Source: Υπουργείο Υγείας (CY) Revision Year: 2022 Publisher: Delorbis Pharmaceuticals Ltd., 17 Athinon Street, Ergates Industrial Area, 2643 Ergates, P.O. Box 28629, 2081 Lefkosia, Cyprus, European Union
In patients whose menopausal status is unclear, luteinising hormone (LH), follicle-stimulating hormone (FSH) and/or oestradiol levels should be measured before initiating treatment with Saderon. Only women of postmenopausal endocrine status should receive Saderon.
Letrozole has not been investigated in a sufficient number of patients with a creatinine clearance lower than 10 ml/min. The potential risk/benefit to such patients should be carefully considered before administration of Saderon.
In patients with severe hepatic impairment (Child-Pugh C), systemic exposure and terminal half-life were approximately doubled compared to healthy volunteers. Such patients should therefore be kept under close supervision (see section 5.2).
Letrozole is a potent oestrogen-lowering agent. Women with a history of osteoporosis and/or fractures, or who are at increased risk of osteoporosis, should have their bone mineral density formally assessed prior to the commencement of adjuvant and extended adjuvant treatment and monitored during and following treatment with letrozole. Treatment or prophylaxis for osteoporosis should be initiated as appropriate and carefully monitored. In the adjuvant setting a sequential treatment schedule (letrozole 2 years followed by tamoxifen 3 years) could also be considered depending on the patient’s safety profile (see sections 4.2, 4.8 and 5.1).
Tendonitis and tendon ruptures (rare) may occur. Close monitoring of the patients and appropriate measures (e.g. immobilisation) must be initiated for the affected tendon (see section 4.8).
Co-administration of Saderon with tamoxifen, other anti-oestrogens or oestrogen-containing therapies should be avoided as these substances may diminish the pharmacological action of letrozole (see section 4.5).
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Metabolism of letrozole is partly mediated via CYP2A6 and CYP3A4. Cimetidine, a weak, unspecific inhibitor of CYP450 enzymes, did not affect the plasma concentrations of letrozole. The effect of potent CYP450 inhibitors is unknown.
There is no clinical experience to date on the use of letrozole in combination with oestrogens or other anticancer agents, other than tamoxifen. Tamoxifen, other anti-oestrogens or oestrogen-containing therapies may diminish the pharmacological action of letrozole. In addition, co-administration of tamoxifen with letrozole has been shown to substantially decrease plasma concentrations of letrozole. Co-administration of letrozole with tamoxifen, other anti-oestrogens or oestrogens should be avoided.
In vitro, letrozole inhibits the cytochrome P450 isoenzymes 2A6 and, moderately, 2C19, but the clinical relevance is unknown. Caution is therefore indicated when giving letrozole concomitantly with medicinal products whose elimination is mainly dependent on these isoenzymes and whose therapeutic index is narrow (e.g. phenytoin, clopidrogel).
Saderon should only be used in women with a clearly established postmenopausal status (see section 4.4). As there are reports of women regaining ovarian function during treatment with letrozole despite a clear postmenopausal status at start of therapy, the physician needs to discuss adequate contraception when necessary.
Based on human experience in which there have been isolated cases of birth defects (labial fusion, ambiguous genitalia), letrozole may cause congenital malformations when administered during pregnancy. Studies in animals have shown reproductive toxicity (see section 5.3).
Saderon is contraindicated during pregnancy (see sections 4.3 and 5.3).
It is unknown whether letrozole and its metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded.
Saderon is contraindicated during breast-feeding (see section 4.3).
The pharmacological action of letrozole is to reduce oestrogen production by aromatase inhibition. In premenopausal women, the inhibition of oestrogen synthesis leads to feedback increases in gonadotropin (LH, FSH) levels. Increased FSH levels in turn stimulate follicular growth, and can induce ovulation.
Letrozole has minor influence on the ability to drive and use machines. Since fatigue and dizziness have been observed with the use of letrozole and somnolence has been reported uncommonly, caution is advised when driving or using machines.
The frequencies of adverse reactions for letrozole are mainly based on data collected from clinical trials.
Up to approximately one third of the patients treated with letrozole in the metastatic setting and approximately 80% of the patients in the adjuvant setting as well as in the extended adjuvant setting experienced adverse reactions. The majority of the adverse reactions occurred during the first few weeks of treatment.
The most frequently reported adverse reactions in clinical studies were hot flushes, hypercholesterolaemia, arthralgia, fatigue, increased sweating and nausea.
Important additional adverse reactions that may occur with letrozole are: skeletal events such as osteoporosis and/or bone fractures and cardiovascular events (including cerebrovascular and thromboembolic events). The frequency category for these adverse reactions is described in Table 1.
The frequencies of adverse reactions for letrozole are mainly based on data collected from clinical trials.
The following adverse drug reactions, listed in Table 1, were reported from clinical studies and from post-marketing experience with letrozole.
Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).
Table 1:
| Infections and infestations | |
| Uncommon | Urinary tract infection |
| Neoplasms benign, malignant and unspecified (including cysts and polyps) | |
| Uncommon | Tumour pain1 |
| Blood and lymphatic system disorders | |
| Uncommon | Leucopenia |
| Immune system disorders | |
| Not known | Anaphylactic reaction |
| Metabolism and nutrition disorders | |
| Very common | Hypercholesterolaemia |
| Common | Decreased appetite, increased appetite |
| Psychiatric disorders | |
| Common | Depression |
| Uncommon | Anxiety (including nervousness), irritability |
| Nervous system disorders | |
| Common | Headache, dizziness |
| Uncommon | Somnolence, insomnia, memory impairment, dysaesthesia (including paraesthesia, hypoaesthesia), dysgeusia, cerebrovascular accident, carpal tunnel syndrome |
| Eye disorders | |
| Uncommon | Cataract, eye irritation, blurred vision |
| Cardiac disorders | |
| Common | Palpitations1 |
| Uncommon | Tachycardia, ischaemic cardiac events (including new or worsening angina, angina requiring surgery, myocardial infarction and myocardial ischaemia) |
| Vascular disorders | |
| Very common | Hot flush |
| Common | Hypertension |
| Uncommon | Thrombophlebitis (including superficial and deep vein thrombophlebitis) |
| Rare | Pulmonary embolism, arterial thrombosis, cerebral infarction |
| Respiratory, thoracic and mediastinal disorders | |
| Uncommon | Dyspnoea, cough |
| Gastrointestinal disorders | |
| Common | Nausea, dyspepsia1, constipation, abdominal pain, diarrhoea, vomiting |
| Uncommon | Dry mouth, stomatitis1 |
| Hepatobiliary disorders | |
| Uncommon | Increased hepatic enzymes, hyperbilirubinemia, jaundice |
| Not known | Hepatitis |
| Skin and subcutaneous tissue disorders | |
| Very common | Hyperhidrosis |
| Common | Alopecia, rash (including erythematous, maculopapular, psoriaform, and vesicular rash), dry skin |
| Uncommon | Pruritus, urticaria |
| Not known | Angioedema, toxic epidermal necrolysis, erythema multiforme |
| Musculoskeletal and connective tissue disorders | |
| Very common | Arthralgia |
| Common | Myalgia, bone pain1, osteoporosis, bone fractures, arthritis |
| Uncommon | Tendonitis |
| Rare | Tendon rupture |
| Not known | Trigger finger |
| Renal and urinary disorders | |
| Uncommon | Pollakiuria |
| Reproductive system and breast disorders | |
| Common | Vaginal haemorrhage |
| Uncommon | Vaginal discharge, vulvovaginal dryness, breast pain |
| General disorders and administration site conditions | |
| Very common | Fatigue (including asthenia, malaise) |
| Common | Peripheral oedema, chest pain |
| Uncommon | General oedema, mucosal dryness, thirst, pyrexia |
| Investigations | |
| Common | Weight increased |
| Uncommon | Weight decreased |
Some adverse reactions have been reported with notably different frequencies in the adjuvant treatment setting. The following tables provide information on significant differences in letrozole versus tamoxifen monotherapy and in the letrozole-tamoxifen sequential treatment therapy:
Table 2. Adjuvant Letrozole monotherapy versus tamoxifen monotherapy – adverse events with significant differences:
| Letrozole, incidence rate | Tamoxifen, incidence rate | |||
|---|---|---|---|---|
| N=2448 | N=2447 | |||
| During treatment (Median 5y) | Any time after randomization (Median 8y) | During treatment (Median 5y) | Any time after randomization (Median 8y) | |
| 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 last dose. "Any time’' includes follow-up period after completion or discontinuation of study treatment.
Differences were based on risk ratios and 95% confidence intervals.
Table 3. Sequential treatment versus Letrozole monotherapy – adverse events with significant differences:
| Letrozole monotherapy | Letrozole → tamoxifen | Tamoxifen → Letrozole | |
|---|---|---|---|
| N=1535 | N=1527 | N=1541 | |
| 5 years | 2 yrs → 3 yrs | 2 yrs → 3 yrs | |
| Bone fractures | 10.0% | 7.7%* | 9.7% |
| Endometrial proliferative disorders | 0.7% | 3.4%** | 1.7%** |
| Hypercholesterolaemia | 52.5% | 44.2%* | 40.8%* |
| Hot flushes | 37.6% | 41.7%** | 43.9%** |
| Vaginal bleeding | 6.3% | 9.6%** | 12.7%** |
* Significantly less than with Letrozole monotherapy
** Significantly more than with Letrozole monotherapy
Note: Reporting period is during treatment or within 30 days of stopping treatment.
In the adjuvant setting, in addition to the data presented in Table 2, the following adverse events were reported for letrozole and tamoxifen, respectively (at median treatment duration of 60 months plus 30 days): angina requiring surgery (1.0% vs. 1.0%); cardiac failure (1.1% vs. 0.6%); hypertension (5.6% vs. 5.7%); cerebrovascular accident/transient ischaemic attack (2.1% vs. 1.9%).
In the extended adjuvant setting for 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 or worsening angina (1.4% vs. 1.0%); myocardial infarction (1.0% vs. 0.7%); thromboembolic event* (0.9% vs. 0.3%); stroke/transient ischaemic attack* (1.5% vs. 0.8%) were reported.
Events marked * were statistically significantly different in the two treatment arms.
For skeletal safety data from the adjuvant setting, please refer to 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%) than patients in the placebo arm (5.8% and 6.4%, respectively). Median duration of treatment was 5 years for letrozole, compared with 3 years for placebo.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions to the Pharmaceutical Services, Ministry of Health, CY-1475, www.moh.gov.cy/phs, Tel: +357 22608607, Fax: +357 22608669.
Not applicable.
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