Instructions Letrozole KRKA film-coated tablets 2.5 mg blister No. 30
Composition
active ingredient: letrozole;
1 film-coated tablet contains 2.5 mg letrozole;
excipients: lactose monohydrate, corn starch, hypromellose, microcrystalline cellulose, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, magnesium stearate;
film coating: hypromellose, titanium dioxide (E 171), yellow iron oxide (E 172), polyethylene glycol 400, talc, purified water.
Dosage form
Film-coated tablets.
Main physicochemical properties: round biconvex, smooth on both sides, yellow tablets, film-coated.
Pharmacotherapeutic group
Agents used for hormonal therapy. Hormone antagonists and similar agents. Aromatase inhibitors. Letrozole. ATC 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 of 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 the drug is used at a dose of 0.5 mg or 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 more pronounced suppression of estrogen synthesis is achieved with these doses of the drug. Estrogen suppression was maintained throughout 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 (ACTH), or renin activity were observed. ACTH stimulation tests performed 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 female volunteers, 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, changes in the level of androstenedione in the blood plasma were also not 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 concentration of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the blood plasma were noted, and no changes in thyroid function, which were assessed by the levels of thyroid-stimulating hormone T4 and T3, were noted.
Pharmacokinetics.
Absorption
Letrozole is rapidly and completely absorbed from the gastrointestinal tract (mean bioavailability is 99.9%). Food slightly reduces the rate of absorption (mean time to reach maximum concentration of letrozole in the blood (tmax) is 1 hour when taking the drug on an empty stomach and 2 hours when taken with food; mean maximum concentration (Cmax) of letrozole in the blood is 129 ± 20.3 nmol/l when taken on an empty stomach and 98.7 ± 18.6 nmol/l when taken with food), but the extent of absorption of letrozole (as assessed by the area under the concentration-time curve (AUC)) does not change. Minor changes in the rate of absorption are considered to be of no clinical significance, so letrozole can be used regardless of food intake.
Letrozole is approximately 60% bound to plasma proteins (55% mainly to albumin). The concentration of letrozole in erythrocytes is approximately 80% of its plasma level. 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 extensively distributed in tissues. The apparent volume of distribution at steady state is approximately 1.87 ± 0.47 l/kg.
Metabolism and excretion
Letrozole is extensively metabolised to a pharmacologically inactive carbinol metabolite (the main 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). Cytochrome P450 isoenzymes CYP3A4 and CYP2A6 have been shown to be able to metabolise letrozole to its metabolite. The formation of a small number of other, as yet unidentified metabolites, as well as the excretion of unchanged drug in urine and faeces, play only a minor role in the overall elimination of letrozole. Within 2 weeks after administration of 2.5 mg of 14C-labelled letrozole to healthy postmenopausal volunteers, 88.2 ± 7.6% of the radioactivity was recovered in the urine and 3.8 ± 0.9% in the faeces. At least 75% of the radioactivity recovered in urine over a period of up to 216 hours (84.7 ± 7.8% of the letrozole dose) was due to glucuronide conjugates of the carbinol metabolite, almost 9% to two other unidentified metabolites, and 6% to unchanged letrozole.
The apparent terminal plasma half-life (t1/2) 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 when letrozole is administered daily at a dose of 2.5 mg, its pharmacokinetics are somewhat nonlinear. Since steady-state concentrations of letrozole are maintained during prolonged use, it can be concluded that letrozole does not accumulate.
Linearity/nonlinearity
The pharmacokinetics of letrozole were dose proportional after single oral doses 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 mg 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 the result of saturation of metabolic elimination processes. Steady-state concentrations were reached after 1-2 months with all studied dosing regimens (0.1-5.0 mg daily).
Pharmacokinetics in specific patient groups
The pharmacokinetics of letrozole are independent of age.
In a study conducted in 19 volunteers with varying degrees of renal function (24-hour creatinine clearance ranging from 9 to 116 ml/min), it was noted that the pharmacokinetics of letrozole were not altered after a single dose of 2.5 mg. In addition, in the aforementioned study, the effect of renal impairment on letrozole was assessed, and an analysis of covariance was performed on the basis of data from two pivotal studies (Studies AR/BC2 and AR/BC3). The estimated creatinine clearance (range in Study AR/BC2: 19-187 ml/min; in Study AR/BC3: 10-180 ml/min) did not show a statistically significant relationship with the minimum steady-state plasma level of letrozole (Cmin). In addition, data from the AR/BC2 and AR/BC3 studies in the second-line treatment of metastatic breast cancer demonstrated no negative effect of letrozole on creatinine clearance or renal function impairment.
In a similar study in volunteers with varying degrees of liver function, mean AUC values were 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 subjects with cirrhosis and severe hepatic impairment (Child-Pugh Class C), AUC and t1/2 were increased by 95% and 187%, respectively, compared with healthy subjects. Thus, higher levels of letrozole are expected in breast cancer patients with severe hepatic impairment than in patients without severe hepatic impairment. Therefore, Letrozole should be used with caution in patients with severe hepatic impairment, taking into account the benefit/risk balance for each individual patient.
Indication
Adjuvant therapy of hormone-positive invasive early breast cancer in postmenopausal women.
Extended adjuvant therapy for early invasive breast cancer in postmenopausal women who have received standard adjuvant tamoxifen therapy for 5 years.
First-line therapy for hormone-dependent advanced breast cancer in postmenopausal women.
Treatment of advanced forms of breast cancer in postmenopausal women (natural or induced) after recurrence or progression of the disease, who have received previous anti-estrogen therapy.
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 other component of the drug.
Endocrine status typical of the premenopausal period.
Pregnancy, breastfeeding period.
Contraindicated in women of 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 antiestrogens 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 the plasma concentration of letrozole. Concomitant use of medicinal products that strongly inhibit these enzymes (potent inhibitors of CYP3A4, including ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin and telithromycin; CYP2A6 (e.g. methoxsalen)) may increase exposure to letrozole. 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 reduce the plasma concentration of letrozole. Concomitant use of medicinal products that induce CYP3A4 (e.g. phenytoin, rifampicin, carbamazepine, phenobarbital and St. John's wort) may reduce the exposure of letrozole. Therefore, caution is advised in patients who are indicated for potent CYP3A4 inducers. CYP2A6 inducers are unknown.
Concomitant administration of letrozole (2.5 mg) and tamoxifen 20 mg once daily resulted in an average 38% decrease in plasma levels of letrozole. Clinical experience from second-line breast cancer trials suggests that the therapeutic effect of letrozole treatment, as well as the incidence of adverse reactions, was not increased when letrozole was administered immediately after tamoxifen. The mechanism of this interaction is unknown.
Drugs whose systemic serum concentrations may be altered by letrozole
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 medication in the target population of letrozole) have shown that the co-administration of letrozole and these medicinal products 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 ratio of the potential risk and the expected effect of treatment should be considered.
Cholesterol
Serum cholesterol monitoring should be considered. In the adjuvant treatment trial, hypercholesterolemia was reported in 52.3% of patients treated with letrozole and 28.6% of patients treated with tamoxifen. Grade 3-4 hypercholesterolemia was reported in 0.4% of patients treated with letrozole and 0.1% of patients treated with tamoxifen, according to the Adverse Reaction Severity Assessment (ADR) criteria. Additionally, in the adjuvant setting, increases of ≥1.5 × ULN (upper limit of normal) in total cholesterol (usually not in the fasting state) were observed in patients receiving monotherapy and with 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 medication was 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 t1/2 of letrozole are approximately twice as long as in healthy subjects. Such patients require closer monitoring.
Effect on bones
Since Letrozole is a potent estrogen-lowering agent, in the adjuvant and extended adjuvant treatment of Letrozole in women with osteoporosis and/or a history of fractures or who are at increased risk of osteoporosis, bone mineral density should be assessed before, during and after treatment with letrozole. 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 safety profile for the patient.
Menopausal status
In patients with unclear menopausal status, LH, FSH and/or estradiol levels should be determined before starting treatment with Letrozole. Only women with postmenopausal endocrine status should take Letrozole.
Tendinitis and tendon rupture
Tendinitis and tendon rupture are possible (rarely). Patients should be carefully examined and appropriate measures (e.g. immobilization) should be taken for the affected tendon (see section 4.8).
Laboratory abnormalities
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 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 changes, whether or not related to the drug, was rare.
Other caveats
The concomitant use of Letrozole and tamoxifen, other estrogen antagonists or estrogen-containing medicinal products should be avoided, as these substances may antagonize the pharmacological effects of letrozole.
Since the drug contains lactose, it is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption.
Use during pregnancy or breastfeeding
Women in perimenopausal state or women of reproductive age
Letrozole should only be used in women who are clearly postmenopausal. There have been postmarketing reports of spontaneous abortions or congenital anomalies in infants born to mothers who have taken the drug. Given the reports of ovarian function returning to normal in women taking Letrozole despite being clearly postmenopausal at the start of therapy, the physician should discuss the use of contraception with the patient, if appropriate.
Based on human experience, which includes isolated cases of congenital malformations (cleft lip, intermediate external genitalia), letrozole is known to cause congenital malformations when administered during pregnancy. Animal studies have shown reproductive toxicity. Letrozole KRKA is contraindicated for use during pregnancy.
Breastfeeding period
It is not known whether letrozole and its metabolites are excreted in human milk. A risk to the newborn or infant cannot be excluded.
Letrozole KRKA is contraindicated for use during breastfeeding.
Fertility
The pharmacological action of letrozole is to reduce estrogen production by inhibiting aromatase. In premenopausal women, inhibition of estrogen synthesis leads to a corresponding increase in gonadotropin levels (LH, FSH). The increase in FSH, in turn, stimulates follicular growth, which can induce ovulation.
Ability to influence reaction speed when driving vehicles or other mechanisms
Letrozole KRKA has little effect on the ability to drive and use machines. Since patients treated with the drug have experienced general weakness and dizziness, and in some cases drowsiness, caution is recommended when driving or operating complex machinery.
Method of administration and doses
Adult patients, including elderly patients. The recommended dose of Letrozole KRKA is 2.5 mg once daily. In the adjuvant and extended adjuvant setting, treatment with Letrozole KRKA should continue for 5 years or until disease relapse occurs.
In patients with metastases, treatment with Letrozole should be continued until evidence of disease progression is evident. In the adjuvant setting, a sequential regimen (letrozole for 2 years followed by tamoxifen for 3 years) should also be considered.
In the neoadjuvant setting, Letrozole should be continued for 4-8 months to achieve optimal tumor reduction. If the response to treatment is inadequate, Letrozole should be discontinued and elective surgery should be performed and/or further treatment options discussed with the patient.
For elderly patients, dose adjustment of the drug is not required.
Children. The drug is not used to treat children. The safety and efficacy of Letrozole KRKA in children have not been established. The available data are limited, so it is not possible to develop dosage recommendations.
Patients with hepatic and/or renal impairment. No dose adjustment is required for patients with mild to moderate hepatic impairment (Child-Pugh class A and B) or renal impairment (creatinine clearance ≥10 mL/min). There are insufficient data in patients with renal impairment with creatinine clearance <10 mL/min or severe hepatic impairment. Patients with severe hepatic impairment (Child-Pugh class C) require close monitoring.
Method of application
Letrozole KRKA is taken orally, regardless of food intake, since food does not affect the degree 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 not be taken 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 drug is not used in children, as the efficacy and safety of the drug for this category of patients have not been studied in clinical trials.
Overdose
Isolated cases of overdose with letrozole have been reported.
Specific treatment for overdose is unknown; treatment should be symptomatic and supportive.
Side effects
The frequency of adverse reactions to letrozole was determined mainly on the basis of data obtained during clinical trials.
Almost one-third of patients treated with letrozole in the metastatic and neoadjuvant settings, and almost 80% of patients in both the adjuvant and extended adjuvant settings, experienced adverse reactions. Most adverse reactions occurred within the first few weeks of treatment.
Important adverse reactions that may occur during treatment with Letrozole include musculoskeletal events such as osteoporosis and/or bone 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 flashes, alopecia or vaginal bleeding). Most adverse reactions occurred within the first few weeks of treatment. The frequency of these adverse reactions is shown in Table 1.
The frequency of adverse reactions is mostly based on data obtained from clinical trials.
The adverse reactions listed in Table 1 were observed during clinical trials and post-marketing use of letrozole.
Adverse reactions are listed by frequency of occurrence, with the most common ones listed first. The following gradations were used to estimate the frequency of occurrence of various adverse reactions: very common – ≥ 10%; common – ≥ 1% to < 10%; uncommon – ≥ 0.1% to < 1%; rare – ≥ 0.01% to < 0.1%; very rare – < 0.01%; frequency unknown (cannot be estimated from the available data).
Table 1
| Frequency | Adverse reactions |
| Infections and infestations |
| Infrequently | Urinary tract infections |
| Benign, malignant and unexplained neoplasms, including cysts and polyps |
| Infrequently | Tumor pain(1) |
| Blood and lymphatic system disorders |
| Infrequently | Leukopenia |
| On the part of the immune system |
| Frequency unknown | Anaphylactic reactions |
| Metabolic disorders |
| 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 | Drowsiness, 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, myocardial ischemia events (including new or worsening angina, angina requiring surgery, myocardial infarction, and myocardial ischemia) |
| Vascular disorders |
| Very often | Hot flashes |
| Often | Arterial hypertension |
| Infrequently | Thrombophlebitis (including superficial and deep vein thrombophlebitis) |
| Rarely | Pulmonary embolism, arterial thrombosis, cerebrovascular infarction |
| Respiratory, thoracic and mediastinal disorders |
| Infrequently | Shortness of breath, cough |
| Gastrointestinal tract |
| Often | Nausea, vomiting, dyspepsia(1), constipation, diarrhea, abdominal pain |
| Infrequently | Stomatitis(1), dry mouth |
| Hepatobiliary system |
| Infrequently | Increased liver enzymes, hyperbilirubinemia, jaundice |
| Frequency unknown | Hepatitis |
| Skin and subcutaneous tissue disorders |
| Very often | Increased sweating |
| Often | Alopecia, rash (including erythematous, maculopapular, psoriatic and vesicular rashes), dry skin |
| Infrequently | Itching, hives |
| Frequency unknown | Toxic epidermal necrolysis, erythema multiforme, angioedema |
| Musculoskeletal and connective tissue disorders |
| Very often | Arthralgia |
| Often | Muscle pain, bone pain(1), osteoporosis, bone fractures, arthritis |
| Infrequently | Tendinitis |
| Rarely | Tendon rupture |
| Frequency unknown | Snapping finger syndrome |
| Urinary system and kidneys |
| Infrequently | Increased frequency of urination |
| Reproductive system and breast disorders |
| Often | Vaginal bleeding |
| Infrequently | Vaginal discharge or dryness, breast pain |
| General disorders and administration site conditions |
| Very often | Fatigue (including asthenia, malaise) |
| Often | Peripheral edema, chest pain |
| Infrequently | Fever, dry mucous membranes, thirst, generalized edema |
| Research |
| Often | Weight gain |
| Infrequently | Weight loss |
(1) Only when treating metastatic disease.
The frequency of some adverse reactions varied significantly in the adjuvant treatment setting.
Adjuvant letrozole therapy compared with tamoxifen monotherapy: adverse events 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) | At 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 completion or discontinuation of study treatment.
The difference was determined by risk ratio and 95% confidence intervals.
Table 3
Sequential treatment compared to letrozole monotherapy: adverse events 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 less than in the letrozole monotherapy group.
** Significantly higher than in the letrozole monotherapy group.
Note: The notification period includes the treatment period or 30 days after treatment is discontinued.
Description of selected adverse reactions
Cardiac adverse reactions
In the adjuvant setting, in addition to those presented in Table 2, the following adverse events were reported with letrozole and tamoxifen, respectively (with a median treatment duration of 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%); cerebral circulation disorder/transient ischemic attack (2.1% vs. 1.9%).
In the extended adjuvant setting, the following adverse events were reported with letrozole (median duration of treatment 5 years) and placebo (median duration of treatment 3 years), respectively: angina requiring surgery (0.8% vs. 0.6%); new angina 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%).
The frequency of events marked with * was statistically significantly different between the two treatment groups.
Musculoskeletal adverse reactions
Musculoskeletal safety data obtained in the adjuvant setting are presented in Table 2.
In the extended adjuvant setting, bone fractures or osteoporosis were observed in a statistically significantly higher number of patients in the letrozole group (bone fractures – 10.4% and osteoporosis – 12.2%) than in the placebo group (5.8% and 6.4%, respectively). The median duration of treatment was 5 years for letrozole compared to 3 years for placebo.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions after the marketing authorisation of a medicinal product is of great importance. This allows for continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national reporting system.
Expiration date
3 years.
Storage conditions
Store at a temperature not exceeding 25 °C in the original packaging to protect from moisture.
Keep out of reach of children.
Packaging
10 tablets in a blister; 3, 6 or 9 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
KRKA, dd, Novo mesto/KRKA, dd, Novo mesto.
TAD Pharma GmbH/TAD Pharma GmbH.
