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Drug Details
FEMARA Film-coated Tablets
- Drug Class Description
Non-steroidal aromatase inhibitor (inhibitor of oestrogen biosynthesis); antineoplastic agent - Generic Name
Letrozole - Presentation
Film-coated tablets. Coated tablet, dark yellow, round, slightly biconvex with bevelled edges. One side bears the imprint FV, the other CG. - Description
Active substance: 4, 4'-[(1H-1, 2, 4-triazol-1-yl)-methylene]bis-benzonitrile (INN/USAN= letrozole). Each film-coated tablet contains 2.5 mg letrozole. - Indications
Adjuvant treatment of postmenopausal women with hormone receptor positive invasive early breast cancer. Treatment of early invasive breast cancer in postmenopausal women who have received prior standard adjuvant tamoxifen therapy. First-line treatment in postmenopausal women with advanced breast cancer. Advanced breast cancer in postmenopausal women in whom tamoxifen or other anti-oestrogen therapy has failed. Pre-operative therapy in postmenopausal women with localised hormone receptor positive breast cancer, to allow subsequent breast-conserving surgery in women not originally considered candidates for breast-conserving surgery. Subsequent treatment after surgery should be in accordance with standard of care. - Adult Dosage
Adult and elderly patients
The recommended dose of Femara is 2.5 mg once daily. In the adjuvant setting, treatment with Femara should continue for 5 years or until tumour relapse occurs, whichever comes first. Following standard adjuvant tamoxifen therapy, treatment with Femara should continue for 4 years or until tumour relapse occurs, whichever comes first. Currently there is a lack of long-term data, therefore the optimal duration of therapy has not yet been established. In patients with metastatic disease, treatment with Femara should continue until tumour progression is evident. Regular monitoring to observe progression during the pre-operative treatment period is recommended. No dose adjustment is required for elderly patients.
Patients with hepatic and/or renal impairment
No dosage adjustment is required for patients with mild to moderate hepatic impairment (Child-Pugh grade A and B) or renal impairment (creatinine clearance
10 mL/min.), - Child Dosage
Not recommended for use in children - Elderly Dosage
See Adult Dosage - Contra Indications
Known hypersensitivity to the active substance or to any of the excipients.
Premenopausal, pregnant or lactating women.
Patients with severe hepatic impairment (Child-Pugh grade C).
Pre-operative use of letrozole is contraindicated if the receptor status is negative or unknown.
- Special Precautions
Femara is not recommended for use in children as efficacy and safety in this patient group have not been assessed in clinical studies. There are no efficacy data to support the use of Femara in men with breast cancer.
Femara has not been investigated in patients with creatinine clearance < 10 mL/min. The potential risk/benefit to such patients should be carefully considered before administration of Femara.
As Femara is a potent oestrogen lowering agent, reductions in bone mineral density can be anticipated. The impact of Femara on long-term fracture risk remains undetermined. During adjuvant treatment with Femara, women with osteoporosis or at risk of osteoporosis should have their bone mineral density formally assessed by bone densitometry e.g. DEXA scanning at the commencement of treatment. Although adequate data to show the effects of therapy in the treatment of the bone mineral density loss caused by Femara are not available, treatment for osteoporosis should be initiated as appropriate and patients treated with Femara should be carefully monitored.
- Interactions
Clinical interaction studies with cimetidine and warfarin indicated that the coadministration of Femara with these drugs does not result in clinically significant drug interactions, even though cimetidine is a known inhibitor of one of the cytochrome P450 isoenzymes capable of metabolising letrozole in vitro.
There was no evidence of other clinically relevant interaction in patients receiving other commonly prescribed drugs (e.g. benzodiazepines; barbiturates; NSAIDs such as diclofenac sodium, ibuprofen; paracetamol; furosemide; omeprazole).
There is no clinical experience to date on the use of Femara in combination with other anti-cancer agents.
Letrozole inhibits in vitro the cytochrome P450-isoenzymes 2A6 and moderately 2C19, however, CYP2A6 does not play a major role in drug metabolism. In in vitro experiments letrozole was not able to substantially inhibit the metabolism of diazepam (a substrate of CYP2C19) at concentrations approximately 100-fold higher than those observed in plasma at steady-state. Thus, clinically relevant interactions with CYP2C19 are unlikely to occur. Nevertheless, caution should be used in the concomitant administration of drugs whose disposition is mainly dependent on these isoenzymes and whose therapeutic index is narrow
- Adverse Drug Reactions
Femara 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 as well as in the treatment of women who have received prior standard tamoxifen therapy. Approximately one third of the patients treated with Femara in the metastatic and neoadjuvant settings, approximately 70-75% of the patients in the adjuvant setting (both Femara and tamoxifen arms), and approximately 40% of the patients treated following standard adjuvant tamoxifen (both Femara and placebo arms) experienced adverse reactions. Generally, the observed adverse reactions are mainly mild or moderate in nature, and most are associated with oestrogen deprivation.
The most frequently reported adverse reactions in the clinical studies were hot flushes, arthralgia, nausea and fatigue. Many adverse reactions can be attributed to the normal pharmacological consequences of oestrogen deprivation (e.g. hot flushes, alopecia and vaginal bleeding).
After standard adjuvant tamoxifen, the following adverse events irrespective of causality were reported significantly more often with Femara than with placebo – hot flushes (60.3 % vs. 52.6 %), arthralgia/arthritis (37.9 % vs. 26.8 %) and myalgia (15.8 % vs. 8.9 %). The majority of these adverse events were observed during the first year of treatment. In the patients in the placebo arm who switched to Femara, a similar pattern of general adverse events was observed. The incidence of self-reported osteoporosis, any time after randomisation was higher in patients who received Femara than in patients who received placebo (12.3 % vs. 7.4 %). The incidence of clinical fractures, at any time after randomisation, was higher in patients who received Femara than for placebo patients (10.9 % vs. 7.2 %). In patients who switched to Femara, newly diagnosed osteoporosis, any time after switching, was reported in 3.6 % of patients while fractures were reported in 5.1 % of patients any time after switching.
The following adverse drug reactions, listed in Table 1, were reported from clinical studies and from post marketing experience with Femara.
Table 1
Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: very common
10%; common 1% to <10%; uncommon 0.1% to <1%; rare 0.01% to < 0.1%; very rare <0.01%, not known (cannot be estimated from the available data).Infections and infestations
Uncommon:
Urinary tract infection
Neoplasms, benign, malignant and unspecified (including cysts and polyps)
Uncommon:
Tumour pain (6)
Blood and the lymphatic system disorders
Uncommon:
Leucopenia
Immune system disorders
Not known:
Angioedema, anaphylactic reactions
Metabolism and nutrition disorders
Common:
Anorexia, appetite increase, raised serum cholesterol
Uncommon:
General oedema
Psychiatric disorders
Common:
Depression
Uncommon:
Anxiety (1)
Nervous system disorders
Common:
Headache, dizziness
Uncommon:
Somnolence, insomnia, memory impairment, dysaesthesia (2) , taste disturbance, Cerebrovascular accident
Eye disorders
Uncommon:
Cataract, eye irritation, blurred vision
Cardiac disorders
Uncommon:
Palpitations, tachycardia
Vascular disorders
Uncommon:
Thrombophlebitis (3) , hypertension, ischemic cardiac events (7)
Rare:
Pulmonary embolism, arterial thrombosis, cerebrovascular infarction
Respiratory, thoracic and mediastinal disorders
Uncommon:
Dyspnoea, cough
Gastrointestinal disorders
Common:
Nausea, vomiting, dyspepsia, constipation, diarrhoea
Uncommon:
Abdominal pain, stomatitis, dry mouth
Hepatobiliary disorders
Uncommon:
Increased hepatic enzymes
Not known:
Hepatitis
Skin and subcutaneous tissue disorders
Common:
Alopecia, increased sweating, rash (4)
Uncommon:
Pruritus, dry skin, urticaria
Not known:
Toxic epidermal necrolysis, erythema multiforme
Musculoskeletal and connective tissue disorders
Very common:
Arthralgia
Common:
Myalgia, bone pain, osteoporosis, bone fractures
Uncommon:
Arthritis
Renal and urinary disorders
Uncommon:
Increased urinary frequency
Reproductive system and breast disorders
Uncommon:
Vaginal bleeding, vaginal discharge, vaginal dryness, breast pain
General disorders and administration site conditions
Very common:
Hot flushes
Common:
Fatigue (5) , peripheral oedema
Uncommon:
Pyrexia, mucosal dryness, thirst
Investigations
Common:
Weight increase
Uncommon:
Weight loss
*Including:
(1) including nervousness, irritability
(2) including paraesthesia, hypoaesthesia
(3) including superficial and deep thrombophlebitis
(4) including erythematous, maculopapular, psoriaform and vesicular rash
(5) including aesthenia and malaise
(6) in metastatic/neoadjuvant setting only
(7) in the adjuvant setting, irrespective of causality, the following adverse events occurred in the Femara and tamoxifen groups respectively: thromboembolic events (1.2% vs. 3.0%), angina pectoris (0.8% vs. 0.8%), myocardial infarction (0.5% vs. 0.4%), cardiac failure (0.8% vs. 0.3%).
Table 2 presents the frequency of pre-specified adverse events grades 1-5 in the BIG 1-98 study, irrespective of causality, reported in patients receiving trial therapy and up to 30 days after cessation of trial therapy.
Table 2
Pre-specified event
Letrozole
N=3975
n (%)
Tamoxifen
N=3988
n (%)
Hot flashes/hot flushes
1367 (34.4)
1534 (38.5)
Arthralgia/arthritis
804 (20.2)
519 (13.0)
Night sweats
578 (14.5)
664 (16.6)
Nausea
394 (9.9)
424 (10.6)
Fatigue (lethargy, malaise, asthenia)
348 (8.8)
352 (8.8)
Vaginal bleeding
190 (4.8)
433 (10.9)
Myalgia
265 (6.7)
236 (5.9)
Edema
236 (5.9)
231 (5.8)
Bone fractures
252 (6.3)
187 (4.7)
Headache
148 (3.7)
139 (3.5)
Vaginal irritation
145 (3.6)
124 (3.1)
Dizziness/light-headedness
101 (2.5)
118 (3.0)
Vomiting
110 (2.8)
107 (2.7)
Total serum cholesterol> 1.5* ULN 1, 2
174 (5.4)
36 (1.1)
Thromboembolic event
48 (1.2)
119 (3.0)
Constipation
62 (1.6)
103 (2.6)
Cerebrovascular accident/transient ischemic attack
48 (1.2)
49 (1.2)
Breast pain
45 (1.1)
50 (1.3)
Cataract
49 (1.2)
43 (1.1)
Endometrial hyperplasia or cancer 3
10 (0.3)
62 (2.0)
Anorexia
33 (0.8)
33 (0.8)
Angina pectoris (new, or worsening or requiring surgical intervention)
30 (0.8)
30 (0.8)
Cardiac failure
32 (0.8)
13 (0.3)
Myocardial infarction
20 (0.5)
15 (0.4)
Ovarian cyst
18 (0.5)
16 (0.4)
1 Based on number of patients with normal serum cholesterol levels at baseline, and developing at least one value greater than 1.5 times the upper limit of normal in the laboratory measuring total serum cholesterol. Approximately 90% of the measured values were non-fasting measurements.
2 Denominator is number of patients with baseline measurements of total serum cholesterol – letrozole, n=3207; tamoxifen, n=3228
3 Denominator is number of patients not having undergone hysterectomy at baseline – letrozole, n=3090; tamoxifen, n=3157