Instructions for Letrozole-Vista AC tablets 2.5 mg No. 30
Composition
active ingredient: letrozole;
1 film-coated tablet contains letrozole 2.5 mg;
excipients: lactose monohydrate; microcrystalline cellulose; pregelatinized corn starch; sodium starch glycolate (type A); magnesium stearate; colloidal anhydrous silicon dioxide;
coating: OPADRY® 03F32518 Yellow (hypromellose (E 464), talc (E 553b), macrogol 8000, titanium dioxide (E 171), iron oxide yellow (E 172)).
Dosage form
Film-coated tablets.
Main physicochemical properties: Yellow, round, biconvex, film-coated tablets, embossed with “L9OO” on one side and “2.5” on the other.
Pharmacotherapeutic group
Agents used for hormone therapy. Hormone antagonists and similar agents. Aromatase inhibitors. Letrozole.
ATX code L02B G04.
Pharmacological properties
Pharmacodynamics.
Letrozole is a nonsteroidal aromatase inhibitor (estrogen biosynthesis inhibitor); an anticancer drug.
In cases where the growth of tumor tissue depends on the presence of estrogens, the elimination of the stimulatory effect mediated by them is a prerequisite for the inhibition of tumor growth. In postmenopausal women, estrogens are formed mainly with the participation of the aromatase enzyme, which converts androgens synthesized in the adrenal glands (primarily androstenedione and testosterone) to estrone (E1) and estradiol (E2). Therefore, by means of specific inhibition of the aromatase enzyme, it is possible to achieve inhibition of estrogen biosynthesis in peripheral tissues and in tumor tissue.
Letrozole inhibits aromatase by competitively binding to the heme subunit of this enzyme, cytochrome P450, which leads to a decrease in estrogen biosynthesis in all tissues.
In healthy postmenopausal women, single doses of letrozole, 0.1 mg, 0.5 mg and 2.5 mg, reduce serum estrone and estradiol levels (compared to baseline) by 75-78% and 78%, respectively. The maximum reduction is achieved after 48-78 hours.
In postmenopausal women with advanced breast cancer, daily administration of letrozole at a dose of 0.1 mg to 5 mg reduces plasma levels of estradiol, estrone, and estrone sulfate by 75-95% of baseline. When using the drug at a dose of 0.5 mg and more, in many cases, the concentrations of estrone and estrone sulfate are found below the sensitivity limit of the method used to determine the hormones. This indicates that with the help of these doses of the drug, a more pronounced suppression of estrogen synthesis is achieved. Estrogen suppression was maintained throughout the course of treatment in all patients.
Letrozole is a highly specific inhibitor of aromatase activity. No impairment of adrenal steroid hormone synthesis has been observed. In postmenopausal patients treated with letrozole at a daily dose of 0.1-5 mg, no clinically significant changes in plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxyprogesterone, adrenocorticotropic hormone, or renin activity were observed. The adrenocorticotropic hormone stimulation test after 6 and 12 weeks of treatment with letrozole at a daily dose of 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2.5 mg, and 5 mg did not reveal any significant reduction in aldosterone or cortisol synthesis. Thus, there is no need to prescribe glucocorticoids or mineralocorticoids.
In healthy postmenopausal women, after a single dose of letrozole at doses of 0.1 mg, 0.5 mg and 2.5 mg, no changes in the concentration of androgens (androstenedione and testosterone) in the blood plasma were detected. In postmenopausal patients who received letrozole at a daily dose of 0.1 mg to 5 mg, no changes in the level of androstenedione in the blood plasma were also noted. All this indicates that the blockade of estrogen biosynthesis does not lead to the accumulation of androgens, which are estrogen precursors. In patients receiving letrozole, no changes in the concentrations of luteinizing and follicle-stimulating hormones in the blood plasma were noted, and no changes in thyroid function, which was assessed by the levels of thyroid-stimulating hormone T4 and T3, were noted.
Pharmacokinetics.
Distribution. The binding of letrozole to plasma proteins is approximately 60% (mainly to albumin - 55%). The concentration of letrozole in erythrocytes is almost 80% of its level in plasma. After administration of 2.5 mg of 14C-labeled letrozole, approximately 82% of the radioactivity in plasma was accounted for by unchanged active substance. Therefore, the systemic exposure of letrozole metabolites is negligible. Letrozole is rapidly and widely distributed in tissues. The apparent volume of distribution at steady state is approximately 1.87 ± 0.47 l/kg.
Metabolism and elimination. Letrozole is extensively metabolized to a pharmacologically inactive carbinol metabolite, the major route of elimination. The metabolic clearance of letrozole (CLm) is 2.1 l/h, which is less than the hepatic blood flow (approximately 90 l/h). The cytochrome P450 isoenzymes CYP3A4 and CYP2A6 have been shown to metabolize letrozole to its metabolites in vitro, but their individual roles in the clearance of letrozole in vivo have not been clearly established. Drug interaction studies have shown that concomitant administration of letrozole and cimetidine, which is an inhibitor of only the isoenzyme 3A4, did not inhibit the clearance of letrozole, suggesting an important role for the isoenzyme 2A6 in the overall clearance in vivo. In this study, a slight decrease in AUC and an increase in Cmax were observed.
The formation of a small number of other, as yet unidentified, metabolites, as well as the excretion of unchanged drug in urine and feces, play only a minor role in the overall elimination of letrozole. Within 2 weeks after administration of 2.5 mg of 14C-labeled letrozole to healthy postmenopausal volunteers, 88.2 ± 7.6% of the radioactivity was recovered in the urine and 3.8 ± 0.9% in the feces. At least 75% of the radioactivity recovered in the urine over a period of up to 216 hours (84.7 ± 7.8% of the letrozole dose) was accounted for by the glucuronide conjugates of the carbinol metabolite, almost 9% by two other unidentified metabolites and 6% by unchanged letrozole.
The apparent terminal plasma half-life is approximately 2-4 days. After daily administration of 2.5 mg of the drug, steady-state concentrations of letrozole are reached within 2-6 weeks and are approximately 7 times higher than after a single dose of the same dose. At the same time, the steady-state concentration is 1.5-2 times higher than the steady-state concentration that would be predicted from calculations based on the values recorded after a single dose of the drug. This indicates that the pharmacokinetics of letrozole at a daily dose of 2.5 mg are somewhat nonlinear. Since steady-state concentrations of letrozole are maintained during long-term treatment, it can be concluded that letrozole does not accumulate.
Linearity/non-linearity. The pharmacokinetics of letrozole were dose proportional after a single oral dose of up to 10 mg (dose range 0.01 to 30 mg) and after daily doses of up to 1.0 mg (dose range 0.1 to 5 mg). A small but more than dose-proportional increase in AUC was observed after a single oral dose of 30 mg. At daily doses of 2.5 and 5 mg, the AUC increased approximately 3.8- and 12-fold, instead of 2.5- and 5-fold, respectively, compared with 1.0 mg/day. Thus, the recommended dose of 2.5 mg/day may be the limit dose at which disproportionality becomes apparent, while at 5 mg/day the disproportionality becomes more pronounced. The dose disproportionality is likely to be the result of saturation of metabolic elimination processes. Steady-state concentrations were reached after 1-2 months for all studied dosing regimens (0.1-5.0 mg daily). Pharmacokinetics in individual patient groups. In studies conducted in volunteers with varying renal function (24-hour creatinine clearance ranging from 9 to 116 ml/min), the pharmacokinetics of letrozole and the urinary excretion of glucuronide conjugates of its carbinol metabolite were not affected after a single 2.5 mg dose. In addition, the above study evaluated the effect of renal impairment on letrozole, and a covariate analysis was performed based on data from two pivotal studies (AR/BC2 and AR/BC3). Estimated creatinine clearance (range in AR/BC2: 19-187 mL/min; in AR/BC3: 10-180 mL/min) did not show a statistically significant association with steady-state plasma levels of letrozole (Cmin). In addition, data from the AR/BC2 and AR/BC3 studies in second-line treatment of metastatic breast cancer demonstrated no adverse effect of letrozole on creatinine clearance or deterioration in renal function.
In a similar study in volunteers with varying degrees of liver function, the mean area under the concentration-time curve (AUC) was 37% higher in subjects with moderate hepatic impairment (Child-Pugh Class B) than in healthy subjects, but remained within the range of values observed in subjects without hepatic impairment. In a single-dose pharmacokinetic study in 8 patients with cirrhosis and severe hepatic impairment (Child-Pugh Class C), AUC was increased by 95% and t½ by 187% compared with healthy subjects. Since no increase in toxicity was observed in patients receiving daily doses of 5 mg to 10 mg/day, dose adjustment in the direction of its decrease is not justified, although such patients should be closely monitored. In addition, no effect of renal dysfunction (estimated creatinine clearance values were 20-50 ml/min) or hepatic dysfunction on the plasma concentration of letrozole was noted in 359 patients with advanced breast cancer. The pharmacokinetics of letrozole are independent of age.
Indication
For the adjuvant treatment of hormone-positive invasive early breast cancer in postmenopausal women.
For the extended adjuvant treatment of early invasive breast cancer in postmenopausal women who have received standard adjuvant tamoxifen therapy for 5 years.
For first-line treatment of hormone-dependent advanced breast cancer in postmenopausal women.
For the treatment of advanced forms of breast cancer in postmenopausal women (natural or artificially induced) after recurrence or progression of the disease, who have received previous antiestrogen therapy.
For neoadjuvant therapy in postmenopausal women with hormone-positive, HER-2-negative breast cancer who are not suitable for chemotherapy and for whom urgent surgery is not indicated.
The effectiveness of the drug for patients with hormone-negative breast cancer has not been proven.
Contraindication
Hypersensitivity to the active substance or to any of the excipients.
Premenopausal endocrine status.
Pregnancy.
Breast-feeding.
The patient's reproductive age.
Interaction with other medicinal products and other types of interactions
Letrozole is metabolised in part by CYP2A6 and CYP3A4. Therefore, the systemic clearance of letrozole may be affected by medicinal products that affect CYP3A4 and CYP2A6. Letrozole metabolism appears to have a low affinity for CYP3A4, as this enzyme is not saturable at concentrations 150-fold higher than the plasma concentrations of letrozole observed at steady state under typical clinical conditions.
There is currently no clinical experience with the use of letrozole in combination with estrogens or other anticancer drugs other than tamoxifen. Tamoxifen, other antiestrogenic drugs or estrogen-containing drugs may antagonize the pharmacological effects of letrozole. In addition, it has been shown that the plasma concentrations of letrozole are significantly reduced when tamoxifen and letrozole are used simultaneously. The simultaneous use of letrozole with tamoxifen, other estrogen antagonists or estrogens should be avoided.
Medicinal products that may increase letrozole serum concentrations. Inhibitors of CYP3A4 and CYP2A6 activity may reduce the metabolism of letrozole and thus increase letrozole plasma concentrations. Concomitant use of medicinal products that strongly inhibit these enzymes (potent inhibitors of CYP3A4 include: ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin and telithromycin; CYP2A6, e.g. methoxsalen) may increase letrozole exposure. Therefore, caution is recommended in patients who are indicated for the use of potent inhibitors of CYP3A4 and CYP2A6.
Medicinal products that may decrease letrozole serum concentrations. CYP3A4 inducers may increase the metabolism of letrozole and thus decrease letrozole plasma concentrations. Concomitant use of medicinal products that induce CYP3A4 (e.g. phenytoin, rifampicin, carbamazepine, phenobarbital and St. John's wort) may decrease letrozole exposure. Therefore, caution is advised in patients who are indicated for potent CYP3A4 inducers. CYP2A6 inducers are unknown.
Drugs whose systemic serum concentrations may be altered by letrozole. In vitro, letrozole inhibits the cytochrome P450 isoenzymes CYP2A6 and, to a lesser extent, CYP2C19, but the clinical significance of this effect is unknown. However, caution should be exercised when administering letrozole concomitantly with drugs that are predominantly metabolised by CYP2C19 and have a narrow therapeutic range (such as phenytoin, clopidogrel). A narrow therapeutic range substrate for CYP2A6 is unknown. Clinical interaction studies with cimetidine (a known non-specific inhibitor of CYP2C19 and CYP3A4) and warfarin (a sensitive substrate for CYP2C9 with a narrow therapeutic range, which is often used as a concomitant drug in the target population of letrozole) have shown that the concomitant use of letrozole and these drugs does not cause clinically significant drug interactions. A review of the database of these clinical studies revealed no evidence of other clinically significant interactions with other commonly prescribed drugs.
Application features
Kidney dysfunction.
There are no data on the use of letrozole in patients with creatinine clearance < 10 ml/min. Before prescribing the drug to such patients, the potential risk and the expected effect of treatment should be weighed.
Cholesterol.
Monitoring of serum cholesterol levels should be considered. In the adjuvant trial, hypercholesterolemia was reported in 52.3% of patients treated with letrozole and 28.6% of patients treated with tamoxifen (based on the severity of adverse reactions (SRS) criteria). Grade 3-4 hypercholesterolemia was reported in 0.4% of patients in the letrozole group and 0.1% of patients in the tamoxifen group. In addition, in the adjuvant setting, increases of ≥ 1.5 × ULN (upper limit of normal) in total cholesterol (usually not in the fasting state) were observed among patients receiving monotherapy who had baseline total serum cholesterol within the normal range (i.e. ≤ 1.5 × ULN) in 151/1843 (8.2%) in the letrozole group versus 57/1840 (3.2%) in the tamoxifen group. Lipid-lowering medicinal products were required in 25% of patients receiving letrozole and 16% of patients receiving tamoxifen.
Liver dysfunction.
In patients with severe hepatic impairment (Child-Pugh class C), systemic exposure and half-life of letrozole are approximately twice as long as in healthy subjects. Such patients require closer monitoring.
Effect on bones.
Since Letrozole-Vista AS is a potent estrogen-lowering agent, in the adjuvant and extended adjuvant setting, bone mineral density should be assessed before, during, and after treatment with letrozole in women with osteoporosis and/or a history of fractures or at increased risk of osteoporosis. In the adjuvant setting, a sequential therapy regimen (letrozole for 2 years followed by tamoxifen for 3 years) should also be considered, depending on the patient's safety profile.
Tendinitis and tendon rupture.
Tendinitis and tendon rupture may occur (rarely). Patients should be carefully examined and appropriate measures (e.g. immobilization) applied to the affected tendon if necessary (see section 4.8).
Menopausal status.
In patients with unclear menopausal status, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and/or estradiol levels should be determined before starting Letrozole-Vista AS. Only women with postmenopausal endocrine status should take Letrozole-Vista AS.
Violations of laboratory parameters.
There was no dose-related effect of letrozole on any hematological or biochemical parameters. Moderate decreases in lymphocyte counts, of uncertain clinical significance, were observed in some patients treated with letrozole at a dose of 2.5 mg. These decreases in lymphocyte counts were transient in approximately half of the affected patients. Two patients treated with letrozole developed thrombocytopenia; the relationship to study drug was unclear. Withdrawal of patients from the study due to laboratory abnormalities, whether drug-related or not, was rare.
Other caveats.
The concomitant use of Letrozole-Vista AC and tamoxifen, other estrogen antagonists or estrogen-containing drugs should be avoided, as these substances may antagonize the pharmacological action of letrozole.
Important information about excipients.
As the tablets contain lactose, Letrozole-Vista AS is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption.
Use during pregnancy or breastfeeding
Letrozole-Vista AS should only be used in women with a clearly defined postmenopausal status. There have been postmarketing reports of spontaneous abortions or congenital anomalies in newborns whose mothers took letrozole. During treatment with letrozole, regardless of a clearly defined postmenopausal status at the start of treatment, the physician should discuss appropriate contraceptive measures with the patient, if necessary.
Pregnancy.
There are isolated cases of congenital defects (fusion of the labia, genitals of an intermediate type).
Letrozole-Vista AC may cause birth defects when used during pregnancy. Animal studies have shown reproductive toxicity. Use of Letrozole-Vista AC is contraindicated during pregnancy. Breastfeeding.
It is not known whether letrozole and its metabolites are excreted in human milk. A risk to the newborn/infants during breastfeeding cannot be excluded. The use of Letrozole-Vista AC during breastfeeding is contraindicated.
Fertility.
The pharmacological action of letrozole is associated with a decrease in estrogen production by inhibiting aromatase. In premenopausal women, inhibition of estrogen synthesis leads to a reverse reaction of increased gonadotropin levels (LH, FSH). In turn, increased FSH levels stimulate follicular growth and may induce ovulation.
Ability to influence reaction speed when driving vehicles or other mechanisms
Letrozole-Vista AC has minor influence on the ability to drive and use machines. Since fatigue and dizziness have been observed during the use of letrozole, and in rare cases somnolence has been reported, caution is recommended when driving or operating other machines.
Method of administration and doses
Adults, including elderly patients.
The recommended dose of letrozole is 2.5 mg once daily. In the adjuvant and extended adjuvant setting, letrozole treatment should be continued for 5 years or until tumor recurrence, whichever comes first.
In patients with metastases, therapy with Letrozole-Vista AS should be continued until signs of disease progression become apparent.
In the adjuvant setting, a sequential treatment regimen (letrozole for 2 years, then tamoxifen for 3 years) should also be considered.
In the neoadjuvant setting, letrozole treatment should be continued for 4 to 8 months to achieve optimal tumor reduction. If the response to treatment is inadequate, letrozole treatment should be discontinued and surgery and/or other treatment options should be considered and discussed with the patient. No dose adjustment is necessary for elderly patients.
Patients with impaired liver and/or kidney function.
No dose adjustment of Letrozole-Vista AC is required for patients with renal impairment with creatinine clearance ≥ 10 ml/min. Limited data are available for patients with renal impairment with creatinine clearance below 10 ml/min.
No dose adjustment of Letrozole-Vista AC is required in patients with mild to moderate hepatic impairment (Child-Pugh Class A or B). Limited data are available in patients with severe hepatic impairment (Child-Pugh Class C). Patients with severe hepatic impairment (Child-Pugh Class C) should be closely monitored.
Method of application.
Letrozole-Vista AS should be taken orally regardless of food intake, as food does not affect the extent of absorption of the drug.
The missed dose should be taken as soon as the patient remembers. However, if the patient remembers shortly before the next dose (2-3 hours), the missed dose should be skipped and the next dose should be taken as scheduled. A double dose should not be taken, as systemic exposure greater than proportional has been observed with daily doses higher than the recommended 2.5 mg.
Children
The medicinal product is not intended for use in children. The safety and efficacy of letrozole in children (under 18 years of age) have not been established. Limited data are available to make dosage recommendations.
Overdose
Isolated cases of overdose with letrozole have been reported. Specific treatment for overdose is unknown; treatment should be symptomatic and supportive.
Side effects
Letrozole was generally well tolerated in all studies as first- and second-line therapy for advanced breast cancer, as adjuvant therapy for early breast cancer, and as extended adjuvant therapy for breast cancer in women who had previously received standard adjuvant therapy with tamoxifen. Adverse reactions were experienced by almost one-third of patients treated with letrozole in the metastatic and neoadjuvant settings, approximately 75% of patients in the adjuvant setting (both groups received both letrozole and tamoxifen; median treatment period was 60 months) and almost 80% of patients in the extended adjuvant setting (both letrozole and placebo; median treatment period was 60 months). In general, the adverse reactions observed were mostly mild to moderate in nature and were mostly related to estrogen deficiency. The most frequently reported adverse reactions in clinical trial reports were hot flushes, hypercholesterolemia, arthralgia, nausea, increased sweating, and fatigue. Important additional adverse reactions that may occur with letrozole treatment include musculoskeletal events such as osteoporosis and/or fractures, and cardiovascular events (including cerebrovascular and thromboembolic events). Many adverse reactions may be due to the natural pharmacological effects of estrogen deficiency (e.g. hot flushes, alopecia, or vaginal bleeding). Most adverse reactions occurred within the first few weeks of treatment.
Adverse reactions are listed by frequency of occurrence: very common: > 10%; common: > 1% to < 10%; uncommon: > 0.1% to < 1%; rare: > 0.01% to < 0.1%; very rare: < 0.01%; not known: frequency cannot be estimated from the available data. The most frequent reactions are listed first.
Table 1
| Infections and infestations |
| Infrequently | Urinary tract infection |
| Neoplasms, benign, malignant and unspecified (including cysts and polyps) |
| Infrequently | Pain in the tumor area 1 |
| Blood and lymphatic system disorders |
| Infrequently | Leukopenia |
| On the part of the immune system |
| Unknown | Anaphylactic reaction |
| Metabolism and nutrition |
| Very often | Hypercholesterolemia |
| Often | Decreased appetite, increased appetite |
| Mental disorders |
| Often | Depression |
| Infrequently | Anxiety (including nervousness), irritability |
| From the nervous system |
| Often | Headache, dizziness |
| Infrequently | Somnolence, insomnia, memory impairment, dysesthesia (including paraesthesia, hypoesthesia), taste disturbance, stroke, carpal tunnel syndrome |
| From the organs of vision |
| Infrequently | Cataract, eye irritation, blurred vision |
| From the heart |
| Often | Increased heart rate(1) |
| Infrequently | Tachycardia, ischemic cardiac complications (including new or worsening angina, angina requiring surgery, myocardial infarction, and myocardial ischemia) |
| Vascular disorders |
| Very often | Tides |
| Often | Arterial hypertension |
| Infrequently | Thrombophlebitis (including superficial and deep vein thrombophlebitis) |
| Rarely | Pulmonary embolism, arterial thrombosis, cerebral infarction |
| Respiratory, thoracic and mediastinal disorders |
| Infrequently | Shortness of breath, cough |
| Gastrointestinal tract |
| Often | Nausea, dyspepsia 1, constipation, abdominal pain, diarrhea, vomiting |
| Infrequently | Dry mouth, stomatitis 1 |
| Liver and biliary tract disorders |
| Infrequently | Increased liver enzymes, hyperbilirubinemia, jaundice |
| Unknown | Hepatitis |
| Skin and subcutaneous tissue disorders |
| Very often | Increased sweating |
| Often | Alopecia, rashes (including erythematous, maculopapular, psoriatic and vesicular), dry skin |
| Infrequently | Itching, hives |
| Unknown | Angioedema, toxic epidermal necrolysis, erythema multiforme |
| Musculoskeletal and connective tissue disorders |
| Very often | Arthralgia |
| Often | Myalgia, bone pain 1, osteoporosis, bone fractures, arthritis |
| Infrequently | Tendinitis |
| Rarely | Tendon rupture |
| Unknown | Snapping finger syndrome |
| Renal and urinary disorders |
| Infrequently | Increased frequency of urination |
| Reproductive system and breast disorders |
| Often | Vaginal bleeding |
| Infrequently | Vaginal discharge, vaginal dryness, breast pain |
| General disorders and administration site conditions |
| Fatigue (including asthenia, malaise) |
| Often | Peripheral edema, chest pain |
| Infrequently | Generalized edema, dry mucous membranes, thirst, fever |
| Laboratory and instrumental studies |
| Often | Weight gain |
| Infrequently | Weight loss |
1 Adverse drug reactions reported only in metastatic cancer.
Some adverse reactions were reported with significantly different frequencies in the adjuvant setting. The tables below provide information on significant differences between letrozole therapy and tamoxifen monotherapy and the letrozole-tamoxifen sequential regimen.
Table 2
Adjuvant letrozole therapy compared with tamoxifen monotherapy:
side effects with significantly different frequencies
| Undesirable side effects | Letrozole, frequency of events | Tamoxifen, frequency of events |
| N = 2448 | N = 2447 |
| During treatment (median 5 years) | Any time after randomization (median 8 years) | During treatment (median 5 years) | Any time after randomization (median 8 years) |
| Bone fracture | 10.2% | 14.7% | 7.2% | 11.4% |
| Osteoporosis | 5.1% | 5.1% | 2.7% | 2.7% |
| Thromboembolic events | 2.1% | 3.2% | 3.6% | 4.6% |
| Myocardial infarction | 1.0% | 1.7% | 0.5% | 1.1% |
| Endometrial hyperplasia/endometrial cancer | 0.2% | 0.4% | 2.3% | 2.9% |
Note: During treatment — includes 30 days after the last dose. At any time — includes the follow-up period after the end or discontinuation of study treatment.
The difference is based on the risk ratio and 95% confidence intervals.
Table 3
Sequential treatment regimen compared to letrozole monotherapy: side effects with significantly different frequencies
| Adverse reactions | Letrozole monotherapy | Letrozole > tamoxifen | Tamoxifen > letrozole |
| N = 1535 | N = 1527 | N = 1541 |
| 5 years | 2 years — > 3 years | 2 years — > 3 years |
| Bone fractures | 10.0% | 7.7%* | 9.7% |
| Endometrial proliferative disorders | 0.7% | 3.4%** | 1.7%** |
| Hypercholesterolemia | 52.5% | 44.2%* | 40.8%* |
| Hot flashes | 37.6% | 41.7%** | 43.9%** |
| Vaginal bleeding | 6.3% | 9.6%** | 12.7%** |
* Significantly lower than with letrozole monotherapy.
** Significantly higher than with letrozole monotherapy.
Note: The reporting period includes the treatment period or the period within 30 days after treatment cessation.
Description of selected adverse reactions.
Adverse cardiac reactions.
In the adjuvant setting, the following adverse events were observed with letrozole and tamoxifen, respectively (median duration of treatment 60 months plus 30 days): angina requiring surgery (1.0% vs. 1.0%); heart failure (1.1% vs. 0.6%); hypertension (5.6% vs. 5.7%); cerebrovascular accident/transient ischemic attack (2.1% vs. 1.9%).
In the extended adjuvant treatment with letrozole (median duration of treatment 5 years) and placebo (median duration of treatment 3 years), the following adverse events were observed, respectively: angina requiring surgery (0.8% vs. 0.6%); new or worsening angina (1.4% vs. 1.0%); myocardial infarction (1.0% vs. 0.7%); thromboembolic event* (0.9% vs. 0.3%); stroke/transient ischemic attack* (1.5% vs. 0.8%). Events marked with * were statistically significantly different between the two treatment groups. Musculoskeletal adverse reactions.
Musculoskeletal safety data obtained during adjuvant treatment are presented in Table 2.
In the extended adjuvant setting, significantly more patients treated with letrozole experienced bone fractures or osteoporosis (bone fractures 10.4% and osteoporosis 12.2%) compared with patients in the placebo group (5.8% and 6.4%, respectively). The median duration of treatment with letrozole was 5 years and with placebo 3 years.
Reporting of suspected adverse reactions.
Reporting suspected adverse reactions after the registration of a medicinal product is an important procedure. It allows for continued monitoring of the benefit/risk balance of the medicinal product in question. Healthcare professionals should report any suspected adverse reactions through the national pharmacovigilance system.
Expiration date
3 years.
Conditions
