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MINT-LETROZOLE is a brand name for Letrozole, supplied as a tablet. The medicine, its uses, side effects and dosage are the same regardless of brand.
Verbatim from this product's HC label. Tap a section to expand.
and 10 CLINICAL PHARMACOLOGY). 7. Drug-Laboratory Test Interactions No clinically significant changes in the results of clinical laboratory tests have been observed. 10. 1. Mechanism of Action Mint-Letrozole tablets (letrozole) are a potent and highly specific non-steroidal aromatase inhibitor.
It inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues. 2. Pharmacodynamics Mint-Letrozole exerts its anti-tumour effect by depriving estrogen-dependent breast cancer cells of one of their growth stimuli.
In postmenopausal women, estrogens are derived mainly from the action of the aromatase enzyme, which converts adrenal androgens - primarily androstenedione and testosterone - to estrone (E1) and estradiol (E2). The suppression of estrogen biosynthesis in peripheral tissues and the malignant tissue can be achieved by specifically inhibiting the aromatase enzyme.
5 mg letrozole suppressed serum estrone by 75-78% and estradiol by 78% from baseline. Maximum suppression is achieved in 48-78 hours. 1 to 5 mg suppress estradiol, estrone and estrone sulphate plasma levels by 75-95% from baseline in all patients treated.
5 mg doses and higher, many plasma levels of estrone and estrone sulphate are below the limit of detection of the assays, indicating that higher estrogen suppression is achieved with these doses. Estrogen suppression was maintained throughout treatment in all patients.
Letrozole is highly specific in inhibiting aromatase activity. Impairment of adrenal steroidogenesis has not been observed. 1 to 5 mg letrozole daily. 1 to 5 mg letrozole did not indicate any attenuation of aldosterone or cortisol production.
Thus, glucocorticoid or Mint-Letrozole (letrozole) Tablets Page 28 of 58 mineralocorticoid supplementation is not required. 1 to 5 mg. These results indicate that accumulation of androgenic precursors does not occur. Plasma levels of LH and FSH are not affected by letrozole in patients, nor is thyroid function as evaluated by TSH, T4 and T3 uptake.
The effect of aromatase inhibitors, including letrozole, on estrogen suppression may consequently decrease bone mineral density (BMD) and increase the rate of bone fractures and of osteoporosis. In both the adjuvant setting and extended adjuvant setting, at a median treatment duration of 60 months, a significantly higher risk of osteoporosis as well as of clinical bone fractures was seen with letrozole compared with tamoxifen (adjuvant treatment) or placebo (extended adjuvant treatment) (see also 10 CLINICAL PHARMACOLOGY).
In a bone substudy (median follow-up of 61 months) in the extended adjuvant setting, a significantly greater decrease in median total hip BMD change from baseline was seen at 2 years for letrozole compared with placebo, but no significant changes were observed in lumbar spine BMD (see also 10 CLINICAL PHARMACOLOGY).
). 1% vs. 4%, respectively. A significantly higher incidence of events was seen for letrozole vs. 8% vs. 2% vs. 0%). 8% vs. 5% vs. 4% vs. 4% vs. 2% vs. 2% respectively). 3% vs. 3%, respectively (a non-significant difference). 80). 37). 67). 53) (see 8 ADVERSE REACTIONS).
0%)], but the difference was not statistically significant. Of the 19 deaths attributed to a cardiovascular cause in the placebo arm, 12 occurred in the group of 1026 patients who did not switch to letrozole after study unblinding, and 7 occurred in the group of 1551 patients who switched to letrozole.
A total of 7 patients died from a stroke – 6 in the letrozole arm and 1 after switching from placebo to letrozole after study unblinding. Driving and operating machinery No studies on the effects of letrozole on the ability to drive and use machines have been performed.
However, since fatigue, dizziness, and uncommonly somnolence have been observed with the use of letrozole, caution is advised when driving or operating machinery while such symptoms persist.
Endocrine and Metabolism Hyperlipidemia:
The use of aromatase inhibitors, including letrozole, may increase lipid levels. 6% of patients treated with tamoxifen. In a smaller study (D2407) comparing 2 years of adjuvant treatment with letrozole or tamoxifen, significant differences were observed between treatments at all time-points in total cholesterol, LDL cholesterol and the HDL: LDL ratio in favour of tamoxifen.
Clinically relevant changes in total cholesterol at 2 years occurred significantly more often for patients treated with letrozole (17%) than with tamoxifen (5%). Monitoring of serum cholesterol is advised for patients treated with Mint- Letrozole (see also 8 ADVERSE REACTIONS, 10 CLINICAL PHARMACOLOGY, 14 CLINICAL TRIALS).
, MUSCULOSKELETAL 03/2024 Table of Contents RECENT MAJOR LABEL CHANGES ............................................................................................ 2 PART I: HEALTH PROFESSIONAL INFORMATION ......................................................................
4 1. INDICATIONS ............................................................................................................... 1. Paediatrics .......................................................................................................................
2. Geriatrics ......................................................................................................................... 4 2. CONTRAINDICATIONS .................................................................................................
4 3. SERIOUS WARNINGS AND PRECAUTIONS BOX ............................................................ 5 4. DOSAGE AND ADMINISTRATION ................................................................................. 1. Dosing Considerations ....................................................................................................
2. Recommended Dose and Dosage Adjustment ............................................................... 4. Administration ................................................................................................................
5. Missed Dose .................................................................................................................... 6 5. OVERDOSAGE..............................................................................................................
6 6. DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................. 6 7. WARNINGS AND PRECAUTIONS .................................................................................. 1. Special Populations .......................................................................................................
section). Isolated cases of birth defects (labial fusion, ambiguous genitalia) have been reported in infants born to women exposed to letrozole during pregnancy. Mint-Letrozole is contraindicated in premenopausal women (see 2 CONTRAINDICATIONS section).
Women who are not premenopausal but have the potential to become pregnant, including women who are perimenopausal or who recently became postmenopausal, should use appropriate contraception (methods that result in less than 1% pregnancy rates) while being treated with letrozole and for 20 days after stopping treatment with letrozole (see also 7 WARNINGS & PRECAUTIONS: Reproductive health: Female and Male Potential).
Women of Unclear Menopausal status:
Women treated with letrozole whose menopausal status has not been confirmed are at an increased risk of becoming pregnant and experiencing spontaneous abortions or congenital anomalies in their infants (see also 7 WARNINGS & PRECAUTIONS: Reproductive health: Female and Male Potential).
In patients whose menopausal status is unclear or who become amenorrheic after chemotherapy, luteinising hormone (LH), follicle-stimulating hormone (FSH) and/or estradiol levels should be measured before initiating treatment with Mint-Letrozole and regularly during the first 6 months of treatment.
Appropriate contraception should be used to avoid pregnancy. Only women of confirmed postmenopausal endocrine status should receive Mint-Letrozole. 2.
Breast-feeding Mint-Letrozole (letrozole) Tablets Page 11 of 58 Nursing Women:
Mint-Letrozole is contraindicated in breast feeding women (see 2 CONTRAINDICATIONS). It is not known if letrozole is excreted in human milk. There are no data on the effects of letrozole on the breastfed child or the effects of letrozole on milk production, however, exposure of letrozole in lactating rats led to impaired fertility of male offspring (See 16 NON-CLINICAL TOXICOLOGY: Reproductive and Developmental Toxicology).
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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In a study comparing 2 years of adjuvant treatment with letrozole or tamoxifen (D2407), significant differences in favour of tamoxifen were observed over the 2 years in BMD changes from baseline (see also 14 CLINICAL TRIALS and 10 CLINICAL PHARMACOLOGY).
In a lipid substudy (median follow-up of 62 months) in the extended adjuvant setting, no significant differences between letrozole and placebo were observed in total cholesterol or in any lipid fraction (see also 14 CLINICAL TRIALS and 10 CLINICAL PHARMACOLOGY).
In the adjuvant setting study comparing 2 years of treatment with letrozole or tamoxifen, median levels of total cholesterol and LDL cholesterol remained stable with letrozole, but decreased with tamoxifen. Consequently, total cholesterol, LDL cholesterol and the HDL:LDL ratio differed significantly between treatments in favour of tamoxifen (see also 10 CLINICAL PHARMACOLOGY).
Adjuvant and extended adjuvant setting Updated results from the extended adjuvant study bone substudy (median follow-up of 61 months) indicated a significantly greater decrease in BMD from baseline for hip BMD at 24 months (Table 8).
7 1 Primary endpoint in bone substudy 2 Secondary endpoint 3 Placebo until switch (if a switch occurred) 4 Statistically significant difference from placebo on Wilcoxon signed rank test (adjusted for bisphosphonate use) Note: All patients should have received vitamin D and calcium supplementation.
Vitamin D was not recorded. Calcium supplementation was reported for 44-66% of patients. Bisphosphonates were received by approximately a third of the patients treated with letrozole, compared with a quarter or fewer patients in the placebo arm.
Table 9 summarizes […]
Monitoring and Laboratory Tests Mint-Letrozole (letrozole) Tablets Page 9 of 58 Plasma Lipids: Women should have their cholesterol levels assessed and managed according to current clinical practice and guidelines (see7 WARNINGS & PRECAUTIONS- Endocrine and Metabolism).
Bone Mineral Density:
Monitoring of overall bone health is recommended during treatment with Mint- Letrozole (see 7 WARNINGS & PRECAUTIONS-Musculoskeletal). In patients whose menopausal status is unclear or who become amenorrheic after chemotherapy, luteinising hormone (LH), follicle-stimulating hormone (FSH) and/or estradiol levels should be measured before initiating treatment with Mint- Letrozole and regularly during the first 6 months of treatment.
Musculoskeletal Bone Mineral Density:
The use of estrogen lowering agents, including letrozole, may cause a reduction in bone mineral density (BMD) with a possible consequent increased risk of osteoporosis and fracture. 7%). 2%). 4%). Similarly, […]
1. Pregnant Women .......................................................................................................... 2. Breast-feeding ...............................................................................................................
3. Pediatrics (< 18 years of age) ........................................................................................ 4. Geriatrics (≥ 65 years of age) ........................................................................................
11 8. ADVERSE REACTIONS ................................................................................................ 1. Adverse Reaction Overview ..........................................................................................
2. Clinical Trial Adverse Reactions .................................................................................... 5. Post-Market Adverse Reactions ....................................................................................
25 9. DRUG INTERACTIONS ................................................................................................ 2. Drug Interactions Overview ..........................................................................................
4. Drug-Drug Interactions ................................................................................................. 5. Drug-Food Interactions .................................................................................................
7. Drug-Laboratory Test Interactions ................................................................................ 27 10. CLINICAL PHARMACOLOGY .......................................................................................
1. Mechanism of Action .................................................................................................... 2. Pharmacodynamics .......................................................................................................
3. Pharmacokinetics .......................................................................................................... 31 11. STORAGE, STABILITY AND DISPOSAL .........................................................................
33 12. SPECIAL HANDLING INSTRUCTIONS ........................................................................... 33 Mint-Letrozole (letrozole) Tablets Page 3 of 58 PART II: SCIENTIFIC INFORMATION .......................................................................................
34 13. PHARMACEUTICAL INFORMATION ............................................................................ 34 14. CLINICAL TRIALS ........................................................................................................
1 Clinical Trials by Indication ............................................................................................ 2. Comparative Bioavailability Studies ..............................................................................
49 15. MICROBIOLOGY ........................................................................................................ 50 16. NON-CLINICAL TOXICOLOGY .....................................................................................
50 17. SUPPORTING PRODUCT MONOGRAPHS .................................................................... 52 PATIENT MEDICATION INFORMATION .................................................................................. 53 Mint-Letrozole (letrozole) Tablets Page 4 of 58 PART I: HEALTH PROFESSIONAL INFORMATION 1.
INDICATIONS Mint-Letrozole (letrozole) film-coated tablets are indicated for: • The adjuvant treatment of postmenopausal women with hormone receptor-positive invasive early breast cancer. Clinical effectiveness is based on superior Disease-Free Survival (DFS) compared to tamoxifen.
Overall, survival was not significantly different between the two treatments (see 14 CLINICAL TRIALS). • The […]
3. Pediatrics (< 18 years of age) Mint-Letrozole is contraindicated in children and adolescents. The safety and efficacy of letrozole in children and adolescents (under 18 years of age) have not been established. 4. Geriatrics (≥ 65 years of age) There have been no age-related effects observed on the pharmacokinetics of letrozole.
No major difference in general safety was observed in patients aged < 65 years versus ≥ 65 years; however, patients ≥ 65 years experienced more bone fractures and more osteoporosis, irrespective of treatment. In the adjuvant setting, more than 8000 postmenopausal women were enrolled in the clinical study (see 14 CLINICAL TRIALS section).
In total, 36% of patients were aged 65 years or older at enrolment, while 12% were 75 or older. Although more adverse events were generally reported in elderly patients irrespective of study treatment allocation, the differences between the two treatment groups were similar to those of younger patients.
In the extended adjuvant study, more than 5000 postmenopausal women were enrolled in the study; 41% of the patients were aged 65 years or older at enrolment, while 12% were 75 or older. 74). These results were obtained prior to study unblinding.
2% (59 / 528) for patients switching from placebo to letrozole. 9% (63 / 528) for letrozole after switch. 8. 1. Adverse Reaction Overview Letrozole was generally well tolerated across all studies as first-line and second-line treatment for advanced breast cancer, as adjuvant treatment of early breast cancer and as extended adjuvant treatment in women who had completed prior standard adjuvant therapy with tamoxifen.
Approximately one third of the patients treated with letrozole in the metastatic setting, and Mint-Letrozole (letrozole) Tablets Page 12 of 58 approximately 80% of the patients in the adjuvant setting (both letrozole and tamoxifen arms, at a median treatment duration of 60 months), and extended adjuvant setting (both letrozole and placebo arms, at a median treatment duration of 60 months) experienced adverse reactions (“Adverse reactions” defined as adverse events (AEs) suspected of being related to study treatment (including AEs with missing relationship)).
The observed adverse reactions are mainly mild or moderate in nature, and many are associated with estrogen deprivation. The updated safety profile of letrozole in both the adjuvant (96 months median follow-up, median treatment duration 60 months) and the extended adjuvant (62 months median follow-up, median treatment duration 60 months) settings did not reveal any new adverse reaction and was consistent with the profile reported at earlier analyses.
Adverse Events in Adjuvant Study BIG 1-98 After reviewing the results of the Primary Core Analysis, at a median treatment duration of 25 months, the independent Data and Safety Monitoring Committee, observed a difference in incidence in grade 5 myocardial infarctions (9 vs.
2 in the letrozole and tamoxifen arms, respectively) and recommended that cardiac events and certain other safety data be reviewed. Consequently, a blinded medical review of more than 2000 […]