Advertisement

Topics

These highlights do not include all the information needed to use letrozole tablets safely and effectively. See full prescribing information for letrozole tablets. LETROZOLE Tablets, USPInitial U.S. Approval: 1997 | Letrozole

04:59 EDT 27th August 2014 | BioPortfolio

Note: While we endeavour to keep our records up-to-date one should not rely on these details being accurate without first consulting a professional. Click here to read our full medical disclaimer.

Letrozole is indicated for the adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer.

Letrozole is indicated for the extended adjuvant treatment of early breast cancer in postmenopausal women, who have received 5 years of adjuvant tamoxifen therapy. The effectiveness of Letrozole in extended adjuvant treatment of early breast cancer is based on an analysis of disease-free survival in patients treated with Letrozole for a median of 60 months [see Clinical Studies (14.2 , 14.3)].

Letrozole is indicated for first-line treatment of postmenopausal women with hormone receptor positive or unknown, locally advanced or metastatic breast cancer. Letrozole is also indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy [see Clinical Studies (14.4 , 14.5)]. 

The recommended dose of Letrozole Tablets is one 2.5 mg tablet administered once a day, without regard to meals.

In the adjuvant setting, the optimal duration of treatment with letrozole is unknown. The planned duration of treatment in the study was 5 years with 73% of the patients having completed adjuvant therapy. Treatment should be discontinued at relapse [see Clinical Studies ( 14.1 )].

In the extended adjuvant setting, the optimal treatment duration with Letrozole is not known. The planned duration of treatment in the study was 5 years. In the final updated analysis, conducted at a median follow-up of 62 months, the median treatment duration was 60 months. Seventy-one percent of patients were treated for at least 3 years and 58% of patients completed at least 4.5 years of extended adjuvant treatment. The treatment should be discontinued at tumor relapse [see Clinical Studies ( 14.2 )].

In patients with advanced disease, treatment with Letrozole should continue until tumor progression is evident [see Clinical Studies ( 14.4 , 14.5 )].

No dosage adjustment is recommended for patients with mild to moderate hepatic impairment, although Letrozole blood concentrations were modestly increased in subjects with moderate hepatic impairment due to cirrhosis. The dose of Letrozole in patients with cirrhosis and severe hepatic dysfunction should be reduced by 50% [see Warnings and Precautions (5.3)]. The recommended dose of Letrozole for such patients is 2.5 mg administered every other day. The effect of hepatic impairment on Letrozole exposure in noncirrhotic cancer patients with elevated bilirubin levels has not been determined.

No dosage adjustment is required for patients with renal impairment if creatinine clearance is ≥10 mL/min. [see Clinical Pharmacology (12.3)].

2.5 mg tablets: yellow, round, biconvex, film-coated (debossed with "2.5" on one side).

Letrozole may cause fetal harm when administered to a pregnant woman and the clinical benefit to premenopausal women with breast cancer has not been demonstrated. Letrozole is contraindicated in women who are or may become pregnant. If Letrozole is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. [see Use in Specific Populations (8.1)]

Use of Letrozole may cause decreases in bone mineral density (BMD). Consideration should be given to monitoring BMD. Results of a substudy to evaluate saftey in the adjuvant setting comparing the effect on lumbar spine (L2-L4) bone mineral density (BMD) of adjuvant treatment with letrozole to that with tamoxifen showed at 24 months a median decrease in lumbar spine BMD of 4.1% in the letrozole arm compared to a median increase of 0.3% in the tamoxifen arm (difference = 4.4%) ( P<0.0001) [ see Adverse Reactions ( 6.1 )].Updated results from the BMD sub-study in the extended adjuvant setting demonstrated that at 2 years patients receiving letrozole had a median decrease from baseline of 3.8% in hip BMD compared to a median decrease of 2.0% in the placebo group. The changes from baseline in lumbar spine BMD in letrozole and placebo treated groups were not statistically different. [see Adverse Reactions (6.2)].

In the adjuvant trial the incidence of bone fractures at any time after randomization was 13.8% for letrozole and 10.5% for tamoxifen. The incidence of osteoporosis was 5.1 % for letrozole and 2.7% for tamoxifen [see Adverse Reactions ( 6.1 )]. In the extended adjuvant trial the incidence of bone fractures at any time after randomization was 13.3% for letrozole and 7.8% for placebo. The incidence of new osteoporosis was 14.5% for letrozole and 7.8% for placebo. [see Adverse Reactions (6.3)].

Consideration should be given to monitoring serum cholesterol. In the adjuvant trail hypercholesterolemia was reported in 52.3% of letrozole patients and 28.6 % of tamoxifen patients. CTC grade 3-4 hypercholesterolemia was reported in 0.4% of letrozole patients and 0.1% of tamoxifen patients. Also in the adjuvant setting, an increase of ≥1.5 X ULN in total cholesterol (generally non-fasting) was observed in patients on monotherapy who had baseline total serum cholesterol within the normal range (i.e. <=1.5 x ULN) in 151/1843 (8.2%) on letrozole vs 57/1840 (3.2%) on. Lipid lowering medications were required for 25% of patients on letrozole and 16% on tamoxifen. [see Adverse Reactions (6.1)].

Subjects with cirrhosis and severe hepatic impairment who were dosed with 2.5 mg of Letrozole experienced approximately twice the exposure to Letrozole as healthy volunteers with normal liver function. Therefore, a dose reduction is recommended for this patient population. The effect of hepatic impairment on Letrozole exposure in cancer patients with elevated bilirubin levels has not been determined. [see Dosage and Administration (2.5)].

Because fatigue, dizziness, and somnolence have been reported with the use of Letrozole, caution is advised when driving or using machinery until it is known how the patient reacts to Letrozole use.

No dose-related effect of Letrozole on any hematologic or clinical chemistry parameter was evident. Moderate decreases in lymphocyte counts, of uncertain clinical significance, were observed in some patients receiving Letrozole 2.5 mg. This depression was transient in about half of those affected. Two patients on Letrozole developed thrombocytopenia; relationship to the study drug was unclear. Patient withdrawal due to laboratory abnormalities, whether related to study treatment or not, was infrequent.

The most serious adverse reactions from the use of Letrozole are:

Because clinical trials are not conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The median treatment duration of adjuvant treatment was 60 months and the median duration of follow-up for safety was 73 months for patients receiving Letrozole and tamoxifen.

Certain adverse reactions were prospectively specified for analysis, based on the known pharmacologic properties and side effect profiles of the two drugs.

Adverse reactions were analyzed irrespective of whether a symptom was present or absent at baseline. Most adverse reactions reported (approximately 75% of patients reporting 1 or more AE) were Grade 1 or Grade 2 applying the Common Toxicity Criteria Version 2.0 / Common Terminology Criteria for Adverse Events, version 3.0. Table 1 describes adverse reactions (Grades 1-4) irrespective of relationship to study treatment in the adjuvant trial for the monotherapy arms analysis (safety population).

When considering all grades during study treatment, a higher incidence of events was seen for Letrozole regarding fractures (10.1% vs 7.1%), myocardial infarctions (1.0% vs 0.5%), and arthralgia (25.2% vs 20.4%) (Letrozole vs tamoxifen respectively). A higher incidence was seen for tamoxifen regarding thromboembolic events (2.1% vs 3.6%), endometrial hyperplasia/cancer (0.3% vs 2.9%), and endometrial proliferation disorders (0.3% vs 1.8%) (Letrozole vs tamoxifen respectively).

At a median follow up of 73 months, a higher incidence of events was seen for Letrozole (13.8%) than for tamoxifen (10.5%) regarding fractures. A higher incidence was seen for tamoxifen compared to Letrozole regarding thromboembolic events (4.5% vs 2.9%), and endometrial hyperplasia or cancer (2.9% vs 0.4%) (tamoxifen vs Letrozole, respectively).

Bone Study: Results of a phase 3 safety trial in 262 post menopausal women with resected receptor positive early breast cancer in the adjuvant setting comparing the effect on lumbar spine (L2-L4) bone mineral density (BMD) of adjuvant treatment with letrozole to that with tamoxifen showed at 24 months a median decrease in lumbar spine BMD of 4.1% in the letrozole arm compared to a median increase of 0.3% in the tamoxifen arm (difference = 4.4%) (P<0.0001). No patients with a normal BMD at baseline became osteoporotic over the 2 years and only 1 patient with osteopenia at baseline (T score of -1.9) developed osteoporosis during the treatment period (assessment by central review). The results for total hip BMD were similar, although the differences between the two treatments were less pronounced. During the 2 year period, fractures were reported by 4 of 103 patients (4%) in the letrozole arm, and 6 of 97 patients (6%) in the tamoxifen arm.

Lipid Study: In a phase 3 safety trial in 262 post menopausal women with resected receptor positive early breast cancer at 24 months comparing the effects on lipid profiles of adjuvant letrozole to tamoxifen, 12% of patients on letrozole had at least one total cholesterol value of a higher CTCAE grade than at baseline compared with 4% of patients on tamoxifen.

Table 1: Patients with Adverse Reactions (CTC Grades 1-4, Irrespective of Relationship to Study Drug) in the Adjuvant Study – Monotherapy Arms Analysis (Median follow-up 73 months; median treatment 60 months)
1 During study treatment, based on Safety Monotherapy population
2 Any time after randomization, including post treatment follow-up
3 Excluding women who had undergone hysterectomy before study entry
Note: Cardiovascular (including cerebrovascular and thromboembolic), skeletal and urogenital/endometrial events and second malignancies were collected life-long. All of these events were assumed to be of CTC grade 3-5 and were not individually graded.
Grades 1-4 Grades 3-4
Adverse Reaction Letrozole N=2448 n (%) tamoxifen N=2447 n (%) Letrozole N=2448 n (%) tamoxifen N=2447 n (%)
Pts with any adverse event 2310 (94.4) 2214 (90.5) 635 (25.9) 604 (24.7)
Hypercholesterolemia 1280 (52.3) 700 (28.6) 11 ( 0.4) 6 ( 0.2)
Hot Flashes/Flushes 821 (33.5) 929 (38.0) 0 - 0 -
Arthralgia/Arthritis 618 (25.2) 501 (20.4) 85 ( 3.5) 50 ( 2.0)
Night Sweats 357 (14.6) 426 (17.4) 0 - 0 -
Bone Fractures2 338 (13.8) 257 (10.5) - - - -
Weight Increase 317 (12.9) 378 (15.4) 27 ( 1.1) 39 ( 1.6)
Nausea 283 (11.6) 277 (11.3) 6 ( 0.2) 9 ( 0.4)
Bone Fractures1 247 (10.1) 174 ( 7.1) - - - -
Fatigue (Lethargy, Malaise, Asthenia) 235 ( 9.6) 250 (10.2) 6 ( 0.2) 7 ( 0.3)
Myalgia 217 ( 8.9) 212 ( 8.7) 18 ( 0.7) 14 ( 0.6)
Edema 164 ( 6.7) 160 ( 6.5) 3 ( 0.1) 1 (<0.1)
Weight Decrease 140 ( 5.7) 129 ( 5.3) 8 ( 0.3) 5 ( 0.2)
Vaginal Bleeding 128 ( 5.2) 320 (13.1) 1 (<0.1) 8 ( 0.3)
Back Pain 125 ( 5.1) 136 ( 5.6) 7 ( 0.3) 11 ( 0.4)
Osteoporosis NOS 124 ( 5.1) 66 ( 2.7) 10 ( 0.4) 5 ( 0.2)
Bone pain 123 ( 5.0) 109 ( 4.5) 6 ( 0.2) 4 ( 0.2)
Depression 119 ( 4.9) 114 ( 4.7) 16 ( 0.7) 14 ( 0.6)
Vaginal Irritation 111 ( 4.5) 77 ( 3.1) 2 (<0.1) 2 (<0.1)
Headache 105 ( 4.3) 94 ( 3.8) 9 ( 0.4) 5 ( 0.2)
Pain in extremity 103 ( 4.2) 79 ( 3.2) 6 ( 0.2) 4 ( 0.2)
Osteopenia 87 ( 3.6) 74 ( 3.0) 0 - 2 (<0.1)
Dizziness/Light-Headedness 84 ( 3.4) 84 ( 3.4) 1 (<0.1) 6 (0.2)
Alopecia 83 ( 3.4) 84 ( 3.4) 0 - 0 -
Vomiting 80 ( 3.3) 80 ( 3.3) 3 ( 0.1) 5 (0.2)
Cataract 49 (2.0) 54 (2.2) 16 (0.7) 17 (0.7)
Constipation 49 ( 2.0) 71 ( 2.9) 3 ( 0.1) 1 (<0.1)
Breast pain 37 ( 1.5) 43 ( 1.8) 1 (<0.1) 0 -
Anorexia 20 ( 0.8) 20 ( 0.8) 1 (<0.1) 1 (<0.1)
Endometrial Hyperplasia/Cancer2,3 11/1909 ( 0.6) 70/1943 ( 3.6) - - - -
Endometrial Proliferation Disorders 10 (0.3) 71 (1.8) 0 - 14 (0.6)
Endometrial Hyperplasia/ Cancer1,3 6/1909 ( 0.3) 57/1943 (2.9) - - - -
Other endometrial disorders 2 (<0.1) 3 ( 0.1) 0 - 0 -
Myocardial Infarction1 24 ( 1.0) 12 ( 0.5) - - - -
Myocardial Infarction2 37 ( 1.5) 25 (1.0) - - - -
Myocardial ischemia 6 ( 0.2) 9 ( 0.4) - - - -
Cerebrovascular accident1 52 ( 2.1) 46 ( 1.9) - - - -
Cerebrovascular accident2 70 ( 2.9) 63 ( 2.6) - - - -
Angina1 26 ( 1.1) 24 ( 1.0) - - - -
Angina2 32 ( 1.3) 31 ( 1.3) - - - -
Thromboembolic Event1 51 ( 2.1) 89 ( 3.6) - - - -
Thromboembolic Event2 71 ( 2.9) 111 ( 4.5) - - - -
Other Cardiovascular1 260 (10.6) 256 (10.5) - - - -
Other Cardiovascular2 312 (12.7) 337 (13.8) - - - -
Second Malignancies1 53 ( 2.2) 78 ( 3.2) - - - -
Second Malignancies2 102 ( 4.2) 119 ( 4.9) - - - -

The median duration of extended adjuvant treatment was 24 months and the median duration of follow-up for safety was 28 months for patients receiving Letrozole and placebo.

Table 2 describes the adverse reactions occurring at a frequency of at least 5% in any treatment group during treatment. Most adverse reactions reported were Grade 1 and Grade 2 based on the Common Toxicity Criteria Version 2.0. In the extended adjuvant setting, the reported drug-related adverse reactions that were significantly different from placebo were hot flashes, arthralgia/arthritis, and myalgia.

Based on a median follow-up of patients for 28 months, the incidence of clinical fractures from the core randomized study in patients who received Letrozole was 5.9% (152) and placebo was 5.5% (142). The incidence of self-reported osteoporosis was higher in patients who received Letrozole 6.9% (176) than in patients who received placebo 5.5% (141). Bisphosphonates were administered to 21.1% of the patients who received Letrozole and 18.7% of the patients who received placebo.

The incidence of cardiovascular ischemic events from the core randomized study was comparable between patients who received Letrozole 6.8% (175) and placebo 6.5% (167).

A patient-reported measure that captures treatment impact on important symptoms associated with estrogen deficiency demonstrated a difference in favor of placebo for vasomotor and sexual symptom domains.

Bone Sub-study: [see Warnings and Precautions ( 5.1 )].

Lipid Sub-study : In the extended adjuvant setting, based on a median duration of follow-up of 62 months, there was no significant difference between Letrozole and placebo in total cholesterol or in any lipid fraction at any time over 5 years. Use of lipid lowering drugs or dietary management of elevated lipids was allowed [see Warnings and Precautions ( 5.2 )].

Manufacturer

Kremers Urban Pharmaceuticals Inc.

Active Ingredients

Source

Drugs and Medications [15 Associated Drugs and Medications listed on BioPortfolio]

Letrozole [APP Pharmaceuticals, LLC]

These highlights do not include all the information needed to use Letrozole Tablets, USP safely and effectively. See full prescribing information for Letrozole Tablets, USP Letrozole Tablets, USPIniti...

Letrozole [Breckenridge Pharmaceutical, Inc.]

These highlights do not include all the information needed to use letrozole tablets safely and effectively. See full prescribing information for letrozole tablets.Letrozole tablets USP, 2.5 mgInitial ...

Letrozole [Sun Pharmaceutical Industries Limited ]

These highlights do not include all the information needed to use letrozole safely and effectively. See full prescribing information for letrozole tablets. Letrozole Tablets, USPInitial U.S. Approval:...

Letrozole [Qualitest Pharmaceuticals]

These highlights do not include all the information needed to use Letrozole Tablets, USP safely and effectively. See full prescribing information for Letrozole Tablets, USP. Letrozole Tablets, USPInit...

Letrozole [Physicians Total Care, Inc.]

These highlights do not include all the information needed to use letrozole safely and effectively. See full prescribing information for letrozole tablets. Letrozole Tablets, USP Initial U.S. Approval...

Clinical Trials [251 Associated Clinical Trials listed on BioPortfolio]

Pilot of Letrozole for Uterine Myomas

PLUM evaluates the drug letrozole as a treatment for uterine fibroids. This study is a randomized, blinded, placebo-controlled trial of oral letrozole among premenopausal women with sympto...

Endocrinology Profile in Patients Undergoing Clomiphene, Letrozole, and Combination Clomiphene and Letrozole Cycles

The goal of the study is to measure serial hormonal levels in patients undergoing clomiphene, letrozole, and a combination clomiphene and letrozole cycle. This information may help us to ...

Trial of Letrozole +/- Palbociclib in Metastatic Endometrial Cancer

This randomized phase 2 trial is evaluating superiority of Letrozole-palbociclib combination versus letrozole alone in ER positive endometrioid adenocarcinoma of endometrium

A Study of Neoadjuvant Letrozole + GDC-0032 Versus Letrozole + Placebo in Post-Menopausal Women With Breast Cancer (LORELEI)

This is a two-arm, randomized, double-blind, multicenter, pre-operative study to evaluate the effect of combining letrozole and GDC-0032 versus letrozole and placebo in postmenopausal wome...

Study Evaluating Bosutinib-Letrozole Combination Versus Letrozole Alone in Post Menopausal Women With Breast Cancer

This is a phase 2 study of bosutinib administered in combination with letrozole versus letrozole alone in post-menopausal women with breast cancer. This is a 2-part study. Subjects in part...

PubMed Articles [25 Associated PubMed Articles listed on BioPortfolio]

Comparison of Congenital Malformations among Babies Born after Administration of Letrozole or Clomiphene Citrate for Infertility Treatment in a Korean Cohort.

This retrospective study investigated and compared the incidence of congenital foetal anomalies after letrozole versus clomiphene citrate (CC) administration for infertility treatment. Data from 142 n...

A Retrospective Study of Letrozole Treatment Prior to Human Chorionic Gonadotropin in Women with Polycystic Ovary Syndrome Undergoing In Vitro Fertilization at Risk of Ovarian Hyperstimulation Syndrome.

BACKGROUND Women with polycystic ovary syndrome (PCOS) undergoing in vitro fertilization (IVF) are given letrozole before a trigger injection of human chorionic gonadotropin (hCG) to lower estrogen (E...

Letrozole for patients with polycystic ovary syndrome: A retrospective study.

This retrospective study investigated the efficacy and safety of letrozole for patients with polycystic ovary syndrome (PCOS).Totally, 136 cases of infertility women with PCOS were analyzed. Of those,...

Effects of letrozole and clomiphene citrate on Wnt signaling pathway in endometrium of polycystic ovarian syndrome and healthy women.

Polycystic ovary syndrome (PCOS) is an endocrine disorder in women of reproductive age. In addition to anovulation, endometrial dysfunction can reduce fertility in PCOS. The cyclical changes of endome...

Misclassification in Assessment of First Trimester In-Utero Exposure to Drugs used Proximally to Conception - The Example of Letrozole Utilization for Infertility Treatment.

Letrozole is an aromatase inhibitor with an unapproved use for ovulation induction with infertility. Because of the proximity of this use to conception, we selected letrozole to explore the effect of ...

Advertisement
Quick Search
Advertisement
Advertisement

 

Relevant Topics

Women's Health
Women's Health - key topics include breast cancer, pregnancy, menopause, stroke Follow and track Women's Health News on BioPortfolio: Women's Health News RSS Women'...

Endocrinology
Diabetes Diabetes Endocrine Obesity Oxycontin Renal Disease Thyroid Disorders Endocrinology is the study of the endocrine glands and the hormones that they secrete (Oxford Medical Dictionary). There are several groups of h...


Drugs and Medication Quicklinks


Searches Linking to this Drug Record

Table 2: Percentage of Patients with Adverse Reactions
Number (%) of Patients with Number (%) of Patients with
Grade 1-4 Adverse Reaction Grade 3-4 Adverse Reaction
Letrozole Placebo Letrozole Placebo
N=2563 N=2573 N=2563 N=2573
Any Adverse Reaction 2232 (87.1) 2174 (84.5) 419 (16.3) 389 (15.1)
Vascular Disorders 1375 (53.6) 1230 (47.8) 59 (2.3) 74 (2.9)
Flushing 1273 (49.7) 1114 (43.3) 3 (0.1) 0 -
General Disorders 1154 (45) 1090 (42.4) 30 (1.2) 28 (1.1)
Asthenia 862 (33.6) 826 (32.1) 16 (0.6) 7 (0.3)
Edema NOS 471 (18.4) 416 (16.2) 4 (0.2) 3 (0.1)
Musculoskeletal Disorders 978 (38.2) 836 (32.5) 71 (2.8) 50 (1.9)
Arthralgia 565 (22) 465 (18.1) 25 (1) 20 (0.8)
Arthritis NOS 173 (6.7) 124 (4.8) 10 (0.4) 5 (0.2)
Myalgia 171 (6.7) 122 (4.7) 8 (0.3) 6 (0.2)
Back Pain 129 (5) 112 (4.4) 8 (0.3) 7 (0.3)
Nervous System Disorders 863 (33.7) 819 (31.8) 65 (2.5) 58 (2.3)
Headache 516 (20.1) 508 (19.7) 18 (0.7) 17 (0.7)
Dizziness 363 (14.2) 342 (13.3) 9 (0.4) 6 (0.2)
Skin Disorders 830 (32.4) 787 (30.6) 17 (0.7) 16 (0.6)
Sweating Increased 619 (24.2) 577 (22.4) 1 (<0.1) 0 -
Gastrointestinal Disorders 725 (28.3) 731 (28.4) 43 (1.7) 42 (1.6)
Constipation 290 (11.3) 304 (11.8) 6 (0.2) 2 (<0.1)
Nausea 221 (8.6) 212 (8.2) 3 (0.1) 10 (0.4)
Diarrhea NOS 128 (5) 143 (5.6) 12 (0.5) 8 (0.3)
Metabolic Disorders 551 (21.5) 537 (20.9) 24 (0.9) 32 (1.2)
Hypercholesterolemia 401 (15.6) 398 (15.5) 2 (<0.1) 5 (0.2)
Reproductive Disorders 303 (11.8) 357 (13.9) 9 (0.4) 8 (0.3)
Vaginal Hemorrhage 123 (4.8) 171 (6.6) 2 (<0.1)