys tems

Anemia

Metabolic and Nutritional

Dis orders

Peripheral Edema

Musculoskeletal System

Bone Pain

Arthritis

Nervous System

Dizziness

Insomnia

Paresthesia

Depression

Anxiety

Respiratory System

Pharyngitis

Dyspnea

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