Letrozole Bluefish: composition and pharmaceutical form
One film-coated tablet contains 2.5 mg of letrozole and 61.5 mg of lactose monohydrate. Because of the lactose, the medicine should not be used in rare hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption syndrome.
The tablet may be taken with or without food. A missed dose is taken as soon as the patient remembers it, but if the next dose is due soon — say, 2 or 3 hours away — the missed dose is skipped and the usual schedule resumed. A double dose is not taken: at doses above the recommended 2.5 mg a greater than proportional rise in systemic exposure was observed.
How Letrozole Bluefish works
Where tumour tissue depends on the presence of oestrogens, a response to endocrine treatment is possible only once oestrogen stimulation of tumour growth has been halted. In postmenopausal women oestrogens are formed mainly through the enzyme aromatase, which converts adrenal androgens — principally androstenedione and testosterone — into oestrone and oestradiol. Stopping oestrogen biosynthesis in peripheral tissues and in the tumour itself can therefore be achieved by selectively inhibiting aromatase.
Letrozole is a non-steroidal aromatase inhibitor. It inhibits the enzyme by binding competitively to the haem of aromatase-cytochrome P450, so that oestrogen biosynthesis falls in every tissue where aromatase is present. In healthy postmenopausal women single doses of 0.1 mg, 0.5 mg and 2.5 mg reduced serum oestrone and oestradiol concentrations by 75%, 78% and 78% respectively, with the maximum reduction reached within 48–78 hours. In postmenopausal patients with advanced breast cancer, daily doses of 0.1 mg to 5 mg reduced plasma oestradiol, oestrone and oestrone sulfate by 75–95% in all treated patients, and at doses from 0.5 mg the measured values of oestrone and its sulfate often failed to reach the limit of detection.
Indications
All of letrozole's indications concern breast cancer in postmenopausal women; what differs is the stage, the line of therapy and its place in the overall treatment sequence.
Three indications belong to adjuvant and first-line treatment, and two more to more particular situations.
- adjuvant treatment of hormone receptor-positive early breast cancer;
- extended adjuvant treatment of hormone-dependent invasive breast cancer after five years of standard adjuvant treatment with tamoxifen;
- first-line treatment of advanced hormone-dependent breast cancer;
- treatment of advanced breast cancer in women with natural or artificially induced menopause who have relapsed or progressed and who previously received medicines with antioestrogenic activity;
- neoadjuvant treatment of HER-2-negative hormone receptor-positive breast cancer in patients for whom chemotherapy is not suitable and immediate surgery is not indicated.
Method of use and dosage
The recommended dose for adult and elderly patients is 2.5 mg a day; in older patients no dose adjustment is needed. The difference between indications lies not in the dose but in the duration. In adjuvant and extended adjuvant treatment letrozole is taken for 5 years or until the tumour recurs, whichever comes first. In adjuvant treatment a sequential regimen may also be considered: 2 years of letrozole followed by 3 years of tamoxifen. In advanced or metastatic breast cancer treatment continues until there is evidence of clear progression of the tumour process.
In renal impairment with a creatinine clearance of at least 10 ml/min no dose adjustment is needed; there are no sufficient data on dosing at clearances below 10 ml/min. In mild and moderate hepatic impairment — Child-Pugh grade A or B — the dose likewise stays the same. Data on patients with severe hepatic impairment are insufficient, and such patients require close monitoring: in them the area under the curve and the terminal half-life were about twice those in healthy volunteers. In children and adolescents the medicine is not recommended: the safety and efficacy of letrozole up to the age of 17 have not been established, the data are limited and there are no dosing recommendations.
Contraindications
Hypersensitivity to the active substance or to any excipient. Premenopausal endocrine status. Pregnancy. Breastfeeding.
The second item on this list is not a formality but the condition on which the medicine works: before the menopause the ovaries continue to produce oestrogens by their own route, and inhibiting aromatase does not solve the problem. That is why, in patients whose postmenopausal status is unclear, luteinising hormone, follicle-stimulating hormone and oestradiol are measured before treatment begins. Only postmenopausal women may receive letrozole.
Special warnings and precautions
Letrozole lowers oestrogen concentrations strongly, and the main consequence of that falls on bone. Women with osteoporosis or fractures in their history, and those in the group at increased risk of osteoporosis, must have a bone density scan before adjuvant or extended adjuvant treatment starts, and are monitored during treatment and after it ends. Where appropriate, treatment or prophylaxis of osteoporosis is started and its result carefully monitored.
- in patients with a creatinine clearance below 10 ml/min the use of letrozole has not been sufficiently studied, so the risk-benefit balance is weighed carefully before prescribing;
- in severe hepatic impairment of Child-Pugh class C the patient must remain under close supervision because exposure to the medicine roughly doubles;
- in adjuvant treatment the sequential regimen — 2 years of letrozole followed by 3 years of tamoxifen — may be considered, depending on the individual patient's safety profile;
- concurrent use of letrozole with tamoxifen, other antioestrogens or products containing oestrogen should be avoided: those substances may weaken letrozole's pharmacological action.
Letrozole has a minor effect on the ability to drive and operate machinery, but caution is warranted: fatigue and dizziness were observed during treatment, and somnolence was reported uncommonly.
Interaction with other medicines
Letrozole is metabolised in part with the involvement of CYP2A6 and CYP3A4. Cimetidine — a weak, non-specific inhibitor of CYP450 enzymes — had no effect on plasma letrozole concentrations; the effect of potent CYP450 inhibitors is unknown. There is as yet no clinical experience of letrozole in combination with oestrogens or other antitumour medicines apart from tamoxifen.
- tamoxifen, other antioestrogens and products containing oestrogens may weaken letrozole's pharmacological action, and concurrent use of tamoxifen and letrozole has been shown to cause a considerable fall in plasma letrozole concentrations;
- combinations of letrozole with tamoxifen, other antioestrogens or oestrogens should therefore be avoided — this is one of the medicine's few interactions and at the same time the most important in practice;
- in vitro letrozole inhibits the 2A6 isoenzyme of cytochrome P450 and, moderately, the 2C19 isoenzyme, though the clinical significance of this effect is not known;
- caution is therefore needed with the concurrent use of medicines eliminated mainly through those isoenzymes and having a narrow therapeutic index, for example phenytoin and clopidogrel.
Letrozole's interaction list is short, and that reflects its place in the treatment plan: the medicine is usually taken for a long time and on its own rather than in combination. All the more so, the main restriction here is not a rare enzyme but perfectly ordinary medicines with oestrogenic or antioestrogenic activity that the patient may be taking for another reason.
Pregnancy and breastfeeding
Letrozole must be used only in women in whom postmenopausal status has been unambiguously confirmed. There are, moreover, reports of ovarian function resuming in patients during treatment with letrozole despite a clearly established postmenopausal state at the start of therapy, so the doctor should discuss suitable contraception with the patient where necessary.
Based on data from use in humans, among which isolated cases of malformations occurred — labial fusion, ambiguous genitalia — letrozole may cause congenital defects if used during pregnancy. Animal studies revealed a harmful effect on reproduction. Letrozole is therefore contraindicated in pregnancy. Whether letrozole and its metabolites pass into human milk is not known, and a risk to newborns and infants cannot be excluded, so the medicine is contraindicated during breastfeeding as well.
Adverse reactions
Adverse reactions occurred in at most about a third of patients receiving letrozole for metastatic disease and in around 80% of patients on adjuvant and extended adjuvant treatment, most of them within the first few weeks. The most common were hot flushes, hypercholesterolaemia, joint pain, nausea, increased sweating and fatigue.
- very common: hypercholesterolaemia, hot flushes, increased sweating, joint pain, fatigue including weakness and general malaise;
- common: decreased or increased appetite, depression, headache, dizziness, arterial hypertension, nausea, vomiting, dyspepsia, constipation, diarrhoea, abdominal pain, alopecia, rash, dry skin, muscle and bone pain, osteoporosis, bone fractures, vaginal bleeding, peripheral oedema, weight gain;
- uncommon: urinary tract infections, leukopenia, anxiety and irritability, somnolence, insomnia, memory disturbance, paraesthesia and hypoaesthesia, taste disturbance, carpal tunnel syndrome, cataract, eye irritation, blurred vision, tachycardia, cardiac ischaemic events, thrombophlebitis, breathlessness, cough, stomatitis, dry mouth, raised liver enzymes, itching, urticaria, arthritis, increased urinary frequency, vaginal discharge and dryness, breast pain, fever, weight loss;
- rare and of unknown frequency: pulmonary embolism, arterial thrombosis, ischaemic stroke, anaphylactic reaction, hepatitis, angioedema, toxic epidermal necrolysis, erythema multiforme, trigger finger.
Bone and blood vessels deserve a separate look — that is where the differences between regimens are expressed in numbers. In extended adjuvant treatment bone fractures were recorded in 10.4% of patients on letrozole against 5.8% on placebo, and osteoporosis in 12.2% against 6.4%, with a median treatment duration of 5 years for letrozole and 3 years for placebo. In adjuvant treatment compared with tamoxifen at a median of 60 months the frequencies were close: angina requiring surgery, 1.0% against 1.0%; heart failure, 1.1% against 0.6%; arterial hypertension, 5.6% against 5.7%; stroke or transient ischaemic attack, 2.1% against 1.9%. In extended adjuvant treatment against placebo: angina requiring surgery, 0.8% against 0.6%; new or worsening angina, 1.4% against 1.0%; myocardial infarction, 1.0% against 0.7%; thromboembolic events, 0.9% against 0.3%.
Overdose
Only isolated cases of letrozole overdose have been reported, and there is no specific management for such a situation.
The practical conclusion is simple: what matters is less the treatment of an overdose than its prevention. That is precisely why a missed dose is not made up with a double one — at doses above the recommended 2.5 mg systemic exposure rises disproportionately — and the daily dose is not increased on one's own initiative, even if the effect seems insufficient.
How to get a prescription for Letrozole Bluefish online
The medicine is prescription-only and is prescribed by an oncologist within a breast cancer treatment plan, so the conversation with the doctor starts with the diagnosis and its details: stage, hormone receptors, HER-2 status, and what has already been done — surgery, chemotherapy, tamoxifen and for how long. Which indication applies and how many years the treatment will last follow from that.
The second thing the doctor will establish without fail is menopausal status, and where this is unclear will order tests for luteinising hormone, follicle-stimulating hormone and oestradiol. Osteoporosis and fractures in the history and the results of bone densitometry are worth reporting separately, along with kidney and liver disease with test results, cardiovascular disease, and every medicine being taken — especially those containing oestrogens, antioestrogens and drugs with a narrow therapeutic index such as phenytoin and clopidogrel. The doctor will assess these circumstances during the online consultation and, if there are no contraindications, will issue an electronic prescription.
