Letrozole Dexcel

/ Dexcel

Adult and elderly patients: The recommended dose of Letrozole is 2.5 mg once daily. No dose adjustment is required for elderly patients.
In patients with advanced or metastatic breast cancer, treatment with Letrozole should continue until tumor progression is evident.
In the adjuvant and extended adjuvant setting, treatment with Letrozole should continue for 5 years or until tumor relapse occurs, whichever is first.
Paediatric population: Letrozole is not recommended for use in children and adolescents. The safety and efficacy of Letrozole in children and adolescents aged up to 17 years have not been established. Limited data are available and no recommendation on a posology can be made.
Renal impairment: No dosage adjustment of Letrozole is required for patients with renal insufficiency with creatinine clearance ≥10 ml/min. Insufficient data are available in cases of renal insufficiency with creatinine clearance lower than 10 ml/min.
Hepatic impairment: No dose adjustment of Letrozole is required for patients with mild to moderate hepatic insufficiency (Child-Pugh A or B). Insufficient data are available for patients with severe hepatic impairment. Patients with severe hepatic impairment (Child-Pugh C) require close supervision.
Method of Administration: A missed dose should be taken as soon as the patient remembers. However, if it is almost time for the next dose (within 2 or 3 hours), the missed dose should be skipped, and the patient should go back to her regular dosage schedule. Doses should not be doubled because with daily doses over the 2.5 mg recommended dose, over-proportionality in systemic exposure was observed.
See prescribing information for full details.

Letrozole Dexcel tablets is indicated for first-line treatment in postmenopausal women with hormone receptor positive or in whom hormone receptor status cannot be determined locally advanced or metastatic breast cancer.
Letrozole Dexcel is also indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following anti-estrogen therapy.
Extended adjuvant treatment of early breast cancer in post menopausal women who have received prior standard adjuvant tamoxifen therapy.
Adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer.

Hypersensitivity to the active substance or to any of the excipients.
Premenopausal endocrine status.
Pregnancy.
Breast-feeding.

Menopausal status: In patients whose menopausal status is unclear, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and/or estradiol levels should be measured before initiating treatment with it. Only women of postmenopausal endocrine status should receive it.
Renal impairment: This drug 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 it.
Hepatic impairment: 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.
Bone effects: This drug is a potent estrogen-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 it. 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.
Other warnings: Co-administration of this drug with tamoxifen, other anti-estrogens or estrogen-containing therapies should be avoided as these substances may diminish the pharmacological action of Letrozole. As the tablets contain lactose, Letrozole Dexcel is not recommended for patients with rare hereditary problems of galactose intolerance, of severe lactase deficiency or of glucose-galactose malabsorption.
See prescribing information for full details.

Summary of the safety profile: The frequencies of adverse reactions for this drug 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.
Tabulated listing of adverse reactions: The frequencies of adverse reactions for this drug are mainly based on data collected from clinical trials. The following adverse drug reactions were reported from clinical studies and from post-marketing experience with it: 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^1.
Blood and the lymphatic system disorders: Uncommon: Leukopenia.
Immune system disorders: Not known: Anaphylactic reaction.
Metabolism and nutrition disorders: Very common: Hypercholesterolaemia.
Common: Anorexia, appetite increase.
Psychiatric disorders: Common: Depression, Uncommon: Anxiety (including nervousness), irritability.
Nervous system disorders: Common: Headache, dizziness. Uncommon: Somnolence, insomnia, memory impairment, dysaesthesia (including  paraesthesia, hypoaesthesia), taste disturbance, cerebrovascular accident, carpal tunnel syndrome.
Eye disorders: Uncommon: Cataract, eye irritation, blurred vision.
Cardiac disorders: Uncommon: Palpitations1, tachycardia, ischaemic cardiac events (including new or worsening angina, angina requiring surgery, myocardial infarction and myocardial ischaemia).
Vascular disorders: Very common: Hot flushes. Common: Hypertension, Uncommon: Thrombophlebitis (including superficial and deep vein thrombophlebitis), Rare: Pulmonary embolism, arterial thrombosis, cerebrovascular 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, Not known: Hepatitis.
Skin and subcutaneous tissue disorders: Very common: Increased sweating, Common: Alopecia, rash (including erythematous, maculopapular, psoriaform, and vesicular rash), dry skin. Uncommon: Pruritus, urticarial, Not known: Angioedema, toxic epidermal necrolysis, erythema multiforme.
Musculoskeletal and connective tissue disorders: Very common: Arthralgia, Common: Myalgia, bone pain¹, osteoporosis, bone fractures, Uncommon: Arthritis, Not known: Trigger finger.
Renal and urinary disorders: Uncommon: Increased urinary frequency.
Reproductive system and breast disorders: Common: Vaginal bleeding, Uncommon: Vaginal discharge, vaginal dryness, breast pain.
General disorders and administration site conditions: Very common: Fatigue (including asthenia, malaise), Common: Peripheral oedema, Uncommon: General oedema, mucosal dryness, thirst, pyrexia.
Investigations: Common: Weight increase, Uncommon: Weight loss, ¹ Adverse drug reactions reported only in the metastatic setting, Some adverse reactions have been reported with notably different frequencies in the adjuvant treatment setting. The following lists provide information on significant differences in it versus tamoxifen monotherapy and in the Letrozole-tamoxifen sequential treatment therapy:
Adjuvant Letrozole monotherapy versus tamoxifen monotherapy – adverse events with significant differences. Letrozole, incidence rate N=2448.
Bone fracture: During treatment (Median 5y) 10.2%, Any time after randomization (Median 8y) 14.7%.
Osteoporosis: During treatment (Median 5y) 5.1%, Any time after randomization (Median 8y) 5.1%.
Thromboembolic events: During treatment (Median 5y) 2.1%, Any time after randomization (Median 8y) 3.2%.
Myocardial infarction: During treatment (Median 5y) 1.0%, Any time after randomization (Median 8y) 1.7%.
Endometrial hyperplasia / endometrial cancer: During treatment (Median 5y) 0.2%,Any time after randomization (Median 8y) 0.4%.
Tamoxifen, incidence rate N=2447.
Bone fracture: During treatment (Median 5y) 7.2%, Any time after randomization (Median 8y) 11.4%.
Osteoporosis: During treatment (Median 5y) 2.7%, Any time after randomization (Median 8y) 2.7%.
Thromboembolic events: During treatment (Median 5y) 3.6%, Any time after randomization (Median 8y) 4.6%.
Myocardial infarction: During treatment (Median 5y) 0.5%, Any time after randomization (Median 8y) 1.1%.
Endometrial hyperplasia / endometrial cancer: During treatment (Median 5y) 2.3%, Any time after randomization (Median 8y) 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.
Sequential treatment versus Letrozole monotherapy – adverse events with significant differences Letrozole monotherapy N=1535 5 years. Bone fractures:  10.0% Endometrial proliferative disorders:  0.7% Hypercholesterolaemia:  52.5% Hot flushes:  37.6% Vaginal bleeding:  6.3%.
Letrozole->tamoxifen N=1527 2 yrs-> 3 yrs Bone fractures:  7.7%* Endometrial proliferative disorders:  3.4%** Hypercholesterolaemia:  44.2%* Hot flushes:  41.7%** Vaginal bleeding:  9.6%**
Tamoxifen->Letrozole N=1541 2 yrs-> 3 yrs Bone fractures:  9.7% Endometrial proliferative disorders:  1.7%** Hypercholesterolaemia:  40.8%* Hot flushes:  43.9%** Vaginal bleeding:  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.
Description of selected adverse reactions: Cardiac adverse reactions: In the adjuvant setting, in addition to the data presented in Table 2, the following adverse events were reported for it 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 it (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.
Skeletal adverse reactions: For skeletal safety data from the adjuvant setting, please refer to Table 2. In the extended adjuvant setting, significantly more patients treated with it 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.
See prescribing information for full details.

Metabolism of this drug is partly mediated via CYP2A6 and CYP3A4. Cimetidine, a weak, unspecific inhibitor of CYP450 enzymes, did not affect the plasma concentrations of it. The effect of potent CYP450 inhibitors is unknown. There is no clinical experience to date on the use of it in combination with estrogens or other anticancer agents, other than tamoxifen. Tamoxifen, other anti-estrogens or estrogen-containing therapies may diminish the pharmacological action of it. In addition, co-administration of tamoxifen with this drug has been shown to substantially decrease plasma concentrations of it. Co-administration of this drug  with tamoxifen, other anti-estrogens or estrogens should be avoided. In vitro, this drug inhibits the cytochrome P450 isoenzymes 2A6 and, moderately, 2C19, but the clinical relevance is unknown. Caution is therefore indicated when giving this drug concomitantly with medicinal products whose elimination is mainly dependent on these isoenzymes and whose therapeutic index is narrow (e.g. phenytoin, clopidrogel).
See prescribing information for full details.

Women of perimenopausal status or child-bearing potential: This drug should only be used in women with a clearly established postmenopausal status (see lit.). 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.
Pregnancy: Based on human experience in which there have been isolated cases of birth defects (labial fusion, ambiguous genitalia), this drug may cause congenital malformations when administered during pregnancy. Studies in animals have shown reproductive toxicity. It is contraindicated during pregnancy.
Breast-feeding: It is unknown whether it and its metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded.  This drug is contraindicated during breast-feeding.
Fertility: The pharmacological action of this drug is to reduce estrogen production by aromatase inhibition. In premenopausal women, the inhibition of estrogen synthesis leads to feedback increases in gonadotropin (LH, FSH) levels. Increased FSH levels in turn stimulate follicular growth, and can induce ovulation.
See prescribing information for full details.

Isolated cases of overdose with this drug have been reported. No specific treatment for overdose is known; treatment should be symptomatic and supportive.
See prescribing information for full details.