FASLODEX SIDE EFFECTS

  • Generic Name: fulvestrant
  • Brand Name: Faslodex
  • Drug Class: How Do Antineoplastic Estrogen Receptor Antagonists Work?
Last updated on MDtodate: 10/05/2022

SIDE EFFECTS

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

  • Risk of Bleeding
  • Increased Exposure in Patients with Hepatic Impairment
  • Injection Site Reaction
  • Embryo-Fetal Toxicity

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 FASLODEX 500 mg and FASLODEX 250 mg (CONFIRM)

The following adverse reactions (ARs) were calculated based on the safety analysis of CONFIRM comparing the administration of FASLODEX 500 mg intramuscularly once a month with FASLODEX 250 mg intramuscularly once a month. The most frequently reported adverse reactions in the FASLODEX 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 FASLODEX 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 FASLODEX 500 mg
N=361
%
FASLODEX 250 mg
N=374
%
Body as a Whole
Injection Site Pain1 12 9
Headache 8 7
Back Pain 8 11
Fatigue 8 6
Pain in Extremity 7 7
Asthenia 6 6
Vascular System
Hot Flash 7 6
Digestive System
Nausea 10 14
Vomiting 6 6
Anorexia 6 4
Constipation 5 4
Musculoskeletal System
Bone Pain 9 8
Arthralgia 8 8
Musculoskeletal Pain 6 3
Respiratory System
Cough 5 5
Dyspnea 4 5
1. Including moresevere injection site related sciatica, neuralgia, neuropathic pain, and peripheral neuropathy.

 

In the pooled safety population (N=1127) from clinical trials comparing FASLODEX 500 mg to FASLODEX 250 mg, post-baseline increases of ≥1 CTC grade in either AST, ALT, or alkaline phosphatase were observed in >15% of patients receiving FASLODEX. 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 FASLODEX arms.

Comparison Of FASLODEX 500 mg And Anastrozole 1 mg (FALCON)

The safety of FASLODEX 500 mg versus anastrozole 1 mg was evaluated in FALCON. The data described below reflect exposure to FASLODEX 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 FASLODEX and in 3 of 232 (1.3%) patients receiving anastrozole. Adverse reactions leading to discontinuation for those patients receiving FASLODEX 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 FASLODEX arm were arthralgia, hot flash, fatigue, and nausea.

Adverse reactions reported in patients who received FASLODEX 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 FASLODEX 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 11 0 10 0
Gastrointestinal Disorders
Nausea 11 0 10 <1
Diarrhea 6 0 6 <1
Musculoskeletal and Connective Tissue Disorders
Arthralgia 17 0 10 0
Myalgia 7 0 3 0
Pain in extremity 6 0 4 0
Back pain 9 <1 6 0
General Disorders and Administration Site Conditions
Fatigue 11 <1 7 <1

 

Table 3: Laboratory Abnormalities in FALCON1

Laboratory Parameters FASLODEX 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) 7 1 3 0
Aspartate aminotransferaseincreased (AST) 5 1 3 <1
1. In FALCON, post-baselineincreasesof≥1CTCgradein eitherAST, ALT, or alkaline phosphatase were observed in >10% of patients receiving FASLODEX. Grade 3-4 increases were observed in 1%-3% of patients.

 

Comparison Of FASLODEX 250 mg And Anastrozole 1 mg In Combined Trials (Studies 0020 And 0021)

The most commonly reported adverse reactions in the FASLODEX 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 FASLODEX and occurred in 7% of patients given the single 5 mL injection (Study 0020) and in 27% of patients given the 2 x 2.5 mL injections (Study 0021) in the two clinicaltrials that compared FASLODEX 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 FASLODEX 250 mg intramuscularly once a month with anastrozole 1 mg orally once a day.

Table 4:AdverseReactionsinStudies0020 and0021 (≥5% fromCombinedData)

Adverse Reactions FASLODEX 250 mg
N=423
%
Anastrozole 1 mg
N=423
%
Body as a Whole 68 68
Asthenia 23 27
Pain 19 20
Headache 15 17
Back Pain 14 13
Abdominal Pain 12 12
Injection Site Pain1 11 7
Pelvic Pain 10 9
Chest Pain 7 5
Flu Syndrome 7 6
Fever 6 6
Accidental Injury 5 6
Cardiovascular System 30 28
Vasodilatation 18 17
Digestive System 52 48
Nausea 26 25
Vomiting 13 12
Constipation 13 11
Diarrhea 12 13
Anorexia 9 11
Hemic and Lymphatic Systems 14 14
Anemia 5 5
Metabolic and Nutritional Disorders 18 18
Peripheral Edema 9 10
Musculoskeletal System 26 28
Bone Pain 16 14
Arthritis 3 6
Nervous System 34 34
Dizziness 7 7
Insomnia 7 9
Paresthesia 6 8
Depression 6 7
Anxiety 5 4
Respiratory System 39 34
Pharyngitis 16 12
Dyspnea 15 12
Cough Increased 10 10
Skin and Appendages 22 23
Rash 7 8
Sweating 5 5
Urogenital System 18 15
Urinary Tract Infection 6 4
1. Including more severe injection site related sciatica, neuralgia, neuropathic pain, and peripheral neuropathy. All patients on FASLODEX received injections, but only those anastrozole patients who were in Study 0021 received placebo injections.

 

Combination Therapy

Combination Therapy with Palbociclib (PALOMA-3)

The safety of FASLODEX 500 mg plus palbociclib 125 mg/day versus FASLODEX plus placebo was evaluated in PALOMA-3. The data described below reflect exposure to FASLODEX plus palbociclib in 345 out of 517 patients with HR-positive, HER2-negative advanced or metastatic breast cancer who received at least 1 dose of treatment in PALOMA-3. The median duration of treatment for FASLODEX plus palbociclib was 10.8 months while the median duration of treatment for FASLODEX plus placebo arm was 4.8 months.

No dose reduction was allowed for FASLODEX in PALOMA-3. Dose reductions of palbociclib due to an adverse reaction of any grade occurred in 36% of patients receiving FASLODEX plus palbociclib.

Permanent discontinuation associated with an adverse reaction occurred in 19 of 345 (6%) patients receiving FASLODEX plus palbociclib, and in 6 of 172 (3%) patients receiving FASLODEX plus placebo. Adverse reactions leading to discontinuation for those patients receiving FASLODEX pluspalbociclib included fatigue(0.6%), infections(0.6%), and thrombocytopenia(0.6%).

The most common adverse reactions (≥10%) of any grade reported in patients in the FASLODEX plus palbociclib arm by descending frequency were neutropenia, leukopenia, infections, fatigue, nausea, anemia, stomatitis, diarrhea, thrombocytopenia, vomiting, alopecia, rash, decreased appetite, and pyrexia.

The most frequently reported Grade ≥3 adverse reactions (≥5%) in patients receiving FASLODEX plus palbociclib in descending frequency were neutropenia and leukopenia.

Adverse reactions (≥10%) reported in patients who received FASLODEX plus palbociclib or FASLODEX plus placebo in PALOMA-3 are listed in Table 5, and laboratory abnormalities are listed in Table 6.

Table 5: Adverse Reactions (≥10%) in PALOMA-3

Adverse Reactions FASLODEX plus Palbociclib
N=345
FASLODEX plus Placebo
N=172
All Grades
%
Grade 3
%
Grade 4
%
All Grades
%
Grade 3
%
Grade 4
%
Infections and Infestations
Infections1 472 3 1 31 3 0
Blood and Lymphatic System Disorders
Neutropenia 83 55 11 4 1 0
Leukopenia 53 30 1 5 1 1
Anemia 30 4 0 13 2 0
Thrombocytopenia 23 2 1 0 0 0
Metabolism and Nutrition Disorders
Decreased appetite 16 1 0 8 1 0
Gastrointestinal Disorders
Nausea 34 0 0 28 1 0
Stomatitis3 28 1 0 13 0 0
Diarrhea 24 0 0 19 1 0
Vomiting 19 1 0 15 1 0
Skin and Subcutaneous Tissue Disorders
Alopecia 184 N/A N/A 65 N/A N/A
Rash6 17 1 0 6 0 0
General Disorders and Administration Site Conditions
Fatigue 41 2 0 29 1 0
Pyrexia 13 <1 0 5 0 0
Grading according to CTCAEv.4.0.
CTCAE=Common Terminology Criteria for Adverse Events; N=number of patients; N/A=notapplicable.
1. Infections includes all reported preferred terms (PTs) that are part of the System Organ Class Infections and infestations.
2. Most common infections (≥1%)include: nasopharyngitis, upper respiratory infection, urinary tract infection, influenza, bronchitis, rhinitis, conjunctivitis, pneumonia, sinusitis, cystitis, oral herpes, respiratory tract infection, gastroenteritis, tooth infection, pharyngitis, eye infection, herpes simplex, paronychia.
3. Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal discomfort, oropharyngeal pain, stomatitis.
4. Grade 1 events – 17%; Grade 2 events – 1%.
5. Grade 1 events – 6%.
6. Rash includes: rash, rash maculo-papular, rash pruritic, rash erythematous, rashpapular, dermatitis, dermatitis acneiform, toxic skin eruption.

 

Additional adverse reactions occurring at an overall incidence of <10.0% of patients receiving FASLODEX plus palbociclib in PALOMA-3 included asthenia (7.5%), aspartate aminotransferase increased (7.5%), dysgeusia (6.7%), epistaxis (6.7%), lacrimation increased (6.4%), dry skin (6.1%), alanine aminotransferase increased (5.8%), vision blurred (5.8%), dry eye (3.8%), and febrile neutropenia (0.9%).

Table 6: Laboratory Abnormalities in PALOMA-3

Laboratory Parameters FASLODEX plus Palbociclib
N=345
FASLODEX plus Placebo
N=172
All Grades
%
Grade 3
%
Grade 4
%
All Grades
%
Grade 3
%
Grade 4
%
WBC decreased 99 45 1 26 0 1
Neutrophils decreased 96 56 11 14 0 1
Anemia 78 3 0 40 2 0
Platelets decreased 62 2 1 10 0 0
Aspartate aminotransferase increased 43 4 0 48 4 0
Alanine aminotransferase increased 36 2 0 34 0 0
N=number of patients; WBC=white blood cells.

 

Combination Therapy With Abemaciclib (MONARCH 2)

The safety of FASLODEX (500 mg) plus abemaciclib (150 mg twice daily) versus FASLODEX plus placebo was evaluated in MONARCH 2. The data described below reflect exposure to FASLODEX in 664 patients with HR-positive, HER2-negative advanced breast cancer who received at least one dose of FASLODEX plus abemaciclib or placebo in MONARCH 2.

Median duration of treatment was12months forpatients receivingFASLODEXplus abemacicliband 8 months for patients receiving FASLODEX plus placebo.

Dose reductions due to an adverse reaction occurred in 43% of patients receiving FASLODEX plus abemaciclib. Adverse reactions leading to dose reductions ≥5% of patients were diarrhea and neutropenia. Abemaciclib dose reduction due to diarrhea of any grade occurred in 19% of patients receiving FASLODEX plus abemaciclib compared to 0.4% of patients receiving FASLODEX plus placebo. Abemaciclib dose reductions due to neutropenia of any grade occurred in 10% of patients receiving FASLODEX plus abemaciclib compared to no patients receiving FASLODEX plus placebo.

Permanent study treatment discontinuation due to an adverse event was reported in 9% of patients receiving FASLODEX plus abemaciclib and in 3% of patients receiving FASLODEX plus placebo. Adverse reactions leading to permanent discontinuation for patients receiving FASLODEX plus abemaciclib were infection (2%), diarrhea (1%), hepatotoxicity (1%), fatigue (0.7%), nausea (0.2%), abdominal pain (0.2%), acute kidney injury (0.2%), and cerebral infarction (0.2%).

Deaths during treatment or during the 30-day follow up, regardless of causality, were reported in 18 cases (4%) of FASLODEX plus abemaciclib treated patients versus 10 cases (5%) of FASLODEX plus placebo treated patients. Causes of death for patients receiving FASLODEX plus abemaciclib included: 7 (2%)patient deaths due to underlying disease, 4 (0.9%) due to sepsis, 2 (0.5%) due to pneumonitis, 2 (0.5%) due to hepatotoxicity, and one (0.2%) due to cerebral infarction.

The most common adverse reactions reported (≥20%) in the FASLODEX plus abemaciclib arm were diarrhea, fatigue, neutropenia, nausea, infections, abdominal pain, anemia, leukopenia, decreased appetite, vomiting, and headache (Table 7). The most frequently reported (≥5%) Grade 3 or 4 adverse reactions were neutropenia, diarrhea, leukopenia, anemia, and infections.

Table 7: Adverse Reactions ≥10% of Patients Receiving FASLODEX Plus Abemaciclib and ≥2% Higher Than FASLODEX Plus Placebo in MONARCH 2

Adverse Reactions FASLODEX plus Abemaciclib
N=441
FASLODEX plus Placebo
N=223
All Grades
%
Grade 3
%
Grade 4
%
All Grades
%
Grade 3
%
Grade 4
%
Gastrointestinal Disorders
  Diarrhea 86 130 1 25 <1 0
  Nausea 45 3 0 23 1 0
  Abdominal pain1 35 2 0 16 1 0
  Vomiting 26 <1 0 10 2 0
  Stomatitis 15 <1 0 10 0 0
Infections and Infestations
  Infections2 43 5 <1 25 3 <1
Blood and Lymphatic System Disorders
  Neutropenia3 46 24 3 4 1 <1
  Anemia4 29 7 <1 4 1 0
  Leukopenia5 28 9 <1 2 0 0
  Thrombocytopenia6 16 2 1 3 0 <1
General Disorders and Administration Site Conditions
  Fatigue7 46 3 0 32 <1 0
  Edema peripheral 12 0 0 7 0 0
  Pyrexia 11 <1 <1 6 <1 0
Metabolism and Nutrition Disorders
  Decreased appetite 27 1 01 2 <1 0
Respiratory, Thoracic, and Mediastinal Disorders
  Cough 13 0 0 11 0 0
Skin and Subcutaneous Tissue Disorders
  Alopecia 16 0 0 2 0 0
  Pruritus 13 0 0 6 0 0
  Rash 11 1 0 4 0 0
Nervous System Disorders
  Headache 20 1 0 15 <1 0
  Dysgeusia 18 0 0 3 0 0
  Dizziness 12 1 0 6 0 0
Investigations
  Alanine aminotransferase increased 13 4 <1 5 2 0
  Aspartate aminotransferase increased 12 2 0 7 3 0
  Creatinine increased 12 <1 0 <1 0 0
  Weight decreased 10 <1 0 2 <1 0
1. Includes abdominalpain, abdominalpain upper, abdominal pain lower, abdominal discomfort, abdominal tenderness.
2. Includesupper respiratory tract infection, urinary tract infection, lunginfection, pharyngitis, conjunctivitis, sinusitis, vaginal infection, sepsis.
3. Includesneutropenia, neutrophil countdecreased.
4. Includes anemia, hematocrit decreased, hemoglobin decreased, red blood cell count decreased.
5. Includes leukopenia, white blood cell count decreased.
6. Includes platelet count decreased, thrombocytopenia.
7. Includes asthenia, fatigue.

 

Additional adverse reactions in MONARCH 2 include venous thromboembolic events (deep vein thrombosis, pulmonary embolism, cerebral venous sinus thrombosis, subclavian vein thrombosis, axillary vein thrombosis, and DVT inferior vena cava), which were reported in 5% of patients treated with FASLODEX plus abemaciclib as compared to 0.9% of patients treated with FASLODEX plus placebo.

Table 8: Laboratory Abnormalities ≥10% in Patients Receiving FASLODEXPlus Abemacicliband ≥2% Higher Than FASLODEX Plus Placebo in MONARCH 2

Laboratory Parameters Fulvestrant plus Abemaciclib
N=441
Fulvestrant plus Placebo
N=223
All Grades
%
Grade 3
%
Grade 4
%
All Grades
%
Grade 3
%
Grade 4
%
Creatinine increased 98 1 0 74 0 0
White blood cell decreased 90 23 <1 33 <1 0
Neutrophil count decreased 87 29 4 30 4 <1
Anemia 84 3 0 33 <1 0
Lymphocyte count decreased 63 12 <1 32 2 0
Platelet count decreased 53 <1 1 15 0 0
Alanine aminotransferase increased 41 4 <1 32 1 0
Aspartate aminotransferase increased 37 4 0 25 4 <1

 

Combination Therapy With Ribociclib (MONALEESA-3)

The safety of FASLODEX 500 mg plus ribociclib 600 mg versus FASLODEX plus placebo was evaluated in MONALEESA-3. The data described below reflect exposure to FASLODEX plus ribociclib in483outof724postmenopausalpatientswithHR-positive,HER2-negative advancedormetastatic breast cancer for initial endocrine based therapy or after disease progression on endocrine therapy who received at least one dose of FASLODEX plus ribociclib or placebo in MONALEESA-3. Median duration oftreatmentwas 15.8 months for FASLODEX plus ribociclib and12 months for FASLODEX plus placebo.

Dose reductions due to adverse reactions occurred in 32% of patients receiving FASLODEX plus ribociclib and in 3% of patients receiving FASLODEX plus placebo. Among patients receiving FASLODEX plus ribociclib, 8% were reported to have permanently discontinued both FASLODEX plus ribociclib, and 9% were reported to have discontinued ribociclib alone due to ARs. Among patients receiving FASLODEX plus placebo, 4% were reported to have permanently discontinued both FASLODEX and placebo and 2% were reported to have discontinued placebo alone due to ARs.

Adverse reactions leading to treatment discontinuation of FASLODEX plus ribociclib (as compared to FASLODEXplus placebo) were ALT increased (5% vs. 0%), AST increased (3% vs. 0.6%), and vomiting (1% vs. 0%).

The most common adverse reactions (reported at a frequency ≥20% on the FASLODEX plus ribociclib arm and ≥2% higher than FASLODEX plus placebo) were neutropenia, infections, leukopenia, cough, nausea, diarrhea, vomiting, constipation, pruritus, and rash. The most frequently reported Grade 3/4 adverse reactions (reported at a frequency ≥5%) in patients receiving FASLODEX plus ribociclib in descending frequency were neutropenia, leukopenia, infections, and abnormal liver function tests.

Adverse reactions and laboratory abnormalities occurring in patients in MONALEESA-3 are listed in Table 9 and Table 10, respectively.

Table 9: Adverse Reactions Occurring in ≥10% and ≥2% higher than FASLODEX plus Placebo Arm in MONALEESA-3 (All Grades)

Adverse Reactions FASLODEX plus Ribociclib
N=483
FASLODEX plus Placebo
N=241
All Grades
%
Grade 3
%
Grade 4
%
All Grades
%
Grade 3
%
Grade 4
%
Infections and Infestations
Infections1 42 5 0 30 2 0
Blood and Lymphatic System Disorders
Neutropenia 69 46 7 2 0 0
Leukopenia 27 12 <1 <1 0 0
Anemia 17 3 0 5 2 0
Metabolism and Nutrition Disorders
Decreased appetite 16 <1 0 13 0 0
Nervous System Disorders
Dizziness 13 <1 0 8 0 0
Respiratory, Thoracic, and Mediastinal Disorders
Cough 22 0 0 15 0 0
Dyspnea 15 1 <1 12 2 0
Gastrointestinal Disorders
Nausea 45 1 0 28 <1 0
Diarrhea 29 <1 0 20 <1 0
Vomiting 27 1 0 13 0 0
Constipation 25 <1 0 12 0 0
Abdominal pain 17 1 0 13 <1 0
Skin and Subcutaneous Tissue Disorders
Alopecia 19 0 0 5 0 0
Pruritus 20 <1 0 7 0 0
Rash 23 <1 0 7 0 0
General Disorders and Administration Site Conditions
Edema peripheral 15 0 0 7 0 0
Pyrexia 11 <1 0 7 0 0
Investigations
Alanine aminotransferase increased 15 7 2 5 <1 0
Aspartate aminotransferase increased 13 5 1 5 <1 0
Grading according to CTCAE4.03.
CTCAE=Common Terminology Criteria for Adverse Events; N=number of patients
1. Infections; urinary tract infections; respiratory tract infections; gastroenteritis; sepsis (<1%).

 

Additional adverse reactions in MONALEESA-3 for patients receiving FASLODEX plus ribociclib included asthenia (14%), dyspepsia (10%), thrombocytopenia (9%), dry skin (8%), dysgeusia (7%), electrocardiogram QT prolonged (6%),dry mouth (5%), vertigo (5%), dry eye (5%), lacrimation increased (4%), erythema (4%), hypocalcemia (4%), blood bilirubin increased (1%), and syncope (1%).

Table 10: Laboratory Abnormalities Occurring in ≥10% of Patients in MONALEESA-3

Laboratory parameters FASLODEX plus Ribociclib
N=483
FASLODEX plus Placebo
N=241
All Grades
%
Grade 3
%
Grade 4
%
All Grades
%
Grade 3
%
Grade 4
%
Hematology
Leukocyte count decreased 95 25 <1 26 <1 0
Neutrophil count decreased 92 46 7 21 <1 0
Hemoglobin decreased 60 4 0 35 3 0
Lymphocyte count decreased 69 14 1 35 4 <1
Platelet count decreased 33 <1 1 11 0 0
Chemistry
Creatinine increased 65 <1 <1 33 <1 0
Gamma-glutamyl transferase increased 52 6 1 49 8 2
Aspartate aminotransferase increased 49 5 2 43 3 0
Alanine aminotransferase increased 44 8 3 37 2 0
Glucose serum decreased 23 0 0 18 0 0
Phosphorous decreased 18 5 0 8 <1 0
Albumin decreased 12 0 0 8 0 0

 

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of FASLODEX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

For FASLODEX 250 mg, other adverse reactions reported as drug-related and seen infrequently (<1%) include thromboembolic phenomena, myalgia, vertigo, leukopenia, and hypersensitivity reactions, including angioedema and urticaria.

Vaginal bleeding has been reported infrequently (<1%), mainly in patients during the first 6 weeks after changing from existing hormonal therapy to treatment with FASLODEX. If bleeding persists, further evaluation should be considered.

Elevation of bilirubin, elevation of gamma GT, hepatitis, and liver failure have been reported infrequently (<1%).

 

SRC: NLM .